Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][OH:20])[CH2:15][C@H:14]1[C@@H:13]([CH3:21])[S:12][C:11]([NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[N:10]2.I[CH2:32][CH3:33].FC1C=C(F)C=CC=1[C@]12CO[C@@H](COC)C[C@H]1[C@@H](C)SC(NC(=O)C1C=CC=CC=1)=N2.CO>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][O:20][CH2:32][CH3:33])[CH2:15][C@H:14]1[C@@H:13]([CH3:21])[S:12][C:11]([NH:22][C:23](=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[N:10]2
Reactant: C[C@H]1SC(NC(=O)c2ccccc2)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CO)C[C@@H]12
Reactant: CCI
Agent: COC[C@H]1C[C@H]2[C@@H](C)SC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Solvent: ClCCl
Solvent: CO
Product: CCOC[C@H]1C[C@H]2[C@@H](C)SC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1

Procedure:
N-[(4R,4aR,6R,8aS)-8a-(2,4-Difluorophenyl)-6-(hydroxymethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (P2) was reacted with iodoethane according to the method described for synthesis of N-[(4R,4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(methoxymethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C20) in Example 2. In this case, additional silica gel chromatography (Gradient: 0% to 5% methanol in dichloromethane) was carried out. The product was obtained as a white solid. Yield: 24.8 mg, 53.8 μmol, 41%. LCMS m/z 461.2 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 8.12 (br d, J=7 Hz, 2H), 7.51-7.57 (m, 1H), 7.39-7.48 (m, 3H), 7.01-7.11 (m, 2H), 4.14 (br d, J=12 Hz, 1H), 3.89 (d, J=11.9 Hz, 1H), 3.82-3.89 (m, 1H), 3.47-3.61 (m, 4H), 3.19-3.27 (br m, 1H), 2.97-3.04 (m, 1H), 1.74-1.82 (m, 1H), 1.51-1.63 (m, 1H), 1.25 (d, J=6.8 Hz, 3H), 1.17 (t, J=7.0 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.P(Cl)(Cl)Cl>O>[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:12]([C:3]2[C:2]([OH:1])=[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=[N:10]3)=[CH:5][CH:4]=2)=[O:14])=[CH:18][CH:17]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(O)c1ccc2cccnc2c1O
Solvent: ClP(Cl)Cl
Solvent: O
Product: O=C(Nc1ccc(Cl)cc1)c1ccc2cccnc2c1O
Reaction time: 8 h
Yield: 32.8 %

Procedure:
A solution of 8-hydroxyquinoline-7-carboxylic acid (3.78 g) of Preparation 1 and 4-chloroaniline (2.55 g) in 250 mL xylenes is heated to reflux. To this is added dropwise PCl3 (1.37 g). Refluxing is continued overnight. The reaction is then cooled and water is added to destroy excess PCl. The resulting solid is collected, washed with water and dried. The crude product is recrystallized from EtOAc/hexanes to yield 1.96 g of the title product as an orange solid.
Reaction SMILES: [CH2:1]([NH:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]([CH3:15])([CH3:14])[CH2:7]1)[CH2:2][CH2:3][CH3:4].[O:16]1[CH2:35][CH:17]1[CH2:18][O:19][C:20]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[C:28]([O:30][CH2:31][CH:32]1[O:34][CH2:33]1)=[O:29])=[O:21]>C(O)(C)(C)C>[CH2:1]([N:5]([CH2:33][CH:32]([OH:34])[CH2:31][O:30][C:28]([CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH:22]1[C:20]([O:19][CH2:18][CH:17]([OH:16])[CH2:35][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]1[CH2:7][C:8]([CH3:14])([CH3:15])[NH:9][C:10]([CH3:13])([CH3:12])[CH2:11]1)=[O:21])=[O:29])[CH:6]1[CH2:7][C:8]([CH3:14])([CH3:15])[NH:9][C:10]([CH3:13])([CH3:12])[CH2:11]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC1CC(C)(C)NC(C)(C)C1
Reactant: O=C(OCC1CO1)C1CCCCC1C(=O)OCC1CO1
Solvent: CC(C)(C)O
Product: CCCCN(CC(O)COC(=O)C1CCCCC1C(=O)OCC(O)CN(CCCC)C1CC(C)(C)NC(C)(C)C1)C1CC(C)(C)NC(C)(C)C1
Reaction time: 8 h

