Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1([C:10]#N)[CH2:9][CH2:8]1.[OH-:12].[Na+].Cl.C[OH:16]>>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1([C:10]([OH:16])=[O:12])[CH2:9][CH2:8]1
Reactant: N#CC1(c2cnccn2)CC1
Reactant: [OH-]
Reactant: CO
Agent: Cl
Agent: [Na+]
Product: O=C(O)C1(c2cnccn2)CC1
Temperature: 75 °C

Procedure:
1-Pyrazin-2-yl-cyclopropanecarbonitrile (849 mg, 5.85 mmol) was dissolved in MeOH (7 mL) and NaOH solution (20 wt % in water, 2.0 mL, 10 mmol) was added via syringe in one portion. The orange mixture was heated to 75° C. for 22 h, cooled to room temperature, and acidified to pH 2-3 with 6N HCl. The mixture was filtered through a pad of celite using MeOH and the filtrate was concentrated. The residue was suspended in EtOAc, dried with Na2SO4, filtered and concentrated to give 111 mg of the title compound as an orange solid, m/z 165.28 [M+1]+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][C:7]1([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[O:15][CH2:14][C:13]2[CH:12]=[C:11]([C:16]#[N:17])[CH:10]=[CH:9][C:8]1=2)[CH3:3].CNCCC[C@]1(C2C=CC(F)=CC=2)OCC2C=C(C#N)C=CC1=2.C=O.O.O.[C:52]([OH:57])(=[O:56])[C:53]([OH:55])=[O:54]>C(O)C.C(O)=O>[CH3:1][N:2]([CH2:4][CH2:5][CH2:6][C@@:7]1([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[O:15][CH2:14][C:13]2[CH:12]=[C:11]([C:16]#[N:17])[CH:10]=[CH:9][C:8]1=2)[CH3:3].[C:53]([OH:55])([C:52]([OH:57])=[O:56])=[O:54]
Reactant: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Agent: C=O
Agent: CNCCC[C@]1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: O
Solvent: O=CO
Product: CN(C)CCC[C@@]1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Temperature: 90 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
To the crude Citalopram (90 g, 0.28 mol) having desmethyl citalopram (7%, HPLC), formic acid (98%, 2.7 g) was added followed by aqueous formaldehyde (35%, 2.37 g). The reaction mass was heated at 85-95° C. for 30 min. HPLC indicated complete conversion of desmethyl impurity into Citalopram. The reaction mass was cooled to 30° C. and diluted with ethanol (900 ml). Oxalic acid dihydrate (41.94 g, 0.33 mol) was added and mass was heated to reflux. The obtained solution was cooled to 20-25° C. and stirring was continued for 2 hours at 20-25° C. The product thus obtained was filtered and crystallized from ethanol to provide highly pure 92 g of crystalline Citalopram oxalate having HPLC purity 99.7% and desmethyl citalopram impurity: Not Detected.
Reaction SMILES: CC(O)C.O.C([C@@](C(O)=O)(O)[C@@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1.[O:32]=[C:33]([N:47]1[CH2:52][CH2:51][N:50]2[C:53]([C:56]([F:59])([F:58])[F:57])=[N:54][N:55]=[C:49]2[CH2:48]1)[CH2:34][CH:35]([NH2:46])[CH2:36][C:37]1[CH:42]=[C:41]([F:43])[C:40]([F:44])=[CH:39][C:38]=1[F:45]>CO>[O:32]=[C:33]([N:47]1[CH2:52][CH2:51][N:50]2[C:53]([C:56]([F:59])([F:58])[F:57])=[N:54][N:55]=[C:49]2[CH2:48]1)[CH2:34][C@@H:35]([NH2:46])[CH2:36][C:37]1[CH:42]=[C:41]([F:43])[C:40]([F:44])=[CH:39][C:38]=1[F:45]
Reactant: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: O=C(O)[C@@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)O)C(=O)c1ccccc1
Solvent: CC(C)O
Solvent: CO
Solvent: O
Product: N[C@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 62.5 °C
Reaction time: 1 h

Procedure:
In a 100 mL three neck flask IPA (27 mL) and Dibenzoyl-L-tartaric acid monohydrate (1.84 g) were taken. It was heated to 60-65° C. 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (2.0 g, % purity-93.8%) dissolved in methanol (17 mL) was added into reaction mixture at 60-65° C. It was stirred for 60 min. at 60-65° C. Solid salt was precipitated. It was gradually cooled to room temperature over a period of 2-3 h. The salt was filtered and washed with a mixture of IPA: MeOH (2:1). An enantiomerically enriched desired Dibenzoyl-L-tartaric acid salt of mixture of (2R) and (2S)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine was obtained (Wt.-0.65 g, % Y-17%, Purity by HPLC-99.8%, % Chiral purity by HPLC of R-isomer 77. %).
