Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].CN(C=O)C.[OH-].[Na+].[CH2:19]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH:27]1[CH2:32]Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCOC(C)=O>[CH2:19]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH:27]1[CH2:32][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCC1COCCN1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC1COCCN1Cc1ccccc1)C(=O)OCC
Temperature: 80 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
Diethyl malonate (1.78 g, 11.1 mmol), DMF (25 mL), sodium hydroxide (0.22 g, 5.55 mmol) and 4-benzyl-3-(bromomethyl)morpholine (1 g, 3.7 mmol) (The compound was synthesized according to the procedure as described in Helvetica Chimica Acta, 87, 2004) were added to a dried flask in turn. The mixture was stirred at 80° C. for 4 hours under N2, and cooled to 25° C. The reaction mixture was diluted with EtOAc (200 mL). The organic layer was washed with brine (100 mL×6), dried over unhydrous Na2SO4. The crude product was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V)=15/1) to give the title compound as colorless oil (1.15 g, 89%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:18])[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6].[N:19]([O-])=[O:20].[Na+]>C(O)(=O)C.O>[OH:20][N:19]=[C:4]([C:3]([CH2:2][Cl:1])=[O:18])[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6]
Reactant: O=N[O-]
Reactant: O=C(CCl)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(CCl)C(=NO)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
In 100 ml of acetic acid is dissolved 50 g (0.184 mol, uncorrected for purity) of the crude p-nitrobenzyl γ-chloroacetoacetate obtained in 1), and the solution is cooled to 5° C. or lower, and a solution of 12.7 g (0.184 mol) of sodium nitrite in 50 ml of water is added dropwise thereto at 5° C. or lower over a period of an hour. After completion of the addition, the mixture is stirred for 30 minutes and poured into 600 ml of ice water and extracted with 300-ml and 200-ml portions of ethyl acetate. The organic layers are combined and washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated to dryness to give 54.0 g of p-nitrobenzyl α-hydroxyimino-γ-chloroacetoacetate as an oil.
Reaction SMILES: [CH:1]1[C:6]([C@H:7]2[O:16][C:15]3[CH:14]=[C:13]([OH:17])[CH:12]=[C:11]([OH:18])[C:10]=3[CH2:9][C@H:8]2[OH:19])=[CH:5][C:4]([OH:20])=[C:3]([OH:21])[CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[CH:29]=[CH2:30]>CC(C)=O>[CH2:30]([O:21][C:3]1[CH:2]=[CH:1][C:6]([CH:7]2[CH:8]([OH:19])[CH2:9][C:10]3[C:11]([OH:18])=[CH:12][C:13]([OH:17])=[CH:14][C:15]=3[O:16]2)=[CH:5][C:4]=1[OH:20])[CH:29]=[CH2:28].[CH2:30]([O:20][C:4]1[CH:5]=[C:6]([CH:7]2[CH:8]([OH:19])[CH2:9][C:10]3[C:11]([OH:18])=[CH:12][C:13]([OH:17])=[CH:14][C:15]=3[O:16]2)[CH:1]=[CH:2][C:3]=1[OH:21])[CH:29]=[CH2:28]
Reactant: C=CCBr
Reactant: Oc1cc(O)c2c(c1)O[C@H](c1ccc(O)c(O)c1)[C@H](O)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(C2Oc3cc(O)cc(O)c3CC2O)ccc1O
Product: C=CCOc1ccc(C2Oc3cc(O)cc(O)c3CC2O)cc1O
Reaction time: 4 h

