Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:16])[NH:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([O:13]C=O)[CH2:9]1)([CH3:4])[CH3:3].C(=O)([O-])O.[K+]>CO.O.C(OCC)(=O)C>[CH3:4][C:2]([O:5][C:6](=[O:16])[NH:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OC=O)C1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.5 %

Procedure:
A solution of (1S-trans)-[3-(formyloxy)cyclopentyl]carbamic acid 1,1-dimethylethyl ester (0.081 g, 0.35 mmol) in methanol (3 ml) was treated with a slurry of potassium hydrogen carbonate (0.707 g, 7.06 mmol) in water (1.5 ml) and stirred at room temperature for 2h. The mixture was then diluted with water (20 ml) and ethyl acetate (20 ml) and the aqueous phase was extracted with ethyl acetate (2×20 ml). The combined organic phase was dried (MgSO4) and evaporated to leave a solid which was purified by column chromatography on flash silica eluting with 30-40% ethyl acetate in cyclohexane to give the title compound (0.037 g) from diisopropyl ether m.p. 83-85° C., [α]D 0.0° (CHCl3 c=0.55%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=O)=[CH:16][CH:15]=3)=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([CH2:29]C#N)=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]4=[N:20][O:22][C:32]([C:23]5[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=5)=[C:16]4[CH:15]=3)=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2nccc2-c2ccc([N+](=O)[O-])cc2)cc1
Reactant: Cc1ccc(CC#N)cc1
Product: COc1ccc(-n2nccc2-c2ccc3noc(-c4ccc(C)cc4)c3c2)cc1

Procedure:
The title compound, light green solid (32 mg, 25%), MS (ISP) m/z=382.3 [(M+H)+], mp 159° C., was prepared in accordance with the general method of example 1 from 1-(4-methoxy-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate G) (100 mg, 353 μmol) and commercially available 2-(p-tolyl)-acetonitrile.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[CH2:22][CH2:21][N:13]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=4[CH:20]=[C:12]3[C:11]2=[O:23])[N:5]=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([N:47]3[CH2:52][CH2:51][N:50]([CH3:53])[CH2:49][CH2:48]3)[N:42]=2)[C:26]1=[O:54]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCCC1>[CH3:24][N:25]1[C:26](=[O:54])[C:27]([NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([N:47]3[CH2:48][CH2:49][N:50]([CH3:53])[CH2:51][CH2:52]3)[N:42]=2)=[CH:28][C:29]([C:2]2[C:7]([CH:8]=[O:9])=[C:6]([N:10]3[CH2:22][CH2:21][N:13]4[C:14]5[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=5[CH:20]=[C:12]4[C:11]3=[O:23])[N:5]=[CH:4][CH:3]=2)=[CH:30]1
Reactant: CN1CCN(c2cccc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)n2)CC1
Reactant: O=Cc1c(Cl)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: CN1CCN(c2cccc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CCCC7)C5=O)c4C=O)cn(C)c3=O)n2)CC1
Temperature: 25 °C
Yield: 75.9 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 4-chloro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino-[1,2-a]indol-2(1H)-yl)nicotinaldehyde 103b (377 mg, 1.15 mmol), 110a (320 mg, 0.78 mmol), Pd(dppf)Cl2 (130 mg, 0.16 mmol), K3PO4.3H2O (52.9 mg, 0.23 mmol), and tetrahydrofuran (20 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux overnight, cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (40:1) to afford 110b as yellow solid (351 mg, 76%). MS: [M+H]+ 593.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[CH3:30][N:31]([C@@H:48]([C:56](=[O:59])[NH:57][CH3:58])[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:32](=[O:47])[C@H:33]([NH:45][CH3:46])[CH2:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[CH:14][C:15](=[O:17])[N:45]([CH3:46])[C@@H:33]([C:32](=[O:47])[N:31]([CH3:30])[C@@H:48]([C:56](=[O:59])[NH:57][CH3:58])[CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:34][C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(=CC(=O)O)CC1
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)NC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.7 %

