Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18][C:19]2C=CC=CC=2)=[O:15])=[N:10][CH:9]=1)(C)[C:3]([OH:5])=[O:4].BrCCC#[N:36]>C(OC(=O)C)C>[C:19]([CH2:18][CH2:17][N:16]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:14](=[O:15])[NH:13][C:11]1[S:12][C:8]([S:7][CH2:2][C:3]([OH:5])=[O:4])=[CH:9][N:10]=1)#[N:36]
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: N#CCCBr
Solvent: CCOC(C)=O
Product: C[C@H]1CC[C@H](N(CCC#N)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl -ureido]-thiazol-5-ylsulfanyl}-propionic acid using 3-bromopropionitrile and 2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: O[C:2]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)([CH3:4])[CH3:3].CS(Cl)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[C:2]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)([CH3:4])=[CH2:3]
Reactant: CC(C)(O)c1cc2ccccc2o1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.7 %

Procedure:
3.10 g of 2-(1-hydroxy-1-methylethyl)benzofuran was dissolved in 100 ml of methylene chloride. Thereto were added 2.22 g of methanesulfonyl chloride and 3.92 g of triethylamine at 0° C. The mixture was stirred at room temperature for 4 hours, then washed with water, 1 N hydrochloric acid, an aqueous saturated sodium hydrogencarbonate solution and an aqueous saturated sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: toluene) to obtain 2.44 g (yield: 88%) of 2-isopropenylbenzofuran as a colorless oily material.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH:13]([CH3:14])[CH2:12][N:11]([C:15]2[C:24]([F:25])=[C:23]3[C:18]([C:19](=[O:32])[C:20]([C:29]([OH:31])=[O:30])=[CH:21][N:22]3[CH:26]3[CH2:28][CH2:27]3)=[C:17]([CH3:33])[C:16]=2[F:34])[CH2:10]1)=O)(C)(C)C.[ClH:35]>C(O)C>[ClH:35].[NH2:8][CH:9]1[CH:13]([CH3:14])[CH2:12][N:11]([C:15]2[C:24]([F:25])=[C:23]3[C:18]([C:19](=[O:32])[C:20]([C:29]([OH:31])=[O:30])=[CH:21][N:22]3[CH:26]3[CH2:28][CH2:27]3)=[C:17]([CH3:33])[C:16]=2[F:34])[CH2:10]1
Reactant: Cc1c(F)c(N2CC(C)C(NC(=O)OC(C)(C)C)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: Cl
Solvent: CCO
Product: Cc1c(F)c(N2CC(C)C(N)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1

Procedure:
A mixture comprising 7-(3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6, 8-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (trans form) (125 mg), ethanol (4 ml) and 10% hydrochloric acid (4 ml) is refluxed for 30 minutes. After concentrating, the obtained residue is recrystallized from ethanol to give 7-(3-amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6, 8-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid monohydrochloride (trans form) (63 mg), as pale yellow powder, m.p. 214°-216° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C1COCC1.CC([O-])(C)C.[K+].C1(S([C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)(=[O:39])=[O:38])=[CH:33][N:32]=2)(=O)=O)CCCCC1>O>[CH:40]1([S:37]([C:34]2[CH:35]=[CH:36][C:31]([O:1][C:2]3[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=3)=[N:32][CH:33]=2)(=[O:39])=[O:38])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: O=S(=O)(c1ccc(S(=O)(=O)C2CCCCC2)nc1)C1CCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc(Oc2ccc(S(=O)(=O)C3CCCCC3)cn2)cc1
Yield: 31 %

Procedure:
To 3.68 g of p-hydroxyacetophenone in a 25 ml THF/25 ml DMSO mixture was added 3.2 g of t-BuOK and then 10.03 g of 2,5-bis(cyclohexylsulfonyl)pyridine, and the resulting mixture was heated at 62° C. for 11/2 hrs. The reaction mixture was cooled overnight, then added to 4 volumes of water and the crude product which formed recovered by filtration. Recrystallization of the crude product from CH2Cl2 /ethanol gave the product, 1-(4-((5-(cyclohexylsulfonyl)-2-pyridinyl)oxy)phenyl)ethanone, (31% yield), as light yellow prisms, m.p. 116°-118° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([Br:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH2:13].O.O.[C:16](O)(=[O:20])[C:17](O)=[O:18]>Cl>[Br:12][C:7]1[C:6]2[CH:5]=[CH:4][C:3]3[N:13]=[C:17]([OH:18])[C:16]([OH:20])=[N:1][C:2]=3[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Nc1ccc2c(Br)cccc2c1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: O
Product: Oc1nc2ccc3c(Br)cccc3c2nc1O
Temperature: 25 °C
Yield: 67.1 %