Procedure:
To a mixture of (−)-epicatechin (1.16 g, 4 0 mmol) and potassium carbonate (1.10 g, 8.0 mmol) in dry acetone was added allyl bromide (0.41 mL, 4.8 mmol). The reaction was heated at reflux, under nitrogen, protected from light with vigorous stirring for 4 h. The reaction was filtered and concentrated onto silica gel. The crude product was purified on a Biotage 50 g silica gel column eluting with a gradient of 40-70% ethyl acetate/hexane and then 70% ethyl acetate/hexane. The major peak, corresponding to a mixture of monoallylated products, was isolated. This mixture was further purified by preparative reverse phase HPLC using a gradient of 1:9 to 8:2 acetonitrile/(0.2% formic acid/water) over 20 min. The appropriate fractions were frozen and lyophilized to give as white powders to provide 2-(4-Allyloxy-3-hydroxy-phenyl)-chroman-3,5,7-triol and 2-(3-Allyloxy-4-hydroxy-phenyl)-chroman-3,5,7-triol.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[H-].[Na+].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:27]3=[N:28][CH:29]=[N:30][C:31](Cl)=[C:26]3[CH:25]=[N:24]2)=[CH:19][CH:18]=1>C1COCC1>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([O:13][C:31]2[N:30]=[CH:29][N:28]=[C:27]3[N:23]([C:20]4[CH:19]=[CH:18][C:17]([Br:16])=[CH:22][CH:21]=4)[N:24]=[CH:25][C:26]=23)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Clc1ncnc2c1cnn2-c1ccc(Br)cc1
Reactant: CC(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)OC(=O)N1CCC(Oc2ncnc3c2cnn3-c2ccc(Br)cc2)CC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A mixture of 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (727 mg, 3.88 mmol), and sodium hydride (465 mg, 19.4 mmol) in THF (12 mL) was stirred for 30 min at 60° C. 1-(4-Bromo-phenyl)-4-chloro-1H-pyrazolo[3,4-d]pyrimidine was added to the mixture at room temperature and stirred for 1.0 hr at RT. The reaction was quenched with water and the product extracted in ethyl acetate. The organic layer was concentrated in vacuo to provide Compound A220 as a white solid (1.3 g, 81%). 1H NMR (CDCl3, 400 MHz) δ 1.19 (d, 6H), 1.73-1.85 (m, 2H), 1.98-2.08 (m, 2H), 3.26-3.34 (m, 2H), 3.78-3.87 (m, 2H), 4.88 (h, 1H), 5.54 (h, 1H), 7.57 (d, 2H), 8.07 (d, 2H), 8.13 (s, 1H), 8.55 (s, 1H). Exact mass calculated for C20H22BrN5O3 460.3, found 462.3 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][NH:6][C:7]1[C:16]2[C:17](=[O:24])[C:18]3[C:23]([C:15]=2[C:14]2[C:9](=[CH:10][C:11]([OH:25])=[CH:12][CH:13]=2)[N:8]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:3].[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:3][N:2]([CH2:4][CH2:5][NH:6][C:7]1[C:16]2[C:17](=[O:24])[C:18]3[C:23]([C:15]=2[C:14]2[C:9](=[CH:10][C:11]([O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:12][CH:13]=2)[N:8]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:1]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CN(C)CCNc1nc2cc(O)ccc2c2c1C(=O)c1ccccc1-2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CN(C)CCNc1nc2cc(OC(=O)C(C)(C)C)ccc2c2c1C(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
To a solution of 6-(((dimethylamino)ethyl)amino)-3-hydroxy-7H-indeno[2,1-c]quinoline-7-on obtained in example 3 (100 mg, 0.3 mmol) in dichloromethane (10 ml) was added 4-dimethylaminopyridine (100 mg, 0.8 mmol) and pivaloyl chloride (37 μl, 0.3 mmol), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added water to wash the organic layer, which was dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (eluent; chloroform:ethanol=10:1(v/v)) and crystallized from hexane to give 105 mg (yield: 80.0%) of title compound. The physicochemical properties thereof are shown in table 1.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:17])[O:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:8]([S:15][CH3:16])=[CH:7][CH:6]=1.C(OO)(=[O:20])C>C(OCC)(=O)C.CCCCCCC>[CH3:1][NH:2][C:3](=[O:17])[O:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:8]([S:15]([CH3:16])=[O:20])=[CH:7][CH:6]=1
Reactant: CC(=O)OO
Reactant: CNC(=O)Oc1ccc(SC)c2c1CCCC2
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CNC(=O)Oc1ccc(S(C)=O)c2c1CCCC2
Yield: 90 %

Procedure:
This compound was prepared in 90% yield by allowing a solution of 4-methylmercapto-5,6,7,8-tetrahydro-1-naphthyl N-methylcarbamate in ethyl acetate to slowly react at 35°-40° with one equivalent of peracetic acid in ethyl acetate. An ice bath was required to maintain the reaction temperature in the proper range. At the conclusion of the reaction, the solution was diluted with heptane and the resulting precipitate collected by filtration and washed thoroughly with heptane. After drying, the product melted at 135°-138°.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][CH2:39][F:40].O>CS(C)=O>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH2:38][CH2:39][F:40])[CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: O=C(NC(COCC1CCNCC1)c1ccccc1Cl)c1ccc2c(Cl)c[nH]c2c1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(NC(COCC1CCN(CCF)CC1)c1ccccc1Cl)c1ccc2c(Cl)c[nH]c2c1
Yield: 32.9 %

Procedure:
To a solution of 3-chloro-N-[1-(2-chlorophenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (600 mg, 1.3 mmol) in 6 mL of DMSO was added potassium carbonate (716 mg, 5.2 mmol) and 2-bromo-1-fluoroethane (0.10 mL, 1.1 mmol). The reaction was allowed to stir at room temperature overnight after which time water was added and the resulting precipitate was isolated by filtration. Purification of the filtrate (SiO2: EtOAc) provided 178 mg (28%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:14].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[C:34]([C:36]1[CH:37]=[C:38]([S:43](Cl)(=[O:45])=[O:44])[CH:39]=[CH:40][C:41]=1[F:42])#[N:35]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([S:43]([C:38]2[CH:39]=[CH:40][C:41]([F:42])=[C:36]([C:34]#[N:35])[CH:37]=2)(=[O:44])=[O:45])[C:6]=1[CH3:14]
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(F)c(C#N)c2)c2ncccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (0.5 g, 2.45 mmol) in DMF (3 mL) is added BEMP (1.13 mL, 3.92 mmol). After 1 hour, a solution of 3-cyano-4-fluoro-benzenesulfonyl chloride (0.86 g, 3.92 mmol) in DMF (3 mL) is added. The reaction mixture is stirred at room temperature overnight, then concentrated under reduced pressure to a minimum volume. The residue is loaded onto a pre-packed Isolute™ silica column and eluted using a gradient eluent from 100% iso-hexane to 50% EtOAc in iso-hexane to afford [1-(3-cyano-4-fluoro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester; MH+=388.
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][N:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:22]1[CH2:26][CH2:25][CH2:24]C1.[CH:27]([Mg]Cl)([CH3:29])[CH3:28]>CCOCC>[C:16]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][N:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([C:26]3([OH:22])[CH2:7][CH2:8][N:9]([CH2:28][CH:27]([C:29]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:6]4[CH:1]=[CH:2][CH:3]=[CH:4][CH:5]=4)[CH2:24][CH2:25]3)[CH2:10]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CCN(CC(c2ccccc2)c2ccccc2)CC1
Reactant: CC(C)[Mg]Cl
Reactant: C1CCOC1
Solvent: CCOCC
Product: O=C1CCN(CC(c2ccccc2)c2ccccc2)CC1C1(O)CCN(CC(c2ccccc2)c2ccccc2)CC1

Procedure:
The solution of 4 parts of 1-(2,2-diphenylethyl)-4-piperidinone in 50 parts by volume of tetrahydrofuran is cooled in an ice bath with stirring. To this solution is added 9.8 parts by volume of 2.2 M solution of isopropylmagnesium chloride in ether, and the resultant mixture is stirred for about 75 minutes at 0° C., and then quenched with the careful addition of 50 parts by volume of 10% ammonium chloride solution. The organic layer is separated and the aqueous phase is extracted with additional ethyl ether. The combined organic fractions are dried and concentrated to give yellow oil. This oil is chromatographed on silica gel using 10% acetone-methylene chloride mixture as the eluant to give yellow glass which upon trituration with heptane and recrystallization from a minimal amount of 95% ethanol affords 1-(2,2-diphenylethyl)-3-[1-(2,2-diphenylethyl)-4-hydroxypiperidin-4-yl]-4-piperidinone, melting at about 125°-127° C. This compound is represented by the following structural formula ##STR37##
Reaction SMILES: [CH3:1][N:2]([CH3:47])[CH2:3][CH2:4][C:5]([NH:7][C@:8]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:9]1[C@@H:10]1[C@@:23]([CH3:26])([CH2:24][CH2:25]2)[C@@:22]2([CH3:27])[C@@H:13]([C@:14]3([CH3:40])[C@@H:19]([CH2:20][CH2:21]2)[C:18]([CH3:29])([CH3:28])[C:17]([C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36]C)=[O:35])=[CH:32][CH:31]=2)=[CH:16][CH2:15]3)[CH2:12][CH2:11]1)=[O:6].C(O)(C(F)(F)F)=O.O.[OH-].[Li+]>C1COCC1.O>[CH3:47][N:2]([CH3:1])[CH2:3][CH2:4][C:5]([NH:7][C@:8]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:9]1[C@@H:10]1[C@@:23]([CH3:26])([CH2:24][CH2:25]2)[C@@:22]2([CH3:27])[C@@H:13]([C@:14]3([CH3:40])[C@@H:19]([CH2:20][CH2:21]2)[C:18]([CH3:29])([CH3:28])[C:17]([C:30]2[CH:31]=[CH:32][C:33]([C:34]([OH:36])=[O:35])=[CH:38][CH:39]=2)=[CH:16][CH2:15]3)[CH2:12][CH2:11]1)=[O:6]
Reactant: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 75 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate, TFA (87.9 mg, 0.116 mmol) in THF (5 mL) was added a solution of lithium hydroxide monohydrate (19.49 mg, 0.464 mmol) in water (1.00 mL). The reaction was stirred at 75° C. After 8 h, the reaction was concentrated to dryness. The crude material was dissolved in THF (1 mL) and MeOH (1.5 mL), filtered and purified by reverse phase preparative HPLC using HPLC method 1 to give the title compound (59.5 mg, 0.078 mmol, 67.6% yield) as a white solid. LCMS: m/e 629.4 (M+H)+, 4.17 min (method 8). 1H NMR (500 MHz, METHANOL-d4) δ=7.95 (d, J=8.2 Hz, 2H), 7.24 (d, J=8.2 Hz, 3H), 5.33 (dd, J=1.5, 6.1 Hz, 1H), 4.80 (d, J=1.5 Hz, 1H), 4.67 (s, 1H), 3.40 (t, J=6.6 Hz, 2H), 2.92 (s, 6H), 2.88-2.69 (m, 4H), 2.42 (dd, J=8.4, 12.4 Hz, 1H), 2.18 (dd, J=6.4, 17.1 Hz, 1H), 2.05-1.89 (m, 2H), 1.83 (d, J=11.3 Hz, 1H), 1.79-1.76 (m, 1H), 1.75 (s, 3H), 1.74-1.71 (m, 1H), 1.66-1.56 (m, 3H), 1.56-1.49 (m, 4H), 1.47-1.28 (m, 5H), 1.22-1.17 (m, 1H), 1.16 (s, 3H), 1.15-1.10 (m, 1H), 1.07 (s, 6H), 0.99 (s, 3H), 0.97 (s, 3H). 13C NMR (MeOD) δ ppm 14.5, 16.1, 16.8, 19.1, 20.6, 21.3, 22.1, 26.2, 28.2, 29.4, 29.7, 30.4, 34.5, 35.5, 37.1, 38.1, 38.2, 41.5, 42.5, 42.8, 43.2, 47.6, 49.3, 50.1, 50.5, 54.0, 55.1, 66.4, 110.4, 124.9, 129.5, 130.9, 147.4, 149.6, 150.8, 169.6, 171.0.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:23]=[CH:22][C:21]3[N:20]([CH3:24])[C:19](=[O:25])[CH2:18][N:17]([CH:26]([CH3:28])[CH3:27])[C:16]=3[N:15]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:6])=[O:5].C(N(C(C)C)C(C)C)C.[S:38](Cl)([CH3:41])(=[O:40])=[O:39].O>ClCCl.CN(C)C1C=CN=CC=1>[CH:26]([N:17]1[C:16]2[N:15]=[C:14]([NH:13][C:9]3[CH:8]=[C:7]([S:4]([CH2:3][CH2:2][O:1][S:38]([CH3:41])(=[O:40])=[O:39])(=[O:5])=[O:6])[CH:12]=[CH:11][CH:10]=3)[N:23]=[CH:22][C:21]=2[N:20]([CH3:24])[C:19](=[O:25])[CH2:18]1)([CH3:28])[CH3:27]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Nc3cccc(S(=O)(=O)CCO)c3)nc21
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cccc(S(=O)(=O)CCOS(C)(=O)=O)c3)nc21
Temperature: 0 °C
Yield: 63 %

Procedure:
2-(3-(2-Hydroxyethylsulfonyl)phenylamino)-8-isopropyl-5-methyl-7,8-dihydropteridin-6(5H)-one (1.45 g; 3.576 mmol) was dissolved in 35 mL dichloromethane, ethyldiisopropylamine (0.92 mL; 5.360 mmol) and 4-dimethylaminopyridine (cat.) were added. Then the mixture was cooled to 0° C. and mesylchloride (0.332 ml; 4.290 mmol) was added slowly. The reaction mixture was allowed to get to room temperature and after 4 h water was added and the mixture was extracted with dichloromethane. Drying of the organic layer with sodium sulphate and removal of the solvents gave 1.1 g (2.275; 63% yield) of intermediate the desired product as foam.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.O.[OH:9][CH:10]([C:14]1[S:18][C:17]([NH2:19])=[N:16][CH:15]=1)[C:11]([OH:13])=[O:12].[CH:20](O)=[O:21]>>[CH:1]([O:9][CH:10]([C:14]1[S:18][C:17]([NH:19][CH:20]=[O:21])=[N:16][CH:15]=1)[C:11]([OH:13])=[O:12])=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: O=CO
Reactant: Nc1ncc(C(O)C(=O)O)s1
Agent: N=c1[nH]cc(C(O)C(=O)O)s1
Solvent: O
Product: O=CNc1ncc(C(OC=O)C(=O)O)s1
Reaction time: 2 h

Procedure:
A mixture of formic acid (10 m mol) and acetic anhydride (10 m mol) was stirred for 2 hours at 50° to 60° C. and then cooled to -7° to -5° C. To the mixture was added 2-hydroxy-2-(2-amino-1,3-thiazol-5-yl)acetic acid hydrate, which can be represented as 2-hydroxy-2-(2-imino-2,3-dihydro-1,3-thiazol-5-yl)acetic acid hydrate, (0.48 g.) at the same temperature, and the mixture was stirred for 3 hours at the same temperature. To the mixture was further added a mixture of formic acid (2.5 m mol) and acetic anhydride (2.5 m mol) at the same temperature and then the mixture was further stirred for 1 hour at the same temperature. After the reaction, the solvent was distilled off. To the residue were added water and methyl isobutyl ketone and then the insoluble material was filtered off. The filtrate was treated with an activated charcoal, and the methyl isobutyl ketone layer was separated. The remaining aqueous layer was further extracted with methyl isobutyl ketone. The methyl isobutyl ketone layers were combined together, dried over magnesium sulfate, treated with an activated charcoal, and then the solvent was distilled off. The residue was pulverized in diethyl ether to give powder of 2-formyloxy-2-(2-formylamino-1,3-thiazol-5-yl)acetic acid, which can be represented as 2-formyloxy-2-(2-formylimino-2,3-dihydro-1,3-thiazol-5-yl)acetic acid, (0.31 g.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[C:11]([F:16])[C:10]=1[N:17]1[S:21](=[O:23])(=[O:22])[NH:20][C:19](=[O:24])[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[I-:26].CN[C@@H]1CCCC[C@H]1NC>O1CCOCC1.[Cu]I>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([I:26])[CH:12]=[C:11]([F:16])[C:10]=1[N:17]1[S:21](=[O:23])(=[O:22])[NH:20][C:19](=[O:24])[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(c2c(F)cc(Br)cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: [I-]
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C1CN(c2c(F)cc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Temperature: 140 °C

Procedure:
A mixture of 5-(2-benzyloxy-4-bromo-6-fluorophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (1.0 g, 2.21 mmol), NaI (1.18 g, 7.87 mmol), CuI (91 mg, 0.48 mmol) and (1R,2R)—N,N′-dimethylcyclohexane-1,2-diamine (136 mg, 0.96 mmol) in dioxane (15.5 mL) is heated at 140° C. for 1.5 h in a microwave. The reaction mixture is filtered through Celite and washed with additional dioxane. It is then concentrated to a smaller volume and used directly in the next step: MS (M−H)−=461.
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][C:8]([CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[S:21]1[CH2:27][C:25](=[O:26])[NH:24][C:22]1=[S:23].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:1]([C:5]1[CH:20]=[CH:19][C:8]([CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[C:27]3[S:21][C:22](=[S:23])[NH:24][C:25]3=[O:26])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(COc2ccc(C=O)cc2)cc1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(COc2ccc(C=C3SC(=S)NC3=O)cc2)cc1

Procedure:
The 4-[(4-t-butyl)benzyloxy]benzaldehyde (2.6 g, 9 mmol) was then coupled with rhodanine (1.4 g, 10.5 mmol) by adding the reactants to sodium acetate (2.9 g, 36 mmol) and acetic acid. The reaction mixture was then heated to reflux and refluxed overnight.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[C:6](/Cl)=[N:7]\[OH:8])=[O:5].[CH2:10]([O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[CH2:11][C:12]#[CH:13].C(N(CC)CC)C>C(OCC)C>[O:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]1[O:14][CH2:10][CH2:11][C:12]1[O:8][N:7]=[C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:13]=1
Reactant: CCOC(=O)/C(Cl)=N\O
Reactant: C#CCCOC1CCCCO1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(CCOC2CCCCO2)on1

Procedure:
Ethyl chlorooximidoacetate (1 g, 6.60 mmol) and 2-(but-3-ynyloxy)tetrahydro-2H-pyran (3.05 g, 19.80 mmol) were dissolved in diethyl ether (20 ml). Triethylamine (0.668 g, 6.60 mmol) was diluted with diethyl ether (10 ml) and added dropwise into previous mixture. After addition the reaction mixture was extracted with water and the organic layer was dried with Na2SO4, filtered and evaporated. LC-MS: [M+1]=172.17.
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[C@@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9](Br)=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].C([Li])(C)(C)C.C[Si]([N:28]=[C:29]=[O:30])(C)C>O1CCCC1>[CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[C@H:5]1[CH2:6][C:7]2[CH:8]=[C:9]([C:29]([NH2:28])=[O:30])[CH:10]=[CH:11][C:12]=2[CH2:13][CH2:14]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)[C@@H]1CCc2ccc(Br)cc2C1
Reactant: C[Si](C)(C)N=C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCCN(CCC)[C@@H]1CCc2ccc(C(N)=O)cc2C1
Reaction time: 0.13 h
Yield: 132.4 %

Procedure:
A solution of (R)-2-(dipropylamino)-7-bromo-1,2,3,4-tetrahydronaphthalene (7) (13.02 g) in dry tetrahydrofuran was cooled to -78° C. t-Butyllithium (1.7 M in pentane, 50.6 ml) was added via syringe over a period of 6 minutes, and the mixture was stirred for an additional 8 minutes. Trimethylsilylisocyanate (13.4 ml, 85% pure, 84.1 mmol) was added in one dose, and the mixture stirred at -78° C. for 10 minutes and at room temperature for 1.5 hours. The reaction mixture was quenched with 10% hydrochloric acid, and after stirring for 30 minutes, it was basified with 15% sodium hydroxide. The free base was extracted with diethylether and 1:1 tetrahydrofuran/diethylether. The combined extracts were washed with brine and dried (MgSO4). The solvent was removed under vacuum to leave an oil (15.25 g). Crystallization from ethyl acetate/hexane gave off-white crystals (6.30 g), m.p. 132-132° C. [α]D =+67° (25° C., CH3OH, c=0.8139).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH:9]1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:22]Br>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([Br:22])[C:10](=[O:14])[CH:9]1[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Br)C(=O)C1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.3 %

Procedure:
To a solution of 2-benzyl-3-oxo-piperidine-1-carboxylic acid tert-butyl ester (25.9 g, 0.09 mol) in CHCl3 (200 mL) was added Br2 (15.8 g, 0.099 mol, dissolved into 80 mL of CHCl3) dropwise at 0° C. After the addition, the mixture was stirred at 25° C. for 2 hrs, and then it was filtered. The filtrate was washed with saturated NaHSO3 and brine, dried over Na2SO4 and concentrated under reduced pressure to afford crude 2-benzyl-4-bromo-3-oxo-piperidine-1-carboxylic acid tert-butyl ester (18 g) as brown oil, which was used directly in the next step.