Reaction SMILES: [C:1](=[O:44])([O:6][CH2:7][CH2:8][N:9]([C:41](=[O:43])[CH3:42])[C:10]1[C:15]([I:16])=[C:14]([C:17]([N:19]([CH:21]2[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22]2)[CH3:20])=[O:18])[C:13]([I:28])=[C:12]([C:29]([N:31]([CH:33]2[CH2:37][O:36][C:35]([CH3:39])([CH3:38])[O:34]2)[CH3:32])=[O:30])[C:11]=1[I:40])[O:2][CH:3](Cl)[CH3:4].[C:45]([NH:48][C:49]1[C:50]([I:65])=[C:51]([N:60]([C:62](=[O:64])[CH3:63])[CH3:61])[C:52]([I:59])=[C:53]([C:56]([O-:58])=[O:57])[C:54]=1[I:55])(=[O:47])[CH3:46].[K+].[I-].[K+]>CN(C=O)C>[C:45]([NH:48][C:49]1[C:50]([I:65])=[C:51]([N:60]([C:62](=[O:64])[CH3:63])[CH3:61])[C:52]([I:59])=[C:53]([C:56]([O:58][CH:3]([O:2][C:1]([O:6][CH2:7][CH2:8][N:9]([C:41](=[O:43])[CH3:42])[C:10]2[C:15]([I:16])=[C:14]([C:17]([N:19]([CH:21]3[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22]3)[CH3:20])=[O:18])[C:13]([I:28])=[C:12]([C:29]([N:31]([CH:33]3[CH2:37][O:36][C:35]([CH3:39])([CH3:38])[O:34]3)[CH3:32])=[O:30])[C:11]=2[I:40])=[O:44])[CH3:4])=[O:57])[C:54]=1[I:55])(=[O:47])[CH3:46]
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Reactant: CC(=O)N(CCOC(=O)OC(C)Cl)c1c(I)c(C(=O)N(C)C2COC(C)(C)O2)c(I)c(C(=O)N(C)C2COC(C)(C)O2)c1I
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(I)c(C(=O)OC(C)OC(=O)OCCN(C(C)=O)c2c(I)c(C(=O)N(C)C3COC(C)(C)O3)c(I)c(C(=O)N(C)C3COC(C)(C)O3)c2I)c(I)c(N(C)C(C)=O)c1I
Temperature: 50 °C
Reaction time: 24 h

Procedure:
1-Chloroethyl 2-(N-(3,5-bis-((2,2-dimethyl-1,3-dioxolan-4-yl)-methylaminocarbonyl)-2,4,6-triiodophenyl)-acetylamino)ethyl carbonate (3.1 g, 3.3 mmol) was added at room temperature to a solution of potassium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (2.00 g, 3 mmol) and potassium iodide (50 mg, 0.3 mmol) in dry DMF. After stirring at 50° C. for 18 hours and at room temperature for one day the solvent was removed at reduced pressure. The residue was suspended in chloroform (50 ml) and DMF (5 ml) and washed twice with a sodium hydrogen carbonate solution and twice with water. After treatment of the organic phase with magnesium sulfate and charcoal the solution was evaporated to dryness. Yield: 2.65 g. FAB-MS: M+1=1528.
