Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][NH:20][CH3:21])[C:12]3[CH:22]=[CH:23][CH:24]=[CH:25][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[CH2:26](I)[CH2:27]C.[C:30](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:30])[CH2:21][CH2:26][CH3:27])[C:12]3[CH:22]=[CH:23][CH:24]=[CH:25][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: CCCI
Reactant: CNCCN1C(=O)[C@H](O)[C@H](c2ccc(OC)cc2)Sc2ccccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCN(C)CCN1C(=O)[C@H](O)[C@H](c2ccc(OC)cc2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.0 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(methylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and 1.0 g of n-propyl iodide are dissolved in 25 ml of dimethylformamide, and 1.16 g of potassium carbonate are added thereto. The mixture is stirred at room temperature for 4 hours. After the reaction, the mixture is poured into ice-water and then extracted with ethyl acetate. The extract is washed with water, dried and then condensed, whereby (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-methyl-N-n-propylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one is obtained as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](=[O:28])([O-])[O-:26].[Na+].[Na+]>O.O1CCCC1.ClC(OCC1C=CC=CC=1)=O.C(OCC)(=O)C>[CH2:14]([O:26][C:25]([N:13]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=1)[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:28])[C:15]1[CH:24]=[CH:23][CH:18]=[CH:17][CH:16]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(CNCCCCNC(=O)OC(C)(C)C)cc1
Agent: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(CN(CCCCNC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 204.8 %

Procedure:
To a solution of the compound 3 (810 mg) and sodium carbonate (383 mg) in water (5 mL) and tetrahydrofuran (2 mL), benzyl chloroformate (413 μl) was added at 0° C. The reaction mixture was stirred at 0° C. for one hour. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→3:1) to obtain the title compound (1.16 g) having the following physical properties.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:16])[NH:9][C@H:10]1[CH2:14][CH2:13][NH:12][C:11]1=[O:15])([CH3:6])([CH3:5])[CH3:4].Br[CH2:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][N:25]=[C:26]2[Cl:29])=[CH:21][C:20]=1[O:30][CH3:31]>C1COCC1.C1COCC1.CN(C=O)C>[C:3]([O:7][C:8](=[O:16])[NH:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:18][C:19]2[CH:28]=[C:27]3[C:22]([CH:23]=[CH:24][N:25]=[C:26]3[Cl:29])=[CH:21][C:20]=2[O:30][CH3:31])[C:11]1=[O:15])([CH3:6])([CH3:4])[CH3:5]
Reactant: COc1cc2ccnc(Cl)c2cc1CBr
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2ccnc(Cl)c2cc1CN1CC[C@H](NC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.7 %

Procedure:
Sodium hydride (0.057 g, 1.4 mmol, 60% mineral oil dispersion) is suspended in anhydrous THF (5 mL) and treated with a solution of (2-oxopyrrolidin-3-(S)-yl)-carbamic acid tert-butyl ester (0.223 g, 1.1 mmol) and 7-bromomethyl-1-chloro-6-methoxy-isoquinoline (0.32 g, 1.1 mmol) in THF/DMF (10 mL, 6:1) at 0° C. The reaction mixture is warmed to ambient temperature, stirred for 3 hours, quenched by the addition of saturated NH4Cl and diluted with EtOAc. The layers are separated. The organic layer is washed with saturated NaCl, dried over Na2SO4, filtered, and concentrated to give a white solid. The solid is collected, washed with a small amount of EtOAc and copious amounts of Et2O to yield the title compound (0.18 g, 0.47 mmol).
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].C([O-])(=O)C.[Na+].[NH2:17][C:18]1[N:22]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[N:21]=[CH:20][CH:19]=1.C([N:32](CC)CC)C.Cl>O>[NH2:17][C:18]1[N:22]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[N:21]=[CH:20][C:19]=1[N:32]=[N:9][C:6]1[CH:5]=[CH:4][C:3]([S:1]([OH:11])(=[O:10])=[O:2])=[CH:8][CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Reactant: CCN(CC)CC
Reactant: Nc1ccnn1-c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1c(N=Nc2ccc(S(=O)(=O)O)cc2)cnn1-c1ccc(Cl)cc1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
20.8 g (0.12 mol) of sulfanilic acid was diazotized and to the mixture was then added with continuing ice cooling 18.9 g (0.23 mol) of sodium acetate. The dimethylformamide solution from Step 10.1 was added dropwise over a period of 30 minutes. During the addition, the suspension changed color from gray to yellow-brown. The mixture was allowed to agitate an additional 2 h at 5° C. after which it was allowed to stand overnight at room temperature. The next day, the reaction product was filtered off, the moist filter cake was suspended in 350 mL of dimethylformamide and heated to about 80° C. Then, first 19.2 g (0.19 mol) of triethylamine and then 100 mL of water were added to dissolve the intermediate product. The clear solution was allowed to agitate in the presence of 3.5 g of activated carbon for about 15 minutes and was then filtered warm. The residue on the filter was washed with a small amount of water. To the still warm filtrate was then added 17.8 mL (0.21 mol) of concentrated hydrochloric acid, and the resulting yellow suspension was cooled to 0 to 5° C. The precipitated product was removed by suction filtration and washed with 15-mL portions of isopropanol. The residue was dried at 60° C. This gave 23.8 g (63% of the theoretical) of 5-amino-1-(4-chlorophenyl)-4-(4-sulfophenylazo)pyrazole. Melting point; 260° C. (decomp.).
Reaction SMILES: [CH2:1]=[C:2]1[C:6](=[CH2:7])[S:5][C:4]([NH2:8])=[N:3]1.[Br:9][CH2:10][CH2:11][OH:12]>>[BrH:9].[NH:8]=[C:4]1[N:3]([CH2:10][CH2:11][OH:12])[C:2]([CH3:1])=[C:6]([CH3:7])[S:5]1
Reactant: OCCBr
Reactant: C=c1nc(N)sc1=C
Product: Br
Product: Cc1sc(=N)n(CCO)c1C
Yield: 46.6 %

