Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])=[CH:23][CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:37][C:38]1[O:42][N:41]=[C:40]([C:43](CN)=O)[CH:39]=1.CS(C)=O.C([N:53](CC)CC)C>C(#N)C>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:24]1[CH:25]=[CH:26][C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:53][CH2:43][C:40]4[CH:39]=[C:38]([CH3:37])[O:42][N:41]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])=[CH:22][CH:23]=1
Reactant: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1
Reactant: CCN(CC)CC
Reactant: Cc1cc(C(=O)CN)no1
Solvent: CC#N
Solvent: CS(C)=O
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cc(C)on4)n3Cc3ccccc32)cc1

Procedure:
The title compound was prepared according to the procedure of Example 2 starting from 2,2,2-trichloro-1-{10-[(2′-methoxy-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 1 (1.483 g, 2.75 mmole), (5-methyl-3-isoxazoyl)methylamine (0.256 g 1.0 eq), dimethylsulfoxide (5.0 eq, 0.896 g, 11.45 mmole), and triethylamine (2.2 eq, 0.510 g, 5 mmole) in 20 mL of acetonitrile. The residue was absorbed on silica gel Merck-60 and flash chromatographed using a gradient from 0 to 20% of ethyl acetate in dichloromethane, to provide a foam (0.460 g) which yielded an off-white solid upon treatment with ethyl acetate/hexane, m.p. 111-113° C.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:19])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2].O.[C:25](O)(=[O:27])[CH3:26]>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:19])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([C:25](=[O:27])[CH3:26])[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2]
Reactant: CC(=O)O
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C(C)=O)CC3)cc21
Yield: 97 %

Procedure:
1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid 3.2 g was dissolved in 20 ml of glacial acetic acid, 2.0 g of anhydrous acetic acid was added thereto and the mixture was heated at 90°-100° C. for 2 hours with stirring. After cooling, 50 ml of water was added thereto. The precipitated crystals were collected by filtration, washed and dried. The crystals were recrystallized from dimethylformamide to obtain 3.5 g (97%) of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-acetyl-1-piperazinyl)quinoline-3-carboxylic acid as colorless needles.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=O)=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[NH2:30][C:31]1[S:32][CH:33]=[CH:34][N:35]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:18]([CH3:22])([CH3:23])[C:19]([NH:30][C:31]4[S:32][CH:33]=[CH:34][N:35]=4)=[O:21])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:6][CH:7]=1
Reactant: Nc1nccs1
Reactant: CC(C)(C(=O)O)C(c1ccccc1)c1ccc2c(ccn2-c2ccc(F)cc2)c1
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: CC(C)(C(=O)Nc1nccs1)C(c1ccccc1)c1ccc2c(ccn2-c2ccc(F)cc2)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 22 %

Procedure:
To a stirred solution of 3-(1-(4-fluorophenyl)-1H-indol-5-yl)-2,2-dimethyl-3-phenylpropanoic acid (23 mg, 0.059 mmol), 2-aminothiazole (18 mg, 0.18 mmol), and diisopropylethylamine (0.03 mL, 0.18 mmol) in anhydrous DMF (0.3 mL) was added HATU (68 mg, 0.18 mmol) under argon. The reaction mixture was stirred at rt for 5 min and at 80° C. for 5 hr. Concentration and purification using reverse phase HPLC (YMC S5 20×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA) gave 3-(1-(4-fluorophenyl)-1H-indol-5-yl)-2,2-dimethyl-3-phenyl-N-(thiazol-2-yl)propanamide (Example 110, 6 mg, 0.013 mmol, 22% yield) as a pink solid. MS found: (M+H)+=470. 1H-NMR (400 MHz, CDCl3) δ ppm 7.67 (1H, s) 7.32-7.43 (5H, m) 7.33 (1H, d, J=8.65 Hz) 7.22-7.28 (3H, m) 7.14-7.20 (4H, m) 6.94 (1H, d, J=3.56 Hz) 6.60 (1H, d, J=3.05 Hz) 4.59 (1H, s) 1.46 (6H, d, J=2.54 Hz).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][Si@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)(=O)=O)=CC=1.[CH2:26]([Si@H:31]1[CH2:36][CH2:35][C@H:34]([CH2:37][Mg]Br)[CH2:33][CH2:32]1)[CH2:27][CH2:28][CH2:29][CH3:30].C1(C)C=CC(S(OC[C@H]2CC[C@H](C3C=CC(F)=CC=3)CC2)(=O)=O)=CC=1.C([Si@H]1CC[C@H](C[Mg]Br)CC1)CC>>[F:24][C:21]1[CH:20]=[CH:19][C:18]([C@H:15]2[CH2:14][CH2:13][Si@H:12]([CH2:11][CH2:37][C@H:34]3[CH2:35][CH2:36][Si@H:31]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:32][CH2:33]3)[CH2:17][CH2:16]2)=[CH:23][CH:22]=1
Reactant: CCCCC[Si@H]1CC[C@H](C[Mg]Br)CC1
Reactant: Cc1ccc(S(=O)(=O)OC[Si@H]2CC[C@H](c3ccc(F)cc3)CC2)cc1
Agent: CCC[Si@H]1CC[C@H](C[Mg]Br)CC1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](c3ccc(F)cc3)CC2)cc1
Product: CCCCC[Si@H]1CC[C@H](CC[Si@H]2CC[C@H](c3ccc(F)cc3)CC2)CC1

Procedure:
The preparation was conducted in the same manner as in Example 22, except that 18.9 g (50 mmol) of (trans-4-(p-fluorophenyl)-1-silacyclohexyl)methyl p-toluenesulfonate and (trans-4-n-pentyl-4-silacyclohexyl)methylmagnesium bromide were used instead of 18.1 g (50 mmol) of (trans-4-(p-fluorophenyl) cyclohexyl)methyl p-toluenesulfonate and (trans-4-n-propyl4-silacyclohexyl)methylmagnesium bromide.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:17]3[CH2:21][C@@H:20]([C@H:22]4[CH2:27][O:26][C@H:25]([C:28]([OH:30])=[O:29])[CH2:24][O:23]4)[O:19][N:18]=3)[CH:11]=2)=[O:9])=[CH:4][C:3]=1[O:33][CH3:34].[C:35](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:17]3[CH2:21][C@@H:20]([C@H:22]4[CH2:27][O:26][C@H:25]([C:28]([O:30][CH3:35])=[O:29])[CH2:24][O:23]4)[O:19][N:18]=3)[CH:11]=2)=[O:9])=[CH:4][C:3]=1[O:33][CH3:34]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(CNC(=O)c2cc(C3=NO[C@H]([C@H]4CO[C@H](C(=O)O)CO4)C3)nc(C)n2)ccc1F
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CO[C@@H]([C@@H]2CC(c3cc(C(=O)NCc4ccc(F)c(OC)c4)nc(C)n3)=NO2)CO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
To a stirred solution of (2S,5R)-5-((S)-3-(6-(4-fluoro-3-methoxybenzylcarbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)-1,4-dioxane-2-carboxylic acid (0.3 g, 0.632 mmol, Example #P.1) in DMF (2 mL) was added potassium carbonate (0.131 g, 0.948 mmol) followed by iodomethane (0.108 g, 0.759 mmol). The reaction mixture was stirred at RT for about 3 h. The reaction mixture was quenched with water (15 mL), the product separated as solids and collected by filtration, washed with water (10 mL) and dried under vacuum to obtain (2S,5R)-methyl 5-((S)-3-(6-(4-fluoro-3-methoxybenzylcarbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)-1,4-dioxane-2-carboxylate 0.270 g, (87%), ES-MS: m/z 489 (m+H)+, LC/MS (Table 1, method d) Rt=2.25 min.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[CH2:12]([N:19]1[CH2:24][CH2:23][C:22]([CH2:37][NH2:38])([N:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[CH2:27][CH2:26]2)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>ClCCl.[Cl-].[Na+].O>[CH2:12]([N:19]1[CH2:24][CH2:23][C:22]([CH2:37][NH:38][C:8](=[O:10])[CH3:9])([N:25]2[CH2:26][CH2:27][N:28]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[CH2:29][CH2:30]2)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)Cl
Reactant: NCC1(N2CCN(c3ccncc3)CC2)CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)NCC1(N2CCN(c3ccncc3)CC2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
