Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N:16]3[C:20](=[O:21])[NH:19][C:18]([CH:22]4[CH2:25][CH2:24][CH2:23]4)=[N:17]3)=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:22]1([C:18]2[NH:19][C:20](=[O:21])[N:16]([C:12]3[CH:11]=[CH:10][C:9]([O:8][C:6]4[CH:5]=[CH:4][N:3]=[C:2]([C:30]5[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=5)[CH:7]=4)=[C:14]([CH3:15])[N:13]=3)[N:17]=2)[CH2:25][CH2:24][CH2:23]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1nc(-n2nc(C3CCC3)[nH]c2=O)ccc1Oc1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1nc(-n2nc(C3CCC3)[nH]c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 100 °C
Yield: 16.3 %

Procedure:
A suspension of 1-(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-cyclobutyl-1H-1,2,4-triazol-5(4H)-one (0.300 g, 0.838 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.250 g, 1.202 mmol), Cs2CO3 (0.600 g, 1.842 mmol) and Pd(PPh3)4 (0.050 g, 0.043 mmol) in acetonitrile (20 mL) was heated at 100° C. under argon for 2 h. The solvent from the reaction mixture was completely evaporated and the residue partitioned between DCM (50 mL) and water (50 mL). The organic layer was separated and the aqueous layer saturated with solid sodium chloride and extracted with DCM (2×20 mL). The combined organics were dried, concentrated, subjected to silica gel chromatography (0-100% THF/EtOAc) to provide 3-cyclobutyl-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one (0.055 g, 15%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.97 (s, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.26 (s, 1H), 7.96 (s, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.20 (d, J=2.4 Hz, 1H), 6.64 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 3.44 (m, 1H), 2.33 (s, 3H), 2.26 (m, 4H), 2.04 (m, 1H), 1.90 (m, 1H); MS (ESI) m/z: 404.2 (M+H+).
Reaction SMILES: [SH:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:13][C:14]([CH3:16])=[O:15]>>[C:14]([CH2:16][S:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1)(=[O:15])[CH3:13]
Reactant: Sc1nnn[nH]1
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)CSc1nnn[nH]1
Reaction time: 2 h

Procedure:
5-Mercapto-1,2,3,4-tetrazole (1 g), potassium carbonate (2 g) and β-chloroacetone (1.4 g) are added to acetone (50 ml) and the solution is refluxed with stirring for 2 hours. The reaction mixture is concentrated to dryness under reduced pressure and the residue is dissolved in chloroform. Insolubles are filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (Kieselgel 60, eluant: benzene-ether (10:1) to obtain 5-acetylmethylthio-1,2,3,4-tetrazole (0.4 g) as colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[C:10]1([S:20]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH2:33][CH2:34][O:35][S:36]([C:39]4[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=4)(=[O:38])=[O:37])[CH:30]=3)[NH:25][N:24]=2)(=[O:22])=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:25]1[C:26]2[C:31](=[CH:30][C:29]([O:32][CH2:33][CH2:34][O:35][S:36]([C:39]3[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=3)(=[O:38])=[O:37])=[CH:28][CH:27]=2)[C:23]([S:20]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)(=[O:21])=[O:22])=[N:24]1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)cc1
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3Cc2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
3-Chlorobenzylbromide (0.90 mL, 6.8 mmol) was added to a stirring suspension of toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (3.24 g, 6.20 mmol) and cesium carbonate (2.21 g, 6.78 mmol) in acetone (80 mL). The mixture was stirred at ambient temperature under nitrogen for 2 hours. It was then poured into excess water and extracted with chloroform. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 30-35% ethyl acetate in hexane. Drying at 65° C. in vacuo for 30 minutes gave toluene-4-sulfonic acid 2-[1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazol -5-yloxy]-ethyl ester as a dark yellow foam (2.55 g, 63.6%); Mass Spectrum (+EI, [M+H]+) m/z 647. 1HNMR (500 MHz, DMSO-d6): δ8.73-8.75 (m, 1H), 8.55-8.57 (m, 1H), 8.27 (d, 1H, J=8.30 Hz), 8.01-8.04 (m, 1H), 7.67-7.75 (m, 4H), 7.56-7.63 (m, 2H), 7.17-7.27 (m, 5H), 7.05-7.07 (m, 2H), 6.98 (dd, 1H, J=9.28 Hz and 2.32 Hz), 5.71 (s, 2H), 4.31-4.33 (m, 2H), 4.15-4.17 (m, 2H), 2.17 ppm (s, 3H). Elemental Analysis for C33H27ClN2O6S2: Calcd: C, 61.25; H, 4.21; N, 4.33; Found: C, 60.93; H, 4.22; N, 4.21.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][NH2:9].[NH2:10][C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[C:15]=2[C:14]([NH2:27])=[C:13]2[C:28](=[O:32])N[C:30](=[O:31])[C:12]=12.N>>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][N:9]1[C:28](=[O:32])[C:13]2[C:12](=[C:11]([NH2:10])[C:24]3[C:23](=[O:25])[C:22]4[C:17]([C:16](=[O:26])[C:15]=3[C:14]=2[NH2:27])=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:30]1=[O:31]
Reactant: Nc1c2c(=O)[nH]c(=O)c2c(N)c2c(=O)c3ccccc3c(=O)c12
Reactant: COCCOCCCN
Agent: N
Product: COCCOCCCn1c(=O)c2c(N)c3c(=O)c4ccccc4c(=O)c3c(N)c2c1=O
Temperature: 40 °C
Yield: 126.6 %

Procedure:
477.2 g of 3-(2-methoxyethoxy)propylamine are charged to a 750 ml sulfonating flask equipped with paddle stirrer and heated to 40° C. With stirring, 141.2 g of 1,4-diaminoanthraquinone-2,3-dicarboximide are added over 11/4 hours. The ensuing reaction is slightly exothermic, with evolution of NH3. The reaction mixture is heated to 40° C. and further stirred at this temperature for 2 hours. The suspension is then cooled to 20° C. and stirred for a further hour at this temperature and filtered with suction. The filter cake is washed with 300 ml of methanol and then with 300 ml of water, affording 246.3 g of N-[3-(2-methoxyethoxy)propyl]-1,4-diaminoanthraquinone-2,3-dicarboximide with a solids content of 74.7%, corresponding to 180.1 g of this compound (100%). After optional replenishment with fresh 3-(2-methoxyethoxy)propylamine, the mother liquor can be re-used repeatedly.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[C:7](O)[N:6]=1)=[O:4].P(Cl)(Cl)([Cl:16])=O>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[C:7]([Cl:16])[N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(C#N)c(O)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C#N)c(Cl)n1

Procedure:
5-Cyano-6-hydroxy-pyridine-2-carboxylic acid methyl ester is treated with phosphorus oxychloride in dimethylformamide in accordance with known methods to give 6-chloro-5-cyano-pyridine-2-carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:19]=[C:18]([N:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])[C:17]2[C:12](=[C:13]([OH:28])[CH:14]=[CH:15][CH:16]=2)[N:11]=1.[Na].[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38]Cl)[CH2:32][CH2:31]1>C(O)C.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:19]=[C:18]([N:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH3:21])[C:17]2[C:12](=[C:13]([O:28][CH2:38][CH2:37][CH2:36][N:33]3[CH2:34][CH2:35][O:30][CH2:31][CH2:32]3)[CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: ClCCCN1CCOCC1
Reactant: Cc1cc(F)ccc1Nc1nc(N(C)c2ccccc2)c2cccc(O)c2n1
Agent: [Na]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1cc(F)ccc1Nc1nc(N(C)c2ccccc2)c2cccc(OCCCN3CCOCC3)c2n1
Reaction time: 0.25 h
Yield: 69.5 %

Procedure:
2-(2-Methyl-4-fluorophenylamino)-4-(N-methylphenylamino)-8-hydroxyquinazoline (1.6 g, 4.3 mmol) was suspended in ethanol (25 ml) and to the stirred suspension was added a solution of sodium (0.1 g, 4.3 mmol) in ethanol (15 ml). Stirring was continued for 15 minutes and the mixture evaporated to dryness. The residue was dissolved in toluene (50 ml) and heated to reflux temperature. To this refluxing solution was added a freshly prepared solution of 3-morpholinopropyl chloride base (from 1.28 g, 6.4 mmol of hydrychloride salt) in toluene (20 ml). Refluxing was continued overnight and after cooling the mixture was washed with sodium carbonate solution and water, dried and evaporared. The residual oil was chromatographed on silica gel using CH2Cl2 as eluting solvent. After evaporation of the relevent fractions the residue was crystallised from diethyl ether/pentane to give the title compound (1.5 g, 71%) m.p. 133°-134°.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6](/[C:8](=[CH:11]/[C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][C:20]=2[F:21])[NH:17][N:16]=[C:15]3[CH3:22])/[C:9]#[N:10])=O)=[CH:4][CH:3]=1.[NH2:25][C:26]([CH:30]([F:32])[F:31])=[CH:27][C:28]#[N:29].C(O)(=O)C>CC(O)C>[F:31][CH:30]([F:32])[C:26]1[NH:25][C:6]([C:5]2[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=2)=[C:8]([C:9]#[N:10])[CH:11]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][C:20]=2[F:21])[NH:17][N:16]=[C:15]3[CH3:22])[C:27]=1[C:28]#[N:29]
Reactant: N#CC=C(N)C(F)F
Reactant: Cc1n[nH]c2cc(F)c(/C=C(\C#N)C(=O)c3ccc(F)cc3)cc12
Solvent: CC(=O)O
Solvent: CC(C)O
Product: Cc1n[nH]c2cc(F)c(C3C(C#N)=C(c4ccc(F)cc4)NC(C(F)F)=C3C#N)cc12
Reaction time: 6 h

Procedure:
A mixture of 200 mg (0.569 mmol) (2E)-2-(4-fluorobenzoyl)-3-(6-fluoro-3-methyl-1H-indazol-5-yl)-prop-2-enenitrile (Example 5A) and 69 mg (0.569 mmol) 3-amino-4,4-difluorobut-2-enenitrile [obtainable by Thorpe reaction of acetonitrile with 2,2-difluoroacetonitrile, cf. Org. React. 15, 1 (1967), ibid. 31, 1 (1984)] in 2-propanol (1 ml) was stirred at reflux for 12 h. Then, acetic acid (1.5 ml) was added, and stirring at reflux was continued for 6 h. Upon cooling, the mixture was concentrated under reduced pressure, and the residue was directly purified by preparative RP-HPLC (methanol/water+0.1% TFA gradient, final mixture 80:20 v/v) to yield 36 mg (15% of th.) of the racemic title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[CH2:24][CH2:23][NH:22][CH2:21][C:20]=5[N:25]=4)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[C:5]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:4][C:3]=1[OH:31].[OH:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1>>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[CH2:24][CH2:23][N:22]([CH2:37][C:36]6[CH:39]=[CH:40][C:33]([OH:32])=[CH:34][CH:35]=6)[CH2:21][C:20]=5[N:25]=4)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[C:5]([CH2:26][C:27]([F:28])([F:29])[F:30])=[CH:4][C:3]=1[OH:31]
Reactant: O=Cc1ccc(O)cc1
Reactant: Oc1cc(CC(F)(F)F)c(-c2ccc3c(-c4nc5c([nH]4)CCNC5)n[nH]c3c2)cc1F
Product: Oc1ccc(CN2CCc3[nH]c(-c4n[nH]c5cc(-c6cc(F)c(O)cc6CC(F)(F)F)ccc45)nc3C2)cc1

Procedure:
The title compound was prepared from 2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-5-(2,2,2-trifluoro-ethyl)-phenol (100 mg, 0.21 mmol) and 4-hydroxybenzaldehyde (56.6 mg, 0.46 mmol) using the method of Example 51. The crude material was purified initially over silica and finally by Prep TLC (Mobile Phase: 10% MeOH-DCM) to afford the title compound as an off white solid in 24.4% yield, 28 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9](OC3CCOCC3)[C:10]=2[N:11]=1.[O:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1.CC(C)([O-])C.[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:25][CH:22]3[CH2:23][CH2:24][O:19][CH2:20][CH2:21]3)[C:10]=2[N:11]=1
Reactant: NC1CCOCC1
Reactant: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1ccc2ncnc(NC3CCOCC3)c2n1
Temperature: 25 °C
Yield: 40.8 %

Procedure:
A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.05 g, 0.250 mmol), tetrahydro-2H-pyran-4-amine (0.029 ml, 0.275 mmol), PdCl2(dppf)-CH2Cl2Adduct (2.041 mg, 2.500 μmol) and sodium tert-butoxide (0.048 g, 0.500 mmol) in dioxane (1.250 ml) was refluxed for 3 hours. After cooling to room temperature, the reaction mixture was filtered through a Celite pad and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=2:1) to give 6-chloro-N-(tetrahydro-2H-pyran-4-yl)pyrido[3,2-d]pyrimidin-4-amine (0.027 g, 41%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.Cl.[CH:17]([NH:20][OH:21])([CH3:19])[CH3:18]>>[CH2:13]([NH:12][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:7]=[C:2]([N:20]([CH:17]([CH3:19])[CH3:18])[OH:21])[N:3]=1)[CH2:14][CH3:15]
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Reactant: CC(C)NO
Agent: Cl
Product: CCCNc1nc(NCCC)nc(N(O)C(C)C)n1
Yield: 61 %

Procedure:
2-Chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) and N-isopropyl-hydroxylamine hydrochloride were reacted as described in Example 13 to yield N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-N-isopropyl-hydroxylamine (LV) (61% yield). ESI-MS (m/z): 269 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)=[O:19])=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[C:39](B3OC(C)(C)C(C)(C)O3)[CH:38]=[CH:37][N:36]=2)[CH2:31][CH2:30]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH3:28][N:29]1[CH2:30][CH2:31][N:32]([C:35]2[CH:40]=[C:39]([C:2]3[CH:7]=[CH:6][C:5]([S:8]([N:11]4[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][O:21][CH:22]5[CH2:27][CH2:26][CH2:25][CH2:24][O:23]5)=[O:19])=[CH:12]4)(=[O:10])=[O:9])=[CH:4][CH:3]=3)[CH:38]=[CH:37][N:36]=2)[CH2:33][CH2:34]1
Reactant: O=C(/C=C/c1ccn(S(=O)(=O)c2ccc(Br)cc2)c1)NOC1CCCCO1
Reactant: CN1CCN(c2cc(B3OC(C)(C)C(C)(C)O3)ccn2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CN1CCN(c2cc(-c3ccc(S(=O)(=O)n4ccc(/C=C/C(=O)NOC5CCCCO5)c4)cc3)ccn2)CC1
Temperature: 100 °C
Yield: 64.3 %

Procedure:
(E)-3-[1-(4-Bromo-benzenesulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (6.8 g) and 1-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-piperazine (5.0 g) are dissolved in DME (300 mL). Under an inert gas atmosphere are added (Ph3P)3PdCl2 (2.1 g) and 2M Na2CO3-solution (44 mL). The mixture is heated to 100° C. for 2.5 h. After filtration and extraction, the crude product from the organic phase is purified by silica gel flash chromatography. By means of chloroform/EtOH (30:1-19:1). 5.3 g of the title compound are obtained as brownish oil.
Reaction SMILES: [CH3:1][NH:2][S:3](Cl)(=[O:5])=[O:4].[NH2:7][C:8]1[C:9]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=O)=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2.[BH4-].[Na+]>N1C=CC=CC=1>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH:18]2[C:9]3[C:8](=[C:17]4[C:12](=[CH:11][CH:10]=3)[CH2:13][CH2:14][CH2:15][NH:16]4)[NH:7][S:3](=[O:5])(=[O:4])[N:2]2[CH3:1])=[CH:21][CH:22]=1
Reactant: CNS(=O)(=O)Cl
Reactant: Nc1c(C(=O)c2ccc(F)cc2)ccc2cccnc12
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1C(c2ccc(F)cc2)c2ccc3c(c2NS1(=O)=O)NCCC3
Temperature: 25 °C
Reaction time: 18 h
Yield: 1.8 %

Procedure:
N-methylsulfamoyl chloride 213 (729.9 mg, 5.63 mmol) was added to a solution of (8-amino-quinolin-7-yl)-(4-fluoro-phenyl)-methanone 367 (500 mg, 1.88 mmol) in pyridine (20 ml) and the mixture was stirred at room temperature for 18 h. NaBH4 (213 mg, 5.63 mmol) was added and stirring was continued at room temperature for 16 h. The reaction was quenched by the addition of water (20 ml) and the aqueous phase was extracted with EtOAc (30 ml). The organic phase was washed with brine (15 ml), dried (Na2SO4) and concentrated n vacuo. The crude residue was purified by column chromatography with heptane/EtOAc as the eluent to give the title compound (12 mg, 2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:5][CH:4]=1.[N+:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])([O-:21])=[O:20].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:10][C:11](=[O:12])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:22]([N+:19]([O-:21])=[O:20])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:7][CH:8]=1
Reactant: COc1ccc(/C=C/C(=O)c2ccccc2)cc1
Reactant: CCOC(=O)C[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(CC(=O)c1ccccc1)c1ccc(OC)cc1)[N+](=O)[O-]
Yield: 92.5 %

Procedure:
A solution of (2E)-3-(4-methoxyphenyl)-1-phenylprop-2-en-1-one (5 g, 20.98 mmol) and ethyl nitroacetate (2.32 ml, 20.98 mmol) in triethylamine (8.77 ml, 62.94 mmol) was stirred at 75° C. for 4 h. Ethyl acetate (500 ml) was added and the solution obtained was washed with HCl 1N (4×250 ml), dried over Na2SO4 and evaporated under reduced pressure, to obtain 7.21 g of ethyl 3-(4-methoxyphenyl)-2-nitro-5-oxo-5-phenylpentanoate.
Reaction SMILES: C([CH2:3][O:4][C:5](=[O:23])[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[N:8][C:7]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)#N.C(N(CC)CC)C>CO>[CH3:3][O:4][C:5](=[O:23])[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[N:8][C:7]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1
Reactant: Cc1ccc(C(=O)OCC#N)c(Nc2cccc([N+](=O)[O-])c2)n1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C)nc1Nc1cccc([N+](=O)[O-])c1
Yield: 97.5 %

Procedure:
A mixture of 6-methyl-2-(3-nitrophenylamino)nicotinic acid cyanomethyl ester (15.44 g, 49.43 mmol) and triethylamine (1.00 g, 9.89 mmol) in dry methanol (160 ml) was heated under reflux overnight. After cooling, crystals were collected by filtration, washed with methanol, and dried to give 6-methyl-2-(3-nitrophenylamino)nicotinic acid methyl ester (13.84 g, 97%).
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][CH2:5][CH:6]([NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:11])[CH2:7][OH:8].[OH-].[Na+]>C1COCC1.CO>[C:15]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:14]=[CH:13][C:12]([C:10]([NH:9][CH:6]([CH2:7][OH:8])[CH2:5][CH2:4][C:3]([OH:24])=[O:2])=[O:11])=[CH:17][CH:16]=1
Reactant: COC(=O)CCC(CO)NC(=O)c1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCC(CO)NC(=O)c1ccc(-c2ccccc2)cc1
Reaction time: 2 h
Yield: 72.3 %

Procedure:
A solution of 4-[(Biphenyl-4-carbonyl)-amino]-5-hydroxy-pentanoic acid methyl ester (333 mg, 1.06 mmol) in THF (10 mL) and MeOH (1.27 mL) was added to 1N NaOH (1.27 mL, 1.27 mmol, 1.2 equiv) at room temperature. The mixture was stirred for 2 hours and TLC indicated the reaction was complete. Solvent was removed and the residue was dissolved in water. After adjusting the pH to 4 with 1N HCl, solid precipitated from the solution. The solid was then collected by filtration, washed with water, and dried under vacuum overnight to afford 240 mg of 4-[(Biphenyl-4-carbonyl)-amino]-5-hydroxy-pentanoic acid in 76.7% yield. MS (ESI) m/z 314.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].[CH:18]1([C:21]2[C:26]([CH2:27]O)=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=[C:23]([C:33]3[CH:38]=[CH:37][C:36]([O:39][C:40]([F:43])([F:42])[F:41])=[CH:35][CH:34]=3)[N:22]=2)[CH2:20][CH2:19]1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:27][C:26]2[C:21]([CH:18]3[CH2:20][CH2:19]3)=[N:22][C:23]([C:33]3[CH:34]=[CH:35][C:36]([O:39][C:40]([F:43])([F:41])[F:42])=[CH:37][CH:38]=3)=[CH:24][C:25]=2[C:29]([F:30])([F:32])[F:31])=[CH:11][C:10]=1[CH3:16])([CH3:6])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: OCc1c(C(F)(F)F)cc(-c2ccc(OC(F)(F)F)cc2)nc1C1CC1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2c(C(F)(F)F)cc(-c3ccc(OC(F)(F)F)cc3)nc2C2CC2)cc1C

Procedure:
In analogy to the procedure described in example 43E], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with [2-cyclopropyl-6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-yl]-methanol in the presence of N,N,N′,N′-tetramethylazodicarboxamide and tributylphosphine to give the title compound as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[CH:14]1([N:19]=[C:20]=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15]1>CN(C)C=O>[NH2:12][S:9]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:20]([NH:19][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:21])[CH:7]=[CH:6][C:5]=1[Cl:8])(=[O:11])=[O:10]
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Reactant: O=C=NC1CCCC1
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1c(Cl)ccc(NC(=O)NC2CCCC2)c1O
Yield: 43.3 %

Procedure:
A solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (200 mg, 0.90 mmol) and cyclopentyl isocyanate (100 mg, 0.90 mmol) in 1.5 mL of N,N-dimethyl-formamide was stirred at room temperature for 20 hours. Purification upon column chromatograph on silica gel, eluting with ethyl acetate/hexane (20/80, v/v), followed by recrystallization from diethyl ether and hexane, gave the desired product (130 mg, 43%). LC-MS (m/z) 334.2 (M+).
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:13]=[O:14].[CH:15]1([Mg]Br)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:13]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[OH:14]
Reactant: Br[Mg]C1CCCCC1
Reactant: COc1ccc2oc(C=O)c(Br)c2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc2oc(C(O)C3CCCCC3)c(Br)c2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution (50 mL) of 3-bromo-5-methoxy-1-benzofuran-2-carbaldehyde (2.26 g) synthesized above in tetrahydrofuran was added a 1.0M solution (13.3 mL) of cyclohexylmagnesium bromide in tetrahydrofuran at −78° C., and the mixture was stirred at −78° C. for 30 min then at 0° C. for 1 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, tetrahydrofuran was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give the title object compound (1.82 g, 67%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10](N(OC)C)=[O:11])[CH:5]=[CH:6][CH:7]=1.[F:23][C:24]1[CH:29]=[C:28](I)[CH:27]=[C:26]([CH3:31])[N:25]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10]([C:28]2[CH:27]=[C:26]([CH3:31])[N:25]=[C:24]([F:23])[CH:29]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(I)cc(F)n1
Reactant: CON(C)C(=O)CC(c1cccc(Br)c1)c1ccccc1C
Product: Cc1cc(C(=O)CC(c2cccc(Br)c2)c2ccccc2C)cc(F)n1

Procedure:
In analogy to example 74, step 5, from 3-(3-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 98, step 4) and 2-fluoro-4-iodo-6-picoline (CAS RN: [884494-45-5]) was prepared the title compound as colorless oil, MS (ESI+): m/z=412.1 ([M+H]+, 1Br).