Procedure:
A mixture of 4,5-dimethlyl-thiazol-2-ylamine (1.0 g, 7.8 mmol) and 2-bromoethanol (0.68 mL, 9.4 mmol) were processed as described in Example 8A to provide 0.92 g (47%) of the title compound 1H NMR (DMSO-d6, 300 MHz) δ ppm 2.19 (s, 6 H), 3.61-3.68 (m, 2 H), 4.03 (t, J=4.9 Hz, 2 H), 5.14 (brs, 1H) 9.27 (s, 1 H); MS (DCI/NH3) m/z 173 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([O-:15])=[O:14]>>[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([S:22]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:24])=[O:23])=[CH:20][CH:21]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-nitrobenzenesulfonyl chloride according to METHOD A, giving 8.66 g (46%) of product: MS (Ionspray, [M+H]+) m/z 372; Anal. Calcd. (found) for C13H13N3O6S2: C, 42.0 (42.5)%; H, 3.5 (3.3)%; N, 11.3 (11.4)%.
Reaction SMILES: [Br:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:3]=1.[CH2:11]=[O:12].C(N(CC)CC)C>CC(C)=O>[Br:1][C:2]1[N:6]([CH2:11][OH:12])[N:5]=[C:4]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:3]=1
Reactant: CC(C)(C)c1n[nH]c(Br)n1
Reactant: C=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(C)c1nc(Br)n(CO)n1
Temperature: 130 °C
Reaction time: 5 h
Yield: 72.8 %

Procedure:
The mixture of 3.45 g of 5-bromo-3-t-butyl-1H-1,2,4-triazole, 0.61 g of paraformaldehyde and 0.17 g of triethylamine was stirred at 130 ° C. for 5 hours. After the reaction mixture was cooled to room temperature, acetone was added. The mixture was filtered. Hexane was added to the residue and filtered. The filtrate was concentrated under reduced pressure to obtain 2.88 g of 5-bromo-3-t-butyl-1H-1,2,4-triazole1-ylmethanol.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[C:17]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)#[N:18].C1C(O)=CC=CC=1C>>[O:10]1[CH2:9][CH2:8][N:7]([CH2:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3][C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[NH:18])[CH2:12][CH2:11]1
Reactant: N#CN1CCOCC1
Reactant: Nc1ccccc1CN1CCOCC1
Agent: Cl
Solvent: Cc1cccc(O)c1
Product: N=C(Nc1ccccc1CN1CCOCC1)N1CCOCC1

Procedure:
A mixture of 4-(2-aminobenzyl)morpholine dihydrochloride (6.8 g), 4-cyanomorpholine (4.3 g) and m-cresol was heated at 90°-95° C. for 12 hours to yield N-(2-morpholinomethylphenyl)morpholine-4-carboxamidine (m.p. 118°-119° C.) which was recrystallised from hexane and then converted into its difumarate salt (m.p. 166°-167° C.) which was recrystallised from propan-2-ol.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]([C:13](=O)[CH2:14][C:15](=O)[CH3:16])[C:9]([CH3:19])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[OH:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[CH2:26][NH:27][NH2:28]>>[OH:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[CH2:26][N:27]1[C:13]([C:10]2[C:9]([CH3:19])=[N:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:11]=2[OH:12])=[CH:14][C:15]([CH3:16])=[N:28]1
Reactant: NNCc1cccc(O)c1
Reactant: CC(=O)CC(=O)C1C(=O)N(c2ccccc2)N=C1C
Agent: Cl
Product: Cc1cc(-c2c(C)nn(-c3ccccc3)c2O)n(Cc2cccc(O)c2)n1

Procedure:
Prepare the title compound from 1-[1-phenyl-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl]-butane-1,3-dione and 3-hydroxybenzyl hydrazine dihydrochloride according to the procedure of Example 28.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[NH:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:21]1>>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:20]4[CH2:24][CH2:23][CH:22]([C:25]5[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=5)[CH2:21]4)[N:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: c1cncc(C2CCNC2)c1
Product: O=C(O)c1cn(C2CC2)c2nc(N3CCC(c4cccnc4)C3)c(F)cc2c1=O
Yield: 82 %

Procedure:
Starting from 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (1.24 g, 4.4 retool) and 3-(3-pyrrolidinyl)pyridine, a procedure analogous to that given in Example 1 provided the title compound(1.43 g, 82%) as a light beige solid, mp 226°-228° C.
Reaction SMILES: [CH:1]1([C:4]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([O:30][CH3:31])=[O:29])=[CH:18][CH:17]=3)[C:7]3=[N:8][CH:9]=[C:10](Br)[C:11]([CH3:12])=[C:6]3[N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.C(O)=O>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([O:30][CH3:31])=[O:29])=[CH:18][CH:17]=3)[C:7]3=[N:8][CH:9]=[CH:10][C:11]([CH3:12])=[C:6]3[N:5]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccccc1-c1ccc(Cn2c(C3CC3)nc3c(C)c(Br)cnc32)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O=CO
Product: COC(=O)c1ccccc1-c1ccc(Cn2c(C3CC3)nc3c(C)ccnc32)cc1
Yield: 91.9 %

Procedure:
Toluene (30 ml) was mixed with 3.0 g (6.3 mmol) of 2-cyclopropyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-6-bromo-7-methyl-3H-imidazo[4,5-b]pyridine, 10% Pd--C (100 mg) and 9.6 g (95 mmol) of triethylamine, followed by the dropwise addition of 2.9 g (63 mmol) of formic acid under stirring. The obtained mixture was heated under reflux for 10 hours. The reaction liquid was brought to room temperature, and filtered to remove the catalyst, and then the filtrate was subjected to vacuum concentration. Chloroform (100 ml) and water (100 ml) were added to the residue and the obtained mixture was caused liquid-liquid separation. The aqueous phase was further extracted with chloroform (50 ml) twice. The organic phases were combined, dried over anhydrous magnesium sulfate and subjected to vacuum concentration. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 2.3 g of the title compound (yield 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].S(Cl)(Cl)=O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=1)[CH3:18]
Reactant: O=C(O)Cc1ccc(O)c(Cl)c1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1ccc(O)c(Cl)c1
Temperature: 25 °C

Procedure:
To an ice-cooled solution of 3-chloro-4-hydroxyphenyl-acetic acid (10.0 g, 53 mmol) in ethanol was dropwise added thionyl chloride (3.9 mL. 53.5 mmol). The mixture was stirred at room temperature over night, concentrated in vacuo and submitted to flash chromatography (eluent: graduated from 10% ethyl acetate in toluene to toluen) to give 11 g of 3-chloro-4-hydroxyphenyl-acetic acid ethyl ester.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=2)=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:24]1[N:25]=[C:26]([NH2:42])[C:27]2[N:28]=[CH:29][N:30]([C:40]=2[N:41]=1)[C@@H:31]1[O:39][C@H:36]([CH2:37][OH:38])[C@@H:34]([OH:35])[C@H:32]1[OH:33]>>[CH3:22][O:21][C:19]([C:16]1[CH:15]=[CH:14][C:13]([O:12][C:10]([N:7]2[CH2:8][CH2:9][CH:4]([CH2:1][C:2]#[C:3][C:24]3[N:25]=[C:26]([NH2:42])[C:27]4[N:28]=[CH:29][N:30]([C:40]=4[N:41]=3)[C@@H:31]3[O:39][C@H:36]([CH2:37][OH:38])[C@@H:34]([OH:35])[C@H:32]3[OH:33])[CH2:5][CH2:6]2)=[O:11])=[CH:18][CH:17]=1)=[O:20]
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C#CCC1CCN(C(=O)Oc2ccc(C(=O)OC)cc2)CC1
Product: COC(=O)c1ccc(OC(=O)N2CCC(CC#Cc3nc(N)c4ncn([C@@H]5O[C@H](CO)[C@@H](O)[C@H]5O)c4n3)CC2)cc1

Procedure:
Batch: AB-9-151. 4-(methoxycarbonyl)phenyl 4-(prop-2-ynyl)piperidine-1-carboxylate, batch JR28-85 (0.670 g, 2.223 mmol) was added to a solution of 2-iodoadenosine (0.675 g, 1.717 mmol) according to general procedure 2. Yield: 0.648 g, 67%. 1H NMR (CD3OD) δ 8.30 (s, 1H), 8.04-7.20 (2×m, 4H), 5.94 (d, 1H), 4.69 (m, 2H), 4.32-3.71 (4×m, 8H), 3.91-2.71 (2×d, 2H), 3.16-2.90 (2×bt, 4H), 2.48 (d, 5H), 1.98-1.45 (2×m, 5H). m/z MH+=567.14. HPLC rt=7.9 min.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:9]([C:10]([OH:12])=O)[C:8]([OH:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:17]=1[NH2:18].P(Cl)(Cl)Cl>C1(C)C(C)=CC=CC=1>[C:1]([C:5]1[CH:13]=[C:9]([C:10]([NH:18][C:17]2[CH:19]=[CH:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][C:16]=2[CH3:15])=[O:12])[C:8]([OH:14])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(O)c(C(=O)O)c1
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Solvent: Cc1ccccc1C
Solvent: ClP(Cl)Cl
Product: Cc1cc([N+](=O)[O-])ccc1NC(=O)c1cc(C(C)(C)C)ccc1O
Yield: 70.1 %

Procedure:
A solution of 9.7 g of 5-tert-butylsalicylic acid and 7.6 g of 2-methyl-4-nitroaniline in 120 ml of xylene is heated at 65° to 70° C. To a reaction solution is added a solution of 2.6 g of phosphorus trichloride in 30 ml of xylene. The whole mixture is refluxed for 2 hours. The hot reaction solution is decanted. The supernatant solution is cooled on an ice bath. The crystalline precipitate is collected by filtration. Recrystallization from methanol gives 11.5 g of the title compound as pale yellow needles, melting at 202°-204° C.
Reaction SMILES: [OH2:1].S([O-])(O)(=O)=O.[Na+].[CH3:8][C:9]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:11]([OH:12])[C:10]=1O>>[CH3:8][C:9]1[CH:10]=[C:11]([OH:12])[CH:13]=[C:14]([CH3:16])[C:15]=1[OH:1]
Reactant: O
Reactant: Cc1cc(C)c(O)c(O)c1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: Cc1cc(O)cc(C)c1O

Procedure:
By following the same manner as in Example 56 except that 0.013 g. of sodium hydrogen sulfate monohydrate (NaHSO4.H2O) was used, 3.42 g. (24.8 m.moles) of 3,5-dimethylcatechol and 1.66 g. (12.0 m.moles) of 2,6-dimethylhydroquinone were obtained. The yield of dihydric alkylphenols was 87.4%.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12](Cl)=[O:13])=[CH:9][CH:8]=[C:7]([O:15][CH3:16])[CH:6]=2.[CH2:23]([C@H:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:24]>C(Cl)Cl.CN(C=O)C>[CH2:23]([C@H:25]([NH:32][C:12]([C:11]1[C:10]2[C:5](=[CH:6][C:7]([O:15][CH3:16])=[CH:8][CH:9]=2)[N:4]=[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:2]=1[CH3:1])=[O:13])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:24]
Reactant: COc1ccc2c(C(=O)Cl)c(C)c(-c3ccccc3)nc2c1
Reactant: CC[C@H](N)c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC[C@H](NC(=O)c1c(C)c(-c2ccccc2)nc2cc(OC)ccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Prepared as described in Ex. 1, starting from 1.27 g (4.09 mmol) of crude 3-methyl-7-methoxy-2-phenylquinoline-4-carbonylchloride, 0.55 g (4.09 mmol) of (S)-(-)-α-ethylbenzylamine and 1.71 ml (12.27 mmol) of TEA in 24 ml of dry CH2Cl2 and 1 ml of DMF to help solubility. The reaction mixture was stirred 12 hours at room temperature.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][OH:10].N1C=CN=C1.Cl[Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19].O>CN(C)C=O.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][O:10][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: OCc1cc(F)ccc1Br
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](OCc1cc(F)ccc1Br)(C(C)C)C(C)C
Temperature: 23 °C
Reaction time: 48 h
Yield: 93 %

Procedure:
To a solution of 5.00 g (24.4 mmol) (2-bromo-5-fluorophenyl)methanol in 100 mL N,N-dimethylformamide were added 2.49 g imidazole, 6.20 mL chloro(triisopropyl)silane, 1.49 g N,N-dimethylpyridin-4-amine and the mixture was stirred at 23° C. for 2 days. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After filtration and removal of the solvent the residue was purified by chromatography to give 8.17 g (93%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[O:21][CH3:22])[CH:10]([CH3:11])[C:6]=2[C:5]([F:24])=[C:4](Cl)[N:3]=1.[NH2:26][C@@H:27]1[CH2:32][CH2:31][O:30][CH2:29][C@@H:28]1[NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37].CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[O:21][CH3:22])[CH:10]([CH3:11])[C:6]=2[C:5]([F:24])=[C:4]([NH:26][C@@H:27]2[CH2:32][CH2:31][O:30][CH2:29][C@@H:28]2[NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Reactant: COc1ccc(CN2C(=O)c3c(Cl)nc(Cl)c(F)c3C2C)c(OC)c1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2C(=O)c3c(Cl)nc(N[C@@H]4CCOC[C@@H]4NC(=O)OC(C)(C)C)c(F)c3C2C)c(OC)c1
Temperature: 95 °C
Yield: 0 %

Procedure:
To a sealed tube was added 4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1-methyl-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (430 mg, 1.12 mol), tert-butyl ((3R,4R)-4-aminotetrahydro-2H-pyran-3-yl)carbamate (7.5 g, 34.2 mol), and DIPEA (0.97 mL, 5.58 mmol). The mixture was heated in the sealed tube at 95° C. for 72 h. The mixture was purified via preparative HPLC to give the title compound as a yellow solid (100 mg, 16%). [M+H] calc'd for C27H34ClFN4O6, 565. found, 565.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:28])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH2:19][CH2:18]3)[CH3:16])[CH:8]=2)=[C:4]([F:31])[CH:3]=1.[C:32]1([CH2:38][C:39]([N:41]=[C:42]=[O:43])=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(OCC)C>O1CCCC1.CCCCCC>[CH3:26][N:25]([CH3:27])[CH2:24][CH2:23][N:20]1[CH2:21][CH2:22][CH:17]([N:15]([CH3:16])[C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:29]=[CH:30][C:2]([NH:1][C:42]([NH:41][C:39](=[O:40])[CH2:38][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[O:43])=[CH:3][C:4]=3[F:31])[CH:12]=[CH:11][N:10]=2)=[O:28])[CH2:18][CH2:19]1
Reactant: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Reactant: O=C=NC(=O)Cc1ccccc1
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccccc4)cc3F)ccn2)CC1
Temperature: 25 °C
Reaction time: 9.5 h
Yield: 21 %

Procedure:
To a solution of 3-[4-(4-amino-2-fluorophenoxy)pyridin-2-yl]-1-[1-(2-dimethylaminoethyl)piperidin-4-yl]-1-methylurea (61 mg) in tetrahydrofuran (3.0 ml) was added a solution of 2-phenylacetyl isocyanate in hexane (0.2 M, 1.70 ml) at room temperature, followed by stirring at room temperature for 9.5 hrs. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=10:1). Fractions containing a target compound were concentrated to give a residue, to which diethyl ether (1 ml) and hexane (1 ml) were added to give a precipitate. The precipitate was filtered off, and dried under aeration to provide the titled compound (17.8 mg, 21%) as white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[CH:5][CH:4]=1.F[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=3)[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cccc(O)c2)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc(Oc3ccc(C=O)cc3)c2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
To a solution of 56 (1.20 g, 6.0 mmol) and 4-fluorobenzaldehyde (745 mg, 6.0 mmol) in DMF (25 mL) was added cesium carbonate (3.90 g, 12.0 mmol). After stirring for 1 h at 100° C., the product was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was washed with water (100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was dissolved in dichloromethane and adsorbed onto silica gel and purified by flash chromatography using hexanes-ethyl acetate (6:1) to yield 57 (1.23 g, 67%) as a white solid after solvent removal.