Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[C:11]2[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[C:11]3[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)c(C)c23)cc1OC
Product: COc1ccc(CNc2nc(-n3ccnc3C)nc3sc(C)c(C)c23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5,6-dimethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5,6-dimethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[O:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:6]=2[N:7]=1.[NH:21]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25](B3OC(C)(C)C(C)(C)O3)[C:24]=2[CH:23]=[CH:22]1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>[NH:21]1[C:29]2[C:24](=[C:25]([C:2]3[N:3]=[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:5]4[O:10][C:9]5[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=5[C:6]=4[N:7]=3)[CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22]1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)c2oc3ccccc3c2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: c1cc(-c2nc(N3CCOCC3)c3oc4ccccc4c3n2)c2cc[nH]c2c1
Temperature: 90 °C
Yield: 87.1 %

Procedure:
Argon gas was bubbled through a mixture of 2-chloro-4-morpholinobenzofuro[3,2-d]pyrimidine (ASA75) (80 mg, 0.276 mmol, 1.0 eq) and Indole-4-boronic acid pinacol ester (MW 243) (267 mg, 1.10 mmol, 4.0 eq) in 1,2 dimethoxyethan and 2 M Na2CO3 (3:1) (6 mL) for 5 min. dichloro 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (MW 732) (5.05 mg, 0.00690 mmol, 0.025 eq) was added and the reaction mixture was heated to reflux (90° C.) for 15 h 30 min, cooled and diluted with EtOAc (20 mL). The organic solution was washed with a mixture of H2O:Na2CO3:NH4OH (conc. 32% in water)=5:4:1 (9 mL), then NH4Cl (sat.) and brine (2×), dried over Na2CO3, filtered and concentrated. Purification by silica gel chromatography (gradient from 100% hexane in EtOAc to 50% hexane) gave a yellowish solid (89.0 mg, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[NH2:27][C:28]1([C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:25])[F:24])[CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([NH:27][C:28]1([C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH2:30][CH2:29]1)=[O:8]
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Oc4cccc(C(F)(F)F)c4)C3)CC2)cc1
Yield: 8.7 %

Procedure:
The title compound (D149) (20 mg) was prepared according to the experimental procedure described in Description 148 starting from 5-chloro-2-(3-(3-(trifluoromethyl)phenoxy)azetidin-1-yl)nicotinic acid (D105) (160 mg, 0.423 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (115.45 mg, 0.507 mmol). The residue obtained from SPE-Si cartridge purification (38 mg) dissolved in a mixture of chloroform/ethanol/n-hexane (70/15/15) (1 ml) was separated by chiral HPLC [Phenomenex Lux1 column (250×20 mm, 5 μm particle size). Mobile phase: isocratic premixed mixture of (hexane 75%, ethanol 25%) containing 0.1% of diethylamine. Flow rate=10 ml/min. UV detection: 235 nm]. Collected fractions, after solvent evaporation afforded the title compound (D149) (20 mg)
Reaction SMILES: C1(C)C=C(C)C=C(C)C=1.N([O:12][C:13](C)(C)[CH3:14])=O.ON1C(=O)C2=CC=CC=C2C1=O.CC1C=C(C=C(C)C=1)C=NO.[CH3:40][C:41]1[CH:42]=[C:43]([CH:46]=[C:47]([CH3:49])[CH:48]=1)[CH:44]=[O:45].CC1C=C(C=C(C)C=1)C#N>C(O)(=O)C>[C:13]([O:45][CH2:44][C:43]1[CH:46]=[C:47]([CH3:49])[CH:48]=[C:41]([CH3:40])[CH:42]=1)(=[O:12])[CH3:14]
Reactant: CC(C)(C)ON=O
Reactant: Cc1cc(C)cc(C=O)c1
Agent: Cc1cc(C)cc(C#N)c1
Agent: Cc1cc(C)cc(C=NO)c1
Agent: O=C1c2ccccc2C(=O)N1O
Solvent: CC(=O)O
Solvent: Cc1cc(C)cc(C)c1
Product: CC(=O)OCc1cc(C)cc(C)c1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
Mesitylene (1 ml), t-butyl nitrite (1 mmol), N-hydroxyphthalimide (0.2 mmol), and acetic acid (1 ml) were placed in a flask and were stirred at 60° C. in an atmosphere of argon gas (1 atm=0.101 MPa) for 20 hours. The resulting reaction mixture was analyzed to find that 3,5-dimethylbenzaldehyde oxime, 3,5-dimethylbenzaldehyde, 3,5-dimethylbenzonitrile, and 3,5-dimethylphenylmethyl acetate were formed in yields of 61%, 3%, 4%, and less than 1%, respectively.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=2)[CH:7]=1.Cl.[CH3:15][O:16][NH:17][CH3:18].Cl.CN(C)CCCN=C=NCC.O>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11](=[O:13])[N:17]([O:16][CH3:15])[CH3:18])[N:10]=2)[CH:7]=1
Reactant: O=C(O)c1cn2cc(Br)ccc2n1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CON(C)C(=O)c1cn2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 36.1 %

