Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([C:18]([O:20]C(C)(C)C)=[O:19])[CH:15]=[CH:14][CH:13]=2)=[N:3]1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[CH:14][CH:13]=2)=[N:3]1
Reactant: CC(C)(C)OC(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: O=C(O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Reaction time: 3 h
Yield: 78.3 %

Procedure:
A mixture of tert-butyl 6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridinecarboxylate (400 mg, 1.1 mmol) and trifluoroacetic acid (10 ml) was stirred under ice cooling condition for 3 hrs. The reaction mixture was combined with diisopropylether to precipitate crystals, which were collected by filtration and recrystallized from methanol-diisopropylether to give the titled compound (245 mg, 73%).
Reaction SMILES: [Br:1][C:2]1[C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[C:10](I)[C:5]=2[S:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Na+].[Na+].[C:38]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])(=[O:41])[CH:39]=[CH2:40]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:12][C:7]1[C:6]2[C:2]([Br:1])=[CH:3][S:4][C:5]=2[C:10](/[CH:40]=[CH:39]/[C:38]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[CH:9][N:8]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Nc1ncc(I)c2scc(Br)c12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)/C=C/c1cnc(N)c2c(Br)csc12
Temperature: 80 °C
Yield: 42.8 %

Procedure:
A solution of Example 21A (2.50 g, 7.04 mmol), PPh3 (0.370 g, 1.41 mmol), and Na2CO3 (1.49 g, 14.1 mmol) in DMF (35 mL) was treated with tert-butyl acrylate (2.00 mL, 14.1 mmol) and palladium(II)acetate (0.158 g, 0.704 mmol). The reaction was heated to 80° C. under an atmosphere of nitrogen for 16 hours. The reaction was cooled to ambient temperature and partitioned between ethyl acetate (100 mL) and brine. The organic phase was washed with brine (2×100 mL), dried (Na2SO4), filtered, and concentrated. The compound was purified by flash chromatography on silica gel using heptane/ethyl acetate (6:1) to (3:1) to provide the desired product (1.70 g, 3.01 mmol). 1HNMR (DMSO-d6, 400MHz) δ 8.24 (s, 1H), 7.94 (s, 1H), 7.62 (d, 1H), 7.17 (br s, 2H), 6.22 (d, 1H), 1.48 (s, 9H); MS m/e 355/357 (M+H)+.
Reaction SMILES: Cl[CH:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[C-:12]#[N:13].[K+]>CN(C=O)C.[OH-].[Na+]>[O:5]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:11]2[CH:2]([C:12]#[N:13])[CH2:3][CH2:4]1
Reactant: ClC1CCOc2ncccc21
Reactant: [C-]#N
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#CC1CCOc2ncccc21
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-chloro-3,4-dihydro-2H-pyrano[2,3-b]pyridine (18.7 mmol) in 60 mL DMF was added KCN (56.1 mmol) and the mixture was stirred at 90° C. overnight. After cooling to RT, the mixture was diluted with aq. 0.5 M NaOH solution and extracted 3 times with EtOAc. The combined organic layers were washed again with aq. 0.5 M NaOH solution and once with brine. The organic phase was dried over MgSO4 and concentrated in vacuo. Purification with CC (KP-SIL™ from Biotage) using Hept/EtOAc (4/1) to EtOAc gives the desired compound as yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([O:28][CH2:29][C:30]2[N:31]=[C:32]([C:35]3[CH:40]=[N:39][CH:38]=[CH:37][N:36]=3)[S:33][CH:34]=2)[CH:27]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:8]1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([O:28][CH2:29][C:30]2[N:31]=[C:32]([C:35]3[CH:40]=[N:39][CH:38]=[CH:37][N:36]=3)[S:33][CH:34]=2)[CH:27]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:9]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:8]1
Reactant: CCOC(=O)CCc1cn(Cc2cc(OC)cc(OCc3csc(-c4cnccn4)n3)c2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(Cn2cc(CCC(=O)O)c(-c3ccccc3)c2)cc(OCc2csc(-c3cnccn3)n2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
A mixture of ethyl 3-[1-[3-methoxy-5-[2-(2-pyrazinyl)-4-thiazolylmethoxy]benzyl]-4-phenyl-3-pyrrolyl]propionate (361 mg), 1N aqueous sodium hydroxide solution (1.5 ml), tetrahydrofuran (3 ml), and ethanol (3 ml) was stirred at room temperature for 4 hours, and 1N hydrochloric acid (1.5 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[1-[3-methoxy-5-[2-(2-pyrazinyl)-4-thiazolylmethoxy]benzyl]-4-phenyl-3-pyrrolyl]propionic acid (338 mg, yield: 99%). This was recrystallized from ethanol-hexane. Melting point: 111–112° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Br:12][C:13]1[CH:14]=[C:15]([N+]([O-])=O)[C:16]([C:19]#[N:20])=[N:17][CH:18]=1.[NH4+].[Cl-]>O.CN(C=O)C>[Br:12][C:13]1[CH:14]=[C:15]([O:8][C:7]2[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][C:6]=2[CH3:9])[C:16]([C:19]#[N:20])=[N:17][CH:18]=1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: Cc1ccnc(C)c1O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccnc(C)c1Oc1cc(Br)cnc1C#N
Reaction time: 0.25 h
Yield: 92.2 %

Procedure:
A flask was charged with 2,4-dimethylpyridin-3-ol (9.0 g, 73.1 mmol) and DMF (80 mL) was added. Sodium hydride (2.03 g, 80.4 mmol) was added and the reaction was stirred for 15 minutes. 5-Bromo-3-nitropicolinonitrile (16.7 g, 73.1 mmol) was added and the reaction was stirred for 25 minutes. The reaction mixture was poured into 600 mL saturated NH4Cl and 600 mL water and then filtered, washed with water and a small amount of hexanes, and dried over high vacuum to provide 5-bromo-3-(2,4-dimethylpyridin-3-yloxy)picolinonitrile (20.5 g, 67.4 mmol, 92.2% yield) as a light tan solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([OH:14])=[O:13].[CH3:15][Si](C=[N+]=[N-])(C)C>CO>[CH3:15][O:13][C:12](=[O:14])[CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[NH:7][CH:6]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)Cc1c[nH]c2ccc(Br)cc12
Solvent: CO
Product: COC(=O)Cc1c[nH]c2ccc(Br)cc12
Yield: 99 %

Procedure:
To a solution of (5-bromo-1H-indol-3-yl)-acetic acid (683 mg, 2.69 mmol) in methanol (6 mL) is added (trimethylsilyl)diazomethane (2.0 M solution in hexanes, approximately 6 mL) over two minutes at room temperature. The yellow mixture is concentrated. The residue is taken up in methanol and is concentrated several times to give of the title compound (710 mg, 99%). ES/MS m/e 266.2 (M−2).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:5]=[N:6][C:7]=1[C:8]#[N:9].[NH2:25][C:26]1[N:31]=[C:30]([CH2:32][N:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[CH:29]=[CH:28][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:20]([O:19][C:18]([NH:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:4]1[CH:3]=[C:2]([NH:25][C:26]2[N:31]=[C:30]([CH2:32][N:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)[CH:29]=[CH:28][CH:27]=2)[C:7]([C:8]#[N:9])=[N:6][CH:5]=1)=[O:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(N)n2)CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Nc2cccc(CN3CCN(C(=O)OC(C)(C)C)CC3)n2)c1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a flask containing tert-butyl {(1S,2R)-2-[(5-bromo-6-cyanopyridin-3-yl)amino]cyclohexyl}carbamate (PrepEx 1.1) (120 mg, 0.30 mmol), tert-butyl 4-[(6-aminopyridin-2-yl)methyl]piperazine-1-carboxylate (89 mg, 0.30 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (29 mg, 0.061 mmol), Pd2(dba)3 (28 mg, 0.031 mmol) and cesium carbonate (198 mg, 0.609 mmol) was added degassed dioxane (3 mL), and the reaction mixture was heated to 100° C. After 16 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and water, and the organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by chromatography on silica gel (0-60% ethyl acetate/hexanes, linear gradient) afforded tert-butyl 4-[(6-{[5-({(1R,2S)-2-[(tert-butoxycarbonyl)amino]cyclohexyl}amino)-2-cyanopyridin-3-yl]amino}pyridin-2-yl)methyl]piperazine-1-carboxylate. MS ESI calc'd for C32H47N8O4 [M+H]+ 607. found 607. 1H NMR (500 MHz, DMSO-d6) δ 8.85 (s, 1H), 7.77 (s, 1H), 7.58 (t, J=7.7 Hz, 1H), 7.52 (s, 1H), 6.94-6.82 (m, 2H), 6.60 (d, J=7.8 Hz, 1H), 6.40 (d, J=7.6 Hz, 1H), 3.74-3.60 (m, 2H), 3.52-3.36 (m, 2H), 3.36-3.24 (m, 4H), 2.34 (s, 4H), 1.75-1.40 (m, 8H), 1.36 (s, 9H), 1.25 (s, 9H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].Cl>[Zn].C1C=CC=CC=1>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][C:2]1([OH:10])[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)[CH3:17]
Reactant: O=C1Cc2ccccc2C1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [Zn]
Solvent: c1ccccc1
Product: CCOC(=O)CC1(O)Cc2ccccc2C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 2-indanone (13.2 g), ethyl bromoacetate (16.7 g), benzene (150 ml) and purified zinc (6.5 g) is stirred and heated at 50° C. Iodine (0.5 g) is added to catalyze the reaction. A rather vigorous reaction sets in after about 30 min. and the heating is discontinued. After the mixture ceases boiling, 4 g of fresh zinc and 10 g of ethyl bromoacetate is added, the reaction mixture is heated at reflux for 2 hr. and allowed to stand overnight at room temperature. The zinc addition-compound is decomposed by adding 200 ml of cold 10% hydrochloric acid. The aqueous layer is separated, extracted twice with benzene, all organic extracts are combined and dried (MgSO4). The filtrate is concentrated and the residue distilled under reduced pressure yielding 2-hydroxyindane-2-acetic acid ethyl ester, bp. 163°-166° C/10 mm.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[CH2:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27].[CH:32]1([CH2:38][NH2:39])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH:32]1([CH2:38][NH:39][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([CH2:22][N:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[C:10]4([CH2:11][O:12][C:13]5[CH:21]=[C:17]6[C:16](=[CH:15][C:14]4=5)[CH2:20][CH2:19][O:18]6)[C:2]3=[O:1])[CH:24]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: NCC1CCCCC1
Reactant: O=C(Cl)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Agent: CN(C)c1ccncc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC1CCCCC1)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Yield: 108.1 %

Procedure:
A suspension of 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid (2.13 g, 5.1 mmol) and N,N-dimethylformamide (0.001 mL, catalytic amount) in anhydrous dichloromethane (30 mL) was treated with oxalyl chloride (4.50 mL, 5.1 mmol). The reaction mixture was stirred at ambient temperature for 3 h. The crude product was concentrated in vacuo to afford 3-(((2′-oxo-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indoline]-1′-yl)methyl)benzoyl chloride as a light yellow solid. A solution of 3-((2′-oxo-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indoline]-1′-yl)methyl)benzoyl chloride (0.27 g, 0.6 mmol), cyclohexanemethylamine (0.17 mL, 1.3 mmol), triethylamine (0.44 mL, 3.2 mmol), and 4-(dimethylamino)pyridine (0.005 g, catalytic amount) in anhydrous dichloromethane (5 mL), was stirred at ambient temperature for 20 h under nitrogen. The reaction mixture was diluted with dichloromethane (10 mL) and aqueous citric acid (10 mL) and the phases were separated. The organic phase was washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography with ethyl acetate in hexanes (0% to 100% gradient) to afford N-(cyclohexylmethyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide (0.33 g, 65%) as a colourless solid: 1H NMR (300 MHz, CDCl3) δ7.80 (s, 1H), 7.63 (d, J=7.4 Hz, 1H), 7.48-7.37 (m, 2H), 7.23-7.15 (m, 2H), 7.08-7.00 (m, 1H), 6.79 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.43 (s, 1H), 6.19-6.09 (m, 1H), 5.08 (d, J=15.7 Hz, 1H), 4.99 (d, J=9.0 Hz, 1H), 4.91 (d, J=15.7 Hz, 1H), 4.72 (d, J=9.0 Hz, 1H), 4.55 (t, J=8.6 Hz, 2H), 3.33-3.23 (m, 2H), 3.07-2.95 (m, 2H), 1.82-1.64 (m, 5H), 1.34-1.13 (m, 4H), 1.07-0.86 (m, 2H); MS (ES+) m/z 509.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:12][C:13](=[O:15])[CH3:14])[S:5][C:6]=1[C:7]1[CH:11]=[CH:10][S:9][CH:8]=1.[Cl:16]N1C(=O)CCC1=O>C(#N)C>[Cl:16][C:8]1[S:9][CH:10]=[CH:11][C:7]=1[C:6]1[S:5][C:4]([NH:12][C:13](=[O:15])[CH3:14])=[N:3][C:2]=1[CH3:1]
Reactant: CC(=O)Nc1nc(C)c(-c2ccsc2)s1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CC(=O)Nc1nc(C)c(-c2ccsc2Cl)s1
Temperature: 25 °C

Procedure:
N-[4-methyl-5-(3-thienyl)-1,3-thiazol-2-yl]acetamide, prepared as in Step I of Example 23 (600 mg; 2.52 mmol; 1 eq) is dissolved in ACN (20 ml) in presence of 100 μl of HClO4 at room temperature. A solution of N-chlorosuccinimide (369.8 mg; 2.77 mmol; 1.10 eq) in ACN (2 ml) is added slowly at room temperature over a period of one hour. Reaction mixture is stirred at room temperature for 1 night before being quenched with water (1 ml). It is then concentrated under vacuo and expected compound extracted with EtOAc, washed with NH4Cl saturated solution, water and dried over MgSO4. After evaporation of the solvents, ACN (5 ml) is added, affording after precipitation, the title compound as a solid (600 mg; 95%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:13][OH:14])=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([CH3:15])[CH:3]=1.[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:13][O:14][CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][O:16]3)=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([CH3:15])[CH:3]=1
Reactant: Cc1cc(Cl)c2cc(C)c(CO)cc2n1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)c2cc(C)c(COC3CCCCO3)cc2n1
Yield: 58.9 %

Procedure:
A solution of (4-chloro-2,6-dimethyl-quinolin-7-yl)-methanol (example 59c, 300 mg, 1.35 mmol), 3,4-dihydro-2H-pyran (342 mg, 4.06 mmol), and pyridinium toluene-4-sulfonate (374 mg, 1.49 mg) in dichloromethane (3 mL) and toluene (3 mL) was stirred at r.t. for 3 d, then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), and evaporated. Flash chromatography (SiO2, hexane/ethyl acetate gradient) afforded the title compound (243 mg, 59%). White solid, ISP-MS: m/e=306.3 ([M+H]+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:19])[N:11]([CH2:15][C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:21]1[C:25](=[O:26])[CH2:24][CH2:23][C:22]1=[O:27].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:10](=[O:19])[N:11]([CH2:15][C:16]([O:18][N:21]2[C:25](=[O:26])[CH2:24][CH2:23][C:22]2=[O:27])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1cccc(OCc2ccccc2)c1=O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(Cn1cccc(OCc2ccccc2)c1=O)ON1C(=O)CCC1=O
Reaction time: 8 h
Yield: 82.2 %

Procedure:
3-Benzyloxy-1-carboxymethylpyrid-2-one (2 g) is dissolved in dimethylformamide (DMF) (25 ml) and to this solution is added N-hydroxysuccinimide (1 g). The resultant solution is cooled and to it is added dicyclohexylcarbodiimide (DCCI) (11.8 g) in DMF (5 ml). The mixture is allowed to stand overnight to give a brown supernatant and a white precipitate. The precipitate is filtered off, washed with a little DMF and then evaporated to dryness under high vacuum. The crude product is dissolved in a minimum volume of dichloromethane and diethyl ether is added to this solution until it becomes cloudy. The solution is then cooled and the resultant precipitate is filtered off and washed with a little diethyl ether to give 3-benzyloxy-1-(succinimidooxycarbonylmethyl)-pyrid-2-one (2.26 g, 82%), m.p. 187°-188° C.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17]CC)=O)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[CH3:21][NH:22][O:23][CH3:24].C([Mg]Cl)(C)C.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Si:1]([O:8][CH:9]1[CH2:10][CH2:11][CH:12]([C:15]([N:22]([O:23][CH3:24])[CH3:21])=[O:17])[CH2:13][CH2:14]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CNOC
Reactant: CCOC(=O)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Agent: CC(C)[Mg]Cl
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CON(C)C(=O)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Ethyl 4-(tert-butyldimethylsilyloxy)cyclohexane-carboxylate (5.73 g, 20.0 mmol) obtained in Step 1 and N,O-dimethylhydroxylamine hydrochloride (2.93 g, 30.0 mmol) were suspended in THF (40 mL), and a 2.0 mol/L solution of isopropylmagnesium chloride in THF (30.0 mL, 60.0 mmol) was added dropwise thereto in a atmosphere of argon at −20° C., followed by stirring at 0° C. for 1 hour. A saturated aqueous solution of ammonium chloride and ethyl acetate were added to the reaction mixture for extraction. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:4) to afford 4-(tert-butyldimethylsilyloxy)-N-methoxy-N-methylcyclo-hexanecarboxamide (6.03 g, 100%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.S(Cl)([Cl:28])=O.O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:28][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:6]1[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=[C:2]([CH3:1])[C:7]=1[CH3:8]
Reactant: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCCCO)c1C
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCCCCl)c1C
Temperature: 0 °C
Yield: 96.2 %

Procedure:
Under a nitrogen atmosphere, a solution of 5-(2,3-dimethyl-5-nitro-6-phenoxy-pyridin-4-ylamino)pentan-1-ol (40.24 g, 114.6 mmol) in dichloromethane (350 mL) was cooled to 0° C. Thionyl chloride (12.5 mL, 172 mmol) was added dropwise, and the reaction was heated at reflux for one hour. The reaction was cooled to 0° C., and water (200 mL) was slowly added followed by solid sodium bicarbonate until the pH of the solution was basic. The solvent was partially removed under reduced pressure, and the aqueous solution was extracted with ethyl acetate (500 mL). The combined organic solutions washed with saturated aqueous sodium bicarbonate (3×50 mL), water (1×50 mL), and brine (2×20 mL), and then dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford a yellow oil, which crystallized overnight. The solid was dried for one hour in a vacuum oven at 70° C. to provide 40.1 g of (5-chloropentyl)-(2,3-dimethyl-5-nitro-6-phenoxy-pyridin-4-yl)amine as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH2:29]([O:31][C:32](=[O:44])[C:33]1[CH:38]=[CH:37][C:36](Cl)=[N:35][C:34]=1[C:40]([F:43])([F:42])[F:41])[CH3:30].C1N2CCN(CC2)C1>>[CH2:29]([O:31][C:32](=[O:44])[C:33]1[CH:38]=[CH:37][C:36]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[N:35][C:34]=1[C:40]([F:41])([F:42])[F:43])[CH3:30]
Reactant: CCOC(=O)c1ccc(Cl)nc1C(F)(F)F
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: C1CN2CCN1CC2
Product: CCOC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)nc1C(F)(F)F

Procedure:
In analogy to Example 62, step 1, 6-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 56, Step 4) was reacted with 6-chloro-2-trifluoromethyl-nicotinic acid ethylester and DABCO (17 h, r.t.) to give the title compound as a white solid. MS (m/e)=633.2 [M+H+]
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([Cl:19])[C:5](=[O:18])[CH2:6][C:7]([CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)(O)[CH2:8][CH2:9][C:10]#[CH:11].C([O-])([O-])=O.[K+].[K+]>CO>[CH2:8]([C:7]1([CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)[O:20][C:3](=[O:2])[CH:4]([Cl:19])[C:5](=[O:18])[CH2:6]1)[CH2:9][C:10]#[CH:11]
Reactant: C#CCCC(O)(CC(=O)C(Cl)C(=O)OC)C1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CCCC1(C2CCCC2)CC(=O)C(Cl)C(=O)O1
Yield: 97.5 %

Procedure:
A slurry of 2-chloro-5-cyclopentyl-5-hydroxy-3-oxo-non-8-ynoic acid methyl ester (6.0 g, 20 mmol) from Step 3 above and K2CO3 (11 g, 80 mmol) in methanol (100 mL) was stirred at 50° C. for 1.5 hours. The reaction was concentrated by rotary evaporation, and then re-dissolved in ethyl acetate. The solution was washed with water, and then saturated Na2CO3. The organic layer was dried over sodium sulfate. After removing the solids by filtration, the organic layer was concentrated by rotary evaporation to yield the desired product (5.24 g, 97% yield).
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[N:4]([CH3:16])[C:5](=[O:15])[N:6]([CH2:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:7]=1.[NH2:18][CH2:19][CH2:20][C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]([CH3:33])([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=1>>[CH3:33][C:26]([O:25][C:24]1[CH:34]=[CH:35][C:21]([CH2:20][CH2:19][NH:18][C:2]2[C:3](=[O:17])[N:4]([CH3:16])[C:5](=[O:15])[N:6]([CH2:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:7]=2)=[CH:22][CH:23]=1)([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN)cc1
Reactant: Cn1c(=O)c(Br)nn(CCCC(F)(F)F)c1=O
Product: CCOC(=O)C(C)(C)Oc1ccc(CCNc2nn(CCCC(F)(F)F)c(=O)n(C)c2=O)cc1

Procedure:
Compound 102 (oil) is prepared from triazine 4a and from intermediate 13a according to synthesis method 1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][N:21]=[CH:20]2>>[NH:22]1[C:23]2[C:19](=[CH:18][CH:17]=[CH:16][C:15]=2[NH:14][C:2]2[N:7]=[C:6]([NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:23]=3[NH:22][N:21]=[CH:20]4)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=2)[CH:20]=[N:21]1
Reactant: CCOC(=O)c1cnc(Cl)nc1Cl
Reactant: Nc1cccc2cn[nH]c12
Product: CCOC(=O)c1cnc(Nc2cccc3cn[nH]c23)nc1Nc1cccc2cn[nH]c12

Procedure:
In like manner to N2,N4-bis(3-hydroxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine, 2,4-dichloro-5-ethoxycarbonylpyrimidine and 7-aminoindazole were reacted to yield N2,N4-bis(7-indazolyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 8.70 (s, 1H), 7.54 (d, 2H J=8.4 Hz), 7.37 (m, 6H), 4.3 (q, 2H, J=7.0 Hz), 1.33 (3H, J=7 Hz); LCMS: ret. time 23.61 min.; purity: 94%; MS (m/e): 415 (MH+).