Triethylamine (2.5 equiv.) followed by acetyl chloride (1.2 equiv.) were added under cooled conditions to a solution of (1-benzyl-4-(4-(pyridin-4-yl)piperazin-1-yl)piperidin-4-yl)methanamine (4.67 mmol, 1 equiv.) in dichloromethane. The resulting solution was warmed to room temperature and stirred for 3 h. The mixture was diluted with dichloromethane and given water and brine washes respectively. The organic layer was dried over sodium sulfate, filtered and the solvent removed. The crude product was purified by column chromatography (silica). Yield: 52%
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].[CH2:12]([O:14][C:15](=[O:25])[CH2:16][C:17](=O)[CH2:18][C:19](OCC)=[O:20])[CH3:13]>>[CH2:12]([O:14][C:15]([CH2:16][C:17]1[CH2:18][C:19](=[O:20])[N:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=2)[N:2]=1)=[O:25])[CH3:13]
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Reactant: NNc1ccc(C(=O)O)cc1
Product: CCOC(=O)CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1

Procedure:
From the reaction of p-hydrazinobenzoic acid and diethyl-3-oxoglutarate, 4-(3-ethoxycarbonylmethyl-4,5-dihydro-5-oxo-1H-pyrazol-1-yl)-benzoic acid is obtained. Subsequent reaction with 2-ethylaniline yields 4-(4-(2-thylanilinomethylene)-3-ethoxycarbonylmethyl-4,5-dihydro-5-oxo-1H-pyrazol-1-yl)-benzoic acid, Mp 246° C.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25](C(F)(F)F)[CH:26]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1I)[C:8](=[O:11])[O:9][CH3:10].[C:33]([Cu])#[N:34].[NH4+].[OH-]>CN(C=O)C>[CH3:10][O:9][C:8](=[O:11])[N:7]([CH2:6][C:5]1[CH:24]=[C:25]([C:2]([F:32])([F:31])[F:1])[CH:26]=[C:3]([C:2]([F:31])([F:1])[F:32])[CH:4]=1)[CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:33]#[N:34]
Reactant: N#C[Cu]
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1I
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1C#N
Temperature: 25 °C

Procedure:
To a solution of Example 5 dissolved in DMF (1.5 mL) was added CuCN (20 mg, 0.22 mmol) and the resultant mixture was heated at 100° C. for 16 h. The reaction was cooled to room temperature, poured into NH4OH (10 mL) and extracted with EtOAC (4×30 mL). The combined organic extracts were washed with H2O and brine (10 mL each), dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography (0 to 25% EtOAc/hexanes) afforded the title compound as a colorless oil. LCMS=485 (M+1)+. H NMR (CDCl3, 500 MHz): δ 7.81 (s, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.67-7.31 (m, 4H), 4.82 (br s, 2H), 4.72 (s, 2H), 3.91 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH3:59])[C@H:3]([NH:54][C:55](=[O:58])[O:56][CH3:57])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]1[NH:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:29]=[C:30]([CH:33]5[CH2:37][C:36]6([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]6)[CH2:35][N:34]5[C:43](=[O:53])[C@@H:44]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH:45]([CH3:47])[CH3:46])[NH:31][CH:32]=4)=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[N:15]=1)=[O:5].C(N(CC)CC)C.[C:67](Cl)(=[O:69])C.[C:71](=O)([O-])[O-:72].[K+].[K+]>C(Cl)Cl>[CH3:52][O:51][C:49]([NH:48][C@H:44]([C:43]([N:34]1[CH:33]([C:30]2[NH:31][CH:32]=[C:28]([C:25]3[CH:24]=[CH:23][C:22]([C:19]4[CH:20]=[CH:21][C:16]([C:14]5[N:15]=[C:11]([C@@H:7]6[CH2:8][CH2:9][CH2:10][N:6]6[C:4](=[O:5])[C@H:3]([CH:2]([CH3:59])[CH3:1])[NH:54][C:55]([O:56][CH3:57])=[O:58])[NH:12][CH:13]=5)=[CH:17][CH:18]=4)=[CH:27][CH:26]=3)[N:29]=2)[CH2:37][C:36]2([CH2:38][CH2:39][N:40]([C:71]([O:69][CH3:67])=[O:72])[CH2:41][CH2:42]2)[CH2:35]1)=[O:53])[CH:45]([CH3:46])[CH3:47])=[O:50]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CCNCC2)CC1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)n4)cc3)cc2)c[nH]1)C(C)C
Reactant: CC(=O)Cl
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N[C@H](C(=O)N1CC2(CCN(C(=O)OC)CC2)CC1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)n4)cc3)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a solution of methyl [(1S)-2-methyl-1-({(2S)-2-[4-(4′-{2-[2-((2S)-3-methyl-2-{[(methyloxy)carbonyl]amino}butanoyl)-2,8-diazaspiro[4.5]dec-3-yl]-1H-imidazol-4-yl}-4-biphenylyl)-1H-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)propyl]carbamate (Example 20) (19 mg, 0.02 mmol) in anhydrous CH2Cl2 (0.5 mL) was added triethylamine (0.016 mL, 0.12 mmol) followed by acetyl chloride (0.011 mL, 0.14 mmol) and the reaction stirred at room temperature for 1 h. The reaction is concentrated in vacuo and dissolved in methanol (0.7 mL) to which was added potassium carbonate (30 mg, 0.22 mmol) and the reaction was stirred at room temperature for 2 h. The reaction was concentrated in vacuo and partitioned between CH2Cl2 and water (3 mL each) and the aqueous layer extracted with CH2Cl2 (3 mL) and the organic layers combined and dried (MgSO4) and concentrated in vacuo to afford the title compound as a yellow solid (15 mg, 74% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.51-7.92 (m, 10H) 7.32 (br. s., 2H) 5.02-5.25 (m, 1H) 4.03-4.31 (m, 2H) 3.75-4.05 (m, 2H) 3.61-3.72 (m, 7H) 3.34-3.60 (m, 4H) 1.82-2.50 (m, 7H) 1.70 (br. s., 2H) 1.44-1.63 (m, 4H) 1.27 (br. s., 4H) 0.77-1.10 (m, 14H). HRMS for C46H60N9O8 (M+H)+ calc: 866.4565, found: 850.4564. Purity (LC-MS): 96%.
Reaction SMILES: [C:1]1([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[Cl:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1.Cl.CN(C)CCCCl>>[ClH:18].[C:1]1([CH:11]2[CH2:16][CH2:15][N:14]([CH2:19][CH2:20][CH2:21][N:22]3[CH2:23][C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:30]3)[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: ClCCCN1Cc2ccccc2C1
Reactant: c1ccc2c(C3CCNCC3)cccc2c1
Agent: CN(C)CCCCl
Agent: Cl
Product: c1ccc2c(c1)CN(CCCN1CCC(c3cccc4ccccc34)CC1)C2
Yield: 77.6 %

Procedure:
Using 4-(1-naphthyl)piperidine (124 mg, 0.50 mmol) and 2-(3-chloropropyl)isoindoline hydrochloride (139 mg, 0.72 mmol) instead of 4-(3-indolyl)piperidine and 3-dimethylaminopropyl chloride hydrochloride respectively, reaction, extraction, and concentration were carried out in the same procedure as Example 4. The resulting crude product was purified by column chromatography on a silica gel (silica gel NH-DM 1020 produced by Fuji Silysia Chemical Ltd., eluent; chloroform:methanol=20:1) to afford a free form (158 mg) of the title compound as a yellow viscous oil. After adding hydrochloric acid/methanol to a solution of the free form in methanol, the mixture was concentrated and was then recrystallized from methanol/ether to afford the title compound (91 mg, yield: 44%) as white crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:14])[CH3:13].Br.C(Cl)Cl.CS(C)=[O:22]>>[CH3:15][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:14])[CH:13]=[O:22]
Reactant: CS(C)=O
Reactant: CC(=O)c1ccccc1OCCN(C)C
Agent: Br
Solvent: ClCCl
Product: CN(C)CCOc1ccccc1C(=O)C=O
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A solution of 1-[2-(2-dimethylamino-ethoxy)-phenyl]-ethanone (4.35 g) in dimethylsulfoxide (8.8 ml) was added with 48% HBr (1.8 ml). The mixture was stirred at 80° C. for 6 hours under nitrogen stream. Then it was poured into methylene chloride (50 ml) and dried over magnesium sulfate. The mixture was neutralized to pH 7 with solid sodium bicarbonate, then filtered and evaporated under high vacuum at low temperature. The title compound was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10](Cl)(=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C1(C)C=CC=CC=1.Cl>N1C=CC=CC=1>[C:10]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)(=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCC(=O)Cl
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCC(=O)Oc1ccc(C=O)cc1
Reaction time: 8 h
Yield: 57.2 %

Procedure:
Commercially available p-hydroxybenzaldehyde (50 g) was dissolved in pyridine (400 ml), followed by dropwise adding octanoyl chloride (80 g) under ice cooling, allowing the mixture to stand overnight, adding toluene (300 ml) and 6N hydrochloric acid, separating the solution, further washing with an aqueous solution of 2N NaOH, washing with water, drying and distilling off toluene to obtain a raw product, which was then distilled under reduced pressure to obtain p-octanoyloxybenzaldehyde (b.p. 174°~7° C./7 mmHg) (58.2 g). This product was dissolved in acetic acid (80 ml), followed by dropwise adding to the solution, a mixed solution of chromium trioxide (23.4 g), water (25 ml) and acetic acid (48 ml), stirring at room temperature for 4 hours, pouring on ice, separating solids by filtering, dissolving them in ethanol (300 ml), adding active carbon, shaking, filtering on heating, ice cooling, filtering crystals and recrystallizing from ethanol (300 ml) to obtain p-octanoyloxybenzoic acid (35 g). M.P.: 151° C. This product (5 g) and oxalic acid chloride (7.2 g) were heated on a water bath at 60° C., followed by allowing the reaction mixture to stand overnight, and distilling off excess oxalic acid chloride in vacuo to obtain p-octanoyloxybenzoyl chloride (5 g). This product was used in the following step without purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([C:8]([OH:10])=O)=[N:3]1.C(N=C=NC(C)C)(C)C.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.CN(C1C=CC=CN=1)C.[NH:44]1[CH2:47][CH2:46][C@H:45]1[C:48]([O:50][CH3:51])=[O:49]>ClCCl>[CH3:51][O:50][C:48]([C@@H:45]1[CH2:46][CH2:47][N:44]1[C:8]([C:4]1[CH:5]=[C:6]([CH3:7])[N:2]([CH3:1])[N:3]=1)=[O:10])=[O:49]
Reactant: Cc1cc(C(=O)O)nn1C
Reactant: COC(=O)[C@@H]1CCN1
Agent: CC(C)N=C=NC(C)C
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCN1C(=O)c1cc(C)n(C)n1
Reaction time: 24 h
Yield: 58.6 %

Procedure:
To a mixture of the 1,5-dimethylpyrazole-3-carboxylic acid (433.1 mg, 3.09 mmol, 1.0 eq), diisopropylcarbodiimide (0.74 mL, 4.73 mmol, 1.5 eq), camphorsulfonic acid (300.6 mg, 1.29 mmol, 0.4 eq) and dimethylaminopyridine (129.7 mg, 1.06 mmol, 0.3 eq) in dry dichloromethane (30 mL) was added (2S)-methyl azetidine-2-carboxylate (474.4 mg, 3.13 mmol, 1.0 eq) in dry dichloromethane (12 mL) at about room temperature. The mixture was stirred at about room temperature for about 24 hours under argon. The solid was filtered off and washed with ether. The organic filtrate was concentrated and the residue subjected to flash chromatography (1-10% methanol in dichloromethane) to give 429.9 mg (58% yield) of the product. 1H NMR (CDCl3) δ 2.22-2.77 (series of s and m, 5H); 3.64-3.84 (series of s, 6H); 4.08-4.73 (series of m, 2H); 4.89 and 5.29 (dd, 1H, J=9.4, 6.0); 6.53 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11](=[O:13])[N:10]([CH2:14][C:15]([NH:17][CH:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH2:19]C)=[O:16])[N:9]=2)=[CH:4][CH:3]=1.[C:31](=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+].Cl[CH2:40][C:41]1[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][CH:42]=1>CC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:40][C:41]3[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][CH:42]=3)[C:11](=[O:13])[N:10]([CH2:14][C:15]([NH:17][C:18]([CH3:31])([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:30])[F:28])[CH:22]=3)[CH3:19])=[O:16])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCC(NC(=O)Cn1nc(-c2ccc(Cl)cc2)[nH]c1=O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(CCl)cc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1ccc(Cn2c(-c3ccc(Cl)cc3)nn(CC(=O)NC(C)(C)c3cccc(C(F)(F)F)c3)c2=O)cc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
100 mg (0.23 mmol) of 2-[3-(4-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-{-methyl-1-[3-(trifluoromethyl)phenyl]ethyl}-acetamide from Example 241A are suspended in 2.5 ml of acetone with 111 mg (0.34 mmol) of caesium carbonate and 34 mg (0.23 mmol) of sodium iodide and treated with 55 mg (0.30 mmol) of methyl 4-(chloromethyl)-benzoate. This is stirred for 4 hrs at 50° C. The suspension is then treated with 1.5 ml of water and extracted four times with 2 ml of ethyl acetate each time. The combined organic phases are dried over sodium sulphate and filtered. After evaporation, the crude product is purified by preparative HPLC [Method 10]. 56.6 mg (42% of theory) of the target compound are thus obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]3[CH2:11][CH2:12][NH:13][C:7]3([C:14]3[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=3)[CH2:6][N:5]2[CH:21]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][C:17]1[N:18]=[CH:19][C:14]([C:7]23[NH:13][CH2:12][CH2:11][N:8]2[C:9](=[O:10])[C:4]2[N:5]([CH:21]=[C:2]([C:24]4[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=4)[CH:3]=2)[CH2:6]3)=[N:15][CH:16]=1
Reactant: Cc1cnc(C23Cn4cc(Br)cc4C(=O)N2CCN3)cn1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: Cc1cnc(C23Cn4cc(-c5cccnc5)cc4C(=O)N2CCN3)cn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a mixture of 7-bromo-10a-(5-methylpyrazin-2-yl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (20 mg, 0.057 mmol), 3-pyridylboronic acid (9 mg, 0.073 mg) in 1,2-dimethoxyethane (0.5 mL) was added a solution of sodium carbonate (16 mg, 0.19 mmol) in water (0.15 mL) and ethanol (0.1 mL). The mixture was flushed with argon and dichlorobis(triphenylphosphine)palladium(II) (3.5 mg, 5×10−3 mmol) was added. The mixture was further degassed with argon, sealed and heated at 100° C. overnight. The following day an additional batch of 3-pyridylboronic acid (20 mg, 0.16 mmol) and dichlorobis(triphenylphosphine)palladium(II) (4 mg, 5.7×10−3 mmol) were added. The mixture was degassed, sealed and heated at 100° C. After 3 hours the reaction was complete. The mixture was then concentrated and purified by flash chromatography (Biotage SP4, gradient 1CV CH2Cl2, 0-10% MeOH in CH2Cl2 and hold 10% MeOH) to give 10a-(5-methylpyrazin-2-yl)-7-(pyridin-3-yl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]-pyrazin-5-one (15 mg, yield: 76%). 1H-NMR (400 MHz, CDCl3): δ 2.53 (s, 3H), 2.99 (dt, 1H, J 7.9 Hz), 3.35 (ddd, 1H, J 10.9, 7.5, 3.7 Hz), 3.77 (ddd, 1H, J 11.2, 7.6, 3.8 Hz), 4.00 (dt, 1H, J 11.1, 7.8 Hz), 4.26 (d, 1H, J 12.0 Hz), 4.87 (d, 1H, J 12.0 Hz), 6.87 (d, 1H, J 1.7 Hz), 7.20-7.25 (m, 2H), 7.66-7.70 (m, 1H), 8.37-8.44 (m, 3H), 8.68 (d, 1H, J 1.8 Hz).
Reaction SMILES: Br[CH2:2][C:3]([N:5]([CH2:7][CH2:8][CH2:9][CH3:10])[CH3:6])=[O:4].[C:11]([O-:14])(=[S:13])[CH3:12].[K+]>CO>[C:11]([S:13][CH2:2][C:3]([N:5]([CH2:7][CH2:8][CH2:9][CH3:10])[CH3:6])=[O:4])(=[O:14])[CH3:12]
Reactant: CCCCN(C)C(=O)CBr
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CO
Product: CCCCN(C)C(=O)CSC(C)=O
Temperature: 40 °C
Yield: 100 %

Procedure:
4.16 g of bromo-N-butyl-N-methylacetamide of Preparation B of Example 78, Step A in 1.5 ml of methanol were added to a suspension of 2.28 g of potassium thioacetate in 10 ml of methanol and the mixture was heated for one hour at 40° C. under an argon atmosphere. After evaporation to dryness under reduced pressure, the residue was dissolved with ethyl ether, the insoluble part filtered off and the solution was evaporated to dryness to obtain 4.06 g of oily product.