Reaction SMILES: C1C2C(COC(=O)[N:17]([CH2:24][CH2:25][CH2:26][CH2:27][C:28](=[O:59])[NH:29][C:30]3[CH:35]=[CH:34][C:33]([N:36]4[C:39](=[O:40])[CH:38]([CH2:41][CH2:42][CH:43]([OH:50])[C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[CH:37]4[C:51]4[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=4)=[CH:32][CH:31]=3)C3C=CC=CC=3)C3C(=CC=CC=3)C=2C=CC=1.C(NCC)C>CN(C)C=O>[OH:50][CH:43]([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[CH2:42][CH2:41][CH:38]1[C:39](=[O:40])[N:36]([C:33]2[CH:32]=[CH:31][C:30]([NH:29][C:28](=[O:59])[CH2:27][CH2:26][CH2:25][CH2:24][NH2:17])=[CH:35][CH:34]=2)[CH:37]1[C:51]1[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=1
Reactant: COc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(NC(=O)CCCCN(C(=O)OCC3c4ccccc4-c4ccccc43)c3ccccc3)cc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: COc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(NC(=O)CCCCN)cc2)cc1

Procedure:
570 mg (0.78 mmol) of product 8 and 0.8 ml of diethylamine are solved in 5 ml of DMF (dimethylformamide). It is evaporated after 1 h at room temperature. The residue is purified by flash chromatography (methylenechloride/methanol/conc. ammoniac 30:10:3) 220 mg (56%) of product 9 is obtained in form of an amorphic solid compound: C30H35N3O4 (501.63) MS (ESI+) 502.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([CH3:11])[C:4]=1[CH3:12].[CH3:13][O:14]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:10][O:9][C:6]1[C:5]([CH3:11])=[C:4]([CH3:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[CH:13]=[O:14]
Reactant: COc1ccc(OC)c(C)c1C
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C=O)c(OC)c(C)c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
To a solution of 1,4-dimethoxy-2,3-dimethylbenzene (100 g, 0.60 mol) and dichloromethyl methyl ether (65 mL, 0.72 mol) in dichloromethane (400 mL) was added dropwise titanium tetrachloride (IV)(100 mL, 0.91 mol) over 30 minutes under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into ice (1 kg), the organic layer was separated, and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washes with water and saturated brine, passed through sodium sulfate-silica gel, dried (eluted with hexane-ethyl acetate 5:1) and concentrated under reduced pressure. The residue was recrystallized from hexane to obtain 107 g of the title compound.
Reaction SMILES: [Mg].[F:2][C:3]([O:7][C:8]1[CH:9]=[C:10](Br)[CH:11]=[CH:12][CH:13]=1)=[C:4]([F:6])[F:5].[CH2:15]([O:17][Si:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])Cl)[CH3:16].C(=O)=O>CCCCCCC.C(#N)C.O1CCCC1>[F:2][C:3]([O:7][C:8]1[CH:9]=[C:10]([Si:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])[O:17][CH2:15][CH3:16])[CH:11]=[CH:12][CH:13]=1)=[C:4]([F:6])[F:5]
Reactant: CCO[Si](Cl)(OCC)OCC
Reactant: FC(F)=C(F)Oc1cccc(Br)c1
Agent: O=C=O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CC#N
Product: CCO[Si](OCC)(OCC)c1cccc(OC(F)=C(F)F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
Magnesium (0.12 mol) and tetrahydrofuran were put in a 2-bulb flask purged with nitrogen. Then, 3-[(trifluorovinyl)oxy]bromobenzene prepared in (2) was dropped very slowly maintaining the reactor temperature at 0° C. The reactor was put in an ice bath to prevent the temperature from rising rapidly. After adding 3-[(trifluorovinyl)oxy]bromobenzene, the reactor was heated to room temperature, and reaction was performed for 2 hours. Then, triethoxychlorosilane (0.95 mol) was dropped keeping the reactor temperature at −48° C. with a constant temperature bath filled with dry ice and acetonitrile. The reaction mixture was mixed at room temperature for 24 hours. After the reaction was completed, excess heptane was added to remove the obtained salt and unreacted magnesium. The filtrate was removed by filtering with filter paper. Heptane remaining in the filtrate was removed using a vacuum evaporator and vacuum-distilled to obtain [3-[(trifluorovinyl)oxy]phenyl]triethoxysilane (PFCBSI) (yield: 80%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1F)([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[CH3:21][O:22][CH2:23][C@@H:24]([NH2:26])[CH3:25]>>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[NH:26][C@@H:24]([CH3:25])[CH2:23][O:22][CH3:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1F
Reactant: COC[C@H](C)N
Agent: O=C([O-])O
Agent: [Na+]
Product: COC[C@H](C)Nc1cc(F)ccc1C(=O)OC(C)(C)C
Temperature: 65 °C
Reaction time: 48 h
Yield: 84 %

Procedure:
