Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[C@@H]1([O:14][C:15]2[C:16]([O:18][C@H:19]([C@H:22]([CH2:24][OH:25])[OH:23])[C:20]=2[OH:21])=[O:17])O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O.O=[C:27]1[O:33][C@H:32]([C@H:34]([CH2:36][OH:37])[OH:35])[C:30]([OH:31])=[C:28]1[OH:29]>C([O-])(=O)C.C(O)[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O>[C@@H:27]1([C@:19]2([C@H:22]([CH2:24][OH:25])[OH:23])[O:18][C:16](=[O:17])[C:15]([OH:14])=[C:20]2[OH:21])[O:33][C@H:32]([CH2:30][OH:31])[C@@H:34]([OH:35])[C@H:36]([OH:37])[C@H:28]1[OH:29]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: CC(=O)[O-]
Agent: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: CO
Product: O=C1O[C@]([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)([C@@H](O)CO)C(O)=C1O
Temperature: 100 °C

Procedure:
Using, as an index, a retention time of 5.2 minutes in LC system manufactured by GILSON (master pump 305 type, UV detector 116 type), column: INERTSIL® ODS-3 (manufactured by GL Science, 4.6×150 mm, 5 μm) , mobile phase: 20% MeOH-20 mM phosphoric acid-5 mM tetra-n-amylammonium bromide, flow rate: 0.5 ml/min, detection wavelength: 254 nm) of a chemically synthesized product of 2-O-(β-D-glucopyranosyl)ascorbic acid, commercially available cellulase, (β-glucosidase, and β-glucanase enzyme preparations were searched. An enzyme reaction system was obtained by being dissolved in a 10 mM acetate buffer (pH 5.0) to 1 ml so that cellobiose became to be 0.3 M and ascorbic acid became to be 0.2 M. After addition of 50 μl of an enzyme solution, the reaction was initiated at 37° C. The reaction was stopped by heating at 100° C. for 5 minutes, and β-D-glucopyranosylascorbic acid produced was analyzed by high performance liquid chromatography. As a result, it was found that cellulase (manufactured by Sigma), β-glucosidase (Toyobo Co., Ltd., Nakarai Tesque), CELLULOSIN T2 (Hankyu Kyoei Bussan), cellulase “ONOZUKA” RS, “ONOZUKA” FA and PANCELLASE BR (Yakult Pharmaceutical Ind. Co., Ltd.) have (β-glucosyltransferase activity. Free ascorbic acid appeared a position of 4.0 minutes, while peaks were recognized at positions of 3.6 minutes and 5.2 minutes before and after that position, and they were designated as substance X and substance Y. A conversion rate of the substance X indicated 15.7%, and a conversion rate of the substance Y indicated 0.8%. By cochromatography analysis of this substance X and substance Y with chemically synthesized products, a retention time of the substance X was consistent with that of 6-O-(β-D-glucopyranosyl)ascorbic acid, and a retention time of the substance Y was consistent with that of 2-O-(β-D-glucopyranosyl)ascorbic acid.
Reaction SMILES: [C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1.COC1C(OC)=C(C=CC=1)C(Cl)(C1C=CC=CC=1)C1C=CC=CC=1.COC1C=CC(C([O:63][C@@H:64]2[C@@H:68]([CH2:69][O:70][C:71]([C:88]3[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=3)([C:80]3[CH:85]=[CH:84][C:83]([O:86][CH3:87])=[CH:82][CH:81]=3)[C:72]3[CH:77]=[CH:76][C:75]([O:78][CH3:79])=[CH:74][CH:73]=3)[O:67][C@@H:66]([N:94]3[CH:102]=[C:100]([CH3:101])[C:98](=[O:99])[NH:97][C:95]3=[O:96])[CH2:65]2)(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1>N1C=CC=CC=1>[CH3:79][O:78][C:75]1[CH:76]=[CH:77][C:72]([C:71]([O:70][CH2:69][C@H:68]2[O:67][C@@H:66]([N:94]3[CH:102]=[C:100]([CH3:101])[C:98](=[O:99])[NH:97][C:95]3=[O:96])[CH2:65][C@@H:64]2[OH:63])([C:88]2[CH:89]=[CH:90][CH:91]=[CH:92][CH:93]=2)[C:80]2[CH:85]=[CH:84][C:83]([O:86][CH3:87])=[CH:82][CH:81]=2)=[CH:73][CH:74]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2OC(c2ccccc2)(c2ccc(OC)cc2)c2ccc(OC)cc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: COc1cccc(C(Cl)(c2ccccc2)c2ccccc2)c1OC
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 250-ml three-necked flask, thymidine and dimethoxytrityl chloride in anhydrous pyridine are introduced in succession under inert gas and stirred for 2 hours at room temperature. The TLC control test of the reaction (V(MeOH):V(CH2Cl2)=1:19) shows the 5′-O-protected compound (Rf=0.26) to be the main product. It also contains one faint spot each for the starting material (Rf=0.00) and the doubly protected byproduct, 3′,5′-bis-O-(4,4′-dimethoxytrityl)thymidine (Rf=0.71). The reaction solution is then decanted slowly into 1.5 l of vigorously stirred ice water. After 30 minutes of stirring, the yellow suspension is suction-filtered, and the residual moisture is removed from the solid in the rotary evaporator by azeotropic distillation two times with ethanol. Alternatively, the raw product is recrystallized from a benzene-acetone mixture or is purified by means of column chromatography (silica gel 60; Ø=6 cm; h=45 cm; V(MeOH):V(CH2Cl2)=1:19+0.1% of triethylamine; absorbed on about 20 g of silica gel 60). After drying in high vacuum, it yields the product, 5′-O-(4,4′-dimethoxytrityl)thymidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[N:13]=[C:12]([F:17])[C:11]=2[O:18]COC)=[O:9])[CH:7]=1.Cl.O.CCOC(C)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[N:13]=[C:12]([F:17])[C:11]=2[OH:18])=[O:9])[CH:7]=1
Reactant: COCOc1c(C(=O)c2cc(Br)ccc2F)cc(Cl)nc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1cc(Br)ccc1F)c1cc(Cl)nc(F)c1O
Temperature: 60 °C
Yield: 77 %

