Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C@@H:4]([C:6]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10](=[O:17])[NH:11]2)[OH:5].C(N(CC)CC)C.[C:25]1([C@H:31]([NH:61][C:62]([O:64][C@@H:65]2[CH:70]3[CH2:71][CH2:72][N:67]([CH2:68][CH2:69]3)[CH2:66]2)=[O:63])[C:32]2[CH:33]=[C:34]([CH:58]=[CH:59][CH:60]=2)[O:35][CH2:36][C:37]2[CH:57]=[CH:56][C:40]([C:41]([O:43][CH2:44][CH2:45][O:46][C:47]3[CH:52]=[CH:51][C:50]([CH:53]=O)=[CH:49][C:48]=3[CH3:55])=[O:42])=[CH:39][CH:38]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CO>[C:25]1([C@H:31]([NH:61][C:62]([O:64][C@@H:65]2[CH:70]3[CH2:71][CH2:72][N:67]([CH2:68][CH2:69]3)[CH2:66]2)=[O:63])[C:32]2[CH:33]=[C:34]([CH:58]=[CH:59][CH:60]=2)[O:35][CH2:36][C:37]2[CH:57]=[CH:56][C:40]([C:41]([O:43][CH2:44][CH2:45][O:46][C:47]3[CH:52]=[CH:51][C:50]([CH2:53][NH:2][CH2:3][C@H:4]([OH:5])[C:6]4[CH:15]=[CH:14][C:13]([OH:16])=[C:12]5[C:7]=4[CH:8]=[CH:9][C:10](=[O:17])[NH:11]5)=[CH:49][C:48]=3[CH3:55])=[O:42])=[CH:39][CH:38]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1cc(C=O)ccc1OCCOC(=O)c1ccc(COc2cccc([C@@H](NC(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)c2)cc1
Reactant: NC[C@H](O)c1ccc(O)c2[nH]c(=O)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: Cc1cc(CNC[C@H](O)c2ccc(O)c3[nH]c(=O)ccc23)ccc1OCCOC(=O)c1ccc(COc2cccc([C@@H](NC(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)c2)cc1
Reaction time: 0.17 h
Yield: 11 %

Procedure:
To a suspension of (R)-5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one hydrochloride (0.211 g, 0.83 mmol) in methanol (6 mL) was added triethylamine (0.229 mL, 1.65 mmol). The mixture was stirred for 10 minutes and then a solution of 2-(4-formyl-2-methylphenoxy)ethyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate (0.445 g, 0.69 mmol) in methanol (2 mL) was added. The mixture was stirred at RT for 1 hour. Sodium triacetoxyborohydride (0.292 g, 1.38 mmol) followed by acetic acid (0.188 mL, 3.28 mmol) added and the reaction continued for a further 18 hours. The reaction mixture was quenched with water and evaporated at reduced pressure. The residue dissolved in iso-butanol and washed with water. The organic phase was evaporated at reduced pressure and the crude material was purified by reverse phase preparative HPLC to afford the title compound (0.065 g, 11%)
Reaction SMILES: [F:1][C:2]1[C:10]([I:11])=[C:9]2[C:5]([CH2:6][NH:7][C:8]2=[O:12])=[CH:4][CH:3]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]#[N:22].C([O-])([O-])=O.[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O.CCCCCC.C(OCC)(=O)C>[F:1][C:2]1[C:10]([I:11])=[C:9]2[C:5]([CH2:6][N:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]#[N:22])[C:8]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=C1NCc2ccc(F)c(I)c21
Reactant: N#Cc1ccccc1CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: N#Cc1ccccc1CN1Cc2ccc(F)c(I)c2C1=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 40.8 %

Procedure:
A mixture of 6-fluoro-7-iodo-2,3-dihydro-isoindol-1-one (0.070 g, 0.25 mmol), 1-bromomethyl-2-cyano-benzene (0.059 g, 0.3 mmol), Cs2CO3 (0.098 g, 0.3 mmol), and 18-crown-6 (0.007 g, 0.025 for mmol) in acetone (5 mL) was stirred at 70° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 6-fluoro-7-iodo-2-(2-cyano-benzyl)-2,3-dihydro-isoindol-1-one (0.040 g, 41%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.33 (s, 2H), 5.04 (s, 2H), 7.04-7.71 (m, 6H), GC-MS: m/z 392 (M)+.
Reaction SMILES: [Ti:1](Cl)(Cl)(Cl)Cl.[C:6]1([N-:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Li+].[C:20]1([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[C:13]1([N-:12][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1.[C:27]1([N-:26][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1.[C:13]1([N-:12][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1.[C:13]1([N-:12][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1.[Ti+4:1]
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: Cl[Ti](Cl)(Cl)Cl
Agent: [Li+]
Agent: c1ccc([N-]c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: [Ti+4]
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
The same apparatus described in Step (1) of Example 1-E is used in this procedure. The 250 ml dropping funnel is charged with toluene, 50 ml, and titanium tetrachloride, 2.4 ml (0.022 mole). This is added dropwise to the flask containing lithium diphenylamide which is maintained at -20° C. during the addition while stirring magnetically. Total addition time is 30 minutes. The mixture is warmed to room temperature and then refluxed for 2 hours. All volatiles are removed under vacuum to give a deep red oily residue. Unreacted diphenylamine is sublimed from the oil under reduced pressure at 120° C. to give a red solid: Extraction of the solid with hexane, 50 ml, followed by solvent volume reduction under vacuum then cooling to -30° C. yields red crystals of titanium tetrakis(diphenylamide).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[NH:3][CH:2]=1.[H-].[Na+].Cl[CH2:17][C:18]1[CH:28]=[CH:27][C:21]2[N:22]=[C:23]([S:25][CH3:26])[S:24][C:20]=2[CH:19]=1.O>CN(C=O)C>[CH3:26][S:25][C:23]1[S:24][C:20]2[CH:19]=[C:18]([CH2:17][N:3]3[C:4]4=[N:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=[C:9]4[N:1]=[CH:2]3)[CH:28]=[CH:27][C:21]=2[N:22]=1
Reactant: COC(=O)c1cnc2[nH]cnc2c1
Reactant: CSc1nc2ccc(CCl)cc2s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc2c(c1)ncn2Cc1ccc2nc(SC)sc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a stirred solution of methyl 3H-imidazo[4,5-b]pyridine-6-carboxylate (1.34 g, 7.56 mmol) from Step 2 of this Example in anhydrous DMF (25 mL) at 0° C. was added in one portion sodium hydride (60% dispersion in mineral oil, 333 mg, 8.32 mmol) and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added a solution of 6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (1.3 g, 5.66 mmol) from Step 4 of Example 36 in DMF (5 mL). The mixture was allowed to warm to rt then stirred for a further 15 h. To the reaction mixture was added water (300 mL) and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and then brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 100% DCM followed by 1% MeOH in DCM to afford methyl 3-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate (1.3 g, 46%) as a white solid. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6) δ 8.95 (d, J=1.9 Hz, 1H), 8.81 (s, 1H), 8.56 (d, J=1.7 Hz, 1H), 8.00 (d, J=1.1 Hz, 1H), 7.80 (d, J=8.5 Hz, 1H), 7.47 (dd, J=1.6, 8.4 Hz, 1H), 5.66 (s, 2H), 3.90 (s, 3H), 2.76 (s, 3H). LCMS (ESI) m/z 371 (M+H)+.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]2([CH2:21][CH2:20]2)[C:12]1=[O:22].CC1(C)C(C)(C)OB(/[CH:31]=[CH:32]/[C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)O1.C(OCC)(=O)C>CN(C=O)C.O.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>[N:35]1[CH:36]=[CH:37][CH:38]=[C:33](/[CH:32]=[CH:31]/[C:2]2[C:10]3[C:5](=[CH:6][C:7]([C@H:20]4[C@@:13]5([C:14]6[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=6)[NH:11][C:12]5=[O:22])[CH2:21]4)=[CH:8][CH:9]=3)[NH:4][N:3]=2)[CH:34]=1
Reactant: Ic1n[nH]c2ccccc12
Reactant: O=C1Nc2ccccc2C12CC2
Reactant: CC1(C)OB(/C=C/c2cccnc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc2c(/C=C/c3cccnc3)n[nH]c2c1
Temperature: 120 °C
Yield: 44 %

