Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1]NN.[F:4][C:5]1C=CC=CC=1N1C(=O)NC(C)=N1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](=[O:30])[NH:28][C:27]([CH3:31])=[N:26]2)=[C:21]([F:32])[CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](=[O:30])[N:28]([CH:5]([F:4])[F:1])[C:27]([CH3:31])=[N:26]2)=[C:21]([F:32])[CH:20]=1
Reactant: Cc1nn(-c2ccc(Cl)cc2F)c(=O)[nH]1
Reactant: NNF
Reactant: Cc1nn(-c2ccccc2F)c(=O)[nH]1
Product: Cc1nn(-c2ccc(Cl)cc2F)c(=O)n1C(F)F

Procedure:
While the efficiency of a multistep process to prepare a complex molecule can be improved by optimizing the yield of each step, even greater efficiency may be achieved by finding a route with fewer steps. It has now been found that the Target Herbicide may be prepared more efficiently by a new route in which there are only six steps. In the first step 2-fluorohydrazine is cyclized to 4,5-dihydro-1-(2-fluorophenyl)-3-methyl-5-oxo-1H-1,2,4-triazole, which is then chlorinated to 1-(4-chloro-2-fluorophenyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole. In the third step the chlorinated product is difluoromethylated, affording 1-(4-chloro-2-fluorophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole. In an alternative, less preferred method, 4,5-dihydro-1-(2-fluorophenyl)-3-methyl-5-oxo-1H-1,2,4-triazole may first be difluoromethylated and then chlorinated. The third step intermediate is nitrated, yielding 1-(4-chloro-2-fluoro-5-nitrophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole, which is reduced to the corresponding 1-(5-amino-4-chloro-2-fluorophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4triazole. In the final step the 5-amino derivative is subjected to diazotization/arylation, yielding the Target Herbicide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:15]([S:18](Cl)(=[O:20])=[O:19])[CH2:16][CH3:17]>C1COCC1.C(Cl)Cl>[CH2:15]([S:18]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)(=[O:20])=[O:19])[CH2:16][CH3:17]
Reactant: Nc1ccncc1
Reactant: CCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)Nc1ccncc1
Temperature: 50 °C
Reaction time: 19 h
Yield: 73 %

Procedure:
47.6 g of 4-aminopyridine (0.506 mol) and 70.0 ml of triethylamine (51.1 g, 0.506 mol) were dissolved at 50° C. in 500 ml of THF. Likewise at 50° C., 57.3 ml of n-propanesulphonyl chloride (72.2 g, 0.506 mol) were added dropwise to this solution over the course of 1 h. After 19 h of stirring at 50° C. the reaction mixture was diluted with 500 ml of methylene chloride and extracted once with 500 ml of 1 N NaOH. The aqueous phase was adjusted to a pH of 5-6 with concentrated HCl, 100 ml of ethanol were added and then the mixture was extracted 5 times with 200 ml of methylene chloride. These organic phases were dried over magnesium sulphate and then the methylene chloride was removed by distillation. The 74 g of crude product obtained were recrystallized from acetonitrile. This gave 20.8 g of clean product. The constitution of the compound was verified by NMR spectroscopy.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[C:8]1[CH:9]=[C:10]([C:15]2[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[C:11]([NH2:14])=[N:12][CH:13]=1.[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)(=[O:26])=[O:25]>O1CCOCC1>[CH3:22][O:21][C:18]1[N:17]=[CH:16][C:15]([C:10]2[C:11]([NH2:14])=[N:12][CH:13]=[C:8]([C:30]3[CH:31]=[CH:32][C:27]([S:24]([CH3:23])(=[O:26])=[O:25])=[CH:28][CH:29]=3)[CH:9]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(-c2cc(Br)cnc2N)cn1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(-c2cc(-c3ccc(S(C)(=O)=O)cc3)cnc2N)cn1
Temperature: 120 °C
Reaction time: 14 h
Yield: 105.1 %

