Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([NH:25][C:26]([NH:28][C:29]3[N:30]([C:38]4[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=4)[N:31]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:33]=3)=[O:27])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:34]([C:32]1[CH:33]=[C:29]([NH:28][C:26]([NH:25][C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]([O:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[N:16][CH:17]=2)=[O:27])[N:30]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)[N:31]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2cnc(OC3CCN(C(=O)OC(C)(C)C)CC3)c3ccccc23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2cnc(OC3CCNCC3)c3ccccc23)cc1
Temperature: 22 °C
Reaction time: 1.5 h

Procedure:
To a cold solution of 4-{4-[3-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-ureido]-isoquinolin-1-yloxy}-piperidine-1-carboxylic acid tert-butyl ester (820 mg, 1.37 mmol) in dichloromethane (50 mL), add trifluoroacetic acid (15 mL). Stir the reaction mixture at 22° C. for 1.5 hours. After removal of solvent, treat the residue with 1N sodium hydroxide saturated with NaCl (50 mL) and extract five times with dichloromethane (50 mL each). Dry the combined organic phases over sodium sulfate. Filter the mixture and subject residue to silica gel chromatography eluting with dichloromethane and methanol to provide a white solid (515 mg, 75% yield, LCMS ES+ (m/z) 499.5 [M+H]).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]3[NH:14][C:13]4[CH2:18][CH2:19][N:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][C:12]=4[C:11]=3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>CN(C)C=O>[C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]3[N:14]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:13]4[CH2:18][CH2:19][N:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][C:12]=4[C:11]=3[CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)N1CCc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCc2c(c3cc(OCc4ccccc4)ccc3n2Cc2ccccc2)C1
Temperature: 10 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
A mixture of intermediate (1) (0.09 mol) in N,N-dimethylformamide (200 ml) was stirred at 10° C. under a N2 flow. Sodium hydride (60%; 0.1 mol) was added portionwise. The mixture was stirred for 1 hour at room temperature, then it was cooled to 5° C. Benzylbromide (0.1 mol) was added dropwise. Stirring was continued for 2 hours. The mixture was cooled to 10° C. and poured out into cold water (500 ml). This mixture was extracted with CH2Cl2 (2×250 ml). The separated organic layer was washed with water (100 ml), dried, filtered and the solvent was evaporated. The solid residue was washed with CH3CN (50 ml), cooled and the resulting precipitate was filtered off and dried, yielding 30.0 g (76%) of ethyl 1,3,4,5-tetrahydro-8-(phenylmethoxy)-5-(phenyl-methyl)-2H-pyrido[4,3-b]indole-2-carboxylate (intermediate 2).
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:9](=[C:10]([CH2:19]O)[CH:11]=[C:12]([CH:15]([CH2:17][CH3:18])[CH3:16])[CH:13]=2)[N:8]=[C:7]([CH3:21])[C:6]=1[CH3:22])(=[O:3])[CH3:2].S(Cl)([Cl:25])=O>>[C:1]([O:4][C:5]1[C:14]2[C:9](=[C:10]([CH2:19][Cl:25])[CH:11]=[C:12]([CH:15]([CH2:17][CH3:18])[CH3:16])[CH:13]=2)[N:8]=[C:7]([CH3:21])[C:6]=1[CH3:22])(=[O:3])[CH3:2]
Reactant: CCC(C)c1cc(CO)c2nc(C)c(C)c(OC(C)=O)c2c1
Reactant: O=S(Cl)Cl
Product: CCC(C)c1cc(CCl)c2nc(C)c(C)c(OC(C)=O)c2c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 23.5 %

Procedure:
50 Milligrams of 4-acetoxy-6-s-butyl-8-hydroxymethyl-2,3-dimethylquinoline obtained in Example 34 was dissolved in 0.3 ml of thionyl chloride and stirred at room temperature for 4.5 hours. After thionyl chloride was evaporated under reduced pressure, 0.5 ml of acetic anhydride was added to the resultant crude product and the mixture was stirred at 120° C. for 2 hours. After acetic anhydride was evaporated under reduced pressure, the resultant residue was purified by column chromatography on silica gel (WAKOGEL® C-200) eluting with n-hexane/ethyl acetate (20:1) to obtain 12.5 mg of 4-acetoxy-6-s-butyl-8-chloromethyl-2,3-dimethylquinoline (yield 23.5%). Its NMR spectral data are shown in the following Table 2.
Reaction SMILES: C(O[C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[C:7]([O:9][C@H:10]1[CH2:15][CH2:14][C@H:13](O)[CH2:12][CH2:11]1)=[O:8])C=C.[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:7]([O:8][C:19]1[CH:20]=[CH:5][C:6]([C:7]([O:9][C@H:10]2[CH2:11][CH2:12][C@H:13]([C:27](=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][Br:21])[CH2:14][CH2:15]2)=[O:8])=[CH:17][CH:18]=1)[CH:6]=[CH2:5]
Reactant: O=C(Cl)CCCCCBr
Reactant: C=CCOc1ccccc1C(=O)O[C@H]1CC[C@H](O)CC1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: C=CCOc1ccc(C(=O)O[C@H]2CC[C@H](C(=O)CCCCCBr)CC2)cc1

Procedure:
55.2 g (0.2 mol) of trans-4-hydroxycyclohexyl allyloxybenzoate prepared as described in Example 1 were dissolved in 300 ml of dry toluene, and 43 g (0.205 mol) of 6-bromohexanoyl chloride (prepared from the free acid by conventional reaction with thionyl chloride; b.p. 60-62° C. at 0.04 mbar) were added dropwise at 105° C. over the course of 60 minutes with stirring. After the mixture had been stirred at 105° C. for a further 90 minutes, the solvent was stripped off under reduced pressure, and the residue was crystallized out using petroleum benzine/methyl tert-butyl ether (20:1), giving 83 g (92%) of trans-[4-(6-bromo-hexanoyl)cyclohexyl] 4-allyloxybenzoate, melting point 56° C. 79 g (0.174 mol) of this ester, 25 g (0.21 mol) of potassium methacrylate and 0.2 g of 2,6-di-tert-butyl-4-methylphenol (stabilizer) were dissolved in 400 ml of dimethylformamide, and the mixture was heated at 70-75° C. for 3 hours with stirring. The solvent was then distilled off under reduced pressure, the residue was taken up in 400 ml of methyl tert-butyl ether, and the solution was washed with water, 0.05 N NaOH, and again with water, dried and evaporated. The residue was recrystallized from methanol, yielding 70 g (87.5%) of the title compound, which melts at 50° C. and clears at 55° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH2:14][CH2:15][O:16][C:17]1([C:29]2[N:30]=[CH:31][N:32]([C:34]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:33]=2)[CH2:26][CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=[CH:19][C:18]1=2>ClCCl>[CH3:8][S:9]([O:13][CH2:14][CH2:15][O:16][C:17]1([C:29]2[N:30]=[CH:31][N:32]([C:34]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:33]=2)[C:18]2[C:23](=[CH:22][C:21]([C:27]#[N:28])=[CH:20][CH:19]=2)[CH2:24][CH2:25][CH2:26]1)(=[O:11])=[O:10]
Reactant: N#Cc1ccc2c(c1)CCCC2(OCCO)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOC1(c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)CCCc2cc(C#N)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5 mmol of triethylamine and 2.0 mmol of methanesulphonyl chloride are added to a solution of 1.0 mmol of 5-(2-hydroxyethoxy)-5-(1-trityl-1H-imidazol-4-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile in 10 ml of dichloromethane at 0° C. The reaction mixture is stirred at 0° C. for 1 hour, diluted with dichloromethane, washed with 1N HCl, dried with sodium sulphate and evaporated. The crude title compound is identified on the basis of the Rf and used without further purification in the next stage.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[C:14]([O:16][C@@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[CH:15]=2)[C:10]([OH:12])=O)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27](=[O:36])[CH2:28][S:29][C:30]1[S:34][C:33]([NH2:35])=[N:32][CH:31]=1)[CH3:25]>>[CH2:24]([O:26][C:27](=[O:36])[CH2:28][S:29][C:30]1[S:34][C:33]([NH:35][C:10](=[O:12])[C:9]2[CH:13]=[C:14]([O:16][C@@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[CH:15]=[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:23][CH:22]=3)[CH:8]=2)=[N:32][CH:31]=1)[CH3:25]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(F)cc2)cc(C(=O)O)c1
Reactant: CCOC(=O)CSc1cnc(N)s1
Product: CCOC(=O)CSc1cnc(NC(=O)c2cc(Oc3ccc(F)cc3)cc(O[C@@H](C)COC)c2)s1

Procedure:
The title compound was prepared from 3-(4-fluoro-phenoxy)-5-((S)-2-methoxy-1-methyl-ethoxy)-benzoic acid and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester following general procedure A
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[CH2:11]O.[Cl:13]CCl>S(Cl)(Cl)=O>[Cl:13][CH2:11][C:3]1[C:2]([F:1])=[C:7]([O:8][CH3:9])[CH:6]=[CH:5][C:4]=1[F:10]
Reactant: COc1ccc(F)c(CO)c1F
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1ccc(F)c(CCl)c1F

Procedure:
A solution of 120 mg (0.689 mmol) of 2,6-difluoro-3-methoxyphenyl)methanol from Example 132A in 3 ml of dichloromethane and 1 ml of thionyl chloride was stirred at room temperature overnight. The solvent was evaporated off under reduced pressure and the residue was purified by flash chromatography using a prepacked silica gel cartridge (eluent:cyclohexane-ethyl acetate 10:1 to 1:1), which gave 50 mg (38% of theory) of the target compound.
Reaction SMILES: C([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:24][C@H:23]([C:25](OC)=[O:26])[C@@H:22]([NH:29][C:30](=[O:52])[C@H:31]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=2)[NH:32][C:33]([O:35]CC2C=CC=CC=2)=O)[C@H:20]1[OH:21])(=O)C1C=CC=CC=1.[CH2:53]([NH2:57])[CH2:54][CH2:55][CH3:56]>CO>[CH2:53]([NH:57][C:25](=[O:26])[C@H:23]1[O:24][C@@H:19]([N:14]2[CH:13]=[N:12][C:11]3[C:15]2=[N:16][CH:17]=[N:18][C:10]=3[NH2:9])[C@H:20]([OH:21])[C@@H:22]1[NH:29][C:30](=[O:52])[C@H:31]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=1)[NH:32][C:33](=[O:35])[NH:14][CH2:19][CH2:20][CH2:22][CH3:23])[CH2:54][CH2:55][CH3:56]
Reactant: COC(=O)[C@H]1O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@H](O)[C@@H]1NC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)OCc1ccccc1
Reactant: CCCCN
Solvent: CO
Product: CCCCNC(=O)N[C@@H](Cc1ccc(OC)cc1)C(=O)N[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1C(=O)NCCCC

Procedure:
A mixture of methyl 1-(6-benzoylamino-9H-purin -9-yl)-1,3-dideoxy-3-(N-benzyloxycarbonyl-O-methyl-L-tyrosylamino)-β-D-ribofuranuronate prepared in Example 56 (355 mg), n-butylamine (5 ml) and methanol (5 ml) was refluxed for 9 hours. The mixture was evaporated to dryness and the residue was triturated in diethyl ether to give N-n-butyl-1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-(N-n-butylcarbamoyl-O-methyl-L-tyrosylamino)-β-D-ribofuranuronamide (208 mg), mp. 111°-115° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>CN(C=O)C.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][N:10]([CH2:20][C:21]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:22])[C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnc2[nH]ccc2c1
Reactant: O=C(CBr)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cn1ccc2cc([N+](=O)[O-])cnc21)Oc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 13.7 %

Procedure:
To a solution of 5-nitro-1H-pyrrolo[2,3-b]pyridine (0.200 g, 1.226 mmol) and anhydrous potassium carbonate (254.2 mg, 1.839 mmol) in anhydrous DMF (6.0 mL) at room temperature was added phenyl 2-bromoacetate (0.755 mg, 3.678 mmol). After 20 h stirring at room temperature, additional phenyl 2-bromoacetate (1.256 g, 6.13 mmol) was added and the mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with methylene chloride (70 mL), quenched with an aqueous pH 7 phosphate buffer solution (30 mL). The aqueous layer was extracted with methylene chloride (3×50 mL). The combined organic extracts were then successively washed with an aqueous pH 7 phosphate buffer solution (50 mL) and brine (50 mL), dried over MgSO4, filtered, and concentrated. The crude residue was purified by C18 reverse phase chromatography (H2O:CH3CN eluant gradient) to give phenyl 2-(5-nitro-1H-pyrrolo[2,3-b]pyridin-1-yl)acetate (C-7) as a beige solid (50.0 mg, 13% yield). MS (M+1): m/e 298.
Reaction SMILES: C([O-])(=O)C.[NH4+].[CH2:6]([N:13]1[CH2:18][CH:17]([CH2:19][CH3:20])[C:16](=O)[CH:15]([CH2:22][CH3:23])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([BH3-])#[N:25].[Na+]>CO>[NH2:25][CH:16]1[CH:17]([CH2:19][CH3:20])[CH2:18][N:13]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:14][CH:15]1[CH2:22][CH3:23]
Reactant: CCC1CN(Cc2ccccc2)CC(CC)C1=O
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC1CN(Cc2ccccc2)CC(CC)C1N
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Ammonium acetate (10 g, 130 mmol) was added to the stirred solution of 1-benzyl-3,5-diethyl-4-piperidone (3.5 g, 14.3 mmol) in methanol (50 ml) and stirring was continued for 4 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (0.45 g, 7.14 mmol) was added to it. Cooling was removed after 10 min. and resulting mixture was stirred for 10 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 2) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1M sodium hydroxide solution (pH 10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to furnish 4-amino-1-benzyl-3,5-diethylpiperidine.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[Cl-].[C:17]([CH2:20][CH2:21][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:19])=[O:18].O1CCCC1.CC(C)([O-])C.[K+]>O>[O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C:8]1[CH:15]=[CH:14][C:11](/[CH:12]=[CH:21]/[CH2:20][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1
Reactant: O=C(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(-n2ccccc2=O)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C/C=C/c1ccc(-n2ccccc2=O)cc1
Temperature: -50 °C
Reaction time: 10 h
Yield: 77 %

Procedure:
3.00 g of 4-(1,2-dihydro-2-oxo-1-pyridyl)benzaldehyde and 6.15 of β-carboxyethyltriphenyl phosphonium chloride were suspended into 30 ml of tetrahydrofuran, cooled to -50° C. and stirred. 20 ml of a tetrahydrofuran solution of 3.72 g of potassium-tert-butoxide was dropped and the temperature was gradually raised to 0° C. After 10 hours, iced water was added and the aqueous layer was washed with ether. The aqueous layer was adjusted to about pH 3 with concentrated hydrochloric acid, and deposited crystals were collected by filtration to obtain 2.96 g of the above-captioned compound as pale brown yellow powder (yield: 77%). Melting point (°C.): 218.5-221.5
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([CH:16]=O)[CH:3]=1.C([O-])(=O)C.[NH4+:22]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:14][CH:15]=1)[N:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:22]=[CH:16]2
Reactant: [NH4+]
Reactant: CCOC(=O)C(=O)Nc1ccc(Cl)cc1C=O
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCOC(=O)c1ncc2cc(Cl)ccc2n1
Temperature: 115 °C
Yield: 87.3 %

Procedure:
To a solution of ethyl 2-(4-chloro-2-formyl-anilino)-2-oxo-acetate (0.14 g, 0.55 mmol, 1 eq) in 5.5 mL of acetic acid was added ammonium acetate (0.42 g, 5.4 mmol, 10 eq). After heating at 115° C. for 1 h, the mixture was concentrated then diluted with H2O and extracted with ethyl acetate. The organic layer was concentrated and the residue was purified on silica gel column chromatography (hex:EtoAc 3:2) to give ethyl 6-chloroquinazoline-2-carboxylate (0.11 g, 0.48 mmol, 88%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:8])[C:6]=1[Br:7].C([Li])CCC.CN([CH:17]=[O:18])C>C(OCC)C>[Br:7][C:6]1[C:5]([Br:8])=[CH:4][S:3][C:2]=1[CH:17]=[O:18]
Reactant: CN(C)C=O
Reactant: Brc1csc(Br)c1Br
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1scc(Br)c1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.4 %

Procedure:
A solution of 2,3,4-tribromothiophene (2.56 g, 0.0080 mol) in 20 mL of diethyl ether was cooled to -78° C. and then n-butyllithium (5.0 mL, 1.6M) in hexanes was added slowly from an addition funnel. When the addition was complete, the reaction mixture was stirred for 15 minutes. Then DMF (0.88 g, 1.2 mol) was added in one portion. The reaction mixture was gradually warmed to room temperature and was left to stir overnight. The reaction was quenched with aqueous ammonium chloride solution and extracted twice with diethyl ether. The organic extracts were combined, washed with two small portions of water and then brine and dried (MgSO4). The solution was filtered and concentrated, and the residue was purified on flash silica gel with 2.5% diethyl ether-hexanes to provide 1.1 g of 3,4-dibromothiophene-2-carboxaldehyde as an off-white solid. The above sequence was repeated as above except that the n-butyllithium was cooled to -78° C. and then was added to the thiophene solution by cannulation. The reaction mixture was stirred for 2 h before DMF was added. The reaction was worked up as before and the crude product was recrystallized from ether to give 0.9 g of product. A third preparation was also done. A solution of 2,3,4-tribromothiophene (4.8 g, 0.015 mol) in 20 mL of diethyl ether was cooled to -78° C. and then n-butyllithium (10.0 mL, 1.6M) was added slowly from an addition funnel. When the addition was complete, the reaction mixture was stirred for 15 minutes. Then DMF (1.82 g, 0.025 mol) was added in one portion. The reaction mixture was gradually warmed to room temperature, and was left to stir overnight. The reaction was quenched with aqueous ammonium chloride solution and extracted twice with diethyl ether. The organic extracts were combined, washed with two small portions of water and then brine and dried (MgSO4). The solution was filtered and concentrated, and the residue was purified on flash silica gel with 2.5% diethyl ether-hexanes. The product was combined with the previous batches of 3,4-dibromothiophene-2-carboxaldehyde and recrystallized from diethylether to give 3.7 g of 3,4-dibromothiophene-2-carboxaldehyde, A8, whose NMR in CDCl3 supported the desired product structure. ##STR48##
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[C:6]([CH2:17][CH3:18])[N:5]=[CH:4][N:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].CCN(C(C)C)C(C)C>O1CCOCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:2]2[C:7]([C:8]#[C:9][C:10]3[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[C:6]([CH2:17][CH3:18])[N:5]=[CH:4][N:3]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCc1ncnc(Cl)c1C#Cc1ccc(N)nc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ncnc(N2CCN(C(=O)OC(C)(C)C)CC2)c1C#Cc1ccc(N)nc1
Temperature: 80 °C
Yield: 91.3 %

Procedure:
The title compound is synthesized according to general procedure GP7 (method 2) starting from 5.0 g (19.3 mmol) 4-chloro-6-ethyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidine and 4.32 g (23.2 mmol) piperazine 1-carboxylic acid tert-butyl ester using 9.86 mL (57.9 mmoL) DIPEA in 50 mL dioxane. The reaction mixture is stirred at 80° C. over night. The solvent is removed under reduced pressure. The residue is taken up in water extracted three times with ethylacetate. The combined organic layers are dried over MgSO4 filtered off and the solvent is removed under reduced pressure. The residue is purified via NP-chromatography (DCM/MeOH 75/25 as eluent) yielding 7.2 g (92%) of the desired product, which is used without further purification for the next step.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:28])[CH2:9][NH:10][C:11]([C@@:13]2([CH3:27])[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[N:14]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:12])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].[F:33][C:34]([F:48])([F:47])[C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]O)=[CH:37][CH:36]=1>C(#N)C.O>[CH3:18][C:15]1([CH3:19])[N:14]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[C@@:13]([CH3:27])([C:11](=[O:12])[NH:10][CH2:9][C:8](=[O:28])[C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][C:38]3[CH:37]=[CH:36][C:35]([C:34]([F:33])([F:47])[F:48])=[CH:40][CH:39]=3)=[C:3]([C:29]([F:31])([F:32])[F:30])[CH:4]=2)[CH2:17][O:16]1
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(C)C(=O)NCC(=O)c1ccc(O)c(C(F)(F)F)c1
Reactant: OCCCCCc1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(C)C(=O)NCC(=O)c1ccc(OCCCCCc2ccc(C(F)(F)F)cc2)c(C(F)(F)F)c1
Yield: 31 %

Procedure:
The title compound was prepared from (R)-tert-butyl 4-(2-(4-hydroxy-3-(trifluoromethyl)phenyl)-2-oxoethylcarbamoyl)-2,2,4-trimethyloxazolidine-3-carboxylate (0.25 mmol, 1.0 equiv) and 5-(4-(trifluoromethyl)phenyl)pentan-1-ol (0.25 mmol, 1.0 equiv) according to the general procedure in 31% yield. HPLC retention time on a C18 column (30×4.6 mm, 3.5 V) was 3.26 min with gradient 50-95% acetonitrile-H2O (0.1% TFA) in 3.5 min as mobile phase. MS (ESI, M+H+)=675.6.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:26]=[CH:27][C:28]([O:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[N:29][CH:30]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])[C:25]1[CH:30]=[N:29][C:28]([O:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:27][CH:26]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Brc1ccc(OC2CCOCC2)nc1
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OC2CCOCC2)nc1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 5-bromo-2-(tetrahydro-pyran-4-yloxy)-pyridine (Intermediate 20) in analogy to Example 1a): MS (ISN): 479.1 and 481.2 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[C:16]([OH:22])=[C:15]([O:23]C)[CH:14]=3)[O:10][N:9]=2)=[C:6]([CH3:25])[C:5]([Cl:26])=[C:4]([CH3:27])[N:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].N1C=CC=CC=1.Cl>CN1C(=O)CCC1>[Cl:1][C:2]1[C:7]([C:8]2[N:12]=[C:11]([C:13]3[CH:14]=[C:15]([OH:23])[C:16]([OH:22])=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=3)[O:10][N:9]=2)=[C:6]([CH3:25])[C:5]([Cl:26])=[C:4]([CH3:27])[N:3]=1
Reactant: COc1cc(-c2nc(-c3c(Cl)nc(C)c(Cl)c3C)no2)cc([N+](=O)[O-])c1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: Cc1nc(Cl)c(-c2noc(-c3cc(O)c(O)c([N+](=O)[O-])c3)n2)c(C)c1Cl
Temperature: 60 °C
Yield: 81.1 %

Procedure:
To an ice-cooled solution of 4-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1,2,4-oxadiazol-5-yl)-2-methoxy-6-nitrophenol (2.40 g, 5.84 mmol) in NMP (19 mL) was added aluminium chloride (0.977 g, 7.33 mmol) followed by addition of pyridine (1.93 mL). The reaction mixture was heated to 60° C. for 1 hour. It was cooled to room temperature and poured into 2 N HCl-solution (ca. 40 mL). The precipitate was filtered off, washed with water and dried under vacuum. Recrystallization from acetic acid yielded 1.88 g (81%) of 5-[3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol.