Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]#[N:21])[CH:15]=[CH:16][CH:17]=1>>[C:20]([CH:19]=[CH:18][C:14]1[CH:13]=[C:12]([NH:11][C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)=[O:10])[CH:17]=[CH:16][CH:15]=1)#[N:21]
Reactant: O=C(O)c1cccc(Br)n1
Reactant: N#CC=Cc1cccc(N)c1
Product: N#CC=Cc1cccc(NC(=O)c2cccc(Br)n2)c1

Procedure:
6-Bromo-pyridine-2-carboxylic acid (350 mg, 1.73 mmol) was coupled to aniline (88) (250 mg, 1.74 mmol) using Method C. The residue was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: S1(CCCC1)(=O)=O.C[C:9]([O:11][CH2:12][C:13]1[CH2:22][S:21][C@@H:16]2[C@H:17]([NH2:20])[C:18](=[O:19])[N:15]2[C:14]=1[C:23]([OH:25])=[O:24])=O.[Sb](Cl)(Cl)(Cl)(Cl)Cl.[Bi](Cl)(Cl)Cl>CO>[NH2:20][CH:17]1[C:18](=[O:19])[N:15]2[C:14]([C:23]([OH:25])=[O:24])=[C:13]([CH2:12][O:11][CH3:9])[CH2:22][S:21][C@H:16]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl[Bi](Cl)Cl
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Solvent: CO
Solvent: O=S1(=O)CCCC1
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 50 °C

Procedure:
To 15 ml of sulfolane were added 2.72 g of 7-ACA, 2.3 g of methanol, 2.8 g of antimony pentachloride and 12 g of bismuth trichloride. The mixture was heated at 50° C. for 40 min to advance a reaction. After completion of the reaction, the reaction mixture was cooled to 5° C. The resulting precipitate was filtered off To the filtrate was added 60 ml of water, and then the resulting mixture was stirred homogeneously. To the resulting solution was added 0.5 g of activated carbon, and then the mixture was stirred, followed by filtration. The filtrate was adjusted to pH 3.5 with sodium bicarbonate. To the resulting mixture was added 30 ml of methanol, thereby to form a white crystalline precipitate. The white crystalline precipitate was collected by filtration, and washed with 10 ml of cold water and, then, with 10 ml of cold methanol to obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 1.29 g. The yield of the desired product was 53 %. .
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28](OCC)=[O:29])[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:43]1[CH2:48][CH2:47][CH:46]([NH2:49])[CH2:45][CH2:44]1>>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:36][C@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([NH:49][CH:46]3[CH2:47][CH2:48][O:43][CH2:44][CH2:45]3)=[O:29])[C:24]=2[CH:33]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Reactant: NC1CCOCC1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc3c(C(=O)NC4CCOCC4)noc3c2F)C[C@H](C)O1

Procedure:
Starting materials: Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and tetrahydro-2H-pyran-4-amine
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][Cl:10].[OH:11][C:12]1[CH:13]=[CH:14][C:15]([C:27]([F:30])([F:29])[F:28])=[C:16]2[C:20]=1[N:19]([CH3:21])[C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17]2.[Cl-].[Na+]>CN(C)C=O.[I-].[K+]>[Cl:10][CH2:9][CH2:8][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:27]([F:30])([F:28])[F:29])=[C:16]2[C:20]=1[N:19]([CH3:21])[C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17]2
Reactant: ClCCBr
Reactant: CCOC(=O)c1cc2c(C(F)(F)F)ccc(O)c2n1C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(C(F)(F)F)ccc(OCCCl)c2n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.5 %