Procedure:
4-Carboxymethylenepiperidine-1-carboxylic acid tert-butyl ester (0.60 g; 2.45 mmol) was dissolved in methylene chloride (50 mL) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.26 g; 1.36 mmol) was added. The reaction mixture was stirred for 15 min at room temperature. (2R)-N-Methyl-2-methylamino-N-((1R)-1-(methyl-carbamoyl)-2-phenylethyl)-3-(2-naphthyl)propionamide (0.5 g; 1.24 mmol, prepared as in example 1) was added and the reaction mixture was stirred for 12 hours at room temperature. The reaction mixture was washed with water (50 mL), an aqueous solution of sodium hydrogen sulfate (50 mL; 10%), an aqueous solution of sodium hydrogen carbonate (50 mL; sat.), dried (magnesium sulfate) and evaporated in vacuo. The residue was chromatographed on silica (2×20 cm) using ethyl acetate as eluent to afford 0.270 g of 4-((N-Methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methyl-carbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)methylene)piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].Cl[CH2:12][CH2:13][N:14]=[C:15]=[O:16].[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:15]1[O:16][CH2:12][CH2:13][N:14]=1
Reactant: Cc1cccc(CN)c1C
Reactant: O=C=NCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cccc(CNC2=NCCO2)c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.6 %

Procedure:
A mixture of 1.0 gram (0.0074 mole) of 2,3-dimethylbenzylamine and 0.69 gram (0.0081 mole) of 2-chloroethylisocyanate in 10 mL of 1,4-dioxane was heated to reflux where it stirred for about 18 hours. The reaction mixture was allowed to cool and an aqueous solution of sodium hydroxide (4.0 mL of a 3.0 molar solution) was added. The reaction mixture was heated to reflux for about 18 hours then allowed to cool to ambient temperature. The reaction mixture was concentrated under reduced pressure to leave a viscous oil residue. The residue was suspended in 50 mL of ethyl acetate and washed with 20 mL of water. The organic phase was extracted with 20 mL of 3.0 molar aqueous hydrochloric acid. The aqueous extract was made basic by adding 3.0 molar aqueous sodium hydroxide and the basic mixture was extracted with 50 mL of ethyl acetate. The extract was dried with sodium sulfate, filtered and the filtrate concentrated under reduced pressure to yield 0.81 gram of the title compound as an oil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=2)[N:13]=1.[Br-].[C:22]([C:24]1[CH:29]=[CH:28][C:27]([Zn+])=[CH:26][CH:25]=1)#[N:23]>O1CCCC1.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:27]3[CH:28]=[CH:29][C:24]([C:22]#[N:23])=[CH:25][CH:26]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: Fc1cccc(F)c1C1=NC(c2ccc(I)cc2)CO1
Reactant: N#Cc1ccc([Zn+])cc1
Agent: Cl[Pd]Cl
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2ccc(C3COC(c4c(F)cccc4F)=N3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The compound of Example 2 (6.5 g, 17 mmol) and bis(triphenylphosphine) palladium dichloride (0.15 g, 0.45 mmol) were dissolved in tetrahydrofuran (60 mL). The compound 4-cyanophenylzinc bromide (Rieke Organometallics, Lincoln, Nebr., 0.28 M in tetrahydrofuran, 72 ml) was added over 2 min and the mixture was stirred at 25° C. for 18 h. The reaction mixture was diluted with water (200 mL) and extracted with ether (100 mL). The aqueous layer was extracted with dichloromethane (100 mL) and the combined organic layers were dried over magnesium sulfate and evaporated. The residue was subjected to silica gel chromatography with hexanes/ethyl acetate 5:1 as eluent. The title compound was isolated as a yellow solid (4.5 g): m.p. 136°-138° C. 1H NMR (CDCl3, 300 MHz) δ 7.8-7.0 (11H), 5.6 (1H), 4.9 (1H), 4.3 (1H)
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=2)[O:3]1.[CH3:17][C:18]([NH2:22])([CH3:21])[C:19]#[CH:20]>CN(C=O)C.CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][C:18]([NH2:22])([CH3:21])[C:19]#[C:20][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:8])([CH3:7])[O:5]2)=[CH:10][CH:11]=1
Reactant: CC1(C)OB(c2ccc(Br)cc2)OC1(C)C
Reactant: C#CC(C)(C)N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(N)C#Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)bromobenzene (J. Organomet. Chem. 2006, 691 (26), 5725) (200 mg; 0.71 mmol) 1,1-dimethyl-prop-2-ynylamine (350 mg; 4.25 mmol) Pd(PPh3)2Cl2 (99 mg; 0.14 mmol) and Cul (27 mg; 0.14 mmol) are dissolved in DMF/NEt3 (3.5 ml/1.5 ml) and microwaved at 100° C. for 20 minutes. The reaction mixture is evaporated and purified via chromatography (SiO2; TBME/MeOH/M/NH3conc 95:5:0.8) to yield the title compound as yellowish crystals. H-NMR (400 Hz; DMSO-d6): 7.64 (d, 2H); 7.38 (d, 2H); 2.08 (bs, 2H); 1.39 (s, 6H); 1.31 (s, 12H). MS (m/z) ES+: 285 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH2:15][C:16](=O)[CH2:17][CH:18]([CH3:20])[CH3:19])(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl.C(OCC)(=O)C>[Cl:14][C:11]1[CH:10]=[C:9]2[C:8](=[CH:13][CH:12]=1)[NH:7][C:16]([CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:15]2
Reactant: CC(C)CC(=O)Cc1cc(Cl)ccc1NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Cc1cc2cc(Cl)ccc2[nH]1
Reaction time: 7 h
Yield: 93 %