Procedure:
A mixture of 5 g of 4-butylamino-2,2,6,6-tetramethylpiperidine and 3 g of bis(2,3-epoxypropyl)1,2-cyclohexanedicarboxylate in 10 ml of t-butanol was refluxed, with stirring, for 8 hours. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure and the resulting residue was purified by column chromatography through silica gel eluted with a 20:1 by volume mixture of ethyl acetate and triethylamine. The desired compound was obtained in the form of a pale yellow, viscous oil having an Rf value of 0.53 on thin layer chromatography on silica gel developed with a 5:1 by volume mixture of ethyl acetate and triethylamine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[N:11][C:10]=1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.CN>CN(C=O)C>[CH3:17][NH:18][C:14]([C:10]1[N:11]=[N:12][S:13][C:9]=1[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)Nc1snnc1C(=O)O
Agent: CN
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1nnsc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 5-tert-butoxycarbonylamino-[1,2,3]thiadiazole-4-carboxylic acid (0.66 g, 2.7 mmol) in DMF (10 ml) was treated with TBTU (1.16 g, 3.5 mmol), N,N-diisopropyl ethyl amine (2.29 ml, 13.5 mmol) and methylamine (1.75 ml, 2M THF solution) and stirred at ambient temperature for 5 h. The reaction mixture was partitioned between potassium hydrogen sulfate (30 ml, 10% aqueous solution) and ethyl acetate (60 ml) and extracted. The organic layer was washed with water and brine, and the aqueous phases were back-extracted with ethyl acetate. The combined organic phases were dried and the solvent was evaporated. The residue was suspended in dichloromethane, sucked off, and the filtrate was evaporated. The product was obtained after purification of the crude material by silica gel chromatography using a heptane/ethyl acetate gradient as colorless solid (0.23 g, 33%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][NH:13][CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][N:13]([C:25](=[O:26])[C:24]4[CH:28]=[CH:29][CH:30]=[C:22]([F:21])[CH:23]=4)[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1ccc(Cl)cc21
Product: CCOC(=O)C1=CN(C(=O)c2cccc(F)c2)CCc2c1[nH]c1ccc(Cl)cc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using ethyl 9-chloro-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate and 3-fluorobenzoyl chloride; 1H-NMR (CDCl3): δ 10.61 (1H, br s), 8.07 (1H, s), 7.46 (2H, m), 7.28 (4H, m), 7.14 (1H, dd), 4.25 (2H, q), 4.19 (2H, t), 3.21 (2H, t), 1.22 (3H, t); MS (ES): 413 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N:11]2[C:20](=[O:21])[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[C:12]2=[O:13])=[C:4]([F:22])[CH:3]=1.C(OCC)(=O)C>C(O)(=O)C.[Fe]>[NH2:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:22])=[C:5]([N:11]2[C:20](=[O:21])[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[C:12]2=[O:13])[CH:6]=1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc([N+](=O)[O-])c(Cl)cc1F
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Reaction time: 0.17 h