Procedure:
K2CO3 aqueous solution (1 M, 5.4 mL) was added to a suspension of 5-bromo-3-(6-methoxypyridin-3-yl)pyridin-2-amine (1.44 g, 5.14 mmol), 4-(methylsulfonyl)phenyl boronic acid (1.08 g, 5.40 mmol, 1.05 equiv.), and Pd(PPh)3 (300 mg, 5 mol %) in dioxane (15 mL) under N2. The reaction mixture was stirred at 120° C. for 14 h, poured onto H2O (50 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc, 2/8) providing 3-(6-methoxypyridin-3-yl)-5-(4-methylsulfonylphenyl)pyridin-2-amine (1) (1.92 g, 65%) as a pale yellow solid. IR (thin film/cm−1): νmax 3378, 1594, 1301, 1148. H1 NMR (400 MHz, CDCl3): δ 8.34 (d, 1H, J=2.0 Hz), 8.26 (d, 1H, J=2.0 Hz), 7.97 (d, 2H, J=8.4 Hz), 7.70 (d, 2H, J=8.4 Hz), 7.69 (d, 1H, J=8.4 Hz), 7.58 (d, 1H, J=2.0 ), 6.86 (d, 1H, J=8.4 Hz), 4.80 (bs, 2H), 3.98 (s, 3H) and 3.06 (s, 3H). C13 NMR (100 MHz, CDCl3): δ 164.16, 156.30, 146.94, 146.82, 145.57, 143.34, 139.02, 138.86, 136.92, 128.17, 126.84, 125.84, 118.88, 111.49, 53.67 and 44.62.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(P(=O)(OCC)OCC)#N.CN1CCOCC1.[NH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[C:41]([S:42]([NH:45][C:46]([CH3:49])([CH3:48])[CH3:47])(=[O:44])=[O:43])[C:36]=2[S:35][N:34]=1>C(Cl)Cl>[C:46]([NH:45][S:42]([C:41]1[C:36]2[S:35][N:34]=[C:33]([NH:32][CH2:31][CH2:30][CH2:29][NH:28][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([I:1])=[CH:10][CH:9]=3)[C:37]=2[CH:38]=[CH:39][CH:40]=1)(=[O:43])=[O:44])([CH3:49])([CH3:48])[CH3:47]
Reactant: O=C(O)c1ccc(I)cc1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc2c(NCCCN)nsc12
Agent: CCOP(=O)(C#N)OCC
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)NS(=O)(=O)c1cccc2c(NCCCNC(=O)c3ccc(I)cc3)nsc12
Reaction time: 0.25 h
Yield: 77.5 %

Procedure:
To a solution of 4-iodobenzoic acid (270 mg, 0.8 mmol) in methylene chloride (2 mL), diethyl cyanophosphonate (130 μL, 0.9 mmol) and 4-methylmorpholine (182 μL, 1.7 mmol) were added at room temperature and allowed to stir for 15 min. A solution of 3-(3-aminopropylamino)-N-t-butylbenzo[d]isothiazole-7-sulfonamide (270 mg, 0.8 mmol) in methylene chloride (4 mL) was then added and the resulting reaction mixture was allowed to stir overnight. The reaction mixture with diluted with methylene chloride (20 mL), washed with 10% HCl aqueous solution and brine, dried anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography, on silica gel, eluting with 6:4 ethyl acetate:hexanes provided N-(3-(7-(N-tert-butylsulfamoyl)benzo[d]isothiazol-3-ylamino)propyl)-4-iodobenzamide (355 mg). 1H NMR (300 MHz, CDCl3): 8.01 (dd, 1H), 7.96 (d, 1H), 7.78 (d, 2H), 7.59 (d, 2H), 7.53 (t, 1H), 7.44 (t, 1H), 6.15 (t, 1H), 5.09 (s, 1H), 3.70 (dd, 2H), 3.57 (dd, 2H), 1.90-1.99 (m, 2H), 1.24 ppm (s, 9H). MS (m/z): 573 (M+H)+ confirmed by LC-MS, tr=13.92 min (Method Y) MW=572 confirmed by LC-MS, tr=13.92 min (Method Y) MH+=573.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1.[Cl:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[C:15]([S:20][CH3:21])[N:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:13]1[CH:18]=[C:17]([C:6]2[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:16]=[C:15]([S:20][CH3:21])[N:14]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: CSc1nc(Cl)cc(Cl)n1
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: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2cc(Cl)nc(SC)n2)cn1
Reaction time: 3 h