Procedure:
To a solution of tert-butyl[4-chloro-2-(4-methyl-2-oxopentyl)phenyl]carbamate (280 mg) in dichloromethane (4 mL) was added trifluoroacetic acid (0.7 mL) at room temperature, and the mixture was stirred for 7 hours. The reaction mixture was diluted with ethyl acetate and stopped the reaction by addition of a saturated aqueous sodium hydrogen carbonate solution. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (166 mg).
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH2:8][C:7]1=[O:24])(=O)[CH2:2][CH2:3][CH3:4].[Cl-].[CH2:26]([O:28][NH3+:29])[CH3:27]>C(O)C.C([O-])(=O)C.[Na+]>[CH2:26]([O:28][NH:29][C:1](=[C:6]1[C:11](=[O:12])[CH:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]([CH2:17][CH:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[CH2:8][C:7]1=[O:24])[CH2:2][CH2:3][CH3:4])[CH3:27]
Reactant: CCO[NH3+]
Reactant: CCCC(=O)C1C(=O)CC(CC2CCOCC2)C(C(=O)OC)C1=O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: CCCC(NOCC)=C1C(=O)CC(CC2CCOCC2)C(C(=O)OC)C1=O
Temperature: 20 °C
Reaction time: 20 h

Procedure:
10.0 parts by weight of 2-butyryl-4-methoxycarbonyl-5-[tetrahydropyran-4-ylmethyl]-cyclohexane-1,3-dione were dissolved in 150 parts by volume of ethanol, and 2.93 parts by weight of ethoxyammonium chloride and 2.71 parts by weight of anhydrous sodium acetate were added. The mixture was stirred at 20° C. for 20 hours, poured into ice-water and extracted with methylene chloride. The organic phase was concentrated to give 10.5 parts by weight of 2-(1-ethoxyaminobutylidene)-4-methoxycarbonyl-5-[tetrahydropyran-4-ylmethyl]-cyclohexane-1,3-dione (compound No. 1) as a viscous oil having the following structure: ##STR7##
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C@@H:9]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]3[C:30]4[CH2:38][CH2:37][NH:36][CH2:35][C:31]=4[N:32]=[CH:33][N:34]=3)(=[O:27])=[O:26])=[CH:21][C:20]=2[S:39]([C:42]([F:45])([F:44])[F:43])(=[O:41])=[O:40])[CH2:10][S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3][CH2:2]1.[Cl:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[CH2:59][N:60]2[CH2:65][CH2:64][C:63](=O)[CH:62]([F:67])[CH2:61]2)=[CH:49][CH:48]=1>>[Cl:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[CH2:59][N:60]2[CH2:65][CH2:64][CH:63]([N:36]3[CH2:37][CH2:38][C:30]4[C:29]([NH:28][S:25]([C:22]5[CH:23]=[CH:24][C:19]([NH:18][C@H:9]([CH2:8][CH2:7][N:4]6[CH2:5][CH2:6][O:1][CH2:2][CH2:3]6)[CH2:10][S:11][C:12]6[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=6)=[C:20]([S:39]([C:42]([F:43])([F:44])[F:45])(=[O:41])=[O:40])[CH:21]=5)(=[O:27])=[O:26])=[N:34][CH:33]=[N:32][C:31]=4[CH2:35]3)[CH:62]([F:67])[CH2:61]2)=[CH:49][CH:48]=1
Reactant: O=S(=O)(Nc1ncnc2c1CCNC2)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Reactant: O=C1CCN(Cc2ccccc2-c2ccc(Cl)cc2)CC1F
Product: O=S(=O)(Nc1ncnc2c1CCN(C1CCN(Cc3ccccc3-c3ccc(Cl)cc3)CC1F)C2)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Yield: 12.1 %

