Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])([O:5][CH2:6][CH3:7])=[O:4].[F:14]N1CC2CCC(C2(C)C)(C)CS1(=O)=O.C(O)(=O)C(O)=O>O1CCCC1>[F:14][C:8]1([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:12][CH2:11][CH2:10][C:9]1=[O:13]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: CC12CCC(CN(F)S(=O)(=O)C1)C2(C)C
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(F)CCCC1=O
Reaction time: 3 h

Procedure:
To a suspension of 1.56 mmol of sodium hydride in 5 ml of tetrahydrofuran are added, at 0° C., 1.3 mmol of 1-carboethoxycyclopentan-2-one and the mixture is stirred for 1 hour at 0° C. Then a solution of 1.4 mmol of (-)-N-fluorocamphor sultam (Example 4) is added dropwise, and stirring is continued for 3 hours at 0° C. The reaction mixture is then poured into 50 ml of 1M oxalic acid and extracted with diethyl ether. The organic phases are washed with 10% NaHCO3 solution and with a saturated solution of NaCl. The resultant mixture is purified over a column of silica gel, affording (+)-1-fluoro-1-carboethoxycyclopentan-2-one in high purity (ee=70%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=1.Br[C:10]1[C:11](=[O:18])[N:12]([CH3:17])[CH:13]=[C:14]([Br:16])[CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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].CN(C=O)C>[Br:16][C:14]1[CH:15]=[C:10]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([OH:8])[N:7]=2)[C:11](=[O:18])[N:12]([CH3:17])[CH:13]=1
Reactant: Nc1cccc(O)n1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: Cn1cc(Br)cc(Nc2cccc(O)n2)c1=O
Temperature: 100 °C
Yield: 19.6 %

Procedure:
A 100 mL round-bottomed flask equipped with a reflux condenser was charged with 6-aminopyridin-2-ol (1.1 g, 10.0 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (2.67 g, 10.0 mmol), cesium carbonate (6.52 g, 20.0 mmol), xantphos (576 mg, 1.0 mmol), Pd2(dba)3 (460 mg, 0.50 mmol), and DMF (35 mL). The system was subject to three cycles of vacuum/argon flush and heated at 100° C. for 3 h. It was then cooled to room temperature and filtered. The filtrate was diluted with DCM (500 mL) and washed with H2O (80 mL×3). The organic layer was dried and concentrated under reduced pressure. The residue solid was purified by silica-gel column-chromatography eluting with DCM/MeOH (30:1 to 15:1) to afford 101a (580 mg, 20%) as yellow solid. MS-ESI: [M+H]+ 296.0
Reaction SMILES: [CH2:1](O)[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH3:10].S(Cl)([Cl:14])=O.N1C=CC=CC=1>O1CCCC1>[CH2:1]([Cl:14])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH3:10]
Reactant: COCCOCCOCCO
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COCCOCCOCCCl
Yield: 90 %

Procedure:
101.16 g (≈0.6 mole) of 3,6,9-trioxadecanol are reacted with 44.6 ml (≈0.6 mole) of thionyl chloride and 51.7 ml (≈0.64 mole) of pyridine in a tetrahydrofuran solution by refluxing for 12 hours to give 3,6,9-trioxadecyl chloride ##STR19## The mixture is cooled and then extracted several times with methyl ethyl ketone (MEK), and the MEK phase is then neutralized with NaHCO3 and dried over Na2SO4. After the MEK has been removed, the residue is distilled under 30 Pa and at 30°-37° C. Yield: 90%.
Reaction SMILES: [NH2:1][C:2]1[S:12][C:5]2[CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:13]([NH2:15])=[O:14].[O-:16][C:17]#[N:18].[Na+]>C(O)(=O)C.O>[CH2:10]([N:7]1[CH2:8][CH2:9][C:4]2[C:3]([C:13]([NH2:15])=[O:14])=[C:2]([NH:1][C:17]([NH2:18])=[O:16])[S:12][C:5]=2[CH2:6]1)[CH3:11]
Reactant: CCN1CCc2c(sc(N)c2C(N)=O)C1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCN1CCc2c(sc(NC(N)=O)c2C(N)=O)C1
Reaction time: 2 h
Yield: 23.3 %

