Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[CH:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([CH3:15])[CH3:14]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH:13]([CH3:15])[CH3:14])=[CH:17][CH:18]=2)(=[O:24])=[O:23])=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2CCCN2)cc1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)c1ccc(S(=O)(=O)N2CCCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, white solid, m.p. 77° C. and MS: m/e=347 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-isopropyl-benzenesulfonyl chloride.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][OH:13])[CH:3]=1.FC(F)(F)C(O)=O.N1C=CC=CC=1.C(O)(=O)C(O)=O>CCOCC.CO.O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH:12]=[O:13])[CH:3]=1
Reactant: Cc1cn(CCO)c2ccccc12
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1cn(CC=O)c2ccccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
N,N-dicyclohexylcarbodiimide (9.0 g) is added to a cooled, stirred solution of 3-methylindole-1-ethanol (3.0 g) in 30 ml of dimethyl sulfoxidebenzene (2:1) containing trifluoroacetic acid (0.6 ml) and pyridine (1.12 ml). The reaction is stirred at room temperature under nitrogen for 5 hours. The reaction mixture is now diluted with 300 ml of ether, followed by the dropwise addition of a solution of oxalic acid (3.78 g) in 11 ml of methanol. After 30 minutes, water (300 ml) is added and the insoluble material is collected. The organic phase is washed with water (2X), 5% aqueous sodium bicarbonate (2X) and water (2X). After drying (MgSO4) the organic phase is evaporated to yield 3-methylindole-1-acetaldehyde. The latter compound is then converted to its corresponding gem-dithiol with hydrogen sulfide and reduced with lithium aluminium hydride according to the method of T.L. Cairns et al., J. Amer. Chem. Soc., 74, 3982 (1952), to yield the title compound, γ maxCHCl3 2570 cm-1.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[CH2:8]([OH:11])[CH:9]=[CH2:10].[H-].[Na+]>O>[CH2:8]([O:11][C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1)[CH:9]=[CH2:10]
Reactant: Brc1cncnc1
Reactant: C=CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: C=CCOc1cncnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.8 %

Procedure:
5-Bromo-pyrimidine (0.063 mol) was slowly added to 2-propen-1-ol (4.03 mol) at 0° C. and this mixture was stirred at room temperature for 1 hour. Then NaH 60% (0.126 mol) was added and the reaction mixture was stirred and refluxed for 48 hours. Water was added and the mixture was extracted with ethyl acetate. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified by short open column chromatography over silica gel (eluent: hexane/ethyl acetate 50/50). The desired fractions were collected and the solvent was evaporated, yielding 2.3 g of 5-(2-propenyloxy)-pyrimidine (intermediate 48).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O.C(Cl)(=O)C(Cl)=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:8][CH2:9][CH2:10][C:11]2=[O:13]
Reactant: O=C(O)CCCc1ccccc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: O=C1CCCc2c(Br)cccc21
Temperature: 0 °C
Yield: 92 %

Procedure:
To a benzene solution (60 ml) of 4-(o- bromophenyl) butyric acid (5 g) was added oxalyl chloride (3.6 ml) and the reaction refluxed for 1 1/2 hrs. The solution was evaporated to dryness, the residue was dissolved in CH2Cl2 (50 ml) then cooled to 0° C., followed by the addition of AlCl3 (3.1 g). The mixture was stirred at 0° C. warming to room temperature overnight. The reaction was poured onto ice, then extracted with CH2Cl2. The organic layer was separated, washed with IN NaOH, then brine, separated, dried (MgSO4), filtered and evaporated affording the desired product (4.26 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:21][C:22]([F:25])([F:24])[F:23])[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:10]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[F:24][C:22]([F:23])([F:25])[CH2:21][N:7]1[C:6]([CH2:4][OH:3])=[CH:10][C:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=2)=[N:8]1
Reactant: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)nn1CC(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1cc(-c2ccc(C(F)(F)F)cc2)nn1CC(F)(F)F