Procedure:
Following General Reductive Amination Procedure 2, (R)-4-(4-Morpholino-1-(phenylthio)butan-2-ylamino)-N-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-(trifluoromethylsulfonyl)benzenesulfonamide (34 mg, 0.05 mmol) and 1-((4′-chlorobiphenyl-2-yl)methyl)-3-fluoropiperidin-4-one (19 mg, 0.059 mmol) afforded the title compound (6 mg, 12% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N+:10]([O-:11])=[N:9][C:8](=[O:12])[N:7]([CH2:13][CH:14]=C)[C:6]=2[CH:16]=1.I([O-])(=O)(=O)=[O:18].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N+:10]([O-:11])=[N:9][C:8](=[O:12])[N:7]([CH2:13][CH:14]=[O:18])[C:6]=2[CH:16]=1
Reactant: C=CCn1c(=O)n[n+]([O-])c2ccc(Cl)cc21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=CCn1c(=O)n[n+]([O-])c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.8 %

Procedure:
6-Chloro-4-(2-propen-1-yl)-1,2,4-benzotriazin-3(4H)-one 1-oxide (104 mg, 0.438 mmol) was dissolved in 1,4-dioxane (4 ml) and water (2 ml). Sodium periodate (234 mg, 1.096 mmol) was added, followed by osmium tetroxide (0.09 ml of 4% aqueous solution). The mixture stirred at rt for 6 h, and then extracted with 20% MeOH/DCM (3×100 ml). The organic extracts were combined, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give (6-Chloro-1-oxido-3-oxo-1,2,4-benzotriazin-4(3H)-yl)acetaldehyde as an impure yellow oil (89 mg, 85%).
Reaction SMILES: S(Cl)(Cl)(=O)=O.[CH3:6][C:7]([C:9]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[C:11]([F:17])[CH:10]=1)=[O:8].[ClH:18].O>ClCCl>[F:15][C:14]1[CH:13]=[C:12]([F:16])[C:11]([F:17])=[CH:10][C:9]=1[C:7](=[O:8])[CH2:6][Cl:18]
Reactant: Cl
Reactant: CC(=O)c1cc(F)c(F)cc1F
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: O=C(CCl)c1cc(F)c(F)cc1F

Procedure:
40.8 g (0 3 mol) of sulphuryl chloride were added dropwise at room temperature (22° C.) to 48 g (0.275 mol) of 2,4,5-trifluoroacetophenone (obtained according to Example 110)dissolved in 400 ml of dichloromethane and the mixture was stirred until evolution of hydrogen chloride had ended (about 2 hours). The reaction mixture was then added to 600 ml of water, the organic phase was separated off, this was washed until neutral with sodium hydrogen carbonate solution and dried over magnesium sulphate, and the solvent was stripped off in a water pump vacuum. 48.6 g of 2,4,5-trifluorophenacyl chloride were obtained as an oily residue, which corresponds to 84.5% of theory. The characterization of the product carried out as in Examples 113 to 119 yielded a & value of 5.29 ppm.
Reaction SMILES: BrCCC[C:5]1[CH:15]=[CH:14][CH:13]=[C:7]2[C:8]([NH:10][C:11](=[O:12])[C:6]=12)=[O:9].[CH:16](N(CC)C(C)C)([CH3:18])[CH3:17].[CH3:25][O:26][C:27]1[CH:58]=[C:57]([O:59][CH3:60])[CH:56]=[CH:55][C:28]=1[CH2:29][NH:30][C:31]1[C:32]2[CH:39]=[CH:38][N:37]([C@H:40]3[C@H:47]4[C@H:43]([O:44][C:45]([CH3:49])([CH3:48])[O:46]4)[C@@H:42]([CH2:50][NH:51][CH:52]([CH3:54])[CH3:53])[O:41]3)[C:33]=2[N:34]=[CH:35][N:36]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)CC.C(OCC)(=O)C>[CH3:25][O:26][C:27]1[CH:58]=[C:57]([O:59][CH3:60])[CH:56]=[CH:55][C:28]=1[CH2:29][NH:30][C:31]1[C:32]2[CH:39]=[CH:38][N:37]([C@H:40]3[C@@H:47]4[O:46][C:45]([CH3:48])([CH3:49])[O:44][C@@H:43]4[C@@H:42]([CH2:50][N:51]([CH:52]([CH3:54])[CH3:53])[CH2:17][CH2:16][CH2:18][N:10]4[C:11](=[O:12])[C:6]5[C:7](=[CH:13][CH:14]=[CH:15][CH:5]=5)[C:8]4=[O:9])[O:41]3)[C:33]=2[N:34]=[CH:35][N:36]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CNC(C)C)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Reactant: O=C1NC(=O)c2c(CCCBr)cccc21
Reactant: CCN(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CCC#N
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(CCCN3C(=O)c4ccccc4C3=O)C(C)C)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 95 °C
Reaction time: 48 h
Yield: 72.1 %