Procedure:
A mixture of 2-methoxy-5-pyridyl-boronic acid (600 mg, 2.04 mmol, Intermediate (37), prepared according to the procedure described in J. Org. Chem., 67, 7541, 2002), 4,6-dichloro-2-methylsulfanyl-pyrimidine [700 mg, 3.59 mmol, Intermediate (29)], and Cs2CO3 (2.9 g, 8.97 mmol) in ethylene glycol dimethyl ether (8 mL) and water (2 mL) is degassed by bubbling with Argon gas for 5 minutes, and treated with tetrakis(triphenylphosphine)palladium (0) (207 mg, 0.18 mmol) at room temperature. After 3 hours at 85° C., the mixture is diluted with water (50 mL), and extracted twice with EtOAc (50 mL). The extracts are dried over magnesium sulfate, filtered, and concentrated to afford 4-chloro-6-(6-methoxy-pyridin-3-yl)-2-methylsulfanyl-pyrimidine [1.1 g, Intermediate (38)] as an oil. LCMS: RT=3.72 minutes, MS: 268 (M+H).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[C:2]2=O.COP([CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])=O)(=O)OC.O.[NH2:28][NH2:29]>>[Cl:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1[C:17]1[N:28]=[N:29][C:2]2[CH:1]3[CH2:7][CH:4]([C:3]=2[CH:16]=1)[CH2:5][CH2:6]3
Reactant: O=C1C(=O)C2CCC1C2
Reactant: NN
Reactant: COP(=O)(CC(=O)c1ccc(Cl)cc1Cl)OC
Solvent: O
Product: Clc1ccc(-c2cc3c(nn2)C2CCC3C2)c(Cl)c1

Procedure:
light yellow crystalline solid. MS (ESI): 291.0 (MH+). Prepared from bicyclo[2.2.1]heptane-2,3-dione, [2-(2,4-Dichloro-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]=[C:6]2[S:20][CH:19]=[C:18]([CH3:21])[N:7]2[C:8](=[O:17])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[CH3:3].Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]2[NH:29][CH:30]=[N:31][C:24]=12.C(N(CC)C(C)C)(C)C>C(O)CCC.CO>[F:16][C:12]1[CH:11]=[C:10]([C:9]2[C:8](=[O:17])[N:7]3[C:18]([CH3:21])=[CH:19][S:20][C:6]3=[N:5][C:4]=2[C@@H:2]([NH:1][C:23]2[CH:28]=[CH:27][N:26]=[C:25]3[NH:29][CH:30]=[N:31][C:24]=23)[CH3:3])[CH:15]=[CH:14][CH:13]=1
Reactant: Clc1ccnc2[nH]cnc12
Reactant: Cc1csc2nc([C@H](C)N)c(-c3cccc(F)c3)c(=O)n12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: CO
Product: Cc1csc2nc([C@H](C)Nc3ccnc4[nH]cnc34)c(-c3cccc(F)c3)c(=O)n12
Temperature: 140 °C
Yield: 10.4 %

Procedure:
A solution of 7-[(1S)-1-aminoethyl]-6-(3-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (50 mg, 0.16 mmol), 7-chloro-3H-imidazo[4,5-b]pyridine (51 mg, 0.33 mmol), and N,N-diisopropylethylamine (57 μL, 0.33 mmol) in 1-butanol (0.5 mL) in a sealable vial was degassed with nitrogen, sealed, and heated at 140° C. for 48 hours. The reaction mixture was diluted with methanol and purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (7 mg, 10%) as a white solid. LCMS for C21H18FN6OS (M+H)+: m/z=420.8. 1H NMR (400 MHz, CD3OD): δ 8.04 (s, 1H), 7.83 (d, J=5.9 Hz, 1H), 7.55-7.49 (m, 1H), 7.23-7.12 (m, 3H), 6.86 (d, J=1.2 Hz, 1H), 5.96 (d, J=5.9 Hz, 1H), 4.69-4.67 (m, 1H), 2.75 (s, 3H), 1.57 (d, J=6.4 Hz, 3H).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][CH:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.Cl.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH2:44][CH2:45][NH:46][CH2:47][CH:48]=2)=[CH:39][CH:38]=1>C(#N)CC.O>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH2:48][CH2:47][N:46]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][CH2:16][CH:8]5[C:7](=[O:17])[NH:6][C:5]=4[CH:4]=3)[CH2:45][CH:44]=2)=[CH:39][CH:38]=1
Reactant: Clc1ccc(C2=CCNCC2)cc1
Reactant: O=C1Nc2cc(CO)cnc2N2CCCCC12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCC#N
Product: O=C1Nc2cc(CN3CC=C(c4ccc(Cl)cc4)CC3)cnc2N2CCCCC12
Temperature: 90 °C
Reaction time: 2 h
Yield: 19 %