Procedure:
After 2.17 g (15.7 mmol) of potassium carbonate, 2.25 g (15.7 mmol) of 1-bromo-2-chloroethane and 0.05 g of potassium iodide were added to a solution of 3.00 g (10.4 mmol) of ethyl 7-hydroxy-1-methyl-4-trifluoromethyl-2-indolecarboxylate in 30 ml of dimethylformamide, the mixture was stirred at room temperature for 3 hours. Subsequently, 1.45 g (10.4 mmol) of potassium carbonate and 0.69 g (5.2 mmol) of 1-bromo-2-chloroethane were further added thereto. The mixture was stirred at 50° C. for an hour. After cooling to room temperature, the reaction mixture was poured into saturated sodium chloride aqueous solution and then extracted with ethyl acetate. The extract was washed with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 2.31 g of ethyl 7-(2-chloroethoxy)-1-methyl-4-trifluoromethyl-2-indolecarboxylate.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][O:6]/[N:7]=[C:8](/[C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:16]([CH2:19][C:20]3[C:21]([F:31])=[C:22]4[C:27](=[CH:28][C:29]=3[F:30])[N:26]=[CH:25][CH:24]=[CH:23]4)=[N:17][N:18]=2)[N:15]=1)\[CH3:9].COCCN(S(F)(F)[F:42])CCOC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:42][CH2:2][CH2:3][CH2:4][CH2:5][O:6]/[N:7]=[C:8](/[C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:16]([CH2:19][C:20]3[C:21]([F:31])=[C:22]4[C:27](=[CH:28][C:29]=3[F:30])[N:26]=[CH:25][CH:24]=[CH:23]4)=[N:17][N:18]=2)[N:15]=1)\[CH3:9]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: C/C(=N\OCCCCO)c1ccc2nnc(Cc3c(F)cc4ncccc4c3F)n2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C/C(=N\OCCCCF)c1ccc2nnc(Cc3c(F)cc4ncccc4c3F)n2n1
Reaction time: 1 h

Procedure:
To a solution of (E)-1-(3-((5,7-difluoroquinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone O-4-hydroxybutyl oxime (30 mg, 0.070 mmol) (example 65) in 4 mL of DCM at −78° C. was added bis(2-methoxyethyl)aminosulfur trifluoride (180 mg, 0.813 mmol). The mixture was stirred at this temperature for 1 h, and stirred at it overnight. The mixture was poured into saturated aqueous NaHCO3, extracted with DCM, dried over Na2SO4, filtered and concentrated in vacuo. Flash chromatography on silica gel eluting with DCM/methanol afforded the title compound. 1H-NMR (400 MHz, CDCl3) δ ppm 8.94 (s, 1H), 8.37 (d, 1H), 7.98 (d, 1H), 7.81 (d, 1H), 7.63 (d, 1H), 7.44 (dd, 1H), 4.81 (s, 2H), 4.58-4.57 (m, 1H), 4.45 (t, 1H), 4.32 (t, 2H), 2.26 (s, 3H), 1.90-1.78 (m, 4H). LCMS (method A): [MH]+=429, tR=5.239 min.
Reaction SMILES: [CH3:1][C:2]([CH3:62])([CH3:61])[C@H:3]([N:45]1[CH2:49][CH2:48][N:47]([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([N+:57]([O-])=O)=[CH:53][CH:52]=2)[C:46]1=[O:60])[C:4]([NH:6][C@@H:7]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@@H:8]([OH:37])[CH2:9][C@@H:10]([NH:24][C:25]([C@@H:27]([NH:32][C:33](=[O:36])[O:34][CH3:35])[C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:14][CH:13]=1)=[O:5]>C(O)C.[Pd]>[NH2:57][C:54]1[CH:55]=[CH:56][C:51]([CH2:50][N:47]2[CH2:48][CH2:49][N:45]([C@@H:3]([C:2]([CH3:62])([CH3:61])[CH3:1])[C:4]([NH:6][C@@H:7]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C@@H:8]([OH:37])[CH2:9][C@@H:10]([NH:24][C:25]([C@@H:27]([NH:32][C:33](=[O:36])[O:34][CH3:35])[C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[CH:14][CH:13]=3)=[O:5])[C:46]2=[O:60])=[CH:52][CH:53]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccc([N+](=O)[O-])cc2)C1=O)C(C)(C)C)C(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccc(N)cc2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 38.5 %

Procedure:
A solution containing the product from Example 124B (0.065 g, 0.076 mmol) in ethanol (1.5 mL) was treated with 10% Pd on carbon (0.024 g), stirred under an atmosphere of hydrogen (balloon pressure) at 25° C. for 2.5 hours, filtered concentrated under reduced pressure. The residue was purified by reversed phase chromatography on a C18 column eluting with a gradient starting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between ethyl acetate and saturated NaHCO3, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound (0.024 g, 39% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.83(s, 9H), 0.87(s, 9H), 1.60-1.48(m, 2H), 2.29-2.20(m, 1H), 2.67-2.53(m, 3H), 2.92-2.75(m, 3H), 3.16-3.08(m, 1H), 3.50(s, 3H), 3.71-3.61(m, 1H), 3.86-3.83(d, J=9.93 Hz, 1H), 4.07(s, 1H), 4.11(s, 2H), 4.23-4.09(m, 2H), 4.56-4.53(d, J=7.72 Hz, 1H), 5.00(s, 2H), 6.55-6.52(d, J=8.46 Hz, 2H), 6.67-6.64(d, J=9.93 Hz, 1H), 6.94-6.91(d, J=8.46 Hz, 2H), 7.10-7.02(m, 5H), 7.23-7.21(d, J=8.46 Hz, 2H), 7.33-7.29(m, 1H), 7.45-7.42(d, J=9.56 Hz, 1H), 7.91-7.82(m, 5H), 8.64-8.62(m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.CON(C)[C:24](=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28]>O1CCCC1.CCOCC>[C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([CH2:15][C:24](=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28])=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCC(=O)N(C)OC
Reactant: Cc1cccnc1NC(=O)OC(C)(C)C
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCC(=O)Cc1cccnc1NC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 57.8 %

Procedure:
A solution of 2-(t-butoxycarbonylamino)-3-methylpyridine (X) (5.3 g) (prepared, e.g., as described in Preparation 17), in tetrahydrofuran (100 ml) was cooled to -50° C. and a solution of sec-butyllithium (46 ml of 1.3M in cyclohexane) was added. After 10 minutes, the dark solution was treated with N-methoxy-N-methylvaleramide (4.4 g) and the resulting solution was stirred 10 minutes. The mixture was diluted with ether, washed with water, dried over sodium sulfate and evaporated. Crystallization of the residue from hexane afforded 1-[2-(t-butoxycarbonylamino)pyridin-3-yl]hexan-2-one (4.3 g), a compound of Formula (Y), as a white solid m.p. 66°-67° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9](=[O:11])[NH:8][C:7]=2[CH:12]=1.N([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=C=O>O1CCOCC1>[O:11]=[C:9]1[NH:8][C:7]2[CH:12]=[C:3]([C:2]([F:14])([F:1])[F:13])[CH:4]=[CH:5][C:6]=2[S:10]1.[CH3:23][CH2:22][CH:21]([C:9]([NH2:8])=[O:11])[CH2:20][CH2:19][CH3:18]
Reactant: CCCCCCN=C=O
Agent: O=c1[nH]c2cc(C(F)(F)F)ccc2s1
Solvent: C1COCCO1
Product: CCCC(CC)C(N)=O

Procedure:
300 mg (1.37 mmol) of 5-trifluoromethyl-3H-benzothiazol-2-one were reacted in analogy to Example 1 with 202 mg (1.37 mmol) of 1-isocyanatohexane in dioxane at 80° C. Yield: 125 mg (26%), M+H+: 347.05.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=O)=[CH:2]1.[NH2:10][CH:11]([CH2:19][CH3:20])[C:12]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13]>>[CH2:15]([O:14][C:12](=[O:13])[CH:11]([NH:10][C:7](=[O:9])[CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[CH2:19][CH3:20])[CH:16]([CH3:17])[CH3:18]
Reactant: CCC(N)C(=O)OCC(C)C
Reactant: O=C(O)Cc1ccsc1
Product: CCC(NC(=O)Cc1ccsc1)C(=O)OCC(C)C

Procedure:
Following General Procedure BI above and using 3-thiopheneacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([C:17]2[C:22](F)=[CH:21][CH:20]=[CH:19][N:18]=2)=O)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:25][NH2:26]>CCO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:22]3[NH:26][N:25]=2)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(OCc2ccccc2)cn1)c1ncccc1F
Reactant: NN
Solvent: CCO
Solvent: O
Product: c1ccc(COc2ccc(-c3n[nH]c4cccnc34)nc2)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of [5-(benzyloxy)pyridin-2-yl] (3-fluoropyridin-2-yl)methanone (2.85 g) and hydrazine monohydrate (1.348 mL) in EtOH (10 mL) was stirred at 50° C. overnight. After cooling, insoluble material was filtrated and washed with EtOH. The filtrate was evaporated, treated with water and extracted with AcOEt. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (0.232 g).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3([C:22]([O:24]CCCC)=[O:23])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[N:9]1>C(Cl)Cl>[N:8]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]3([C:22]([OH:24])=[O:23])[CH2:21][CH2:20]3)=[CH:17][CH:18]=2)[CH:12]=[CH:11][CH:10]=[N:9]1
Reactant: CCCCOC(=O)C1(c2ccc(-n3cccn3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C1(c2ccc(-n3cccn3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (1.0 mL) was added to butyl 1-[4-(1H-pyrazol-1-yl)phenyl]cyclopropanecarboxylate (60 mg) in methylene chloride (1.0 mL). The mixture was stirred at room temperature overnight, and then concentrated to give a crude product which was directly used in the reaction of next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])/[CH:10]=[CH:11]\[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[OH2:16].[OH-].[Na+:18]>O1CCCC1>[OH2:13].[OH2:16].[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])/[CH:10]=[CH:11]\[C:12]([O-:14])=[O:13])=[CH:6][CH:7]=1.[Na+:18]
Reactant: Nc1ccc(NC(=O)/C=C\C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(NC(=O)/C=C\C(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Under a nitrogen atmosphere, into a reaction vessel were charged 10.49 g (content: 86%, net quantity: 9.02 g (47.3 mmol)) of (2Z)-4-[(4-aminophenyl)amino]-4-oxo-2-butenoic acid and 30 ml of water. To this was added 47.3 ml (47.3 mmol) of a 1 mol/L sodium hydroxide aqueous solution. After completion of the reaction, the solution was condensed to dryness to obtain a solid to which 30 ml of tetrahydrofuran was added, and the mixture was stirred at room temperature for 30 minutes, then, the deposited crystal was isolated by filtration, and dried to obtain 11.28 g of sodium (2Z)-4-[(4-aminophenyl)amino]-4-oxo-2-butenoate di-hydrate as a yellow solid. Yield: 90%
Reaction SMILES: C(O)C.[CH2:4]1[CH2:22][O:21][C:6]2([CH2:11][CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[O:5]1>[Pd].C1(C)C=CC=CC=1>[CH2:22]1[CH2:4][O:5][C:6]2([CH2:7][CH2:8][CH:9]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][CH3:20])=[CH:16][CH:17]=3)[CH2:10][CH2:11]2)[O:21]1
Reactant: CCCc1ccc(C2=CCC3(CC2)OCCO3)cc1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCc1ccc(C2CCC3(CC2)OCCO3)cc1
Yield: 104.2 %

Procedure:
To a mixed solution comprising 250 ml of ethanol and 250 ml of toluene was dissolved 80 g of the 1,1-ethylenedioxy-4-(4-n-propylphenyl)-4-cyclohexene, 5 g of palladium/carbon (5%) was added as catalyst thereto, and subjected to a catalytic reduction under hydrogen gas atmosphere. After finishing of the reaction, the catalyst was filtered off and the solvent was distilled off under a reduced pressure to obtain 84 g of 1,1-ethylenedioxy-4-(4-n-propylphenyl)cyclohexane.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][CH2:12][C:13]1[C:14]([NH2:21])=[N:15][C:16]([S:19][CH3:20])=[N:17][CH:18]=1.C(N(CC)CC)C.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[CH2:12][C:13]2[C:14](=[N:15][C:16]([S:19][CH3:20])=[N:17][CH:18]=2)[NH:21][C:30]1=[O:32]
Reactant: CSc1ncc(CNc2cc([N+](=O)[O-])ccc2C)c(N)n1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CSc1ncc2c(n1)NC(=O)N(c1cc([N+](=O)[O-])ccc1C)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 218.2 %

Procedure:
To a stirred solution of 5-[(2-methyl-5-nitro-phenylamino)-methyl]-2-methylsulfanyl-pyrimidin-4-ylamine (112 mg, 0.37 mmol) and triethylamine (112 μL, 0.80 mmol) in THF (5 mL) is added a solution of triphosgene (38 mg, 0.13 mmol) in THF (1 mL) at 0° C., and the mixture is stirred for 3 hours at room temperature. The reaction mixture is diluted with EtOAc (10 mL), and washed with saturated aqueous sodium bicarbonate solution. The organic layer is dried over MgSO4, concentrated under reduced pressure and recrystallized from dichloromethane to give 3-(2-methyl-5-nitro-phenyl)-7-methylsulfanyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (94 mg, 76%) as a white crystalline solid.
Reaction SMILES: [N+](C(C)C)([O-])=[O:2].[Na].[Br:8][C:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([CH2:18]Br)[C:12]=2[S:11][CH:10]=1>C(O)C>[Br:8][C:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([CH:18]=[O:2])[C:12]=2[S:11][CH:10]=1
Reactant: CC(C)[N+](=O)[O-]
Reactant: BrCc1cccc2c(Br)csc12
Agent: [Na]
Solvent: CCO
Product: O=Cc1cccc2c(Br)csc12