Procedure:
To a solution of (1R,2S)-2-(3-iodo-1H-indazol-spiro[cyclopropane-1,3′-indolin]-2′-one (50 mg, 0.12 mmol) in DMF (0.4 mL) and water (0.1 mL) was added (E)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)pyridine (50 mg, 0.2 mmol) potassium fluoride (14 mg, 0.24 mmol) and Pd(PPh3)4 (7 mg, 0.006 mmol). The mixture was heated to 120° C. for 2 h under microwave irradiation. Ethyl acetate (50 mL) was added and the solution was washed with water (2×5 mL), brine (5 mL) and dried over MgSO4. Purification by reverse phase preparatory HPLC gave the title compound as a yellow solid (20 mg, 44%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[NH2:31])([CH3:4])([CH3:3])[CH3:2].Cl.N1C=C[CH:37]=[CH:36][CH:35]=1.C(OC)(OC)(OC)CC>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:13]2[C:22]3[CH:21]=[CH:20][C:19]([O:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:31]=[C:35]1[CH2:36][CH3:37])([CH3:4])([CH3:2])[CH3:3]
Reactant: c1ccncc1
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Agent: CCC(OC)(OC)OC
Agent: Cl
Solvent: Cc1ccccc1
Product: CCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 206.3 %

Procedure:
tert-Butyl[4-(3-amino-7-benzyloxyquinolin-4-ylamino)butyl]carbamate (20.7 g, 43.6 mmol) was dissolved in toluene (225 mL). Pyridine hydrochloride (2.03 g) and trimethyl orthopropionate (6.2 mL, 43.6 mmol) were added, and the mixture was heated at reflux for 3.25 hours. The reaction was allowed to cool to room temperature; a fine precipitate formed. The precipitate was isolated by filtration and washed with toluene. The off-white solid was allowed to dry for 2 hours under vacuum. The filtrate was evaporated, and the residue was dissolved in dichloromethane. The resulting solution was washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford a brown amorphous solid. The solids were combined to provide 17.2 g of tert-butyl[4-(7-benzyloxy-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[N:19]1([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[C:16]([NH:32][C:29]3[CH:28]=[CH:27][C:26]([CH2:25][N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:31][CH:30]=3)=[O:18])=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Product: O=C(/C=C/c1ccc(-c2ccc(Cl)cc2)cn1)Nc1ccc(CN2CCCCC2)cc1

Procedure:
Prepared analogously to Example 143 starting from (E)-3-[5-(4-chloro-phenyl)-pyridin-2-yl]-acrylic acid (Z34b) and 4-piperidin-1-ylmethyl-phenylamine. The crude product was purified by column chromatography (silica gel, dichloromethane/EtOH/conc. aqueous ammonia 50:10:0.1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11].C(O)(=O)C>C(O)C.C([O-])(=O)C.[NH4+]>[C:10]([C:12](=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11]
Reactant: CCOC(=O)CC#N
Reactant: O=Cc1ccc(O)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=Cc1ccc(O)cc1
Temperature: 0 °C
Yield: 121.8 %