Procedure:
850 mg of 6-bromo-2-hydroxycarbonyl-imidazo[1,2-a]pyridine, 519 mg of N-methoxy-N-methyl-amine hydrochloride, and 1.12 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were dissolved in 10 ml of pyridine, and the mixture was stirred at room temperature for 2 days. Water was added to the obtained solution, and the products were extracted with ethyl acetate. Organic layer was washed with saturated sodium chloride aqueous solution, and dried with anhydrous magnesium sulfate. Then, the solvents were distilled outunder reduced pressure. The obtained residues were purified by silicagel column chromatography (ethyl acetate) to obtain 362 mg of the above compound.
Reaction SMILES: OS(O)(=O)=O.[N+:6]([O-:9])(O)=[O:7].[CH3:10][N:11]1[C:16]([CH3:17])=[CH:15][C:14](=[O:18])[N:13]([CH3:19])[C:12]1=[O:20]>>[CH3:10][N:11]1[C:16]([CH3:17])=[C:15]([N+:6]([O-:9])=[O:7])[C:14](=[O:18])[N:13]([CH3:19])[C:12]1=[O:20]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(=O)n(C)c(=O)n1C
Agent: O=S(=O)(O)O
Product: Cc1c([N+](=O)[O-])c(=O)n(C)c(=O)n1C
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
A mixture of concentrated H2SO4 (7.0 mL) and fuming HNO3 (7.0 mL) was cooled to 0-5° C. and 1,3,6-trimethylpyrimidine-2,4(1H,3H)-dione (3.5 g, 22.702 mmol) was gradually added to the reaction mixture. After stirring for 2 h. at the same temperature the reaction mixture was partitioned between ethyl acetate (200 mL) and water (100 mL). The organic layer was washed with brine (2×50 mL), dried (Na2SO4) and evaporated under reduced pressure. Crude product obtained was purified by column chromatography to give 1.30 g of the product as yellow solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 2.38 (s, 3H), 3.20 (s, 3H), 3.40 (s, 3H); APCI-MS (m/z) 198.30 (M−H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][SH:10])=[CH:7][CH:6]=1.[C:13]([O:17][C:18]([N:20]1[CH2:24][C@@H:23](OS(C)(=O)=O)[CH2:22][C@H:21]1[C:30](=[O:34])[NH:31][CH2:32][CH3:33])=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl-].[Na+]>CN(C)C=O>[C:13]([O:17][C:18]([N:20]1[CH2:24][C@@H:23]([S:10][CH2:9][C:8]2[CH:11]=[CH:12][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[CH2:22][C@H:21]1[C:30](=[O:34])[NH:31][CH2:32][CH3:33])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCNC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reactant: COc1ccc(CS)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
3.57 g of sodium hydride (as a 55% w/w suspension in mineral oil) was added, whilst ice-cooling, to a solution of 11.31 ml of 4-methoxybenzyl mercaptan dissolved in 150 ml of dry dimethylformamide and the mixture was stirred at 0° to 5° C. for 30 minutes. A solution of 26.00 g of (2S, 4S)-1-t-butoxycarbonyl-2-ethylcarbamoyl-4-methanesulfonyloxypyrrolidine in 100 ml of dry dimethylformamide was then added to the resulting mixture, and the whole was stirred at room temperature for 2 hours. At the end of this time, the reaction mixture was poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel using a 1:1 by volume mixture of hexane and ethyl acetate as an eluent, to afford 17.00 g of the title compound as colorless crystals, melting at 92°-94° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N+:9]([O-])[CH:10]=1.C(Cl)(=O)C1C=CC=CC=1.C[Si]([C:30]#[N:31])(C)C>C(Cl)Cl>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:10]([C:30]#[N:31])=[N:9][C:8]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][CH:6]=1
Reactant: COCOc1ccc(CC(C)(C)C)[n+]([O-])c1
Reactant: C[Si](C)(C)C#N
Solvent: ClCCl
Solvent: O=C(Cl)c1ccccc1
Product: COCOc1ccc(CC(C)(C)C)nc1C#N
Reaction time: 4 h
Yield: 73.6 %