Procedure:
With stirring, 68.2 g (0.74 mole) of 2-nitropropane are added dropwise at room temperature, over a period of 45 minutes, to a Na-ethoxide solution prepared under an argon atmosphere from 14.2 g (0.61 mole) of sodium and 800 ml of abs. ethanol. 137 g (0.61 mole) of 3-bromo-7-bromomethylbenzothiophene are then added dropwise at room temperature, over a period of 1.5 hours, to the resulting white suspension. After the reaction mixture has been stirred for one day, the solvent is evaporated off from the reaction mixture in vacuo, the resulting residue of 101.2 g is dissolved in a mixture of hexane:diethyl ether 1:1 and the solution is purified by chromatography on silica gel. After evaporation of the solvent, 81 g (80% of the theoretical amount) of 3-bromo-7-benzothiophene-carbaldehyde are obtained as residue.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][C:33]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:36]([NH2:38])=[O:37])[CH2:32][CH2:31]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=CC=C(C(OO)=[O:53])C=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][C:33]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:36]([NH2:38]=[O:53])=[O:37])[CH2:32][CH2:31]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)[NH2+][O-])(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Combine 1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylic acid amide (1.0 mmol) and dichloromethane (10 mL). Cool to 0° C. Add portionwise, m-chloroperbenzoic acid (1.0 mmol). After the addition is complete, warm to ambient temperature. After 18 hours, extract the reaction mixture with water. Separate the organic layer, dry over MgSO4, filter, and evaporate in vacuo to give a residue. Purify the residue by chromatography to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:15]2[C:23]3[C:18](=[C:19]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)([CH2:13][CH3:14])[C:9]([O:11]C)=O)=[CH:4][CH:3]=1.[CH3:29][Li]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:15]2[C:23]3[C:18](=[C:19]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)([CH2:13][CH3:14])[C:9](=[O:11])[CH3:29])=[CH:4][CH:3]=1
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reactant: [Li]C
Solvent: C1CCOC1
Product: CCC(C(C)=O)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reaction time: 0.5 h

Procedure:
To a solution of methyl 2-(4-chlorophenyl)-2-(4-(methylsulfonamido)-1H-indol-1-yl)butanoate (1 g, 2.38 mmol), as described in Example 3 Step C, in THF (30 mL) was added CH3Li (3.2 mL, 4.76 mmol, 1.5 M in ether) dropwise at 0° C. and stirred for 0.5 h. The mixture was quenched with saturated ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with PE/EA (15/1 to 6/1, v/v) to afford the title compound as a colorless amorphous solid. LC/MS m/z=427.1 [M+Na]+.
Reaction SMILES: C1(C)C=CC=CC=1.F[C:9]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:10]=1[CH:11]=[O:12].Cl.[CH3:22][NH:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[CH3:22][N:23]([CH3:24])[C:9]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:10]=1[CH:11]=[O:12]
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)c1ccc(C(F)(F)F)cc1C=O
Temperature: 120 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To toluene (5 ml) are added 2-fluoro-5-trifluoromethyl-benzaldehyde (650 mg) and dimethylamine hydrochloride (2.76 g), followed by addition of potassium carbonate (1.4 g), and the mixture is stirred at 120° C. overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=49:1→4:1) to give 2-dimethylamino-5-trifluoromethyl-benzaldehyde (529 mg). MS (m/z): 218 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([C:16](O)=[O:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:19]=1.C1C2CCC3C=CC=CC=3SC=2C=C(C(O)=O)C=1>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([CH2:16][OH:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:19]=1
Reactant: Nc1ccc2c(c1)C=Cc1ccc(C(=O)O)cc1S2
Agent: O=C(O)c1ccc2c(c1)Sc1ccccc1CC2
Product: Nc1ccc2c(c1)C=Cc1ccc(CO)cc1S2

Procedure:
Repeat the process of Example 1, substituting an equivalent quantity of 8-aminodibenzo[b,f]thiepin-3-carboxylic acid for the 10,11-dihydrodibenzo[b,f]thiepin-3-carboxylic acid, to obtain the title product.