Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16]([C:30](O)=[O:31])=[N:17][N:18]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[C:19](=[O:21])[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=[N:39][C:37]=2C=1.C(Cl)CCl.CN.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[Cl:29][C:24]1[CH:23]=[C:22]([N:18]2[C:19](=[O:21])[CH:20]=[C:15]([O:14][CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]3)[C:16]([C:30](=[O:31])[NH:39][CH3:37])=[N:17]2)[CH:27]=[CH:26][C:25]=1[Cl:28]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(Cl)c(Cl)c3)nc2C(=O)O)CC1
Reactant: On1nnc2ccccc21
Agent: CN
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CNC(=O)c1nn(-c2ccc(Cl)c(Cl)c2)c(=O)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
To a mixture of 4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(3,4-dichlorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (23 mg, 0.047 mmol) in THF (1 ml) at room temperature under argon was added HOBt (8.0 mg, 0.052 mmol), EDC (10.01 mg, 0.052 mmol), and was followed by 1 M methylamine in THF (0.237 mL, 0.237 mmol). The reaction mixture was stirred at room temperature overnight. EtOAc (10 mL) and 1 N NaOH (10 mL) were added to the reaction mixture. Layers were separated. Organic layer were washed with water (10 mL), and brine (10 mL). Organic phase was dried (MgSO4), filtered and concentrated. The crude product was purified by preparative HPLC (C18 column; 10-100% methanol in water without TFA) to give tert-butyl 4-(1-(3,4-dichlorophenyl)-3-(methylcarbamoyl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate (10 mg, white solid, 40.9%). 1H NMR (400 MHz, CDCl3) δ ppm 1.45 (s, 9H) 1.78-2.05 (m, 4H) 2.96 (d, J=5.27 Hz, 3H) 3.43-3.57 (m, 2H) 3.57-3.72 (m, 2H) 4.49-4.71 (m, 1H) 6.28 (s, 1H) 6.58-6.69 (m, J=3.95 Hz, 1H) 7.46 (dd, 1H) 7.54 (d, 1H) 7.70 (d, J=2.20 Hz, 1H). MS (ESI) 441 (M+H-tBu).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][NH:6][C@@H:7]([C@@H:15]([CH3:18])[CH2:16][CH3:17])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:2].ClS([N:24]=[C:25]=[O:26])(=O)=O.O>ClCCl>[NH2:24][C:25]([N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:19])[C@@H:7]([C@@H:15]([CH3:18])[CH2:16][CH3:17])[C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])=[O:26]
Reactant: CCOC(=O)CN[C@H](C(=O)OC(C)(C)C)[C@@H](C)CC
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CN(C(N)=O)[C@H](C(=O)OC(C)(C)C)[C@@H](C)CC
Temperature: 0 °C
Reaction time: 16 h
Yield: 103.3 %

Procedure:
A solution containing the product from Example 36A (5.7 g, 20.9 mmol) in dichloromethane (60 mL) at 0° C. was treated with chlorosulfonyl isocyanate (2.7 mL, 31.0 mmol) and the mixture was stirred at 0° C. for 16 hours. Water (60 mL) was added to the cold reaction and the mixture was warmed to 25° C. and stirred for 4 hours. The reaction was partitioned between dichloromethane and water, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound (6.83 g), which was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[OH:26].[Cl-].[NH4+]>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[O:26][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1
Reactant: C#CCOc1cc(Cl)ncn1
Reactant: Oc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(Oc2ccc(Cl)cc2Cl)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 68.5 %

Procedure:
To 5 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-propynyloxy)pyrimidine, 0.25 g of potassium carbonate, and 0.21 g of 2,4-dichlorophenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.24 g of 4-(2,4-dichlorophenoxy)-6-(2-propynyloxy)pyrimidine (the present compound (22)), m.p.: 106.7° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][C:5]2([CH3:14])[CH3:13].C([Sn](CCCC)(CCCC)[C:20]([O:22]CC)=[CH2:21])CCC.Cl>C1COCC1.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>[C:20]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][C:5]2([CH3:14])[CH3:13])(=[O:22])[CH3:21]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC1(C)CC(=O)Nc2ccc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)C(C)(C)CC(=O)N2
Temperature: 80 °C
Reaction time: 18 h
Yield: 66.9 %

Procedure:
A solution of 6-bromo-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (Intermediate 4, 270 mg, 1.06 mmol) in 5 ml of THF was first degassed by bubbling with argon for 30 min. Tributyl(1-ethoxyvinyl)tin (766 mg, 2.12 mmol) and PdCl2(PPh3)2 (37mg, 0.05 mmol) were added. After stirring at 80° C. for 18 h, the mixture was cooled to room temperature and 3 mL of 10% HCl was added. The mixture was then stirred for another 30 min before extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with brine (1×10 mL), dried (MgSO4) and concentrated at reduced pressure. Purification by flash chormatography (50:50 hexane/ethyl acetate) yielded the title compound as a white solid (154 mg, 67% yield).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:9]=[C:8]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:7]([O:19][CH2:20][CH2:21][CH3:22])[CH:6]=1)=[O:4].[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24]>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([C:8]2[N:7]([O:19][CH2:20][CH2:21][CH3:22])[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][N:25]([CH2:26][CH3:27])[CH2:23][CH3:24])[CH:9]=2)=[O:18])=[CH:12][CH:13]=1
Reactant: CCNCC
Reactant: CCCOn1cc(C(=O)CCl)cc1C(=O)c1ccc(Cl)cc1
Product: CCCOn1cc(C(=O)CN(CC)CC)cc1C(=O)c1ccc(Cl)cc1
Yield: 25.4 %

Procedure:
A solution of 3.19 g (0.0094 mole) of 2-chloro-1-[5-(4-chlorobenzoyl)-1-ethylmethoxy-1H-pyrrol-3-yl]ethanone, 75 mL of 2-PrOH, and 2.9 mL (0.028 mole) of diethylamine was heated under reflux for 4 h. The solvent was evaporated in vacuo. The residue was partitioned between Et2O and 2N NaOH. The organics were washed with water, brine and dried (Na2SO4). The solvent was evaporated in vacuo and the residue chromatographed on silica gel (9:1 CH2Cl2: MeOH). The oil was treated with ethereal HCl and the resulting solid recrystallized from 2-PrOH to give 0.9 g (26%) of Compound 9. mp 149-151° C. CIMS m/z 377 (MH+). 1H NMR (300 MHz, DMSO-d6) δ 8.2 (Ar, 1H); 7.8 (Ar, 2H); 7.7 (Ar, 2H); 7.2 (Ar, 1H); 4.7 (m, 2H); 4.6 (t, 2H); 3.65 (t, 2H); 3.2 (m, 3H); 3.15 (m, 4H); 1.2 (t, 6H). Calc'd for: C20H25CIN2O3.HCl: C, 5.12; H, 634; N, 6.78. Found: C, 58.29; H, 6.31; N, 6.55.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.[NH:33]1[CH2:38][CH2:37][CH:36]([N:39]2[C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[N:41]=[CH:40]2)[CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.CN(C=O)C>[N:39]1([CH:36]2[CH2:35][CH2:34][N:33]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:6][N:5]([C@H:14]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[C:15]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)=[O:16])[CH2:4]3)[CH2:38][CH2:37]2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[CH:40]1
Reactant: c1ccc2c(c1)ncn2C1CCNCC1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(n4cnc5ccccc54)CC3)[C@@H](c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.8 %

Procedure:
To a solution of 60 mg of α-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid, 4-methoxy-benzyl ester (prepared above as Aldehyde 5) and 70 mg of 1-piperidin-4-yl-1-H-benzoimidazole (from Step C) in 4 mL THF and 1 mL of DMF was added 1 spatula tip of 4Å molecular sieves. After stirring at room temperature for 10 minutes, 80 mg sodium triacetoxyborohydride was added. Continued to stir at room temperature for another 10 hours. The reaction was concentrated and diluted with 20 ml of EtOAc and washed with 10 mL saturated NaHCO3 aqueous solution. After separating layers, the aqueous phas was extracted with 2×10 mL EtOAc. The combined organic phases were washed with 8 mL of brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 100% EtOAc, then 90% EtOAc in CH3OH to give 40 mg of the title compound as an oil. 1H NMR (400 MHz, CDCl3): δ1.17-3.73 (m, 31H), 4.07 (m, 1H), 5.10(d, J=2.1 Hz, 2H), 6.86 (d, J=8.5, 2H), 7.16-7.36 (m, 10H), 7.78(m, 1H), 7.93(s. 1H). ESI-MS 621 (M+H); HPLC A: 2.96 min.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[N:10]=[CH:11][NH:12][CH:13]=1.[C:14](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])O.[Na+]>ClCCl>[Br:8][C:9]1[N:10]=[CH:11][N:12]([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:13]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1c[nH]cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Brc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 11 h

Procedure:
0.3787 g of triethylamine is added dropwise over 15 minutes to a solution of 0.500 g of 4-bromoimidazole, 1.043 g of trityl chloride and 25 ml of dichloromethane. The reaction mixture is stirred at room temperature for 11 hours and then poured onto 50 ml of aqueous saturated sodium hydrogencarbonate solution. The mixture is extracted twice with 75 ml of dichloromethane. The combined organic phases are washed with 50 ml of brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a white solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.38 (1:3 EtOAc-heptane); Rt=5.02.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[CH:12]1[C:19](=[O:20])[CH:18]2[CH:14]([CH2:15][CH:16]([CH2:21][CH2:22][CH2:23][CH:24]=O)[CH2:17]2)[C:13]1=[O:26])[CH3:2].Cl.[CH3:28][O:29][NH2:30].C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[CH2:10]([C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[CH:12]1[C:13](=[O:26])[CH:14]2[CH:18]([CH2:17][CH:16]([CH2:21][CH2:22][C:23](=[N:30][O:29][CH3:28])[CH3:24])[CH2:15]2)[C:19]1=[O:20])[CH3:11]
Reactant: CON
Reactant: CCc1cc(C)cc(CC)c1C1C(=O)C2CC(CCCC=O)CC2C1=O
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCc1cc(C)cc(CC)c1C1C(=O)C2CC(CCC(C)=NOC)CC2C1=O
Yield: 71.5 %

Procedure:
267 mg (0.82 mmol) of 2-(2,6-diethyl-4-methylphenyl)-5-(oxobutyl)-tetrahydropentalene-1,3-dione (example I-a-39), 102 mg (1.23 mmol) of O-methylhydroxylamine hydrochloride and 0.5 ml of triethylamine in 10 ml of acetonitrile are stirred at room temperature overnight. The mixture is then taken up in ethyl acetate, washed with water and dried (magnesium sulphate) and the solvent is distilled off Chromatography on silica gel (mobile phase ethyl acetate/hexane 1:4) gives 225 mg (77%) of the target compound in the form of colourless crystals of m.p. 79-80° C.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:18])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:17].[CH2:19]([CH:24]1[CH2:30][CH:29]2[NH:31][CH:26]([CH2:27][CH2:28]2)[CH2:25]1)[CH2:20][CH2:21][CH2:22][CH3:23]>CCCCCCC.CCOC(C)=O>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]2[O:8][CH2:7][C:6](=[O:17])[N:5]([CH2:4][C@H:3]([CH3:18])[CH2:2][N:31]3[CH:26]4[CH2:27][CH2:28][CH:29]3[CH2:30][CH:24]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:25]4)[C:10]=2[CH:11]=1
Reactant: CCCCCC1CC2CCC(C1)N2
Reactant: COc1ccc2c(c1)N(C[C@H](C)CI)C(=O)CO2
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)COc2ccc(OC)cc21
Yield: 43.5 %

Procedure:
The compound (S)-4-(3-Iodo-2-methylpropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one (111MF36) (0.226 g, 0.63 mmol) and 3-pentyl-8-azabicyclo[3.2.1]octane (0.101 g, 0.56 mmol) were mixed according to GP16. CC (SiO2; heptane/EtOAc 4:1-4) and prep HPLC gave the title compound (111MF41) (0.101 g, 39%). 1H NMR (CDCl3) d 6.89 (d, J=8.8 Hz, 1H), 6.81 (d, J=2.8 Hz, 1H), 6.49 (dd, J=8.8 Hz, J=2.8 Hz, 1H), 4.60-4.46 (m, 2H), 4.01 (d, J=6.8 Hz, 2H), 3.77 (s, 3H), 3.15-3.02 (m, 2H), 2.32-2.26 (m, 1H), 2.20-1.79 (m; 7H), 1.68-1.51 (m, 3H), 1.42-1.16 (m, 10H), 0.89-0.85 (m, 6H); 13C NMR (CDCl3) d 168.4, 155.6, 139.8, 129.8, 117.0, 106.9, 103.8, 68.0, 60.6, 59.1, 58.1, 56.0, 45.3, 39.4, 36.6, 36.4, 32.2, 31.5, 28.4, 28.4, 28.0, 27.3, 22.8, 16.8, 14.2; HPLC-MS (ammonium acetate) [M+H]+=415.3.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:15]2[CH:14]([S:16]([NH2:19])(=[O:18])=[O:17])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O.O>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][C:14]1([S:16]([NH2:19])(=[O:17])=[O:18])[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:7]2[C:15]1=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH3:26]
Reactant: NS(=O)(=O)C1c2ccccc2-c2ccccc21
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC1(S(N)(=O)=O)c2ccccc2-c2ccccc21
Reaction time: 3 h
Yield: 25.2 %

Procedure:
To a stirred, 15° C. suspension of sodium hydride (60% in mineral oil, 500 mg, 12.2 mmoL, 1 eq) in 50 mL of dry dimethylformamide (from molecular sieves) under nitrogen was added dropwise over 15 minutes a solution of (8) (3 g, 12.2 mmoL) in 100 mL of dimethylformamide. A solution of ethyl bromoacetate (2.0 g, 12.2 mmoL, 1 eq) in 20 mL of dimethylformamide was then added dropwise over 10 minutes. After 3 h at room temperature, the reaction was diluted with water (100 mL), acidified (pH 5) and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with brine (5×100 mL), dried (MgSO4), filtered and evaporated. The crude oil was purified by chromatography on silica gel using a gradient of 10%-30% ethyl acetate in hexane to provide 1 g (25%) of product: mp 167°-170° C., 1H NMR (CDCl3) 7.8-7.2 (m, 8H, aromatic protons), 3.9 (broad single, 2H), 3.6 (s, 2H), 3.5 (q, 2H), 1.7 (t, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[CH3:13][C:14]([C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)([CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[CH3:15].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.C(Cl)CCl>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([C:14]([CH3:15])([CH:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)[CH3:13])=[CH:24][CH:25]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Reactant: CN1CCC(C(C)(C)c2ccc(N)cc2)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CN1CCC(C(C)(C)c2ccc(NC(=O)c3ccccc3[N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-nitrobenzoic acid (400 mg), 4-[1-methyl-1-(1-methylpiperidin-4-yl)-ethyl]phenylamine (Preparation IV (aw)) (600 mg) and DIEA (0.6 mL) in CH2Cl2 (80 mL) was added EDC (600 mg) and HOBt (350 mg). The reaction was stirred at RT overnight and washed with saturated NaHCO3 (30 mL), H2O (50 mL) and brine (30 mL). The organic layer was dried over Na2SO4 and evaporated to give 2-nitro-N-{4-[1-methyl-1-(1-methylpiperidin-4-yl)ethyl]phenyl}benzamide which was used in the next step without further purification.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:14]=[C:13]([CH2:15]B2OCC(C)(C)CO2)[O:12][C:11]=1[CH3:24])(C)C)(C)(C)C.ClC1[N:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH3:24][C:11]1[O:12][C:13]([C:15]2[N:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[CH:14][C:10]=1[CH2:9][OH:8]
Reactant: Cc1ccc(Cl)nn1
Reactant: Cc1oc(CB2OCC(C)(C)CO2)cc1CO[Si](C)(C)C(C)(C)C
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: COCCOC
Solvent: O
Product: Cc1ccc(-c2cc(CO)c(C)o2)nn1
Reaction time: 8 h
Yield: 31.6 %

Procedure:
A mixture of tert-butyl({5-[(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)methyl]-2-methylfuran-3-yl}methoxy)dimethylsilane (2.4 g), 3-chloro-6-methylpyridazine (1.5 g), tetrakis(triphenylphosphine)palladium(0) (0.4 g), 2N aqueous sodium carbonate solution (7 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), 1N tetrabutylammonium fluoride in tetrahydrofuran (10 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (50% ethyl acetate/hexane to 100% ethyl acetate/hexane) to give the title compound (0.44 g, 31%) as a yellow crystal.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:25]([O:29][C:30](=[O:43])[N:31]=[C:32]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])SC)([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>CN(C=O)C.[Hg](Cl)Cl>[C:39]([O:38][C:36]([NH:35][C:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:23][CH:24]=1)=[N:31][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:43])=[O:37])([CH3:42])([CH3:41])[CH3:40]
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: CCOC(Cc1ccc(OCCc2ccc(N)cc2)cc1)C(=O)O
Agent: Cl[Hg]Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(Cc1ccc(OCCc2ccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)cc1)C(=O)O
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
3-{4-[(4-Aminophenethyl)oxy]phenyl}-2-ethoxypropanoic acid (20 mg, 0.061 mmol) and tert-butyl-[(tert-butoxycarbonyl)amino](methylsulfanyl)methylidenecarbamate (18.6 mg, 0.064 mmol) were mixed in 0.3 ml DMF. Triethylamine (25.5 ml, 0.183 mmol) was added. The mixture was then cooled in an ice-bath. Mercury (II)chloride (18 mg, 0.066 mmol) was added. After 30 minutes, the cooling bath was removed. The reaction mixture was stirred overnight. Water (1 ml) and ethyl acetate (0.5 ml) were added and then hydromatrix (ca. 0.5 g) was added. After a while, the mixture was filtered. The filtrate was evaporated to dryness. Chromatography of the residue on an ISOLUTE column (SI, 500 mg/3 ml) using ethyl acetate/heptane (10:90, then 25:75, and then 50:50) as eluant gave 15.4 mg, yield 44% of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[C:13]([Cl:15])[C:12]([S:16][CH3:17])=[CH:11][C:10]=2[Cl:18])[CH:5]=[CH:4][N:3]=1.[OH:19]O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[C:13]([Cl:15])[C:12]([S:16]([CH3:17])=[O:19])=[CH:11][C:10]=2[Cl:18])[CH:5]=[CH:4][N:3]=1
Reactant: CSc1cc(Cl)c(Oc2ccnc(Cl)c2)cc1Cl
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)c1cc(Cl)c(Oc2ccnc(Cl)c2)cc1Cl
Temperature: 50 °C
Reaction time: 3 h

Procedure:
An amount of 32.6 gm (0.1 mol) of 2-chloro-4-(2,5-dichloro-4-methylmercaptophenoxy)-pyridine, prepared analogously to Example 1, was suspended in 100 ml of glacial acetic acid. The mixture was warmed to 45° to 50° C., and 11 ml (0.11 mol) of 30% H2O2 were added dropwise at such a rate that the internal temperature did not exceed 50° C. The mixture was then stirred for 3 hours at 50° C., after which it was cooled and poured into 300 ml of water. The batch was stirred until crystallization was complete, and the product was recovered by suction filtration, washed with water, dried, and recrystallized from ethyl acetate.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:22][CH2:21][CH:20]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]4)[C:6]=3[C:5]1=2)#[N:2].[OH:32][Li].O.OO>CO>[C:1]([CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:18][CH2:19][CH:20]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22]4)[C:6]=3[C:5]1=2)(=[O:32])[NH2:2]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC#N)CC4)CC1
Reactant: [Li]O
Agent: OO
Solvent: CO
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A solution of tert-butyl N-(4-[[(3R)-3-(cyanomethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (709 mg, 1.60 mmol, 1.00 equiv) in 6 mL of MeOH was added LiOH.H2O (135 mg, 3.21 mmol, 2.01 equiv) and H2O2 (30%, 1 mL) at 0° C. The resulting solution was stirred for 2 h at room temperature and quenched with saturated aqueous NaHSO3 solution and extracted with 3×50 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4) to give tert-butyl N-(4-[[(3R)-3-(carbamoylmethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (524 mg, 71%) as a white solid. MS: m/z 461 [M+H]+.