A mixture of 2,4-difluoro-benzoic acid tert-butyl ester (30 g, 140.05 mmol) and (S)-2-methoxy-1-methyl-ethylamine (100 mL) was stirred at 65° C. for 2 days. A saturated solution of NaHCO3 was added and the mixture was extracted with dichloromethane (3 times). The organic phase was washed twice with water then with brine, dried over sodium sulfate filtered and evaporated to dryness to obtain a crude, which was purified by column chromatography on silica gel (exane/ethyl acetate 9:1). The title compound (33.38 g, 84%) was obtained as oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=1[O:16][CH3:17].[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.O>C(Cl)(Cl)Cl.CO>[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1[N:27]1[CH2:28][CH2:29][N:30]([C:11]([C:10]2[CH:14]=[CH:15][C:7]([N:3]3[CH2:4][CH2:5][CH2:6][S:2]3(=[O:1])=[O:18])=[C:8]([O:16][CH3:17])[CH:9]=2)=[O:13])[CH2:31][CH2:32]1
Reactant: COc1cc(C(=O)O)ccc1N1CCCS1(=O)=O
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc(C(=O)N2CCN(c3ccc(C)cc3C)CC2)ccc1N1CCCS1(=O)=O
Temperature: 25 °C
Yield: 88.6 %

Procedure:
4-(1,1-Dioxo-1λ6-isothiazolidin-2-yl)-3-methoxybenzoic acid (285 mg) described in Preparation Example 21 and 1-(2,4-dimethylphenyl)piperazine (199 mg) were dissolved in a solution of chloroform (2.1 mL) and methanol (2.1 mL), 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (349 mg) was added, and the mixture was stirred at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (411 mg).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].[CH2:45]([Cl:47])[Cl:46]>C(O)(=O)C>[NH3:1].[CH2:45]([Cl:47])[Cl:46].[CH3:19][N:20]([CH2:15][C:14]1[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:12][CH:13]=1)[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: O=Cc1ccc(OCCCN2CCCCC2)cc1
Reactant: CNCCc1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(CCc1ccccn1)Cc1ccc(OCCCN2CCCCC2)cc1
Product: N
Reaction time: 16 h

Procedure:
A solution of the product of Example 9 (256 mg), methyl-(2-pyridin-2-yl-ethyl)-amine (143 mg), and acetic acid (0.06 mL) in DCM (4 mL) was treated with sodium triacetoxyborohydride (330 mg). After 16 h, the resulting mixture was treated with 10% sodium hydroxide (5 mL) and extracted with DCM (3×10 mL). The combined organic phases were dried (sodium sulfate) and evaporated. Chromatography of the residue (1–5% 2 M methanolic ammonia/DCM) gave the title compound as a colorless oil (325 mg). 1H NMR (400 MHz, CDCl3): 8.51 (m, 1H), 7.57 (m, 1H), 7.18–7.12 (m, 3H), 7.10 (m, 1H), 6.82 (d, J=8.6 Hz, 2H), 3.98 (t, J=6.3 Hz, 2H), 3.49 (s, 2H), 2.99 (m, 2H), 2.78 (m, 2H), 2.46 (m, 2H), 2.39 (br, 4H), 2.25 (s, 3H), 1.96 (m, 2H), 1.61–1.54 (m, 4H), 1.47–1.40 (m, 2H).
Reaction SMILES: [OH-].C([N+](CCCC)(CCCC)CCCC)CCC.C[Si]([C:23]#[C:24][C:25]1[CH:26]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:28]=[CH:29][CH:30]=1)(C)C.ClCCl.O>O1CCCC1>[C:24]([C:25]1[CH:26]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:28]=[CH:29][CH:30]=1)#[CH:23]
Reactant: C[Si](C)(C)C#Cc1cccc(-c2ccccn2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: C#Cc1cccc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
Tetra-n-butylammonium hydroxide (22 cm3, 1 M in methanol) was added to a solution of (16) (1.87 g, 7.4 mmol) in tetrahydrofuran (20 cm3), and the solution was stirred at room temperature for 1 hour. Dichloromethane (20 cm3) and water (50 cm3) were added, and the layers were separated. The aqueous layer was extracted with dichloromethane (3×10 cm3). The combined organic extracts were washed with brine (50 cm3) and dried over magnesium sulfate, and the solvent was removed to leave an orange oil. The crude product was passed through a silica plug using dichloromethane: light petroleum (1:1) as eluent, and the solvent was completely removed to give (17) as a colourless oil (1.31 g, 99%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[N:4]=[CH:5][C:6]2[CH2:12][CH2:11][NH:10][C:9](=[O:13])[C:7]=2[N:8]=1.[C:16](=O)([O-])[O-].[Na+].[Na+].F[B-](F)(F)F.C[O+](C)C.O>ClCCl>[CH3:16][O:13][C:9]1[C:7]2[N:8]=[C:3]([C:2]([F:1])([F:14])[F:15])[N:4]=[CH:5][C:6]=2[CH2:12][CH2:11][N:10]=1
Reactant: O=C1NCCc2cnc(C(F)(F)F)nc21
Reactant: O=C([O-])[O-]
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC1=NCCc2cnc(C(F)(F)F)nc21
Reaction time: 5.5 h

Procedure:
To a vigorously stirred mixture of 336 mg (1.33 mmol) of 2-(trifluoromethyl)-6,7-dihydropyrido[3,4-d]pyrimidin-8(5H)-one and 2.94 g (27.7 mmol) of anhydrous sodium carbonate in 15 mL of dichloromethane was added 979 mg (6.6 mmol) of trimethyloxonium tetrafluoroborate. Vigorous stirring was continued at room temperature for 5.5 h. Then 15 mL of water was added, and the mixture was shaken. After separation of the phases, the aqueous layer was extracted twice with dichloromethane. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (0-2% methanol in dichloromethane) yielded the title compound as a yellow solid. LC-MS 232 (M+1).