Procedure:
5-(Methoxymethoxy)-2-neopentylpyridine-N-oxide (11.5 g, 51 mmol) was dissolved in CH2Cl2 (50 mL) to which benzoyl chloride-(12 ml, 102 mmol) and (trimethylsilyl)formonitrile (14 ml, 102 mmol) were added. The mixture was stirred under N2 4 h, quenched with saturated NaHCO3 (150 mL), and extracted with CH2Cl2 (3×100 mL). The combined organic layers were washed with saturated NaHCO3 (2×50 mL), dried (MgSO4), and evaporated to give the crude product as a brown oil, which was purified by ISCO (330 g SiO2, 0-40% EtOAc/Hexane) to give 3-(methoxymethoxy)-6-neopentylpicolinonitrile (8.8 g, 74% yield) as a clear oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH:17]([Mg]Cl)([CH3:19])[CH3:18]>O1CCCC1.[Ni](Cl)Cl.C1(P(C(P(C2C=CC=CC=2)C2C=CC=CC=2)(C)C)C2C=CC=CC=2)C=CC=CC=1>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH:17]([CH3:19])[CH3:18])=[CH:3][CH:4]=2)=[O:9])=[CH:11][CH:12]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Br)cc1
Reactant: CC(C)[Mg]Cl
Agent: Cl[Ni]Cl
Agent: CC(C)(P(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)c1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 198 %

Procedure:
(4-bromophenyl)(4-chlorophenyl)methanone (10.0 g, 12.3 mmol) and bis(diphenylphosphino)propane nickel(II) chloride (0.4 g, 0.7 mmol) were dissolved in purified tetrahydrofuran (200 mL) under a nitrogen atmosphere, and isopropyl magnesium chloride (18.7 mL, 37.4 mmol) was slowly added thereto at 0° C. The reaction mixture solution was stirred at room temperature for 24 hours. The reaction mixture solution was subjected to extraction with dichloromethane and distilled water, and the extracted material was subjected to column chromatography (hexane:ethylacetate=8:2). The reaction solvent was removed, and then the residue material was dried in vacuum to thereby obtain a white solid (6.3 g, yield: 72%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc(S)cc1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Product: COc1ccc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-methoxy-thiophenol.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:17])[C:11]=2[CH:10]=[C:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21][O:22][C:23](=[O:32])[CH:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:21][O:22][C:23](=[O:32])[CH:24]([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH3:18])[N:8]2[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: Cc1cc2c(O)cccc2n1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1cccc2c1cc(C)n2Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
1-Benzyl-2-methyl-1H-indol-4-ol 3 (0.3 g 1.26 mmole) was dissolved in anhydrous dimethylformamide (20 mL). To the solution sodium hydride 60% in mineral oil (66 mg 1.65 mmole) was added. The mixture was stirred at room temperature for 1 h. To the mixture bromo-phenyl-acetic acid methyl ester (0.24 mL, 1.512 mmole) was added. The mixture was stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (300 mL) and washed with H2O (4×100 mL) and brine (1×100 mL). The organic layer was separated, dried with magnesium sulfate and concentrated. The residue was purified by column chromatography (10:1 Hexane:EtOAc) to afford 8 (0.3 g, 62%) as a white solid.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[N:11]=2)[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+].O>CO>[F:16][C:12]1[N:11]=[C:10]([N:7]2[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]2)[CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)N1CCN(c2cccc(F)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Fc1cccc(N2CCNCC2)n1
Yield: 103 %

Procedure:
A solution of 1-acetyl-4-(6-fluoropyridin-2-yl)piperazine (5.5 g) and sodium hydroxide (3.0 g) in methanol (30 ml)—water (30 ml) was refluxed under heating for 5 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The solvent was evaporated to give the title compound (4.6 g) as a pale-yellow oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]1([NH2:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>>[N:6]1([NH:12][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: NN1CCCCC1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)NN1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
TEA (2.43 mL, 17.46 mmol) and methanesulfonylchloride (2.0 g, 17.46 mmol). were added to a solution of piperidin-1-ylamine Compound 1i1 (1.75 g, 17.46 mmol) at 0° C., under a N2 atmosphere. The mixture was stirred for 3 hrs, while warming to r.t. The reaction was quenched with water (20 mL) and the organic layer was diluted with CH2Cl2 (100 mL), washed with water and brine, separated and dried with anhydrous sodium sulfate, then filtered and concentrated in vacuo to yield N-piperidin-1-yl-methanesulfonamide Compound 1i2 as an oil.
Reaction SMILES: [O:1]([C:3]1[CH:26]=[CH:25][C:6]2[N:7]=[C:8]([C:10]3[CH:24]=[CH:23][C:13]([CH2:14]P(=O)(OCC)OCC)=[CH:12][CH:11]=3)[S:9][C:5]=2[CH:4]=1)[CH3:2].[N+:27]([C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O)([O-:29])=[O:28].C[O-].[Na+]>CO>[N+:27]([C:30]1[CH:31]=[C:32]([CH:33]=[CH:14][C:13]2[CH:12]=[CH:11][C:10]([C:8]3[S:9][C:5]4[CH:4]=[C:3]([O:1][CH3:2])[CH:26]=[CH:25][C:6]=4[N:7]=3)=[CH:24][CH:23]=2)[CH:35]=[CH:36][CH:37]=1)([O-:29])=[O:28]
Reactant: CCOP(=O)(Cc1ccc(-c2nc3ccc(OC)cc3s2)cc1)OCC
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2nc(-c3ccc(C=Cc4cccc([N+](=O)[O-])c4)cc3)sc2c1