Procedure:
4-hydroxybenzaldehyde (30 g), ethyl cyanoacetate (31.7 g), acetic acid (4.5 ml) and ammonium acetate (1.9 g) were refluxed in ethyl alcohol (100 ml) for 4 hours with heating. After the reaction, the reaction solution was poured into 500 ml of ice water to separate crystals. The resulting crystals were recrystallized from methyl alcohol (400 ml) to obtain 65 g of ethyl 2-cyano-3-(4-hydroxyphenyl)acrylate which melted at 89° to 91° C. The resulting compound (10.9 g) and pyridine (4.3 g) were dissolved in tetrahydrofuran (100 ml), and acryloyl chloride (4.5 g) was added dropwise thereto. The reaction was carried out for 2 hours while keeping the reaction temperature below 40° C. After the reaction, the reaction solution was poured into ice water to separate crystals, and the resulting crystals were recrystallized from methyl alcohol (100 ml) to obtain 11 g of the desired compound which melted at 82° to 85° C. The desired compound was confirmed by the results of IR, NMR and elemental analysis.
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:5]=[C:6]([C:10]2[C:14]([CH2:15][OH:16])=[C:13]([CH3:17])[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1.Cl[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][N:20]=1.[Cl-:29].[Na+]>C1COCC1>[CH3:26][O:25][C:23](=[O:24])[C:22]1[CH:27]=[CH:28][C:19]([O:16][CH2:15][C:14]2[C:10]([C:6]3[CH:7]=[CH:8][C:9]([Cl:29])=[CH:4][CH:5]=3)=[N:11][O:12][C:13]=2[CH3:17])=[N:20][CH:21]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: [Cl-]
Reactant: Cc1onc(-c2cccc(F)c2)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a suspension of sodium hydride (55% dispersion in mineral oil, 852 mg, 20 mmol) in THF (27 mL) was added a solution of [3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (3.68 g, 18 mmol) in THF (54 mL) at 0° C. and the reaction mixture warmed to room temperature over 30 min. Then a solution of methyl 6-chloronicotinate (3.35 g, 20 mmol) in THF (1.5 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=7:3) afforded 6-[3-(4-Chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (74%) which was obtained as a light yellow solid. To a solution of 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (1.1 mmol) in THF (5 mL) was added a solution of lithium hydroxide monohydrate (94 mg, 2.2 mmol) in water (5 mL) and methanol (1 mL) added and the resulting mixture stirred at room temperature overnight. The mixture was acidified to pH 4 with HCl (25%, 3 drops) and methanol (2 drops) added. A gum began to form and the mixture was cooled at 0° C. for 1.5 h and then the aqueous layer decanted off. Trituration with diethylether and hexane afforded the title compound (832 mg, 98%) which was obtained as an off white solid. MS: m/e=343.1 [M−H]−.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6]N=C1)=[O:2].[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=CC=1N.C1COCC1.NC1C=[CH:48][C:35]([O:36][C:37]2[CH:42]=[CH:41][N:40]=[C:39]([NH:43][CH2:44][CH2:45][CH2:46][OH:47])[N:38]=2)=[CH:34][CH:33]=1>ClCCl>[OH:47][CH2:46][CH2:45][CH2:44][NH:43][C:39]1[N:38]=[C:37]([O:36][C:35]2[CH:48]=[CH:11][C:12]([NH:8][C:1]([NH:3][C:7]3[CH:6]=[C:19]([C:22]([F:23])([F:24])[F:25])[CH:20]=[CH:21][C:15]=3[O:14][CH3:13])=[O:2])=[CH:33][CH:34]=2)[CH:42]=[CH:41][N:40]=1
Reactant: Nc1ccc(Oc2ccnc(NCCCO)n2)cc1
Reactant: COc1ccc(C(F)(F)F)cc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(C(F)(F)F)cc1NC(=O)Nc1ccc(Oc2ccnc(NCCCO)n2)cc1
Reaction time: 2 h

Procedure:
205.6 mg (1.268 mmol) 1,1′-Carbonyl-diimidazol (CDI) were given to a solution of 220.3 mg (1.153 mmol) 2-methoxy-5-(trifluoromethyl)aniline in 4.0 ml dichloromethane. After stirring for 2 h a formed precipitate was dissolved by addition of 5 ml THF and the mixture stirred for 12 h at r.t. A solution of 300.0 mg (1.153 mmol) 3-[4-(4-Amino-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol in 6 ml dichloromethane was added and the mixture stirred for 5 d at r.t. The reaction mixture was evaporated and the residue was purified by chromatography on silica gel (dichloromethane/methanol 95:5). The obtained material was washed with ether and dissolved in hot ethanol and evaporated. After treatment with a small amount of ethanol the precipitate was isolated by filtration and dried. Yield: 172 mg (31%) of the title compound.
Reaction SMILES: C([Li])CCC.CCCCCC.[Cl:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][NH:19]2)=[CH:15][CH:14]=1.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1.O>[Cl:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][N:19]2[S:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:30])=[O:29])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Clc1ccc2cc[nH]c2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: O=S(=O)(c1ccccc1)n1ccc2ccc(Cl)cc21
Temperature: -40 °C

Procedure:
At −78° C., n-butyl lithium (a 1.61M hexane solution, 3.34 ml) was added to a solution of 6-chloroindole (777 mg) in tetrahydrofuran (25 ml), followed by heating to −40° C. over 1 hour. The reaction mixture was cooled back to −78° C. and added with benzenesulfonyl chloride (867 μl). The resulting mixture was heated to room temperature over 3 hours. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (40 g of silica gel, hexane:ethyl acetate=5:7). The white solid so obtained was recrystallized from ethanol, whereby the title compound (826 mg, 55%) was obtained as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[C:4]([C:11]([OH:13])=O)=[N:3]1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:27]=[C:28]([CH:45]=[CH:46][CH:47]=1)[O:29][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([N:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[N:38]=2)[CH:35]=1>CN(C)C=O.CN(C)C(=O)C>[CH:42]1([C:40]([NH:39][C:37]2[N:38]=[C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:27]=[C:26]([NH:25][C:11]([C:4]5[C:5]([C:7]([F:10])([F:9])[F:8])=[CH:6][N:2]([CH3:1])[N:3]=5)=[O:13])[CH:47]=[CH:46][CH:45]=4)=[CH:35][N:34]3[N:36]=2)=[O:41])[CH2:43][CH2:44]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: Cn1cc(C(F)(F)F)c(C(=O)O)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cn1cc(C(F)(F)F)c(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)n1
Yield: 47.8 %

Procedure:
In the same manner as in Example 18-4 and using 1-methyl-4-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (194 mg, 1.00 mmol), tetrahydrofuran (7 mL), oxalyl chloride (95.6 μL, 1.10 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (281 mg, 0.910 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (211 mg, 48%) was obtained as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[O:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[C:10]([O-:13])(=[O:12])[CH3:11].C([N+]1C=CN(C)C=1)C>CC#N>[C:10]([O:13][CH2:2][C:3]1[O:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)(=[O:12])[CH3:11]
Reactant: O=Cc1ccc(CCl)o1
Reactant: CC(=O)[O-]
Agent: CC[n+]1ccn(C)c1
Solvent: CC#N
Product: CC(=O)OCc1ccc(C=O)o1

Procedure:
In a round flask, 2 mL of methyl cyanide (acetonitrile) as an organic solvent was introduced, 0.145 g (1 mmol) of 5-chloromethylfurfural (CMF, compound I) was dissolved in the organic solvent, 0.170 g (1 mmol) of 1-ethyl-3-methylimidazolium acetate was added to the solution, and then the mixed solution was reacted at normal pressure and room temperature for 5 minutes. After the reaction, the reaction product was extracted by the addition of a small amount of water (5 mL) and ethyl acetate (added twice by 20 mL) to obtain an organic layer. The obtained organic layer was concentrated under reduced pressure to obtain light yellow liquid 5-acetoxymethylfurfural (AcHMF, compound II). The yield thereof is 36%.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=1>C1COCC1>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2([CH3:8])[CH2:20][O:21]2)=[CH:17][N:18]=1
Reactant: CC(=O)c1ccc(C)nc1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C2(C)CO2)cn1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents stirred for 10 min. after which the solution of 1-(6-methylpyridin-3-yl)ethanone (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. After completion, the reaction mixture is poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.
Reaction SMILES: [CH2:1]([C:3]1[C:8](C#N)=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].[CH3:11][Mg]I.Cl.[C:15](=[O:18])(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(OC)(C)(C)C>[CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:15](=[O:18])[CH3:11])[CH3:2]
Reactant: O=C([O-])O
Reactant: C[Mg]I
Reactant: CCc1ccncc1C#N
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Product: CCc1ccncc1C(C)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Magnesium (7.90 g) was suspended in t-butylmethyl ether (300 ml) and iodine (20 mg) was added. Methyl iodide (20 ml) was added dropwise while maintaining the mixture at not higher than 25° C. The mixture was stirred at room temperature for 3 hrs. to give a solution of methylmagnesium iodide in t-butylmethyl ether. To a solution of 4-ethylnicotinonitrile (2.00 g) in toluene (30 ml), which was cooled to −10° C., was gradually added a solution (45 ml) of methylmagnesium iodide in t-butylmethyl ether and the mixture was stirred at room temperature for 12 hrs. The reaction mixture was added to 1N hydrochloric acid (80 ml) and the mixture was stirred at room temperature for 30 min. Sodium bicarbonate was added to neutralize the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=20:1–1:3) for purification to give the title compound (1.84 g) as a yellow oil.