Procedure:
A mixture of γ-bromopropylphthalimide (2.37 g, 8.85 mmol), tetra-n-butylammonium iodide (0.234 g, 0.632 mmol), N,N-diisopropylethylamine (1.40 mL, 8.04 mmol) and N-(2,4-dimethoxybenzyl)-7-((3aR,4R,6R,6aR)-6-((isopropylamino)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (3.42 g, 6.32 mmol) was taken up in propanenitrile (25 mL) and was heated at 95° C. After 48 h at 95° C., HPLC indicated that the reaction was nearly complete. The reaction mixture was cooled to room temperature, the mixture was diluted with 200 mL ethyl acetate and washed with two 100 mL portions of H2O and 100 mL brine. The organic phase was dried over Na2SO4, filtered and concentrated to yield a glass. The crude material was purified by flash chromatography (250 g silica gel, 2-4% 7N NH3 in CH3OH/CH2Cl2) to yield the title compound (3.12 g, 72%) as a foam: MS (ESI+) for C37H44N6O7 m/z 685.2 (M+H)+, (ESI−) for C37H44N6O7 m/z 729 (M+HCO2)−; HPLC purity 99% (ret. time, 3.17 min).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]([CH3:11])[N:9]=[CH:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.[CH3:22][C@H:23]1[CH2:28][O:27][CH2:26][CH2:25][NH:24]1>CN(C=O)C.CCOCC>[Cl:1][C:2]1[N:3]=[C:4]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][C@@H:23]2[CH3:22])[C:5]2[N:10]([CH3:11])[N:9]=[CH:8][C:6]=2[N:7]=1
Reactant: C[C@H]1COCCN1
Reactant: Cn1ncc2nc(Cl)nc(Cl)c21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: C[C@H]1COCCN1c1nc(Cl)nc2cnn(C)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.5 %

Procedure:
To a stirred solution of 5,7-dichloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidine (200.0 mg, 0.98 mmol) in anhydrous DMF (2 mL) was added N,N-diisopropylethylamine (0.21 mL, 1.18 mmol, 1.2 eq.) followed by (S)-3-methylmorpholine (199.3 mg, 1.9 mmol, 2.0 eq.). The reaction mixture was stirred at RT under N2 for 4 h and diluted with ether (50 mL). The organic layer was washed with saturated aqueous solution of sodium bicarbonate, water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resultant residue was purified by column chromotagraphy (Si-PPC, gradient 0 to 100% ethyl acetate in heptane) to afford the desired product (k-1) as a foam (245.4 mg, 93.0%). 1H NMR (CDCl3, 500 MHz) δ ppm 8.03 (s, 1H), 4.21 (broad d, J=6.2 Hz, 1H), 4.15 (s, 3H), 3.97 (d, J=10.7 Hz, 1H), 3.90 (d, J=9.8 Hz, 1H), 3.81 to 3.65 (m, 3H), 3.56 (d, J=12.4 Hz, 1H), 1.38 (d, J=6.6 Hz, 3H); LC-MS m/z (method A)=268 [M+H]+, RT=1.71 min.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([N+:20]([O-:22])=[O:21])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[CH2:23]([SH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[CH3:31]I>CN(C)C=O>[CH3:31][O:12][C:10](=[O:11])[C:9]1[CH:13]=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=[C:16]([N+:17]([O-:19])=[O:18])[C:8]=1[S:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CI
Reactant: SCc1ccccc1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1SCc1ccccc1
Temperature: -5 °C
Reaction time: 16 h

Procedure:
332 g (2.40 mol) of potassium carbonate are introduced into 500 ml of dimethylformamide and cooled to -5° C. 375 g (1.14 mol) of 2-chloro-3,5-dinitrobenzoic acid (75% with 25% water; transport and storage form) in 1.1 l of dimethylformamide are then added over a period of 30 minutes, during which time the internal temperature is maintained at from -5° to 4° C. 142 g (1.14 mol) of benzyl mercaptan are then added dropwise at from 0° to 3° C. over a period of 2.5 hours. The temperature is subsequently raised to 20° C. over a period of 16 hours. 170 g (1.2 mol) of methyl iodide are then added dropwise at room temperature over a period of 5 hours. The reaction mixture is then stirred for 16 hours at room temperature and afterwards poured onto 3 l of ice/water, stirred and filtered. The material obtained by filtering with suction is washed four times with 700 ml of water each time and is hydrogenated in the next stage while still damp (see Example 1.15). The dried product has a melting point of 113°-114° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[C:34]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)(=[O:37])[CH2:35][CH3:36]
Reactant: CCC(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A163) and propionyl chloride the title compound is obtained as colorless solid.