Procedure:
Prepared as described in the Alkene Formation section using diethyl 4-(6-methoxyl benzothiazol-2-yl)benzylphosphonate (0.10 g, 0.25 mmol) and 3-nitrobenzaldehyde (0.39 g, 0.25 mmol) in dry MeOH (10 ml) and 0.5 M sodium methoxide (1.02 ml, 0.51 mmol) to give the title compound as (0.079 g, 80%) yellow, feathery crystals after work-up and recrystallisation from CHCl3.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:12]([C:14]2[N:15]=[CH:16][C:17]([O:20][C:21]3[CH:22]=[C:23]([C:35]([NH:37][C:38]4[CH:42]=[CH:41][N:40](C(OC(C)(C)C)=O)[N:39]=4)=[O:36])[CH:24]=[C:25]([O:27][C@@H:28]([CH3:34])[CH2:29][O:30][CH:31]([F:33])[F:32])[CH:26]=3)=[N:18][CH:19]=2)=[O:13])[CH2:11][CH2:10][CH2:9]1>C(Cl)Cl>[N:8]1([C:12]([C:14]2[N:15]=[CH:16][C:17]([O:20][C:21]3[CH:22]=[C:23]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:34])[CH2:29][O:30][CH:31]([F:33])[F:32])[CH:26]=3)[C:35]([NH:37][C:38]3[CH:42]=[CH:41][NH:40][N:39]=3)=[O:36])=[N:18][CH:19]=2)=[O:13])[CH2:9][CH2:10][CH2:11]1
Reactant: C[C@@H](COC(F)F)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](COC(F)F)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(C(=O)Nc2cc[nH]n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 112 %

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of 1,1-dimethylethyl 3-({[3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)phenyl]carbonyl}amino)-1H-pyrazole-1-carboxylate (115 mg, 0.17 mmol) in DCM (16 mL) and stirred at RT for 2 hours. The solvent was removed in vacuo, DCM (20 mL) added and the mixture washed with water (20 mL), a saturated solution of sodium bicarbonate (20 mL), brine (20 mL), dried (MgSO4), filtered and reduced in vacuo to give the desired compound as a white foam (93 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][NH2:20].C(N(CC)CC)C>>[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][NH:20][S:12]([C:3]1[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[Cl:1])(=[O:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Reactant: CN(C)CCN
Solvent: CCN(CC)CC
Product: CN(C)CCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Yield: 101.6 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (400 mg, 1.38 mmol), N,N-dimethylethylenediamine (121 mg, 1.38 mmol) and triethylamine(0.39mL, 2.76 mmol) were reacted to form the crude product (480 mg) which was carried on to the hydrolysis without purification.. EI-MS (m/z) 341.88 (M−).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(N(CC)CC)C.[C:17](Cl)(=[O:20])[CH2:18][CH3:19]>ClCCl>[CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][C:17](=[O:20])[CH2:18][CH3:19])=[O:5]
Reactant: Nc1ccccc1C=O
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Nc1ccccc1C=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 93.1 %