Procedure:
A mixture of 1,0 g (4,2 mmol) 1,2-diamino-5-bromonaphthalene and 1,2 g (9,5 mmol) oxalic acid dihydrate in 20 ml 4 N hydrochloric acid was refluxed for 2,5 h. After cooling to 25° C., the precipitate was filtered off and washed with water. The crude product was dissolved in 200 ml 2 N sodium hydroxide, and reprecipitated with 4N hydrochloric acid (to pH 1-2) to give 820 mg (67%) of pure 7-bromo-2,3-dihydroxybenzo(f)quinoxaline, m.p. >300° C.1H NMR (DMSO-d6 ): 8,6 (1H,d), 7,8 (1H,d), 7,7 (1H,d), 7,4 (1H,d), 7,3 (1H,d).
Reaction SMILES: Cl.C([O:4]C(=O)[C@H](CC1C=CC=CC=1)N)C.[CH:16]([N:19]=[C:20]=[N:21][CH:22]([CH3:24])[CH3:23])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C>O>[CH:16]([NH:19][C:20](=[O:4])[NH:21][CH:22]([CH3:24])[CH3:23])([CH3:18])[CH3:17]
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)N=C=NC(C)C
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)NC(C)C
Reaction time: 20 h

Procedure:
Then 11.5 g (50 mM) of Phenylalanine Ethyl Ester hydrochloride and 7.75 mL (45 mM) of diisopropylcarbodiimide were added. Then 8.6 mL (50 mM) of diisopropylethylamine was added via the dropping funnel for 10 min. The reaction mixture was kept for 20 hours at a room temperature, then 10 mL of H2O was added, a precipitate of diisopropylurea formed was filtered off, a resulted solution was analyzed by HPLC. According analysis, the reaction was completed at 50%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=1)C(OC)=O.[Cl-].[Li+].O>CS(C)=O.O>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=1
Reactant: COC(=O)C(C(=O)OC)c1cc(Cl)cc(OCc2ccccc2)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)Cc1cc(Cl)cc(OCc2ccccc2)c1
Temperature: 150 °C
Reaction time: 5 h

Procedure:
A mixture of 2-(3-benzyloxy-5-chloro-phenyl)-malonic acid dimethyl ester (21 g, 60.2 mmol) and lithium chloride (3.06 g, 72.2 mmol) in DMSO:H2O (10:1; 200 mL) was stirred at 150° C. for 5 hours. After cooling to room temperature, H2O (500 mL) was added, and the mixture was extracted with EtOAc:hexanes (1:10; 1.5 L total) to give the title compound.
Reaction SMILES: CC1(C)CC(C2C=CC=C([C:18]([F:21])([F:20])[F:19])C=2)C2C(=CC(OC)=CC2)N1.[CH3:25][C:26]1([CH3:45])[CH2:35][CH:34]([C:36]2[CH:41]=[CH:40][C:39](Cl)=[CH:38][CH:37]=2)[CH:33]2[C:28](=[CH:29][C:30]([O:43][CH3:44])=[CH:31][CH2:32]2)[NH:27]1>>[CH3:25][C:26]1([CH3:45])[CH2:35][CH:34]([C:36]2[CH:41]=[CH:40][C:39]([C:18]([F:21])([F:20])[F:19])=[CH:38][CH:37]=2)[CH:33]2[C:28](=[CH:29][C:30]([O:43][CH3:44])=[CH:31][CH2:32]2)[NH:27]1
Reactant: COC1=CCC2C(=C1)NC(C)(C)CC2c1ccc(Cl)cc1
Reactant: COC1=CCC2C(=C1)NC(C)(C)CC2c1cccc(C(F)(F)F)c1
Product: COC1=CCC2C(=C1)NC(C)(C)CC2c1ccc(C(F)(F)F)cc1

Procedure:
2,2-dimethyl-7-methoxy-4-(3-trifluoromethylphenyl)tetrahydroquinoline; and 2,2-dimethyl-7-methoxy-4-(4-chlorophenyl)tetrahydroquinoline (using Pt as catalyst).
Reaction SMILES: CC(C)([O-:4])C.[K+].[N+]([CH:10]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:14][C:13](=[O:22])[CH2:12][CH2:11]1)([O-])=O>ClCCl.CO>[O:4]=[C:10]1[CH2:11][CH2:12][C:13](=[O:22])[NH:14][CH:15]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCC([N+](=O)[O-])C(c2ccccc2)N1
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: O=C1CCC(=O)C(c2ccccc2)N1
Temperature: -78 °C

Procedure:
Potassium t-butoxide (1.68 g, 15 mmol) was added to a solution of 5-nitro-2-oxo-6-phenylpiperidine (3 g, 13.6 mmol; Example 2a) in a mixture of dichloromethane (50 ml) and methanol (50 ml) and the mixture was cooled to -78° C. under nitrogen. Ozone was bubbled through the solution for 3 h. A yellow-green solution resulted, and TLC indicated no starting material remained. The reaction mixture was purged with oxygen for 5 min to remove excess ozone, then dimethylsulfide (7 ml) was added and the reaction mixture was allowed to warm to 23° C. The solvent was removed in-vacuo and the residue was partitioned between dichloromethane and water. The layers were separated, and the aqueous phase was extracted twice with dichloromethane. The combined organic extracts were washed with brine, then dried (K2CO3) and concentrated to leave 3,6-diketo-2-phenylpiperidine as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](C)([CH3:11])[C:9]#N)=[CH:4][CH:3]=1.C[Li].Cl.C([O:18][CH2:19][CH3:20])C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:9])[C:19](=[O:18])[CH3:20])=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: CC(C)(C#N)c1ccc(F)cc1
Agent: Cl
Agent: [Li]C
Product: CC(=O)C(C)(C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5.84 g 2-(4-fluorophenyl)-2-methylpropionitrile in abs. diethylether are added dropwise at -30° and under inert gas, 22 ml of a 1.6M solution of methyllithium in diethylether. The cooling bath is then taken away and the mixture stirred for 3 hours at room temperature. The reaction mixture is poured onto ice, the organic phase stirred overnight with 6N HCl, washed after separation of the acid phase, dried and evaporated in vacuum. The thus obtained oily residue is reacted further without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=O.C(=O)([O-])O.[Na+].C(O)CC>O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:1]=2)[CH:4]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: Nc1ccc(Br)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCCO
Product: Clc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 89.1 %

Procedure:
2.5 g (14.45 mmol) of 2-amino-5-bromopyridine, 3.37 g (14.45 mmol) of 2-bromo-4′-chloroacetophenone, 1.82 g (21.67 mmol) of sodium hydrogen carbonate and 110 ml of 1-propanol are introduced into a 250 ml three-necked flask, equipped with a magnetic stirrer and maintained under a nitrogen atmosphere. After stirring for 18 hours at 80° C., the reaction mixture is brought back to ambient temperature and diluted with 400 ml of water. The precipitate formed is recovered by filtration, washed with water, and then dried at 80° C. under reduced pressure. 3.96 g of expected product are thus isolated in the form of a beige powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C@@:11]1([CH3:24])[N:20]=[C:19]([NH2:21])[C:14]2([CH2:18][CH2:17][CH2:16][CH2:15]2)[S:13](=[O:23])(=[O:22])[CH2:12]1.C(N(CC)CC)C>C(O)C.[Pd]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C@@:11]2([CH3:24])[N:20]=[C:19]([NH2:21])[C:14]3([CH2:18][CH2:17][CH2:16][CH2:15]3)[S:13](=[O:22])(=[O:23])[CH2:12]2)[CH:4]=1
Reactant: C[C@@]1(c2cc([N+](=O)[O-])ccc2F)CS(=O)(=O)C2(CCCC2)C(N)=N1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@@]1(c2cc(N)ccc2F)CS(=O)(=O)C2(CCCC2)C(N)=N1
Temperature: 23 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a solution of (R)-8-(2-fluoro-5-nitro-phenyl)-8-methyl-6,6-dioxo-6λ6-thia-9-aza-spiro[4.5]dec-9-en-10-ylamine (210 mg, 591 μmol, Eq: 1.00) in ethanol (10 ml) was added at 23° C. under inert atmosphere triethylamine (59.8 mg, 82.4 μl, 591 μmol, Eq: 1.00) and after inertisation Pd/C 10% (62.9 mg, 59.1 μmol, Eq: 0.1). The suspension was set under hydrogen (balloon) and stirred at 23° C. for 1 hour. The catalyst was filtered off, washed three times with ethanol and evaporated to give the crude and nearly pure (R)-8-(5-amino-2-fluoro-phenyl)-8-methyl-6,6-dioxo-6λ6-thia-9-aza-spiro[4.5]dec-9-en-10-ylamine (182 mg, 559 μmol, 94.7% yield) as an off-white foam. MS (ISP): m/z=326.5 [M+H]+.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([CH:19]([C:21]3[CH:22]=[N:23][C:24]([CH2:27][NH:28][C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)=[CH:25][CH:26]=3)[OH:20])=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[K+].O.[CH3:39]O>>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([NH:28][CH2:27][C:24]2[CH:25]=[CH:26][C:21]([CH:19]([O:20][CH3:39])[C:12]3[C:13]4[C:14](=[N:15][CH:16]=[CH:17][CH:18]=4)[NH:10][CH:11]=3)=[CH:22][N:23]=2)=[CH:30][CH:31]=1
Reactant: CO
Reactant: O=S(=O)(c1ccccc1)n1cc(C(O)c2ccc(CNc3ccc(Cl)cc3)nc2)c2cccnc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC(c1ccc(CNc2ccc(Cl)cc2)nc1)c1c[nH]c2ncccc12
Temperature: 50 °C

Procedure:
To (1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-[(4-chloro-phenylamino)-methyl]-pyridin-3-yl-methanol (56, 120.0 mg, 0.24 mmol) in methanol (20.0 mL) were added potassium hydroxide (0.400 g, 7.13 mmol) and water (5.0 mL, 0.28 mol). The reaction was heated to 50° C. for 10 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give compound (57, 30 mg, 33.0%). MS (ESI) [M+H+]+=379.4.
Reaction SMILES: [Br:1][C:2]1[C:3](=O)[C:4]2[C:12](=[CH:13][CH:14]=1)[C:11]1[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=1)[CH:5]=2.[C:17](O)(=O)[CH3:18]>CCOCC>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]3([C:18]4[CH:17]=[CH:8][CH:7]=[CH:6][C:5]=4[C:4]4[C:3]3=[CH:2][CH:14]=[CH:13][CH:12]=4)[C:4]=2[CH:3]=1
Reactant: O=C1C(Br)=CC=C2C1=Cc1cc(Br)ccc12
Reactant: CC(=O)O
Solvent: CCOCC
Product: Brc1ccc2c(c1)C1(c3ccccc3-c3ccccc31)c1cc(Br)ccc1-2
Temperature: 25 °C
Yield: 60 %

Procedure:
According to a method similar to that of synthesis example 3, 2,7-dibromofluorenone (0.1 mol) and 2-biphenyl magnesium bromide are agitated in ether for 3 hr, followed by cooling to room temperature, further followed by slowly adding 50 ml of acetic acid. Ether is distilled away under reduced pressure, followed by adding thereto substantially 5 ml of HCl. Thereafter, the solution is refluxed for 1 hr, followed by filtering precipitate by suction, further followed by washing with water and recrystallizing with methanol. Thereby, 2,7-dibromo-9,9′-spirobifluorene is obtained (yield: 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[S:14][CH:15]=[CH:16][C:12]=3[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:13]3[S:14][CH:15]=[CH:16][C:12]=3[CH2:11][CH2:10][N:9]2[C:23]([C:22]2[CH:26]=[CH:27][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[O:24])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Clc1ccc(C2NCCc3ccsc32)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)N2CCc3ccsc3C2c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
7-(4-Chloro-phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin (100 mg) in toluene (20 ml), 4-methoxybenzoyl chloride (68.3 mg) and triethylamine (1 ml) were mixed and the mixture stirred at RT for 2 h. The reaction mixture was extracted once with NaOH (1 M) and once with water, the organic phase dried (MgSO4) and evaporated to dryness resulting in yellow oil which was purified on silica gel using methylene chloride/methanol 19/1 as eluent. The resulting oil was treated with abs ethanol resulting in precipitation of crystals. Yield 91%, m.p. 129.5-130.0 C. MS. M+=383.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([NH2:16])[C:13]([NH:17][CH3:18])=[CH:12][C:11]=2[F:19])=[CH:4][C:3]=1[Cl:21].[Cl:22][C:23]1[C:36]([N:37]=[C:38]=S)=[C:35]([Cl:40])[CH:34]=[CH:33][C:24]=1[CH2:25][NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29].CC(C)N=C=NC(C)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:10]2[C:11]([F:19])=[CH:12][C:13]3[N:17]([CH3:18])[C:38]([NH:37][C:36]4[C:35]([Cl:40])=[CH:34][CH:33]=[C:24]([CH2:25][NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[C:23]=4[Cl:22])=[N:16][C:14]=3[CH:15]=2)=[O:20])=[CH:4][C:3]=1[Cl:21]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Reactant: CNc1cc(F)c(C(=O)Nc2ccc(F)c(Cl)c2)cc1N
Agent: CC(C)N=C=NC(C)C
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)Nc3ccc(F)c(Cl)c3)c(F)cc21

Procedure:
The title compound is prepared from N-(4-fluoro-3-chloro-phenyl)-2-fluoro-4-methylamino-5-amino-benzoic acid amide and N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide with DIC in analogy to examples 7b/7c.
Reaction SMILES: [N+](=[CH2:3])=[N-].[C:4]([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14]([CH3:17])([CH3:16])[N:13]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:11]=2[CH:24]=1)([OH:6])=[O:5]>C(OCC)C.O1CCCC1>[CH3:3][O:5][C:4]([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14]([CH3:17])([CH3:16])[N:13]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:11]=2[CH:24]=1)=[O:6]
Reactant: C=[N+]=[N-]
Reactant: CC1(C)N=C(c2ccccn2)c2cc(C(=O)O)ccc2O1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc2c(c1)C(c1ccccn1)=NC(C)(C)O2

Procedure:
A solution of diazomethane in diethyl ether was added to a solution of Compound 113 (0.70 g) in tetrahydrofuran (5 ml) at room temperature until the starting material disappeared. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 6-methoxycarbonyl-2,2-dimethyl-4-(2-pyridyl)-2H-1,3-benzoxazine (0.49 g) (Compound 6).
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[ClH:8].[CH3:9]O>>[ClH:8].[CH3:9][O:4][C:3](=[O:5])[C:2]([NH2:1])([CH3:7])[CH3:6]
Reactant: CO
Reactant: CC(C)(N)C(=O)O
Agent: Cl
Product: COC(=O)C(C)(C)N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-aminoisobutyric acid in 125 ml of methanol is added 125 ml of methanol saturated with HCl. The initial mixture becomes a solution and the reaction is sealed and allowed to stir at room temperature overnight. The next day the reaction is evaporated, first neat and then from toluene to give a solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:27]([CH3:28])=[CH:26][C:8]([C:9]([NH:11][NH:12][C:13](=O)[C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([CH2:21][CH:22]([CH3:24])[CH3:23])=[N:16][CH:15]=2)=[O:10])=[CH:7][C:6]=1[CH3:29])[CH:2]=[CH2:3].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1.CC(=O)OCC>[CH2:1]([O:4][C:5]1[C:27]([CH3:28])=[CH:26][C:8]([C:9]2[O:10][C:13]([C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([CH2:21][CH:22]([CH3:23])[CH3:24])=[N:16][CH:15]=3)=[N:12][N:11]=2)=[CH:7][C:6]=1[CH3:29])[CH:2]=[CH2:3]
Reactant: C=CCOc1c(C)cc(C(=O)NNC(=O)c2cnc(CC(C)C)c(C)c2)cc1C
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOc1c(C)cc(-c2nnc(-c3cnc(CC(C)C)c(C)c3)o2)cc1C
Yield: 94.6 %