Procedure:
To a solution of (5-bromo-2-fluorophenyl)(6-chloro-2-fluoro-3-(methoxymethoxy)pyridin-4-yl)methanone (1200 g, 3.06 mol) in THF (4.8 L) was added 6 N aqueous HCl solution (1600 mL, 9.17 mol) and the reaction mixture was heated to 60° C. for 5 hours. The reaction mixture was cooled to RT, and then water (3 L) and EtOAc (3 L) were added. After the phases were separated, the aqueous layer was extracted with EtOAc (3 L×2). The combined organic layers was washed with brine (2 L×1) and dried over Na2SO4. The solution was concentrated under reduced pressure. The residue was dissolved in hot MTBE (˜700 mL). The solution was triturated with hexanes until a solid began to precipitate. The slurry was cooled to RT overnight. The solid was filtered, washed with hexanes (500 mL×2), and dried to give 821 g of (5-bromo-2-fluorophenyl)(6-chloro-2-fluoro-3-hydroxypyridin-4-yl)methanone as a yellow solid.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=2[F:24])=[C:12]([C:25]2([O:30][CH3:31])[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:11]=1)(C)C)(C)(C)C.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CO>[F:24][C:17]1[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=1[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][OH:8])=[CH:11][C:12]=1[C:25]1([O:30][CH3:31])[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: COc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2C2(OC)CCCC2)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(CO)cc2C2(OC)CCCC2)c1
Reaction time: 8 h
Yield: 54 %

Procedure:
To a solution of 20.5 (66 mg, 168 μmol) in MeOH (3 mL), was added PPTS (11 mg, 45 μmol). The resulting mixture was stirred overnight. Solvent was removed in vacuo to give a residue which was purified by CombiFlash® chromatography to give an oil (30 mg, 61%). MS ESI m/e: 331.2 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:17]([NH2:18])=[N:16][C:10]3[N:11]=[C:12]([NH2:15])[N:13]=[CH:14][C:9]=3[CH:8]=2)[CH:2]=1.[C:19]([N:23]=[C:24]=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[NH2:15][C:12]1[N:13]=[CH:14][C:9]2[CH:8]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[C:17]([NH:18][C:24]([NH:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])=[N:16][C:10]=2[N:11]=1
Reactant: Nc1ncc2cc(-c3cccnc3)c(N)nc2n1
Reactant: CC(C)(C)N=C=O
Product: CC(C)(C)NC(=O)Nc1nc2nc(N)ncc2cc1-c1cccnc1

Procedure:
By following the procedure of Example 2, 0.30 g of 2,7-diamino-6-(3-pyridyl)-pyrido[2,3-d]pyrido[2,3-d]-pyrimidine from Example 107 was reacted with 0.16 mL of tert-butyl isocyanate. The product was purified by medium pressure chromatography using silica gel and eluting with 90:10:1 EtOAc:MeOH:TEA to afford the title compound; mp >300° C.; CIMS (1% ammonia in methane): m/z (relative intensity) 338 (MH+ +1, 8), 339 (MH+ +2, 1), 84 (100).
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:10][CH2:9][CH2:8][N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[C:6](=[O:28])[NH:5]1.[CH:37]1([N:40]2[CH:45]=[CH:44][C:43]([I:46])=[CH:42][C:41]2=[O:47])[CH2:39][CH2:38]1>>[CH:37]1([N:40]2[CH:45]=[CH:44][C:43]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:8][CH2:9][CH2:10][C@:4]([CH2:3][C:2]([OH:1])([CH3:35])[CH3:36])([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[NH:5][C:6]4=[O:28])[CH3:12])=[CH:18][CH:17]=3)=[CH:42][C:41]2=[O:47])[CH2:39][CH2:38]1.[CH:37]1([N:40]2[CH:45]=[CH:44][C:43]([I:46])=[CH:42][C:41]2=[O:47])[CH2:39][CH2:38]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CCC[C@](CC(C)(C)O)(c2ccccc2)NC1=O
Agent: O=c1cc(I)ccn1C1CC1
Product: C[C@@H](c1ccc(-c2ccn(C3CC3)c(=O)c2)cc1)N1CCC[C@](CC(C)(C)O)(c2ccccc2)NC1=O

Procedure:
The title compound was prepared from (S)-4-(2-hydroxy-2-methylpropyl)-4-phenyl-1-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-diazepan-2-one and 1-cyclopropyl-4-iodopyridin-2(1H)-one following a procedure analogous to that described in Example 11 Step 2. 1-cyclopropyl-4-iodopyridin-2(1H)-one was prepared as described below.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6]([C:9]([OH:11])=O)=[CH:5][N:4]=1.[NH2:14][C:15]1[N:20]=[CH:19][C:18]2[C:21]([CH3:29])([CH3:28])[C:22](=[O:27])[N:23]([CH:24]3[CH2:26][CH2:25]3)[C:17]=2[CH:16]=1>>[CH:24]1([N:23]2[C:17]3[CH:16]=[C:15]([NH:14][C:9]([C:6]4[CH:7]=[N:8][C:3]([C:2]([F:1])([F:13])[F:12])=[N:4][CH:5]=4)=[O:11])[N:20]=[CH:19][C:18]=3[C:21]([CH3:28])([CH3:29])[C:22]2=[O:27])[CH2:26][CH2:25]1
Reactant: O=C(O)c1cnc(C(F)(F)F)nc1
Reactant: CC1(C)C(=O)N(C2CC2)c2cc(N)ncc21
Product: CC1(C)C(=O)N(C2CC2)c2cc(NC(=O)c3cnc(C(F)(F)F)nc3)ncc21

Procedure:
Prepared in analogy to example 26 from 2-(trifluoromethyl)pyrimidine-5-carboxylic acid and 6-amino-1-cyclopropyl-3,3-dimethyl-1H-pyrrolo[3,2-c]pyridin-2(3H)-one (example 79c). The title compound was obtained as off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8](=O)[NH:7][C:6]=2[CH:16]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:18]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8](=[S:18])[NH:7][C:6]=2[CH:16]=1
Reactant: O=C1Nc2cc(F)ccc2Nc2cscc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Product: Fc1ccc2c(c1)NC(=S)c1cscc1N2

Procedure:
In a similar fashion 7-fluoro-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one is treated with phosphorus pentasulfide to give 7-fluoro-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-thione.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:24][CH:25]2[S:29][C:28](=[O:30])[NH:27][C:26]2=[O:31])=[C:7]2[C:12]=1[N:11]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)[C:10](=[O:23])[CH2:9][CH2:8]2>[C].[Pd].CN(C=O)C>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:11]2[C:12]3[C:7](=[C:6]([CH2:24][CH:25]4[S:29][C:28](=[O:30])[NH:27][C:26]4=[O:31])[CH:5]=[CH:4][C:3]=3[O:2][CH3:1])[CH2:8][CH2:9][C:10]2=[O:23])=[CH:19][CH:18]=1
Reactant: COc1ccc(CC2SC(=O)NC2=O)c2c1N(Cc1ccc([N+](=O)[O-])cc1)C(=O)CC2
Agent: [Pd]
Solvent: CN(C)C=O
Product: COc1ccc(CC2SC(=O)NC2=O)c2c1N(Cc1ccc(N)cc1)C(=O)CC2
Reaction time: 5 h
Yield: 85.6 %

Procedure:
10 g of 10% palladium carbon was added to a DMF solution (100 ml) of 10.0 g of 5-[8-methoxy-1-(4-nitrobenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl]thiazolidine-2,4-dione, and the mixture was subjected to a catalytic reduction at 40° C. for 5 hours. The catalyst was removed by filtration, and the filtrate was concentrated. Ethyl acetate and water were added to the residue, and celite filtration was carried out. The filtrate was washed with water and dried over magnesium sulfate, followed by concentration. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1→1:4), and the purified product was recrystallized from ethyl acetate, giving 7.98 g (86% yield) of 5-[1-(4-aminobenzyl)-8-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl]thiazolidine-2,4-dione as a white powder.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[NH:12][N:13]=[C:8]3[C:9]2=[C:4]([CH2:5][CH:6]([CH3:23])[N:7]3[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:3]=1.[C:24]1([C@H:30]([NH:32][C:33]([NH2:35])=[O:34])[CH3:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:7]2[CH:6]([CH3:23])[CH2:5][C:4]3[N:3]=[C:2]([NH:35][C:33]([NH:32][C@@H:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:31])=[O:34])[CH:11]=[C:10]4[NH:12][N:13]=[C:8]2[C:9]=34)=[CH:16][CH:17]=1
Reactant: C[C@@H](NC(N)=O)c1ccccc1
Reactant: COc1ccc(CN2c3n[nH]c4cc(Cl)nc(c34)CC2C)cc1
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(CN2c3n[nH]c4cc(NC(=O)N[C@H](C)c5ccccc5)nc(c34)CC2C)cc1
Temperature: 100 °C

Procedure:
7-chloro-3-(4-methoxybenzyl)-4-methyl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridine (150 mg, 0.263 mmol), (R)-1-(1-phenylethyl)urea (64.7 mg, 0.394 mmol), cesium carbonate (257 mg, 0.788 mmol) and BrettPhos pre-catalyst (23.8 mg, 0.026 mmol) were charged in a 1 dram vial, evacuated and backfilled with nitrogen and taken in 1,4-dioxane (1.4 mL). The mixture was heated at 100° C. for 1 hour before it was diluted with DCM, washed with water, brine, dried with sodium sulfate and concentrated. Purification of the residue by flash column (0-80% EtOAc-hexanes) gave 1-(3-(4-methoxybenzyl)-4-methyl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridin-7-yl)-3-((R)-1-phenylethyl)urea. MS ESI calc'd. for C26H28N6O2[M+H]+ 699. found 699.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].[C:7]1([C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCCCCC>ClC(Cl)Cl>[CH3:6][O:5][C:1](=[O:4])[CH:2]([C:13]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[SH:3]
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CS
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: COC(=O)C(S)C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 97.1 %

Procedure:
Dissolve 5.0 mL (55.0 mmol) methyl thioglycolate and 14.3 g (55.0 mmol) triphenylmethanol in 80 mL trichloromethane. Then slowly drop 6.9 mL (55.0 mmol) boron trifluoride ethyl ether complex into the solution and stir the solution at room temperature. Use thin layer chromatography (TLC)(chloroform:hexane=1:1) to follow the reaction. After starting material disappeared completely, wash the reaction solution with water (2×100 mL). The organic phase is dried by anhydrous sodium sulfate and then the solvent is removed by vacuum evaporation to get 18.6 g (97.5%) triphenylmethyl thioglycolic acid methyl ester (hereafter referred to as compound 1).
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([NH:15][CH:16]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:17]1[CH:18]=[C:19]([CH:39]=[CH:40][CH:41]=1)[O:20][CH2:21][C:22]1[CH:38]=[CH:37][C:25]([C:26]([O:28][CH2:29][CH2:30][CH2:31][CH:32]2[O:36][CH2:35][CH2:34][O:33]2)=[O:27])=[CH:24][CH:23]=1)=O)(C)(C)C>>[ClH:1].[NH2:15][CH:16]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:17]1[CH:18]=[C:19]([CH:39]=[CH:40][CH:41]=1)[O:20][CH2:21][C:22]1[CH:38]=[CH:37][C:25]([C:26]([O:28][CH2:29][CH2:30][CH2:31][CH:32]2[O:33][CH2:34][CH2:35][O:36]2)=[O:27])=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(OCc2ccc(C(=O)OCCCC3OCCO3)cc2)c1
Agent: Cl
Solvent: C1COCCO1
Product: NC(c1ccccc1)c1cccc(OCc2ccc(C(=O)OCCCC3OCCO3)cc2)c1
Yield: 100 %

Procedure:
Hydrogen chloride in dioxan (4.0 M, 6 mL, 24 mmol) was added to 3-(1,3-dioxolan-2-yl)propyl 4-((3-(((tert-butoxycarbonyl)amino)(phenyl)methyl)phenoxy)-methyl)benzoate (0.756 g, 1.38 mmol), and the resultant solution was stirred at ambient temperature for 2 hours. The solvent was evaporated at reduced pressure to afford the title compound (0.750 g, 100%).
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[C:9][CH2:10]Br.[F:12][C:13]1[CH:14]=[C:15]([OH:29])[CH:16]=[C:17]([C:19]([C:24]2[S:25][CH:26]=[CH:27][N:28]=2)([O:22][CH3:23])[CH2:20][CH3:21])[CH:18]=1>>[F:12][C:13]1[CH:14]=[C:15]([O:29][CH2:10][C:9]#[C:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[CH:16]=[C:17]([C:19]([C:24]2[S:25][CH:26]=[CH:27][N:28]=2)([O:22][CH3:23])[CH2:20][CH3:21])[CH:18]=1
Reactant: BrCC#Cc1ccccn1
Reactant: CCC(OC)(c1cc(O)cc(F)c1)c1nccs1
Agent: Br
Product: CCC(OC)(c1cc(F)cc(OCC#Cc2ccccn2)c1)c1nccs1
Yield: 54 %

Procedure:
Using a similar procedure to that described in Example 8, 3-(2-pyridyl)prop-2-yn-1-yl bromide hydrobromide was reacted with 2-[1(5-fluoro-3-hydroxyphenyl)-1-methoxypropyl]thiazole to give 2-[1-[5-fluoro-3-(3 (2-pyridyl)prop-2-yn-1-yloxy)phenyl]-1-methoxypropyl]-thiazole in 54% yield, as an oil.
Reaction SMILES: [ClH:1].[C:2]1([C:8]2([C:15]([O:17][CH2:18][CH2:19][N:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[O:16])[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:38](O)[CH2:39][OH:40]>C1(C)C=CC=CC=1>[ClH:1].[C:2]1([C:8]2([C:15]([O:17][CH2:18][CH2:19][N:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:22])[CH3:23])=[O:16])[CH2:9][CH2:10][C:11]3([O:40][CH2:39][CH2:38][O:14]3)[CH2:12][CH2:13]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N(CCOC(=O)C1(c2ccccc2)CCC(=O)CC1)C(C)C
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)N(CCOC(=O)C1(c2ccccc2)CCC2(CC1)OCCO2)C(C)C

Procedure:
2-(Diisopropylamino)ethyl 1-phenyl-4-oxocyclohexanecarboxylate hydrochloride (3 mmol), prepared in Example 119, was refluxed for 4 h with p-toluenesulfonic acid (1.5 mmol) and ethyleneglycol (4 mmol) in toluene (50 mL) using a Dean-Stark trap. The reaction mixture was partitioned between Et2O and 2 M NaHCO3. The organic layer was dried (Na2SO4) and evaporated. The residue was dissolved in Et2O and HCl (g)/Et2O was added. The amine salt was recrystallized from acetone/Et2O to yield 0.53 g (43%); mp 121-128° C.; 1H NMR (CD3OD) δ 1.25 (d, 12H), 1.72 (m, 4H), 2.13 (m, 2H), 2.47 (m, 2H), 3.35 (t, 2H), 3.59 (m, 2H), 3.93 (m, 4H), 4.42 (t, 2H), 7.26-7.47 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:14]1[O:22][C:21]2[CH:20]=[CH:19][C:18]([CH2:23][C:24](O)=[O:25])=[CH:17][C:16]=2[O:15]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:24](=[O:25])[CH2:23][C:18]2[CH:19]=[CH:20][C:21]3[O:22][CH2:14][O:15][C:16]=3[CH:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Reactant: COc1ccc(CCN)cc1OC
Product: COc1ccc(CCNC(=O)Cc2ccc3c(c2)OCO3)cc1OC

Procedure:
prepared by reaction of 3,4-dimethoxyphenylethylamine and 3,4-methylenedioxyphenylacetic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CON(C)[C:11](=[O:23])[CH2:12][C:13]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:16][CH2:15][CH2:14]1>O1CCCC1.CCOCC.[NH4+].[Cl-]>[C:17]1([C:13]2([CH2:12][C:11]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[O:23])[CH2:16][CH2:15][CH2:14]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Brc1ccccn1
Reactant: CON(C)C(=O)CC1(c2ccccc2)CCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(CC1(c2ccccc2)CCC1)c1ccccn1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromopyridine (1.0 g, 4.3 mmol) in dry tetrahydrofuran (30 mL) 1.6 M n-butyl lithium in hexanes (4.8 mL) was added dropwise at −78° C. The mixture was kept at this temperature for 1 hour, followed by addition of a solution of Example 68D in tetrahydrofuran. At the end of addition, the mixture was allowed to reach ambient temperature and stirred at 60° C. for 2 hours. The mixture was then cooled to 0° C., and diluted with ether (50 mL) and saturated aqueous NH4Cl (60 mL). The organic phase was separated, dried over Na2SO4, filtered, and concentrated. The crude product was used in the next step without further purification (1.5 g, 5.97 mmol).
Reaction SMILES: [CH2:1]([NH:8][CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[N:12]=[C:13]([N:22]2[CH2:27][CH2:26][S:25](=[O:28])[CH2:24][CH2:23]2)[C:14]2[N:20]=[CH:19][N:18]=[C:17](Cl)[C:15]=2[N:16]=1>O1CCOCC1.O>[CH2:1]([N:8]([CH3:9])[C:17]1[C:15]2[N:16]=[C:11]([Cl:10])[N:12]=[C:13]([N:22]3[CH2:27][CH2:26][S:25](=[O:28])[CH2:24][CH2:23]3)[C:14]=2[N:20]=[CH:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNCc1ccccc1
Reactant: O=S1CCN(c2nc(Cl)nc3c(Cl)ncnc23)CC1
Solvent: O
Solvent: C1COCCO1
Product: CN(Cc1ccccc1)c1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12

Procedure:
A solution of 12.2 gm (0.1 mol) of N-benzyl-methylamine in 50 ml of dioxane was slowly poured, while stirring, into a suspension of 15.9 gm (0.05 mol) of 2,8-dichloro-4-(1-oxido-thiomorpholino)-pyrimido[5,4-d]-pyrimidine in about 250 ml of dioxane, and the resulting mixture was heated at 30°-40° C. for about 30 minutes. The reaction mixture was taken up in about 1 liter of water, whereby the reaction product was precipitated as a slightly yellow precipitate. After standing for a little while, the precipitate was filtered off, washed with water and dried at about 60° C.
Reaction SMILES: [OH-:1].[Na+].[C:3]([N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9](=O)[C:7]1=[O:8])(=[O:5])[CH3:4]>O>[C:7]([C:9]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:6][C:3](=[O:5])[CH:4]=1)([OH:1])=[O:8]
Reactant: CC(=O)N1C(=O)C(=O)c2ccccc21
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(=O)[nH]c2ccccc12
Yield: 77.6 %

Procedure:
To a solution containing 30 g of sodium hydroxide in 1.5 liter of water was added 58 g of the above-mentioned N-acetylisatin and the mixture was refluxed for 1 hour. Then the reaction mixture was cooled a certain extent, then activated carbon was added and further refluxed for 30 minutes. The activated carbon was removed from the reaction mixture by filtration while the mixture being hot, and the mother liquor was cooled, then 6N-hydrochloric acid was added to the mother liquor to adjust the pH thereof to pH 3-4. The crystals precipitated were colledted by filtration, washed with water, dried to obtain 45 g of 4-carboxycarbostyril.
Reaction SMILES: [Na].Br[CH:3]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:4]([CH3:9])([CH3:8])[C:5](=[O:7])[CH3:6]>C(O)C.O>[CH3:8][C:4]1([CH3:9])[CH:3]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:6][C:5]1=[O:7]
Reactant: CC(=O)C(C)(C)C(Br)c1ccc(Cl)cc1
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CC1(C)C(=O)CC1c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 15 h
Yield: 63.9 %

Procedure:
0.91 g (0.04 mol) of sodium is dissolved in 100 ml of ethanol and, at 20° C., 10.5 g (0.036 mol) of 1-bromo-1-(4-chlorophenyl)-2,2-dimethyl-3-butanone in 20 ml of ethanol are added. The reaction mixture is stirred at 20° C. for about 15 hours, diluted with water and neutralized. It is extracted with methylene chloride, dried with sodium sulphate and the solvent is distilled off from the filtrate under waterpump vacuum. The residue is purified by distillation under high vacuum. 4.8 g (65% of theory) of 2,2-dimethyl-3-(4-chlorophenyl)cyclobutanone of boiling point 98° to 107° C./0.05 mbar are obtained.