Procedure:
To a solution of 2-aminobenzaldehyde (1.21 g, 10 mmol), and triethylamine (1.39 mL, 10 mmol) in dichloromethane (50 mL) was added propionyl chloride (1.04 mL, 12 mol). The reaction was stirred at room temperature for 3 days. The reaction solution was washed with water and then dried over magnesium sulfate and concentrated in vacuo to yield the crude product (1.65 g, 93%). The product was used without further purification. 1H NMR (400 MHz, CDCl3) δ 11.16 (s, 1H), 9.93 (s, 1H), 8.77 (d, J=8.5 Hz, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.62 (t, J=7.1 Hz, 1H), 7.22 (t, J=7.5 Hz, 1H), 2.51 (q, J=7.6 Hz, 2H), 1.29 (t, J=7.6 Hz, 3H); HPLC ret. time 1.34 min, 10-99% CH3CN, 5 min run; ESI-MS m/z 177.2 (M+1)+.
Reaction SMILES: [Cl:1][C:2]([F:10])([F:9])[C:3](=[O:8])[CH2:4][C:5](=[O:7])[CH3:6].[CH:11]([O-])([O-])[O:12][CH2:13][CH3:14].C(OC(=O)C)(=O)C>O>[Cl:1][C:2]([F:10])([F:9])[C:3](=[O:8])[C:4](=[CH:11][O:12][CH2:13][CH3:14])[C:5](=[O:7])[CH3:6]
Reactant: CC(=O)CC(=O)C(F)(F)Cl
Reactant: CCOC([O-])[O-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(C)=O)C(=O)C(F)(F)Cl
Reaction time: 2 h
Yield: 48.5 %

Procedure:
A mixed solution containing 50 g of 1-chloro-1,1-difluoro-2,4-pentanedione, 60 g of ethyl orthoformate and 82 g of acetic anhydride was refluxed with stirring for 2 hours. After a Dean-Stark apparatus (water separator) was fixed, the solution was refluxed for additional 4 hours, while about 100 ml of water was removed. After it was allowed to cool, vacuum distillation was conducted to obtain 32.2 g of the desired product as a pale red liquid. Boiling point 95°-118° C./1.6 mmHg.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[CH2:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][CH2:14][NH:13][CH2:12]1>C(OCC)(=O)C>[CH:5]([N:13]1[CH2:12][CH2:11][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][CH2:14]1)=[O:7]
Reactant: c1ccc2c(c1)CCNCC2
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: CCOC(C)=O
Product: O=CN1CCc2ccccc2CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (40 ml) was added dropwise to formic acid (80 ml) at room temperature and after the mixture was stirred for 30 minutes, a solution of 2,3,4,5-tetrahydro-1H-3-benzazepine (30 g),in ethyl acetate (80 ml) was added dropwise at room temperature. The mixture was then stirred for 30 minutes, after which it was diluted with ice-water and extracted with ethyl acetate. The extract was washed successively with water, aqueous solution of sodium hydroxide (NaOH/H2O), and saturated NaCl/H2O and dried over MgSO4. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) and recrystallized from-n-hexane to provide the title compound (29 g) as colorless crystals melting at 65-66° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[C:6]([NH:8][CH2:9][C:10]1[S:11][C:12]([S:15]([N:18]2[CH2:23][CH2:22][CH:21]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[CH2:20][CH2:19]2)(=[O:17])=[O:16])=[CH:13][CH:14]=1)=[O:7].[CH3:39]CN(C(C)C)C(C)C.C=O.C([BH3-])#N.[Na+]>C1COCC1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[C:6]([NH:8][CH2:9][C:10]1[S:11][C:12]([S:15]([N:18]2[CH2:19][CH2:20][CH:21]([N:24]([CH3:39])[CH2:25][C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:34])([F:33])[F:35])=[CH:30][CH:31]=3)[CH2:22][CH2:23]2)(=[O:17])=[O:16])=[CH:13][CH:14]=1)=[O:7]
Reactant: COc1cccc(C(=O)NCc2ccc(S(=O)(=O)N3CCC(NCc4ccc(C(F)(F)F)cc4)CC3)s2)c1
Reactant: CCN(C(C)C)C(C)C
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cccc(C(=O)NCc2ccc(S(=O)(=O)N3CCC(N(C)Cc4ccc(C(F)(F)F)cc4)CC3)s2)c1

Procedure:
A solution of the hydrochloride salt of 1 (50 mg, 0.08 mmol), DIEA (12 ul, 0.08 mmol), formaldehyde solution 37% aq. (32 ul, 0.4 mmol) and Sodiumcyanoborohydride (10 mg, 0.16 mmol) in THF were heated under reflux for 15 h, whereupon complete alkylation took place. The reaction was diluted with DCM and the inorganic salts were extracted with water. The crude was dried over MgSO4, and the solution was evaporated to dryness. The oily residue was taken up in THF, 1N HCl in ether was added slowly upon which colourless crystalls of compound 205 were formed (yield: 51 mg, 97%). Anal. HPLC: R.t=4.39 min (method b). M/Z APCI: 582.1 (M+1), 580.4 (M−1). The following compound was prepared in a similar fashion according to the example 205 described above: