Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30](O)=[O:31])[CH:28]=2)[CH:23]=[CH:22]1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:30]([C:27]3[CH:28]=[C:29]4[C:24]([CH:23]=[CH:22][NH:21]4)=[CH:25][CH:26]=3)=[O:31])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc2cc[nH]c2c1

Procedure:
1H-Indole-6-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate D and 1H-Indole-6-carboxylic acid. MS calcd. for C25H19ClN3O2 [(M+H)+] 428.1, obsd. 427.9.
Reaction SMILES: [NH2:1][C:2](=[O:31])[CH:3]([OH:30])[CH:4]([NH:12][C:13]([C:15]1[C:16]([C:21]2[S:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.ClCCl.ClC(Cl)C(O)=O>CS(C)=O>[NH2:1][C:2](=[O:31])[C:3](=[O:30])[CH:4]([NH:12][C:13]([C:15]1[C:16]([C:21]2[S:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:14])[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: NC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-c1nc2ccccc2s1
Agent: O=C(O)C(Cl)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)c1cccnc1-c1nc2ccccc2s1
Temperature: 25 °C
Yield: 52.1 %

Procedure:
To a solution of N-(4-Amino-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-2-(1,3-benzothiazol-2-yl)pyridine-3-carboxamide (0.5 g, 1.16 mmol) in 1.5 ml of DMSO und 15 ml of dichloromethane 3.04 g N-cyclohexylcarbodiimid-N′-methylpolystyrole (1.9 mmol/g; 5.78 mmol) and 0.24 ml dichloroacetic acid (0.38 g, 2.89 mmol) were added, and the reaction mixture stirred over night at room temperature. For work up the polymer was filtered off, washed with dichloromethane, and the combined organic layers evaporated to dryness. Treatment with a mixture of n-hexane/ethylacetate, filtration and drying afforded 260 mg of the title compound, as white amorphous solid:
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[N:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[C:16]1([C:3]2[C:2]([C:25]3[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=3)[N:4]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1ccncc1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(-c3ccncc3)nc2c1
Yield: 31.6 %

Procedure:
The product was obtained via a Suzuki coupling reaction using the method previously shown in Example 20, Step 3, with methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv) and pyridin-4-yl boronic acid (54 mg, 0.44 mmol, 1.50 equiv) as reactants. Purification by Prep-TLC (silica gel) yielded 30 mg (30%) of 2-phenyl-3-(pyridin-4-yl)quinoxaline-6-carboxylic acid as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:7]1[C:12]2[N:13]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH2:14][C:15]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[N:18][C:16]=3[NH:17][C:11]=2[CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3](O)=[O:4].C[N:41](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N>CN(C=O)C.O>[CH3:1][C:2]([C:7]1[C:12]2[N:13]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]([F:37])([F:38])[F:39])=[CH:31][CH:30]=3)(=[O:27])=[O:28])[CH2:14][C:15]3[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[N:18][C:16]=3[NH:17][C:11]=2[CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3]([NH2:41])=[O:4]
Reactant: CC(C)(C(=O)O)c1cccc2c1N(S(=O)(=O)c1ccc(OC(F)(F)F)cc1)Cc1ccc(C(F)(F)F)nc1N2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C(N)=O)c1cccc2c1N(S(=O)(=O)c1ccc(OC(F)(F)F)cc1)Cc1ccc(C(F)(F)F)nc1N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of the product of Example 435 (217 mg, 0.4 mmol) in DMF (10 mL) was added HATU (169 mg, 0.4 mmol), Hunig's base (0.1 ml, 0.4 mmol) and NH3 (0.5 M in dioxane) (2.2 mL, 0.7 mmol). The resulting solution was stirred at rt overnight, diluted with H2O, and extracted with EtOAc(3×50 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give an oil which was purified by flash chromatography (0-7% MeOH/CH2Cl2) to give the title compound as a racemic mixture. The racemic mixture was separated by HPLC on a chiralcel OD column with 20% MeOH/CO2 as the mobile phase. The faster eluting enantiomer (E1) has a retention time of 4.0 minutes, while the slower enantiomer (E2) has a retention time of 4.6 minutes. E1: 1H NMR (500 MHz, (CD3)2CO): δ 8.11 (s, 1H), 7.73 (d, J=7.5 Hz, 1H), 7.31-7.35 (m, 3H), 7.28 (dd, J=1.5, 7.5 Hz, 1H), 7.18 (dd, J=1.5, 7.5 Hz, 1H), 7.13 (d, J=7.5 Hz, 1H), 7.09 (d, J=7.5 Hz, 2H), 6.55 (s, 1H), 6.31 (s, 1H), 5.11 (d, J=17.5 Hz, 1H), 4.81 (d, J=17.5 Hz, 1H), 1.85 (s, 3H), 1.74 (s, 3H). LCMS: m/e 587.08 (M+H)+.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH:34]([CH3:36])[CH3:35]>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH:34]([CH3:36])[CH3:35])[C:18]([C:23]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCOCC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1c(C(=O)N2CCOCC2)cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc21
Yield: 31 %

Procedure:
The title compound was synthesized in analogy to example 51, from (4-cyclopentyl-piperazin-1-yl)-[2-(morpholine-4-carbonyl)-1H-indol-5-yl]-methanone (example 10), sodium hydride and 2-bromopropane in N,N-dimethylformamide, to give the desired product as a colorless foam (31%).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9](=[O:11])[CH3:10])[C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.Cl[Si:20]([CH3:23])([CH3:22])[CH3:21]>C(#N)C>[CH3:1][O:2][N:3]=[C:4]([C:9]([O:11][Si:20]([CH3:23])([CH3:22])[CH3:21])=[CH2:10])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CON=C(C(C)=O)C(=O)OC
Reactant: C[Si](C)(C)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=C(O[Si](C)(C)C)C(=NOC)C(=O)OC
Reaction time: 1 h
Yield: 86.5 %

Procedure:
In 15 ml of acetonitrile was dissolved 795 mg of methyl 2-methoxyimino-3-oxobutyrate, followed by addition of 2.1 ml of triethylamine. Then, 1.9 ml of chlorotrimethylsilane was added dropwise with ice-cooling and the mixture was stirred at 20°-25° C. for 1 hour for silylation. The reaction mixture was concentrated under reduced pressure and the residue was suspended in 10 ml of carbon tetrachloride and the suspension was filtered in a nitrogen gas stream to remove insolubles. The filtrate was concentrated under reduced pressure to give 1.00 g of methyl 2-methoxyimino-3-trimethylsilyloxy-3-butenoate as oil. Yield 86.5%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:5]=1)([O-])=O.[OH-].[Na+]>C(O)(=O)C.O.[Fe]>[S:11]1[CH:12]=[CH:13][N:14]=[C:10]1[C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(-c2nccs2)cc1
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(-c2nccs2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
Iron powder (0.5 g, 8.92 mmol) was added portion wise to a solution of 2-(4-nitrophenyl)-thiazole (200 mg, 0.97 mmol) in acetic acid (5 ml) and stirred at room temperature for 2 hr. The reaction mixture was diluted with water, basified with dilute sodium hydroxide, filtered and the filtrate was extracted with ethyl acetate. The organic layer was washed with water, brine and dried. Evaporation of the solvent yielded 4-thiazol-2-yl-phenylamine (150 mg, 88%) as solid.
Reaction SMILES: [Cl:1][C:2]([Cl:27])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([N:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[C:8]([Cl:26])[CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-].[OH-].[Na+]>C(Cl)Cl>[Cl:27][C:2]([Cl:1])=[CH:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([Cl:26])[C:9]([N:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)=[C:10]([Cl:12])[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)CC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: ClC(Cl)=CCOc1cc(Cl)c(N2CCNCC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.4 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 1.8 gram (0.0039 mole) of tert-butyl 4-[4-(3,3-dichloroprop-2-enyloxy)-2,6-dichlorophenyl]piperazinecarboxylate in 30 mL of methylene chloride was cooled to about 0° C. and 0.53 gram (0.0039 mole) of aluminum chloride was added portion-wise. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature where it stirred during a five hour period. After this time 20 mL of an aqueous solution of 10% sodium hydroxide was added dropwise, then the mixture was extracted with two 25 mL portions of ethyl acetate. The combined extracts were washed with one 25 mL portion of an aqueous solution saturated with sodium chloride, dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 1.2 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:28])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([S:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:28])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2c(Sc3ccccc3)ccnc2c1
Solvent: ClCCl
Product: COc1ccc2c(S(=O)c3ccccc3)ccnc2c1
Temperature: 25 °C

Procedure:
To 7-methoxy-4-(phenylthio)quinoline (1.38 g, 5.16 mmol) in CH2Cl2(50 mL) at −78° C. was added m-CPBA (77%) (1.25 g, 7.23 mmol) portionwise. The mixture was allowed to slowly warm to RT (3 hrs). The reaction mixture was diluted with CH2Cl2 then neutralized with NaHCO3(sat.). The aqueous phase was extracted three times with DCM then the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude mixture was purified by silica gel chromatography using 0-10% CH2Cl2:MeOH to afford 7-methoxy-4-(phenylsulfinyl)quinoline as a off-white foam. MS: M+H+=284.0.
Reaction SMILES: [CH3:1][P:2]1(=[O:21])[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+].FC1[CH:37]=[CH:38][C:39]([N+:44]([O-:46])=[O:45])=[C:40]([O:42][CH3:43])[CH:41]=1>C(Cl)Cl>[CH3:43][O:42][C:40]1[CH:41]=[C:14]([N:11]2[CH2:10][CH2:9][CH:8]([N:5]3[CH2:4][CH2:3][P:2](=[O:21])([CH3:1])[CH2:7][CH2:6]3)[CH2:13][CH2:12]2)[CH:37]=[CH:38][C:39]=1[N+:44]([O-:46])=[O:45]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCP(C)(=O)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2CCC(N3CCP(C)(=O)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 85.1 %

Procedure:
To a stirring solution of tert-butyl 4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidine-1-carboxylate (178 mg, 0.563 mmol) in CH2Cl2 (2 mL) was added trifluoroacetic acid (0.5 mL). After 20 min, the solution was concentrated and the resulting residue was redissolved in DMF (2 mL). Potassium carbonate (160 mg, 1.16 mmol) was added portionwise to the stirring solution followed by 5-fluoro-2-nitroanisole (158 mg, 0.930 mmol). The reaction mixture was heated to 50° C. After 2 h, the reaction mixture was concentrated and the residue was purified by silica gel chromatography (0-10% 7N ammonia in methanol:dichloromethane) to afford the compound as a bright yellow solid (176 mg, 86% yield).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH:9]1([CH2:14][N:15]2[CH2:19][C:18]34[CH2:29][CH:22]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[CH:17]3[CH2:16]2)[C:21]2[CH:30]=[CH:31][CH:32]=[CH:33][C:20]4=2)[CH2:13][CH2:12][CH2:11][CH2:10]1.Cl>C(Cl)Cl>[C:5]([C:32]1[CH:31]=[CH:30][C:21]2[CH:22]3[CH2:29][C:18]4([CH2:19][N:15]([CH2:14][CH:9]5[CH2:13][CH2:12][CH2:11][CH2:10]5)[CH2:16][CH:17]4[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=43)[C:20]=2[CH:33]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)C1CC3(CN(CC4CCCC4)CC23)c2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)C13CC2c2ccccc2C1CN(CC1CCCC1)C3
Yield: 110 %

Procedure:
To a suspension of 5.0 g (37.39 mmoles) of aluminum chloride in 75 ml of methylene chloride, cooled to 0°, was added dropwise 3.0 g (38.2 mmoles) of acetyl chloride. Then 5.0 g (13.7 mmoles) of 2-cyclopentylmethyl-2,3,8,12b-tetrahydro1H-3a,8methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole was added portionwise. The reaction mixture was heated at reflux for several hours and then poured into 1N aqueous hydrochloric acid. The product was extracted with methylene chloride, and the extracts were washed with water, with 1N aqueous sodium hydroxide, with water and dried over potassium carbonate. The solvent was evaporated to leave 5.6 g of 5-acetyl-2-cyclopentylmethyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole as an oil; nmr spectrum: δ 1.0-4.0 (m, 19); 2.5 (s, 3); 7.1-7.25 (m, 5); 7.7-7.9 (m, 2). The 220MHz nmr spectrum showed that the product contained approximately 83% of the 5-acetyl isomer. A sample was purified by crystallization of the trifluoroacetate salt from ether/ethyl acetate and then of the hydrochloride salt from acetone, mp, 160-172° (dec.); ir. 1700 cm-1 (COCH3).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[N:9]=[N:10][S:11][CH:12]=1)[C:5]([OH:7])=O.[NH2:13][CH:14]1[C:32](=[O:33])[N:16]2[C:17]([C:29]([OH:31])=[O:30])=[C:18]([CH2:21][S:22][C:23]3[N:27]([CH3:28])[N:26]=[N:25][N:24]=3)[CH2:19][S:20][C@H:15]12>>[CH3:1][O:2][N:3]=[C:4]([C:8]1[N:9]=[N:10][S:11][CH:12]=1)[C:5]([NH:13][CH:14]1[C:32](=[O:33])[N:16]2[C:17]([C:29]([OH:31])=[O:30])=[C:18]([CH2:21][S:22][C:23]3[N:27]([CH3:28])[N:26]=[N:25][N:24]=3)[CH2:19][S:20][C@H:15]12)=[O:7]
Reactant: CON=C(C(=O)O)c1csnn1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1csnn1
Yield: 56.4 %

Procedure:
2-Methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetic acid (anti isomer) (1 g.) and 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.9 g.) were reacted according to similar manners to those of Examples 1(b) and 8 to give pale yellow powder of 7-[2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (anti isomer) (1.5 g.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7](Cl)=[O:8].[C:10]([O:13][C:14]1[C:23]2[C:18](=[C:19]([NH2:24])[CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[CH:15]=1)(=[O:12])[CH3:11].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl>[C:10]([O:13][C:14]1[C:23]2[C:18](=[C:19]([NH:24][C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)=[O:8])[CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=2)[CH:15]=1)(=[O:12])[CH3:11]
Reactant: O=C(Cl)c1cnccn1
Reactant: CC(=O)Oc1cc(-c2cccc(C(F)(F)F)c2)nc2c(N)cccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cc(-c2cccc(C(F)(F)F)c2)nc2c(NC(=O)c3cnccn3)cccc12
Temperature: 40 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
Pyrazine-2-carbonyl chloride 40 (100 mg) was added to a solution of 8-amino-2-(3-(trifluoromethyl)phenyl)quinolin-4-yl acetate 39 (50 mg, 0.145 mmol) and triethylamine (0.20 mL) in dichloromethane (3 mL). The reaction mixture was stirred at 40° C. for 16 h. The reaction mixture was poured into dilute NaHCO3 (10 mL), and extracted with 3×30 mL dichloromethane. The combined organic layers were dried (MgSO4) and the solvent removed in vacuo. The crude residue was purified by MPLC (97:3 dichloromethane:methanol) to give 41 (33 mg, 50% yield).
Reaction SMILES: N1([C:6]([NH:8][CH2:9][CH2:10][O:11][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])=[O:7])C=CN=C1.CS(O)(=O)=O.ClCl>>[N:8]([CH2:9][CH2:10][O:11][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])=[C:6]=[O:7]
Reactant: C=C(C)C(=O)OCCNC(=O)n1ccnc1
Agent: CS(=O)(=O)O
Agent: ClCl
Product: C=C(C)C(=O)OCCN=C=O

Procedure:
This substance was synthesized according to the procedure described in Example 4, second step. 2-Methyl-acrylic acid 2-[(imidazole-1-carbonyl)-amino]-ethyl ester was used from Example 5. Dry methane sulfonic acid was used to protononate and decompose the 2-Methyl-acrylic acid 2-[(imidazole-1-carbonyl)-amino]-ethyl ester. 39.1 g MOI were received after fractionation (62.1% of theory); purity of 97.5%; residual chlorine: not detectable.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH3:6])=O.[CH3:7][CH2:8][CH2:9][CH2:10]CC>>[O:3]1[C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[CH:1]=[CH:2]1
Reactant: CCOC(C)=O
Reactant: CCCCCC
Product: c1ccc2occc2c1
Yield: 62.9 %

Procedure:
A solution of 30 (10.3 g; 39.3 mmol), EtOH (250 mL) and saturated NaHCO3 (100 mL) were heated to reflux for 1 h. The reaction mixture was cooled to room temperature and the EtOH removed in vacuo. Ice was added to the residue aqueous solution and the reaction carefully acidified to about pH 2 with 2 N HCl. The resulting mixture was extracted with EtOAc (2×300 mL) and the combined organic phase washed with brine, dried (NaSO4), filtered and evaporated to yield a brown oil (8.8 g). The crude product was run through a silica gel column with 15% EtOAc:hexane to yield 31 (5.44 g; 62.9%) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([C:10]3[C:14]([CH3:15])=[N:13][NH:12][C:11]=3[NH2:16])[S:9][C:5]=2[CH:4]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)C>[CH3:15][C:14]1[C:10]([C:8]2[S:9][C:5]3[CH:4]=[C:3]([CH2:2][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[CH:18]=[CH:17][C:6]=3[N:7]=2)=[C:11]([NH2:16])[NH:12][N:13]=1
Reactant: C1CCNC1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(CBr)cc2s1
Solvent: CCO
Product: Cc1n[nH]c(N)c1-c1nc2ccc(CN3CCCC3)cc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-(6-bromomethylbenzothiazol-2-yl)-5-methyl-2H-pyrazol-3-ylamine (20 mg) in ethanol (1 mL) was added excess pyrrolidine. The reaction mixture was stirred at room temperature overnight. The solvent was then removed by evaporation and the residue was purified by flash column chromatography eluting with CHCl3:MeOH=9:1 to yield 2.7 mg of the title compound as a cream coloured solid. MS (m/z, ES+): 314.1 (M+1, 45%), 243.0 (M-C4H8N, 100%).
Reaction SMILES: [C:1]([NH:5][S:6]([CH2:9][CH2:10][CH2:11]Cl)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:13](I)[CH3:14].C(NS(C1(C)CC1)(=O)=O)(C)(C)C>>[C:1]([NH:5][S:6]([C:9]1([CH2:13][CH3:14])[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCI
Reactant: CC(C)(C)NS(=O)(=O)CCCCl
Agent: CC(C)(C)NS(=O)(=O)C1(C)CC1
Product: CCC1(S(=O)(=O)NC(C)(C)C)CC1

Procedure:
Step 28a) This compound was prepared form N-tert-Butyl-(3-chloro) propylsulfonamide (59 g, 276 mmol) and ethyl iodide (86.11 g, 552 mmol) according to the procedure of Steps 3Ib-3Ic (Example 2) described in the synthesis of N-tert-Butyl-(1-methyl) cyclopropylsulfonamide. The compound was used as crude: 1H NMR (CHLOROFORM-D) □ ppm 0.82 (m, 2H), 0.99 (t, J=7.48 Hz, 3H), 1.33 (m, 11H), 1.92 (q, J=7.53 Hz, 2H), 3.91 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15]#[N:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>O1CCOCC1.O>[OH:3][CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:14][C:13]([C:15]#[N:16])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC(=O)c1ccc(-c2ccc(C#N)o2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(O)c1ccc(-c2ccc(C#N)o2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.6 %

Procedure:
A solution of 46 g (0.22 mole) of 5-(4-acetylphenyl)-2-furonitrile in 800 ml of 95% dioxane/H2O was treated portionwise with 8.3 g (0.22 mole) of NaBH4 while keeping the temperature below 20° by means of an ice bath. The resulting solution was stirred at ambient temperature for 21/2 hours and then added to an ice/H2O mixture. After standing 48 hours, the reaction mixture was extracted with ether and the combined ethereal extracts dried over MgSO4. The ether was removed on the Calab evaporator yielding 27 g (58%) of product as a residual oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[CH:15]=[C:14]([C:19]([OH:21])=O)[CH:13]=[CH:12][C:11]=2[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:38]=[CH:37][C:27]([CH2:28][NH:29][CH2:30][CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19](=[O:21])[N:29]([CH2:28][C:27]3[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:38][CH:37]=3)[CH2:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:15]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CNCC2CCOCC2)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2cc(C(=O)O)ccc2C1
Product: COc1ccc(CN(CC2CCOCC2)C(=O)c2ccc3c(c2)CC[C@H](NC(=O)OC(C)(C)C)C3)cc1

Procedure:
According to method G, (S)-6-tert-butoxycarbonylamino-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid was reacted with (4-methoxybenzyl)(tetrahydropyran-4-ylmethyl)amine. The crude product was purified by chromatography on silica gel (eluent: 30% n-heptane in ethyl acetate). The product was thus obtained with the molecular weight of 508.66 (C30H40N2O5); MS (ESI): 509 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=3)=[N:12][N:13]=2)[CH:5]=[C:6](Br)[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:48][Si:49]([C:52]#[CH:53])([CH3:51])[CH3:50]>CCN(CC)CC.CO.[Cu]I.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:48][Si:49]([CH3:51])([CH3:50])[C:52]1[C:3]([C:2]#[CH:7])=[C:4]([C:9]2[O:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=3)=[N:12][N:13]=2)[CH:5]=[C:6]([Si:49]([CH3:51])([CH3:50])[CH3:48])[CH:53]=1
Reactant: CCCCCCCCOc1ccc(-c2nnc(-c3cc(Br)cc(Br)c3)o2)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: CCN(CC)CC
Product: C#Cc1c(-c2nnc(-c3ccc(OCCCCCCCC)cc3)o2)cc([Si](C)(C)C)cc1[Si](C)(C)C
Temperature: 25 °C
Yield: 11.8 %

Procedure:
To an ice-cold mixture of 2-(3,5-dibromophenyl)-5-[4-(octyloxy)phenyl]-1,3,4-oxadiazole (11.47 g, 24.4 mmol), triphenylphosphine (0.1816 g, 0.692 mmol), copper (I) iodide (0.062 g, 0.326 mmol) and palladium (II) acetate (0.0594 g, 0.265 mmol) in 100 mL Et3N was added trimethylsilyl acetylene (6.0 g, 61.1 mmol). The mixture was stirred in the ice bath for 30 minutes. The ice bath was removed and after a further 30 minutes warming to room temperature the mixture was heated at reflux for 20 hours. The cooled reaction mixture was slurried in 150 mL methanol. The insoluble material was filtered off and dissolved in chloroform. Precipitation with hexane and evaporation to dryness of the hexane solution gave 2-(3,5-bis-trimethylsilanylethynylphenyl)-5-(4-octyloxyphenyl)-[1,3,4]oxadiazole (1.5 g, 11% yield). The methanol soluble filtrate was evaporated to dryness and dissolved in 250 mL chloroform. About 1.5 L of hexane was added. Filtration gave a dark solid material (3.5 g). Evaporation to dryness of the filtrate gave a further crop of 2-(3,5-bis-trimethylsilanylethynyl-phenyl)-5-(4-octyloxyphenyl)-[1,3,4]oxadiazole (3.5 g, 34% yield in total).