Procedure:
Iron powder (7.30 g, 130.7 mmol) is added portionwise to a mixture. of N-(4-chloro-2-fluoro-5-nitrophenyl)-1-cyclohexene-1,2-dicarboximide (10.6 g, 32.7 mmol) in acetic acid (100 mL) at 65° C. After the addition is complete, the reaction mixture is stirred for 10 minutes, and filtered through diatomaceous earth. The filtrate is concentrated in vacuo to obtain a dark solid. A mixture of the solid in an ethyl acetate/saturated sodium hydrogen carbonate solution is filtered through diatomaceous earth, and the phases are separated. The organic phase is washed sequentially with saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title product as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.[CH2:26]([C:28]1[O:29][CH:30]=[CH:31][C:32](=[O:35])[C:33]=1[OH:34])[CH3:27].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O>[Cl:17][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[O:15][CH3:16])[NH:8][C:6]1[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=[C:2]([O:34][C:33]2[C:32](=[O:35])[CH:31]=[CH:30][O:29][C:28]=2[CH2:26][CH3:27])[N:7]=1
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Reactant: CCc1occc(=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1occc(=O)c1Oc1nc(Nc2ccc(OC)c(Cl)c2)nc(NC2CCCCCC2)n1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of 133 (0.3 g, 0.78 mmol), 2-ethyl-3-hydroxy-4H-pyran-4-one (0.11 g, 0.78 mmol) and K2CO3 (0.54 g, 3.91 mmol) in dimethylformamide (15 mL) was stirred at 80° C. for 6 hours under nitrogen atmosphere. After completion of the reaction the mixture was cooled to 25° C. and diluted with water (50 mL). The precipitated solid was filtered off and dried under vacuum to afford the title compound E19 as an off-white solid (0.2 g, 52%). mp 124-126° C.; HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns 50:50 [0.01 M KH2PO4 (0.1% TFA):CH3CN], 223 nm, Rt 18.47 min, 98.18% purity); MS (CI): m/z 486 (M+, 100), 382 (90).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])[CH:5]=[C:6]([F:8])[CH:7]=1.[Br:16]Br>C(Cl)(Cl)Cl>[Br:16][CH:11]1[CH2:12][CH2:13][CH2:14][CH:9]([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)[C:10]1=[O:15]
Reactant: O=C1CCCCC1c1cc(F)cc(F)c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=C1C(Br)CCCC1c1cc(F)cc(F)c1
Temperature: 25 °C
Yield: 112.4 %

Procedure:
2-(3,5-Difluoro-phenyl)-cyclohexanone (50 mg, 0.24 mmol) was dissolved in chloroform (1 mL). To this solution bromine (39.9 mg, 0.25 mmol) in chloroform (0.5 mL) was added drop wise at room temperature. The reaction was stirred for 1½ hours at room temperature. The solvent was removed under reduced pressure to yield the crude title compound (78 mg) which was used directly in the next step without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:16]([O-:18])=[O:17])=[C:12]([F:15])[CH:13]=2)[N:8]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]=1[CH:26]([CH3:28])[CH3:27])=[O:5])C.[OH-].[Na+]>CCO.CCOC(C)=O>[CH2:19]([N:8]1[C:9]2[C:14](=[CH:13][C:12]([F:15])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)[C:6]([C:4]([OH:5])=[O:3])=[C:7]1[CH:26]([CH3:28])[CH3:27])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1c(C(C)C)n(Cc2ccccc2)c2cc([N+](=O)[O-])c(F)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)c1c(C(=O)O)c2cc(F)c([N+](=O)[O-])cc2n1Cc1ccccc1
Temperature: 80 °C

Procedure:
General Procedure Z. To a solution of ethyl1-benzyl-5-fluoro-2-isopropyl-6-nitro-1H-indole-3-carboxylate (Compound 169, 546 mg, 1.54 mmol) in EtOH (10 ml) was added 5 M NaOH (3.1 ml, 15.5 mmol). The reaction was heated at 80° C. for 5 h, diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound as a brown solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)(Cl)(Cl)[Cl:35].CO>CC#N>[Cl:35][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: OC(c1ccccn1)c1ccccn1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CO
Product: ClC(c1ccccn1)c1ccccn1
Reaction time: 8 h
Yield: 56 %

Procedure:
To di(2-pyridinyl)methanol (8.73 g, 46.94 mmol) in CH3CN (100 ml) at 0° C. was added a solution of PPh3 (14.77 gram, 56.32 mmol) in of CCl4 (80 mL) in 1.5 h. The solution was left standing overnight. After addition of MeOH (10 ml) and stirring for 15 min the mixture was concentrated in vacuum to ca 50 ml. To the residue was added of water (100 ml) and the mixture was acidified with 2M HCl to pH=1, and washed twice with 100 ml of CHCl3, the aqueous layer was neutralized with K2CO3 and extracted 4 times with 75 ml of ether. Drying and evaporation of the solvent yielded 2-[chloro(2-pyridinyl)methyl]pyridine (5.41 gram, 56%) as a pale brown solid. Analytically pure material was obtained by column chromatography on silica (ether). 1H-NMR (200 MHz, CDCl3) δ 6.20 (s, 1H), 7.14-7.20 (m, 2H), 7.60-7.73 (m, 4H). 8.51-8.54 (m, 2H). 13C-NMR (50.3 MHz, CDCl3) δ 62.84 (d), 121.3 (d), 121.5 (d), 135.7 (d), 147.7 (d), 156.9 (s). Anal. Cald. for C11H9ClN2: C 64.56, H 4.43, Cl 17.32, N 13.69; Found: C 64.48, H 4.45, Cl 17.29, N 13.49.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[C:4](Cl)[N:3]=1.[I-].[Na+].[NH2:17][C:18]1[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[CH3:23][C:21]1[NH:20][N:19]=[C:18]([NH:17][C:4]2[N:3]=[C:2]([Cl:1])[N:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=2)[CH:22]=1
Reactant: CCOC(=O)Cc1cc(Cl)nc(Cl)n1
Reactant: Cc1cc(N)n[nH]1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cc(Nc2cc(C)[nH]n2)nc(Cl)n1
Temperature: 25 °C
Yield: 41.4 %

Procedure:
A solution of ethyl 2-(2,6-dichloropyrimidin-4-yl)acetate (1.0 g, 4.25 mmol), sodium iodide (0.637 g, 4.25 mmol), 3-amino-5-methylpyrazole (0.413 g, 4.25 mmol), and N,N-diisopropylethylamine (0.96 ml, 5.53 mmol) was heated at 90° C. until reaction was complete (˜3 h). Reaction mixture was then cooled to room temperature, diluted with ethyl acetate (100 ml), washed with sat. sodium hydrogen carbonate solution (1×30 ml), water (3×30 ml), brine (30 ml), dried (MgSO4), filtered and evaporated in vacuo to leave an orange oil. Crude product was purified by flash chromatography (SiO2, 60-100% EtOAc/Petrol) to give title compound as a red sticky oil (0.520 g, 41%). 1H NMR (CDCl3) 1.29 (3H, t), 2.41 (3H, s), 3.52 (2H, s), 4.23 (2H, q), 5.20-4.60 (2H, very broad signal); ES+296.
Reaction SMILES: C[O:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[CH2:8][CH2:9][CH:10]([NH:16][C:17](=[O:19])[CH3:18])[CH2:11][C:12]=3[NH:13]2)=[CH:5][CH:4]=1.C(Cl)Cl.B(Br)(Br)Br>CO>[OH:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[CH2:8][CH2:9][CH:10]([NH:16][C:17](=[O:19])[CH3:18])[CH2:11][C:12]=3[NH:13]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c3c([nH]c2c1)CC(NC(C)=O)CC3
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CC(=O)NC1CCc2c([nH]c3cc(O)ccc23)C1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
A solution of 25.8 g (0.1 mol) of N-(1,3,4,9-tetrahydro-7-methoxy-2H-carbazol-2-yl)acetamide in 2 l. of CH2Cl2 was stirred at -50° to -60° C. under N2 while adding 101 g (0.4 mol) of BBr3 dropwise during 15-30 min. Stirring was continued for 30 min at -55° C. and then 3 hr at room temperature. After cooling to -40° C., 600 ml of MeOH was cautiously added dropwise during 45 min. The reaction mixture was allowed to warm to room temperature (ca. 1 hr) and then evaporated. The residue was dissolved in one l. of 1 N KOH, filtered from insolubles, and the cold filtrate was acidified (pH 3) with conc. HCl. The precipitate was filtered, washed with H2O, and recrystallized from i-PrOH to give the title compound, mp 245°-246°.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[C:11](S(C)(=O)=O)[N:10]3[N:17]=[CH:18][CH:19]=[C:9]3[CH:8]=2)=[CH:3][CH:2]=1.[C:26]([O:30][C:31](=[O:50])[NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40](=[O:49])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=2)=[CH:36][CH:35]=1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31](=[O:50])[NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40](=[O:49])[NH:41][C:42]2[CH:43]=[CH:44][C:45]([NH:48][C:11]3[N:10]4[N:17]=[CH:18][CH:19]=[C:9]4[CH:8]=[C:7]([C:4]4[CH:5]=[CH:6][C:1]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:2][CH:3]=4)[N:12]=3)=[CH:46][CH:47]=2)=[CH:36][CH:35]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CS(=O)(=O)c1nc(-c2ccc(-c3ccccc3)cc2)cc2ccnn12
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccc(N)cc2)cc1
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccc(Nc3nc(-c4ccc(-c5ccccc5)cc4)cc4ccnn34)cc2)cc1
Temperature: 130 °C

Procedure:
Under an inert gas atmosphere at 130° C. bath temperature is heated neat a mixture of 5-biphenyl-4-yl-7-methanesulfonyl-pyrazolo[1,5-c]pyrimidine (compound B1) and [4-(4-amino-phenylcarbamoyl)-benzyl]-carbamic acid tert-butyl ester (compound G1) overnight. The crude product is purified by silica gel flash chromatography.
Reaction SMILES: FC1C=C(F)C=CC=1C1C=C(CO)C(=O)N(CC(C)C)N=1.[F:22][C:23]1[CH:24]=[C:25]([C:31]2[CH:32]=[C:33]([C:38]([O:40][CH3:41])=[O:39])[C:34](=[O:37])[NH:35][N:36]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].[F:42][C:43]1[CH:44]=[C:45]([CH:48]=[CH:49][C:50]=1[F:51])[CH2:46]Br>>[F:42][C:43]1[CH:44]=[C:45]([CH:48]=[CH:49][C:50]=1[F:51])[CH2:46][N:35]1[C:34](=[O:37])[C:33]([C:38]([O:40][CH3:41])=[O:39])=[CH:32][C:31]([C:25]2[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([F:22])[CH:24]=2)=[N:36]1
Reactant: Fc1ccc(CBr)cc1F
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)n[nH]c1=O
Agent: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CO)c1=O
Product: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nn(Cc2ccc(F)c(F)c2)c1=O
Yield: 92.1 %

Procedure:
Following the procedure of Example 1 (6), 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 3,4-difluorobenzyl bromide were reacted to yield the title compound as a yellow crystalline powder (yield: 92.1%)
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:19][CH:20]([CH:28]([CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH:20]([CH:28]([CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:19][N:18]([CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:11]([O:10][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:12])[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)NCCCCC(NC(=O)OC(C)(C)C)C(CCCCCCO)CN(CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCC(NC(=O)OC(C)(C)C)C(CCCCCCOS(C)(=O)=O)CN(CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methanesulphonyl chloride (1.25 ml, 16.21 mmol) was added to a stirred solution of B6 (9.67 g, 13.5 mmol) in dry dichloromethane (100 ml) containing triethylamine (2.82 ml, 20.26 mmol) at 0° C. The flask was stirred at 0° C. for 1 hr, then overnight at room temperature. The solvent was removed and the residue chromatographed (silica—50% ethyl acetate in hexane) to yield the title compound (8.5 g, 79%. C38H74N4O11S requires 794. Found DCl: M+ +1, 795.6. δH(CDCl3) 3.45(2H, t, CH2O), 2.9-3.3 (12H, m, CH2N), 2.99 (3H, s, MeS), 1.95 (1 H, brm, CH2CH(CH2)2), 1.2-1.8 (50H, m, CH2).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]#[N:5].[CH3:6][S:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11].[OH-].[Na+]>O.O1CCCC1>[CH3:6][S:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:5][CH2:4][C:3]#[N:2])=[O:11]
Reactant: CSc1ncccc1C(=O)Cl
Reactant: N#CCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CSc1ncccc1C(=O)NCC#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To a stirred solution of aminoacetonitrile hydrochloride (5.95 g) in a mixture of water (100 ml) and tetrahydrofuran (100 ml) was added slowly 2 -(methylthio)nicotinoyl chloride (10 g) at 0° C. while adjusting pH to 8-9 with 4N-aqueous sodium hydroxide. After stirring for 30 minutes at 0° C., the solvent was evaporated to give a residue, which was chromatographed on silica gel (350 ml) eluting with ethyl acetate to give [2-(methylthio)nicotinoyl]aminoacetonitrile (9.9 g).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][C:6]1[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:8][N:9]2[CH:14]=[CH:13][CH:12]=[N:11][C:10]=12)C.[OH-].[Na+].O>C(O)C>[C:15]1([C:7]2[C:6]([CH2:5][C:4]([OH:21])=[O:3])=[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)Cc1c(-c2ccccc2)nn2cccnc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1c(-c2ccccc2)nn2cccnc12
Yield: 75.8 %

Procedure:
A solution of 12.25 g (0.043 mole) of 2-phenylpyrazolo[1,5-a]pyrimidine-3-acetic acid ethyl ester in 100 ml of absolute ethanol was treated with 6.9 g (0.087 mole) of 50% sodium hydroxide and 35 ml of water and refluxed for 4 hours under a nitrogen atmosphere. The solvent was evaporated under reduced pressure and the residue was dissolved in water (100 ml). Acidification with glacial acetic acid produced a solid precipitate. The solid was collected by filtration to yield 10.8 g of crude product, mp 78°-90° C. Recrystallization from acetone-water, and then from toluene provided 8.25 g (75%) of product, mp 153°-156° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([NH:17][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([F:12])[C:9]([F:11])=[CH:10][C:2]=1[F:1])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C(O)c1cc(F)c(F)cc1F
Reactant: CC(C)(C)N
Product: CC(C)(C)NC(=O)c1cc(F)c(F)cc1F

Procedure:
The title compound was prepared by the same method as that described in Example 26, using 2,4,5-trifluorobenzoic acid and t-butylamine.
Reaction SMILES: C[Li].[OH:3][C:4]1[C:9]2[C:10](=[O:24])[C:11]3[C:16]([C:17]4([CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)[C:8]=2[CH:7]=[CH:6][CH:5]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3.Cl.[C:26](=O)([O-])[O-].[Na+].[Na+]>CCOCC.O>[OH:3][C:4]1[C:9]2[C:10]([OH:24])([CH3:26])[C:11]3[C:16]([C:17]4([CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]4)[C:8]=2[CH:7]=[CH:6][CH:5]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3
Reactant: O=C([O-])[O-]
Reactant: CN1CCC2(CC1)c1ccccc1C(=O)c1c(O)cccc12
Agent: Cl
Agent: [Li]C
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CN1CCC2(CC1)c1ccccc1C(C)(O)c1c(O)cccc12
Reaction time: 1 h

Procedure:
Methyl lithium in ether (5 ml., 1.5M) is added dropwise with stirring under nitrogen to 4-hydroxy-1'-methyl-10-oxo-9,10-dihydroanthracene-9-spiro-4'-piperidine (0.7 g.) in dry ether (25 ml.) and the mixture is stirred for 1 hour then diluted with water, acidified (2N hydrochloric acid), basified with sodium carbonate, and extracted with ethyl acetate. The ethyl acetate extract is washed with water and with brine, dried (MgSO4), evaporated, and the residue is recrystallised from ethanol to give 4,10-dihydroxy-1',10-dimethyl-9,10-dihydroanthracene-9-spiro-4'-piperidine, m.p. 151°-154°C.