Procedure:
To a stirred mixture of compound F4 (451 mg, 2.00 mmol) in acetic acid (6 mL) at room temperature was added a solution of sodium cyanate (169 mg, 2.60 mmol) in water (2.5 mL) dropwise over 2 min. After addition, the reaction mixture was stirred for another 2 h and then concentrated under reduced pressure. The resulting residue was mixed with saturated aqueous sodium bicarbonate (50 mL) and extracted with methylene chloride (3×150 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with methanol/methylene chloride (15:85) to afford compound M1 as a yellow solid (125 mg, 23%): 1H NMR (300 MHz, DMSO-d6) δ 10.45 (s, 1H), 7.31 (bs, 1H), 6.77 (bs, 3H), 3.41 (s, 2H), 2.73 (d, J=4.8 Hz, 2H), 2.63 (d, J=4.8 Hz, 2H), 2.50-2.45 (m, 2H), 1.06 (t, J=7.0 Hz, 3H). MS (M+H) 269.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[F:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[N:48]=[C:49]=[S:50].NC(N)=S>>[F:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[NH:48][C:49]([N:27]1[C:17]2[N:18]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:20]=[C:15]([C:12]3[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=4)[CH2:30][C:31]4[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=4)=[N:14][CH:13]=3)[C:16]=2[CH2:29][CH2:28]1)=[S:50]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: Fc1ccccc1N=C=S
Agent: NC(N)=S
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=S)Nc3ccccc3F)cn2)cc1
Yield: 117 %

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (80.0 mg, 0.148 mmol) and 2-fluorophenyl isothiocyanate (54.6 μl, 0.445 mmol) instead of o-tolyl isothiocyanate, thiourea was formed in the same manner as Example 1-D-210, to obtain a crude product of 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carbothioic acid (2-fluoro-phenyl)-amide as a brown solid (120 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-222) as a yellow powder (54.5 mg, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:22][CH:23]=1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Reactant: COc1ccc(CNc2ccc(OC)cc2)cc1
Product: COc1ccc(CN(C(=O)C2CCCc3ccc(OC)cc32)c2ccc(OC)cc2)cc1
Yield: 46.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.5 g) and [(4-methoxyphenyl)methyl](4-methoxyphenyl)amine (0.88 g) as starting materials, N-[(4-methoxyphenyl)methyl]-N-(4-methoxyphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.72 g) was obtained. melting point: 89-90° C.
Reaction SMILES: II.Br[C:4]1[CH:5]=[CH:6][C:7](Cl)=[C:8](OC)[CH:9]=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[C:13]([C:8]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:9]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cc(Br)ccc1Cl
Reactant: O=C(Cl)c1ccccc1
Agent: II
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
After 8.7 g (357.06 mmol) of Mg and a small amount of iodine were dissolved in 200 ml of THF, 71.9 g (324.6 mmol) of 5-bromo-2-chloroanisole dissolved in 500 ml of THF was added dropwise to the resulting solution. After addition, the resulting mixture was refluxed for 3 hours to prepare a Grignard reagent which was then cooled to room temperature. After that, the prepared Grignard reagent was added dropwise to 50.2 g (357.06 mmol) of benzoyl chloride and stirred for 5 hours. After a reaction, the reaction solution was washed with water, the solvent was removed, and the obtained product was purified by column chromatography to obtain a benzophenone derivative represented by the following formula (32) as 32.0 g (129.8 mmol, yield of 40%) of a white solid.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[Cl:6][C:7]1[C:8]([CH3:14])=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.P(=O)(O)(O)O.O>ClC1C=CC=CC=1Cl.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[Cl:6][C:7]1[C:8]([CH3:14])=[C:9]([OH:13])[CH:10]=[C:11]2[C:12]=1[CH2:1][CH2:2][C:3]2([CH3:5])[CH3:4]
Reactant: C=CC(=C)C
Reactant: Cc1c(O)cccc1Cl
Agent: O=P(O)(O)O
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: Clc1ccccc1Cl
Solvent: O
Product: Cc1c(O)cc2c(c1Cl)CCC2(C)C
Reaction time: 8 h
Yield: 24.1 %

Procedure:
437 g of isoprene stabilized with 1.3 g of phenothiazine were added dropwise in the course of 6 hours to a solution of 832 g of 3-chloro-2-methyl-phenol, 74.4 g of 85% strength phosphoric acid and 5.8 ml of water in 1.4 liters of o-dichlorobenzene at 110° C. To complete the reaction, stirring was continued overnight at 110° C. The acid phase was separated off and the organic phase was washed until neutral. Fractional distillation gave 296 g of 7-chloro-5-hydroxy-3,3,6-trimethyl-indan; boiling point: 161°-164° C./11 mm Hg; melting point: 109°-109.5° C. ##STR8##
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:9]1[CH:10]=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C(Cl)Cl.[CH:28]1C=C2C(C(O)(O)C(=O)C2=C[CH:29]=1)=O>O1CCCC1.[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.CO>[C:4]([O:3][C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:9]1/[CH:10]=[CH:28]\[CH3:29])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: C/C=C\[C@H]1CCCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 8 h

Procedure:
To a solution of Boc-D-prolinal (0.5 g, 2.5 mmol) in tetrahydrofuran (10 mL) was added ethyltriphenylphosphonium bromide (3.7 g, 10.0 mmol) and cooled to −78° C. Then added dropwise lithium hexamethyldisilazide 1.0 M in THF (12 mL) and continued stirring from −78° C. to rt overnight. Upon completion as determined by TLC (99:1 methylene chloride to methanol with ninhydrin) the mixture was quenched with 20% ammonium chloride solution and extracted with ethyl acetate. The organic washed with brine, dried over sodium sulfate anhydrous and concentrated in vacuo very carefully as the product is volatile. Crude product was purified on silica gel using a 99:1 mixture of methylene chloride to methanol as mobile phase with ninhydrin to develop. Pure fractions were combined and dried to yield tert-butyl-(2R)-2-[(1Z)-prop-1-enyl]pyrrolidine-1-carboxylate. LC-MS m/z (minus t-butyl+1)=156. 1H NMR (CD3OD, 400 Mhz) 5.47-5.41 ppm (m, 1H), 5.34-5.28 (m, 1H), 4.58-4.53 (m, 1H), 3.42-3.34 (m, 3H), 2.14-2.06 (m, 1H), 1.96-1.77 (m, 2H), 1.70-1.58 (m, 3H), 1.42 (s, 9H).
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]3[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:24])([CH3:23])[C:17]=3[CH:25]=2)=[CH:11][CH:10]=[C:9]1[C:26]#[N:27])(C)(C)C.[OH-].[Na+].Cl>C(O)C>[C:26]([C:9]1[N:8]([CH2:7][C:6]([OH:28])=[O:5])[C:12]([C:13]2[CH:14]=[CH:15][C:16]3[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:24])([CH3:23])[C:17]=3[CH:25]=2)=[CH:11][CH:10]=1)#[N:27]
Reactant: CC(C)(C)OC(=O)Cn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)OC(=O)Nc2ccc(-c3ccc(C#N)n3CC(=O)O)cc21
Temperature: 25 °C

Procedure:
A solution of tert-butyl[2-cyano-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrol-1-yl]acetate (2.2 g, 5.8 mmol), and sodium hydroxide (1.6 g, 40 mmol) in ethanol (200 ml) was heated to reflux for 2 hours. After cooling to room temperature the mixture was acidified with diluted hydrochloric acid, and extracted with ethylacetate. The ethylacetate solution was dried over magnesium sulfate, filtered, and concentrated in vacuo. Recrystallization from ethylacetate/hexane afforded the title compound, m.p. 207-209° C. (1.2 g, 64%), 1H-NMR (DMSO-d6) δ1.61 (s, 6H), 4.77 (s, 2H), 6.35 (d, J=4 Hz, 1H), 6.98 (d, J=8.1 Hz, 1H), 7.09 (d, J=4.1 Hz, 1H), 7.26 (m, 2H), 10.43 (s, 1H), MS (APCI (−)) m/z 324 (M−H)−.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH2:7])=[CH:2]1.[Cl:8][C:9]1[N:14]=[C:13](Cl)[C:12]([N:16]([CH3:21])[C:17](=[O:20])[CH:18]=[CH2:19])=[CH:11][N:10]=1.C(N(CC)CC)C>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4].C(Cl)Cl>[Cl:8][C:9]1[N:10]=[C:11]2[C:12]([N:16]([CH3:21])[C:17](=[O:20])[CH2:18][CH2:19][N:7]2[CH2:6][C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[CH:13][N:14]=1
Reactant: NCc1ccoc1
Reactant: C=CC(=O)N(C)c1cnc(Cl)nc1Cl
Agent: [Ti+4]
Agent: CC[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C(=O)CCN(Cc2ccoc2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.3 %

Procedure:
3-Furylmethylamine (Maybridge; 175 mg, 1.8 mmol), N-(2,4-dichloropyrimidin-5-yl)-N-methyl-prop-2-enamide (Intermediate 113; 347 mg, 1.5 mmol), Triethylamine (420 μL, 3 mmol), Titanium Tetra-ethoxide (157 μL, 0.75 mmol) and DCM (5 mL) were combined and stirred at room temp for 1 hr, heated at 40° C. overnight then cooled to room temperature. The reaction mixture was washed with water then gravity filtered through a PTFE cup, the aqueous layer containing the titanium emulsion was washed with further DCM (3×10 mL) and the combined organic solutions gravity filtered through a PTFE cup and solvents evaporated. The residue was dissolved in DCM and purified by chromatographic separation on silica eluting with a shallow gradient (25 column volumes) of 10-50% Ethyl Acetate/iso-hexane. Product containing fractions were combined and evaporated to give the title compound as a yellow gum (67 mg, 15%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[N:11]([S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:10]1[C:9](=[O:26])[CH2:8][CH2:7][CH2:6][C:5]2=1.[Li+].[CH3:28][Si]([N-][Si](C)(C)C)(C)C.CI.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[N:11]([S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:10]1[C:9](=[O:26])[CH:8]([CH3:28])[CH2:7][CH2:6][C:5]2=1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4cc(Cl)c(Cl)cc42)CCCC3=O)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1ccc(S(=O)(=O)n2c3c(c4cc(Cl)c(Cl)cc42)CCC(C)C3=O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 394.6 %

Procedure:
6,7-Dichloro-9-tosyl-2,3,4,9-tetrahydro-1H-carbazol-1-one 0.1 g, 0.024 mmol) was dissolved in dry THF, cooled to −78° C. and LiHMDS (0.6 mL, 0.61 mmol) was added dropwise. The reaction mixture was slowly warmed to 0° C. and stirred for an additional 30 min. The reaction mixture was cooled to −78° C. and MeI (0.040 mL, 0.61 mmol) was added slowly, warmed to room temperature and stirred for 4 h. Saturated NH4Cl (10 mL) was added to the reaction mixture and extracted with EtOAc (2×50 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by column chromatography [EtOAc-hexane (1:9) as eluant] to obtain the title compound (0.04 g, 40%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.49 (s, 1H), 8.03 (d, J=8.0 Hz, 2H), 7.67 (s, 1H), 7.32 (d, J=8.0 Hz, 2H), 2.98-2.85 (m, 2H), 2.71-2.66 (m, 1H), 2.43 (s, 3H), 2.27-2.23 (m, 1H), 1.96-1.89 (m, 1H), 1.25-1.17 (m, 3H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)=[O:12].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[O:37]([NH2:39])[CH3:38].C(N(CC)CC)C>CN(C=O)C>[CH3:38][O:37][NH:39][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)=[O:12]
Reactant: O=C(O)CCCCCCC(=O)c1ccc2ccccc2c1
Reactant: CON
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CONC(=O)CCCCCCC(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
To a solution of 7-(2-naphthoyl)heptanoic acid 50 g (500 mg, 1.76 mmol) in DMF (10 mL) were added HOBT (309 mg, 2.29 mmol) and EDC (504 mg, 2.64 mmol). The mixture was stirred at room temperature for 1 hour, after which methoxylamine-HCl (176 mg, 2.11 mmol) and triethylamine (300 μL, 2.11 mmol) were added and the solution was stirred at room temperature for 16 hours, then at 45° C. for 2 hours. The DMF was evaporated under high vacuum, deionized water was added, and the mixture was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with saturated sodium bicarbonate (10 mL), washed with brine (10 mL), and dried (MgSO4). The solvents were removed in vacuo and the title compound 64 (308 mg, 56%) was isolated by recrystallization from acetone. 1H NMR (400 MHz, 5:1 CDCl3:CD3OD): 8.37 (s, 1H), 7.89 (m, 2H), 7.78 (m, 2H), 7.48 (m, 2H), 3.59 (s, 3H), 3.01 (t, J=7.3 Hz, 2H), 1.96 (t, J=7.3 Hz, 2H), 1.67 (m, 2H), 1.54 (m, 2H), 1.31 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[CH:11]=[CH:10][NH:9][C:7]=2[N:8]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[C:17](Cl)=[O:18].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.C([Mg]Br)C.[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[C:11]([C:17]([C:16]3[CH:20]=[C:21]([O:25][CH3:26])[C:22]([O:23][CH3:24])=[C:14]([O:13][CH3:12])[CH:15]=3)=[O:18])=[CH:10][NH:9][C:7]=2[N:8]=1
Reactant: COc1ncc2cc[nH]c2n1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: CC[Mg]Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ncc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c[nH]c2n1
Reaction time: 1 h
Yield: 16 %

Procedure:
To a mixture of 2-methoxy-7H-pyrrolo[2,3-d]pyrimidine (0.220 g, 1.476 mmol) and anhydrous zinc chloride (0.407 g, 2.953 mmol) in dry CH2Cl2 (20 mL), ethylmagnesium bromide (0.65 mL, 3.0 M solution in diethyl ether) was added over 10 min at room temperature. The suspension was stirred for 1 h, and then 3,4,5-trimethoxybenzoyl chloride (0.510 g, 2.2 mmol) in dry CH2Cl2 (10 mL) was added dropwise over 5 min. The reaction mixture was stirred for another 1 h and then aluminum chloride (0.196 mg, 1.476 mmol) was added. The resulting thick mixture was vigorously stirred for 5 h. The reaction was quenched with water (10 mL) and extracted with CH2Cl2 (20 mL). The combined organic layers were dried over anhydrous MgSO4 and evaporated to give a brown oil, which was purified on a silica gel column (EtOAc:Hexane=1:1 to MeOH:CH2Cl2=1:20) to give compound 16 (0.081 g, 20%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].N1CCC[C@H]1C(O)=O.[NH:15]1[CH:19]=[CH:18][N:17]=[N:16]1.[OH:20][C:21]1[C:26](I)=[CH:25][C:24]([N+:28]([O-:30])=[O:29])=[CH:23][N:22]=1.Cl>[Cu](I)I.C(OCC)(=O)C.O.CS(C)=O>[N+:28]([C:24]1[CH:25]=[C:26]([N:16]2[N:17]=[CH:18][CH:19]=[N:15]2)[C:21]([OH:20])=[N:22][CH:23]=1)([O-:30])=[O:29]
Reactant: c1c[nH]nn1
Reactant: O=[N+]([O-])c1cnc(O)c(I)c1
Agent: I[Cu]I
Agent: Cl
Agent: O=C(O)[C@@H]1CCCN1
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cnc(O)c(-n2nccn2)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 78.8 %

Procedure:
Cesium carbonate (550 mg), L-proline (65 mg), and 1H-1,2,3-triazole (92 mg) were added to a dimethyl sulfoxide (3 ml) solution containing 2-hydroxy-3-iodo-5-nitropyridine (300 mg), and copper iodide (106 mg) was further added in a nitrogen atmosphere, followed by stirring at 100° C. for 3 hours. The reaction solution was adjusted to room temperature. Water and ethyl acetate were added. The pH was adjusted to pH 7 with 1M hydrochloric acid. Insoluble matter was filtered, followed by extraction with ethyl acetate (×3). The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (chloroform:methanol=1:0 to 10:1), and an orange solid of a mixture (184 mg) of 5-nitro-3-(2H-1,2,3-triazol-2-yl)pyridin-2-ol and 5-nitro-3-(1H-1,2,3-triazol-1-yl)pyridin-2-ol was thus obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:28][CH2:29][CH2:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.COCCOC.C([O-])([O-])=O.[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(C)=O>[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:28][CH2:29][CH2:30][N:31]1[CH:35]=[C:34]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][C:12]4[CH:13]=[C:14]5[C:19](=[CH:20][CH:21]=4)[N:18]=[CH:17][CH:16]=[CH:15]5)=[CH:9][N:10]=3)[N:7]=2)[CH:33]=[N:32]1
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Reactant: Clc1ccc2ncc(Cc3ccc4ncccc4c3)n2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: c1cnc2ccc(Cc3cnc4ccc(-c5cnn(CCOC6CCCCO6)c5)nn34)cc2c1
Temperature: 90 °C
Reaction time: 5.5 h
Yield: 80 %

Procedure:
6-(6-Chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-quinoline (Example 14, 500 mg, 1.679 mmol) was introduced in a microwave reactor together with 1-[2-(tetrahydro-pyran-2-yloxy)ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Stage 171.4, 812 mg, 2.52 mmol) and DME (10 mL). The solution was degassed with argon before adding Pd(PPh3)2Cl2 (36 mg, 0.051 mmol) and 2 M K2CO3 (2.267 mL, 4.53 mmol). The mixture was stirred at 90° C. for 5.5 h. The RM was taken up with EtOAc and washed with NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to afford a first batch of the desired product as a brownish oil (80% pure). 10% of the residue was dissolved in DCM and purified by flash chromatography (DCM/MeOH=100:0→93.5:6.5) to afford the title compound as a brownish oil (tR 2.30 min (8), MH+=455.1).