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[N:5][N:6]([CH3:8])[N:7]=1.CS(Cl)(=O)=O.C(N(CC)CC)C.[C:21]([O-:24])(=[S:23])[CH3:22].[K+]>ClCCl.CN(C)C=O>[C:21]([S:23][CH2:2][C:3]1[N:4]=[N:5][N:6]([CH3:8])[N:7]=1)(=[O:24])[CH3:22]
Reactant: Cn1nnc(CO)n1
Reactant: CC([O-])=S
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)SCc1nnn(C)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 5-hydroxymethyl-2-methyltetrazole (1.83 g, 11.7 mmol) in dry dichloromethane (25 mL) at 0° C. was added methanesulfonyl chloride (1.47 g, 12.9 mmol) followed by triethylamine (1.30 g, 12.9 mmol) added dropwise over five min. The mixture was stirred at 0° C. for 1 h, and then treated with a solution of potassium thioacetate (1.60 g, 14.0 mmol) in dry N,N-dimethylformamide (10 mL). The resulting gel was stirred at 0° C. for 3 h. The reaction mixture was diluted with dichloromethane (200 mL), washed with brine (20 mL) and dried over anhydrous sodium sulfate. Evaporation of the solvent under vacuum and chromatography of the resulting oil over silica gel (2×15 cm, eluting with dichloromethane and dichloromethaneacetone 5%) gave the title compound as a clear oil: 1.31 g (65%); ir (film) νmax : 1696 cm-1 (C=O of thioester); 1Hmr (CDCl3) δ: 2.43 (3H, s, SAc), 4.36 (3H, s, 2-CH3), 4.38 ppm (2H, s, 5-CH2).
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:11])=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[I-].[NH4+].B(Cl)(Cl)Cl>ClCCl>[OH:2][C:3]1[C:4]([CH3:11])=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7]
Reactant: COc1cccc(C#N)c1C
Agent: ClB(Cl)Cl
Agent: [I-]
Agent: [NH4+]
Solvent: ClCCl
Product: Cc1c(O)cccc1C#N
Temperature: -78 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
A solution of 3-methoxy-2-methylbenzonitrile [(1 g, 6.79 mmol) U.S. Pat. No. 5,965,766, p 6] and tetra nbutyl ammonium iodide (4.12 g, 17 mmol) in dichloromethane (15 mL) was cooled to −78° C. and purged with nitrogen. Boron trichloride (1M in dichloromethane, 17 mL, 17 mmol) was added dropwise and the mixture was stirred for 15 minutes at −78° C. and at room temperature for 3 hours. The reaction mixture was quenched with water, stirred for 30 minutes and concentrated in vacuo. The aqueous residue was extracted with diethyl ether and the organic solution was washed with water (×5), dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a brown solid in 91% yield, 826 mg. 1H NMR (400 MHz, CDCl3) δ: 2.20 (s, 3H), 7.10 (m, 1H), 7.20 (d, 1H), 10.10 (s, 1H); LRMS APCI m/z 132 [M−H]−
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[NH2:8][C:9]1[N:10]=[C:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[N:21]=2)=[N:13][C:14]=1Br.O>O1CCOCC1.C(Cl)(Cl)Cl>[NH2:8][C:9]1[N:10]=[C:11]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:12]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[N:21]=2)=[N:13][C:14]=1[N:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1