Procedure:
A solution of 6-isobutyl-5-methyl-nicotinic acid N′-(4-allyloxy-3,5-dimethyl-benzoyl)-hydrazide (89 mg, 0.224 mmol) and Burgess reagent (162 mg, 0.68 mmol) in THF (4 mL) is heated in a microwave oven at 110° C. for 6 min. The mixture is diluted with EA (15 mL) and washed with 1M aq. NaH2PO4 (5 mL), 1M aq. NaOH (5 mL) and water (5 mL). The org. phase is dried (MgSO4), filtered and evaporated to provide crude 5-[5-(4-allyloxy-3,5-dimethyl-phenyl)-[1,3,4]oxadiazol-2-yl]-2-isobutyl-3-methyl-pyridine (80 mg); LC-MS: tR=1.07 min, [M+1]+=378.3.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH:11][C@@H:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH3:13])=[O:10])[CH2:5][CH2:4]1.CCN(CC)CC.[OH:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][C:30]=1[O:39][CH3:40]>C(Cl)Cl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:12]([NH:11][C:9]([C@H:6]2[CH2:7][CH2:8][C@H:3]([NH:2][S:35]([C:32]3[CH:33]=[CH:34][C:29]([OH:28])=[C:30]([O:39][CH3:40])[CH:31]=3)(=[O:37])=[O:36])[CH2:4][CH2:5]2)=[O:10])[CH3:13])=[CH:15][CH:16]=1
Reactant: C[C@@H](NC(=O)[C@H]1CC[C@H](N)CC1)c1ccc(F)cc1
Reactant: COc1cc(S(=O)(=O)Cl)ccc1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(S(=O)(=O)N[C@H]2CC[C@H](C(=O)N[C@H](C)c3ccc(F)cc3)CC2)ccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trans-4-Amino-N—((R)-1-(4-fluorophenyl)ethyl)cyclohexanecarboxamide hydrochloride (Intermediate 45, 200 mg, 0.66 mmol) and Et3N (371 ul, 2.66 mmol) were dissolved in DCM (10 ml). 4-Hydroxy-3-methoxy-benzenesulphonyl chloride (178 mg, 0.798 mmol) was added, and the reaction mixture was stirred for 3 hr at room temperature, after which LCMS indicated that the reaction was complete. The mixture was concentrated in vacuo, and the crude material was purified via reverse phase chromatography on prep-HPLC (150 mm, C8 luna, 15-20 min run, 10%-100% MeCN in water containing 0.1% TFA). Fractions containing the product were lyophilized to yield the title compound as a white solid (14 mg, 0.031 mmol). MS MH+ 451.1
Reaction SMILES: OOS([O-])=O.[K+].[N+:7]([C:10]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:11]=1[CH:12]=O)([O-])=O.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH2:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[NH2:7][C:10]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:11]=1[C:12]1[NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]=1
Reactant: Cc1ccc(C=O)c([N+](=O)[O-])c1
Reactant: Nc1ccccc1N
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc3ccccc3[nH]2)c(N)c1
Temperature: 20 °C

Procedure:
33.8 g (55 mmol) of oxone [70693-62-8] are added in portions to a solution of 13.5 g (100 mmol) of 2-nitro-4-methylbenzaldehyde [20357-22-6] and 11.9 g (110 mmol) of 1,2-diaminobenzene in a mixture of 150 ml of DMF and 5 ml of water with stirring and cooling to 20° C. at such a rate that the temperature does not exceed 35° C. The reaction mixture is subsequently stirred at room temperature until conversion of the aldehyde is complete (about 4 h). The reaction mixture is stirred into a solution of 40 g of potassium carbonate in 2000 ml of water, stirred for a further 15 min., extracted with three 300 ml portions of dichloromethane in each case, the organic phase is washed twice with 300 ml of water, once with 500 ml of sat. sodium chloride solution and dried over sodium sulfate. The dichloromethane solution is filtered through silica gel, and the dichloromethane is removed in vacuo. The yellow residue is taken up in 500 ml of methanol, blanketed with nitrogen with stirring, 3 g of 10% Pd/C are added, and the mixture is hydrogenated at room temperature in an autoclave at a hydrogen pressure of 2 bar. When the uptake of hydrogen is complete, the catalyst is filtered off via a Celite bed, and the methanol is removed in vacuo. Yield: 18.5 g (83 mmol), 83%. Purity: >95% according to 1H-NMR.