Procedure:
3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (100 mg, 0.43 mmol) was suspended in propionitrile (1 mL) and (cyanomethyl)trimethylphosphonium iodide (103 mg, 0.41 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol). To the stirred mixture was then added 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (94.0 mg, 0.41 mmol). The reaction was heated to 90° C. with stirring 2 h. The reaction was then cooled to room temperature and diluted with water (3 mL) and filtered. The solids were collected and refluxed in ethanol (5 mL) for 1 h. The suspension was cooled back to room temperature and filtered. The precipitate was filtered off and dried in vacuum to afford the title compound (31.8 mg, 18%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.47 (s, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.41-7.48 (m, 2H), 7.33-7.40 (m, 2H), 6.98 (d, J=2.0 Hz, 1H), 6.18 (s, 1H), 4.43-4.57 (m, 1H), 3.84 (d, J=11.4 Hz, 1H), 3.42 (s, 2H), 3.01 (d, J=2.8 Hz, 2H), 2.55-2.66 (m, 3H), 2.44 (br. s., 2H), 1.98-2.09 (m, 1H), 1.78-1.92 (m, 1H), 1.57-1.70 (m, 1H), 1.33-1.56 (m, 3H). [M+H] calc'd for C23H25ClN4O, 409. found, 409.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[Cl:27])[NH2:23]>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:3]3[C:10]4[CH2:11][N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:9]=4[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)N1Cc2sc3ncnc(Cl)c3c2C1
Product: CCOC(=O)N1Cc2sc3ncnc(Nc4ccc(Cl)c(Cl)c4)c3c2C1
Yield: 57 %

Procedure:
In analogy to Example 22A, the title compound was prepared from ethyl 4-chloro-5,7-dihydro-6H-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidine-6-carboxylate from Example 21A (250 mg, 0.88 mmol) and 3,4-dichloroaniline (150 mg, 0.93 mmol) to yield 324 mg (64% purity, 57% yield), which was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:30])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]2[N:23]=C(C3C=NC=CN=3)C=[CH:20][N:19]=2)=[CH:12][CH:11]=1.N1C=CN=CC=1C(=O)C.[CH3:40][C:41]1[O:42][C:43]([C:47](=O)[CH3:48])=[C:44]([CH3:46])[N:45]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:30])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]2[N:23]=[C:47]([C:43]3[O:42][C:41]([CH3:40])=[N:45][C:44]=3[CH3:46])[CH:48]=[CH:20][N:19]=2)=[CH:12][CH:11]=1
Reactant: CC(=O)c1oc(C)nc1C
Reactant: Nc1ccccc1NC(=O)c1ccc(CNc2nccc(-c3cnccn3)n2)cc1
Agent: CC(=O)c1cnccn1
Product: Cc1nc(C)c(-c2ccnc(NCc3ccc(C(=O)Nc4ccccc4N)cc3)n2)o1

Procedure:
Title compound was obtained according to the scheme 6 similarly to the compound 26a (Example 29) using instead of 1-pyrazin-2-yl-ethanone as the starting material 1-(2,4-dimethyl-oxazol-5-yl)-ethanone (Table 11). Characterization of the title compound is provided in the Table 12.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32]2[C:33](=[O:47])[NH:34][C:35](=O)[C:36]=2[C:37]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[NH:39][CH:38]=2)=[CH:24]1>C(COC)OC>[S:10]=[C:35]1[NH:34][C:33](=[O:47])[C:32]([C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:23][CH:24]=2)=[C:36]1[C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[NH:39][CH:38]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1NC(=O)C(c2c[nH]c3ccccc23)=C1c1c[nH]c2ccccc12
Solvent: COCCOC
Product: O=C1NC(=S)C(c2c[nH]c3ccccc23)=C1c1c[nH]c2ccccc12
Yield: 8.7 %

Procedure:
820 mg of Lawesson's reagent was added to a solution of 330 mg of 3,4-bis(3-indolyl)-1H-pyrrole-2,5-dione in 50 ml of dimethoxyethane and the mixture was heated to reflux for 1 hour. 410 mg of Lawesson's reagent were then added and the mixture was heated to reflux for a further 1 hour. The solvent was evaporated and the residue was purified on silica gel with ethyl acetate/hexane (1:4). Recrystallization from diethyl ether/hexane gave 30 mg of 5-thioxo-3,4-bis(3-indolyl)-3-pyrrolin-2-one, m.p. 254°-257° C.
Reaction SMILES: [CH:1]([CH:3]=O)=[O:2].[CH2:5]([NH:12][N:13]=[CH:14][C:15](=[O:17])[CH3:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O.CO>[CH2:5]([N:12]1[CH:16]=[C:15]([OH:17])[C:14]([C:1](=[O:2])[CH3:3])=[N:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=CC=O
Reactant: CC(=O)C=NNCc1ccccc1
Solvent: O
Solvent: CO
Product: CC(=O)c1nn(Cc2ccccc2)cc1O
Temperature: 25 °C
Yield: 33 %

Procedure:
To a 40% aqueous solution of glyoxal (8.28 g, 6.55 mL, 57.1 mmol) was added a slurry of 2-oxopropanal benzylhydrazone (10.1 g, 57.1 mmol) in water (250 mL) and methanol (25 mL). The resulting mixture was heated at reflux for 3 hours before cooling to room temperature. The mixture was extracted with EtOAc (2×100 mL) and the combined organic extracts were washed with water, saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated. The crude material was purified by CombiFlash (120 g column, 0-100% EtOAc/heptane gradient) to provide 1-(1-benzyl-4-hydroxy-1H-pyrazol-3-yl)ethanone (4.07 g, 33%).
Reaction SMILES: [CH:1]1([C:4]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([O:30][CH3:31])=[O:29])=[CH:18][CH:17]=3)[C:7]3=[N:8][CH:9]=[C:10](Br)[C:11]([CH3:12])=[C:6]3[N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.C(O)=O>[Pd].C1(C)C=CC=CC=1>[CH:1]1([C:4]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([O:30][CH3:31])=[O:29])=[CH:18][CH:17]=3)[C:7]3=[N:8][CH:9]=[CH:10][C:11]([CH3:12])=[C:6]3[N:5]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccccc1-c1ccc(Cn2c(C3CC3)nc3c(C)c(Br)cnc32)cc1
Agent: [Pd]
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1-c1ccc(Cn2c(C3CC3)nc3c(C)ccnc32)cc1
Yield: 91.9 %

Procedure:
Toluene (30 ml) was mixed with 3.0 g (6.3 mmol) of 2-cyclopropyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-6-bromo-7-methyl-3H-imidazo[4,5-b]pyridine, 10% Pd-C (100 mg) and 9.6 g (95 mmol) of triethylamine, followed by the dropwise addition of 2.9 g (63 mmol) of formic acid under stirring. The obtained mixture was heated under reflux for 10 hours. The reaction liquid was brought to room temperature, and filtered to remove the catalyst, and then the filtrate was subjected to vacuum concentration. Chloroform (100 ml) and water (100 ml) were added to the residue and the obtained mixture was caused liquid--liquid separation. The aqueous phase was further extracted with chloroform (50 ml) twice. The organic phases were combined, dried over anhydrous magnesium sulfate and subjected to vacuum concentration. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 2.3 g of the title compound (yield 92%).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6](=[O:8])[CH3:7])[CH2:3]1.[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:1][CH:2]1[CH2:5][N:4]([C:6](=[O:8])[CH3:7])[CH2:3]1
Reactant: CC(=O)N1CC(O)C1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CC(OC2CCCCO2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 10 mL of methylene chloride was dissolved 1.00 g of 1-(3-hydroxy-1-azetidinyl)-1-ethanone, and 1.19 mL of 3,4-dihydro-2H-pyran and 0.08 g of p-toluenesulfonic acid monohydrate were added to the solution, after which the resulting mixture was stirred overnight at room temperature. To the reaction mixture was added 10 mL of water and the pH was adjusted to 8 with a saturated aqueous sodium hydrogencarbonate solution, after which the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform˜chloroform:methanol=25:1) to obtain 1.79 g of 1-[3-(tetrahydro-2H-pyran-2-yloxy)-1-azetidinyl]-1-ethanone as a yellow oil.
Reaction SMILES: [CH2:1](SC1C=C[C:7]([C:10]2[O:11][CH:12]([C:17]3C=CC=CC=3)C(O)CN=2)=CC=1)C.CN(C)C1C=C[C:28]([C:31]2[O:32][CH:33]([C:38]3C=CC=CC=3)[CH:34](O)CN=2)=CC=1.[O:45]1[CH:60]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH:46]1[CH2:47][NH:48][C:49](=[O:59])[C:50]1[CH:55]=[CH:54][C:53]([S:56][CH2:57][CH3:58])=[CH:52][CH:51]=1.B(F)(F)F.CCOCC>ClCCl>[C:10]([O:11][CH2:12][CH3:17])(=[O:32])[CH3:7].[CH:33]([O:32][CH:31]([CH3:28])[CH3:1])([CH3:34])[CH3:38].[CH2:57]([S:56][C:53]1[CH:54]=[CH:55][C:50]([C:49]2[O:59][CH:60]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[CH:46]([OH:45])[CH2:47][N:48]=2)=[CH:51][CH:52]=1)[CH3:58]
Reactant: CCSc1ccc(C(=O)NCC2OC2c2ccccc2)cc1
Reactant: CN(C)c1ccc(C2=NCC(O)C(c3ccccc3)O2)cc1
Agent: CCSc1ccc(C2=NCC(O)C(c3ccccc3)O2)cc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)OC(C)C
Product: CCOC(C)=O

Procedure:
(5RS, 6SR)-2-[4-(Ethylthio)phenyl]-6-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol may be prepared in the following manner: working as in Example 38 for the preparation of 2-[4-(dimethylamino)phenyl]-6-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol, but starting with N-[(2RS, 3RS)-2,3-epoxy-3-phenylpropyl]-4-(ethylthio)benzamide (10 g) and boron trifluoride etherate (4.3 cc) in dichloromethane (100 cc), and after crystallization of the residue obtained in an ethyl acetate/diisopropyl ether mixture (30:70 by volume), (5RS, 6SR)-2-[4-(ethylthio)phenyl]-6-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (4.2 g), m.p. 120° C., is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:29])([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)=[C:4]([Br:32])[CH:3]=1.Cl[C:34](OC1C=CC([N+]([O-])=O)=CC=1)=[O:35].[O:46]1[CH2:51][CH2:50][CH:49]([NH2:52])[CH2:48][CH2:47]1.C(N(CC)CC)C>O1CCCC1>[Br:32][C:4]1[CH:3]=[C:2]([NH:1][C:34]([NH:52][CH:49]2[CH2:50][CH2:51][O:46][CH2:47][CH2:48]2)=[O:35])[CH:31]=[CH:30][C:5]=1[O:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([OH:29])([C:25]([F:28])([F:26])[F:27])[C:21]([F:22])([F:23])[F:24])=[CH:18][CH:19]=2)[CH2:9][CH2:8]1
Reactant: Nc1ccc(OC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c(Br)c1
Reactant: NC1CCOCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(OC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c(Br)c1)NC1CCOCC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 43.1 %

Procedure:
2-(4-((4-(4-Amino-2-bromophenoxy)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.379 mmol, 200 mg) and 4-nitrophenyl chloroformate (0.379 mmol, 76 mg) were combined in tetrahydrofuran (1 mL) and the mixture stirred at room temperature for 45 minutes. Tetrahydro-2H-pyran-4-amine (0.379 mmol, 38.4 mg) followed by triethylamine (1.138 mmol, 115 mg) were added and the mixture stirred overnight. The mixture was concentrated under reduced pressure and the resulting residue was purified by HPLC then treated with strong cation exchange column chromatography to afford the title compound (107 mg).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:34]=[C:35]([O:37][CH3:38])[CH:36]=1)[O:28][CH2:29][CH2:30][CH2:31][CH2:32]Br>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:27]3[CH:34]=[C:35]([O:37][CH3:38])[CH:36]=[C:25]([O:24][CH3:23])[CH:26]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(OC)cc(OCCCCBr)c1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(OC)cc(OCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)c1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 4-(3,5-dimethoxyphenoxy)butyl bromide are reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-N-((1-(4-(3,5-dimethoxyphenoxy)butyl)piperidin-4-yl)methyl)-2-methoxybenzamide.