Reactant: CC(C)n1nc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Reactant: c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1nc(-c2nc(-n3cccc3)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 27.5 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (60% in oil suspension) (77.7 mg) in dioxane (0.6 ml) was added 1H-pyrrole (0.161 ml) and the mixture was stirred at 25-30° C. for 30 minutes. After addition of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (150 mg), the mixture was heated at 100-105° C. for 2 hours. A mixture of water and chloroform was added to the reaction mixture. An organic layer was collected, dried over MgSO4, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (75:25 v/v) to give a solid. The solid was crystallized from a mixture of IPE and n-hexane to give 6-[5-amino-3-phenyl-6-(1H-pyrrol-1-yl)-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (38 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:25][O:24][C:22](=[O:23])[CH:21]([O:20][CH3:19])[CH:13]([C:12]1[CH:15]=[CH:16][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([O:17][CH3:18])[CH:11]=1)[OH:14]
Reactant: COCC(=O)OC
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(OC)C(O)c1ccc(OCc2ccccc2)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.6 %

Procedure:
A solution of 4-benzyloxy-3-methoxy-benzaldehyde (0.44 g, 1.92 mmol) and methyl methoxyacetate (0.19 mL, 1.92 mmol) in THF (10 mL) at −78° C. was added dropwise to sodium bis(trimethylsilyl)amide (20 mL, 2.11 mmol, 1N in THF) at −78° C. The reaction mixture was stirred for 3 h and quenched with 1N HCl (5 mL). The mixture was allowed to warm to room temperature, diluted with water (15 mL), and extracted with ethyl acetate (3×15 mL). The combined organic layers were dried (MgSO4) and concentrated. The residue was purified by silica gel column chromatography (silica gel, hexanes/ethyl acetate, 1:1) to produce 3-(4-benzyloxy-3-methoxy-phenyl)-3-hydroxy-2-methoxy-propionic acid methyl ester as an oil (350 mg, 52%); 1H-NMR (200.15 MHz, CDCl3): δ 7.45–7.20 (m, 5H), 6.9 (s, 1H), 6.8 (b, 2H), 5.1 (s, 2H), 4.90–4.80 (m, 1H), 4.10 (m, 1H), 3.90 (s, 3H), 3.65 (s, 3H), 3.31 (s, 3H), 3.10–2.96 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([C:14]([NH:16][C@:17]2([C:22]([OH:24])=O)[CH2:19][C@H:18]2[CH:20]=[CH2:21])=[O:15])[C:11]2=[N:25][NH:26][CH:27]=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:40]1([S:43]([NH2:46])(=[O:45])=[O:44])[CH2:42][CH2:41]1.C1CCN2C(=NCCC2)CC1>ClCCCl>[CH:40]1([S:43]([NH:46][C:22]([C@@:17]2([NH:16][C:14]([CH:12]3[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][C:10]4=[CH:27][NH:26][N:25]=[C:11]34)=[O:15])[CH2:19][C@H:18]2[CH:20]=[CH2:21])=[O:24])(=[O:45])=[O:44])[CH2:42][CH2:41]1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)C1CN(C(=O)OC(C)(C)C)Cc2c[nH]nc21)C(=O)O
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCCl
Product: C=C[C@@H]1C[C@]1(NC(=O)C1CN(C(=O)OC(C)(C)C)Cc2c[nH]nc21)C(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of acid 8b (47.0 mg, 0.125 mmol) and CDI (22.3 mg, 0.150 mmol) in dry DCE (1.0 mL) was stirred at rt for 8 h. The cyclopropyl sulfonamide 9b (18.2 mg, 0.150 mmol) and DBU (22.8 mg, 0.150 mmol) were sequentially added and the mixture stirred at rt for 48 h. The solvent was evaporated and the residue diluted with EtOAc (2 mL). The mixture was washed sequentially with 0.5 M HCl (2×), deionized H2O and brine. The EtOAc solution was dried over MgSO4, filtered through a Celite plug capped with a layer of MgSO4 and concentrated. The crude product was purified via a SiO2 column (CH2Cl2, 25% EtOAc/hexanes then 50% EtOAc/hexanes) to give compound 104 as an ivory solid; 3:2 mixture of diastereomers, 27 mg, 45% (3:2 mixture of diastereomers), MS m/z 478.1 (APCI−, M−1).