Procedure:
In analogy to the procedure described for example 1 a], 2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethyl-phenyl)-2H-pyrazole-3-carboxylic acid ethyl ester was reduced with lithium aluminium hydride to give [2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-methanol as colorless crystals.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][O:26][C:27](=[O:37])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]=[C:35]=[O:36])[CH:29]=1>O1CCCC1>[C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:35]([NH:34][C:30]4[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=4)[C:27]([O:26][CH3:25])=[O:37])=[O:36])[CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc(N=C=O)c1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added methyl-3-isocyanatobenzoate (216 mg, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 102 mg (29.7%) of the desired product as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[CH3:2].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.BrBr.[ClH:25]>O1CCOCC1.CCOCC>[ClH:25].[N:18]1([C:9]2[NH:10][C:11]3[C:16]([C:8]=2[CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:17])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)CCCc1c[nH]c2ccccc12
Agent: BrBr
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCOC(=O)CCCc1c(-n2ccnc2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl-4-(3-indolyl)butyrate (3.00 g) and imidazole (4.43 g) in dioxane (75 ml) stirring at 10° is added dropwise while stirring a solution of bromine (0.65 ml) in dioxane (25 ml) over a period of 2.5 hours. Immediately upon the addition of bromine the reaction mixture becomes a thick suspension. Additional dioxane (30 ml) is added to keep the reacton mixture more mobile. Upon complete addition to cooling bath is removed and the reaction mixture allowed to stir at room temperature overnight. The suspended solid is removed by vacuum filtration and the filtrate concentrated in vacuo to give an orange oil. This oil is suspended in either (100 ml) and extracted with 1N hydrochloric acid (1×50 ml). The aqueous layer is washed with ether (1×100 ml), made basic with 3 N sodium hydroxide (12 ml), and extracted with ether (2×100 ml). This ether extract is washed with brine, dried (MgSO4 ), filtered, and concentrated in vacuo to give an orange oil which becomes partially crystalline. This material (1.38 g) is dissolved in 20 ml ether and to the solution is added 0.65 ml of 7.1M ethanolic hydrogen chloride. The salt separates as an oil which crystallizes on addition of a few milliliters of ethanol to yield 2-(1-imidazolyl)-3-(-3-ethoxycarbonylpropyl)indole hydrochloride, m.p. 152°-155°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([CH2:15][C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])[C:12]3[N:24]=[CH:25][N:26](COCC[Si](C)(C)C)[C:11]=3[C:10]=2[C:35]#[N:36])[CH:5]=[CH:4][C:3]=1[N:37]1[CH2:42][CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39][CH2:38]1.O.C(=O)(O)[O-:52].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([CH2:15][C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])[C:12]3[N:24]=[CH:25][NH:26][C:11]=3[C:10]=2[C:35]([NH2:36])=[O:52])[CH:5]=[CH:4][C:3]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(Cc4c(Cl)cccc4Cl)c4ncn(COCC[Si](C)(C)C)c4c3C#N)cc2Cl)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NC(=O)c1c(Nc2ccc(N3CCNCC3)c(Cl)c2)nc(Cc2c(Cl)cccc2Cl)c2nc[nH]c12
Temperature: 95 °C

Procedure:
To a solution of the product of Example 18C (100 mg, 0.14 mmol) in concentrated sulfuric acid (5 mL) was added water (1 mL) at 0° C. and the mixture was heated at 95° C. for 20 minutes. After cooling to ambient temperature, water (3 mL) was added, and the mixture was adjusted to pH 8-9 with saturated aqueous sodium bicarbonate and extracted with dichloromethane (3×20 mL). The combined organic phase was concentrated and the residue was purified by preparative HPLC using a gradient of 10/90 to 75/25 acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound. 1H NMR (DMSO-d6, 300 MHz): δ 13.62 (s, 1 H), 11.85 (s, 1 H), 9.62 (s, 1 H), 8.69 (s, 2 H), 8.61 (s, 1 H), 7.85 (br, 1 H), 7.58 (m, 1 H), 7.55 (m, 1 H), 7.52 (d, J=2.4 Hz, 1 H), 7.42-7.37 (m, 1 H), 7.15 (dd, J=9, 2.4 Hz, 1 H), 6.85 (d, J=9 Hz, 1 H), 4.74 (s, 2 H), 3.27 (m, 4 H), 2.08-1.70 (m, 4 H). MS: 530 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4](/[CH:12]=[CH:13]\[S:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:5]([C:7](OCC)=[O:8])[N:6]=1.[NH3:34].O1CCOCC1>>[NH2:1][C:2]1[S:3][C:4](/[CH:12]=[CH:13]\[S:14][C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:5]([C:7](=[O:8])[NH2:34])[N:6]=1
Reactant: N
Reactant: CCOC(=O)c1nc(N)sc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: NC(=O)c1nc(N)sc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
In the same manner as in step b) in Example 3 and step c) in Example 3, 197 mg of the title compound was prepared from 501 mg of 2-amino-4-ethoxycarbonyl-5-((Z)-2-tritylthioethen-1-yl)thiazole and 8 ml of a 0.5 M ammonia/dioxane solution.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:8]([CH2:27][CH2:28][CH2:29][OH:30])[N:9]2[C:14]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[N:10]2)=[O:5])[CH3:2].CI.[CH3:38]COCC.CCCCCC>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:8]([CH2:27][CH2:28][CH2:29][O:30][CH3:38])[N:9]2[C:14]=1[C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([N:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1)=[N:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCOCC3)nn2c1CCCO
Reactant: CCOCC
Solvent: CCCCCC
Solvent: CC#N
Solvent: CI
Product: CCOC(=O)c1c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCOCC3)nn2c1CCCOC

Procedure:
A solution of 41 (10.4 mg, 0.022 mmol), MeI (24 μL, 0.389 mmol), and Ag2O (25 mg, 0.108 mmol) in CH3CN (1 mL) was heated at 80° C. for 24 h. The reaction mixture was filtered through celite and washed with CH2Cl2. The filtrate was concentrated in vacuo and purified by TLC (silica gel, 35% EtOAc/hexane) to provide a yellow oil. The oil was sonicated in 2:1 Et2O/hexane to provide the title compound as an off-white solid. 1H NMR (DMSO-d6) δ 0.88 (t, J=7.1 Hz, 3H), 1.21 (t, J=7.1 Hz, 3H), 1.87 (m, 2H), 3.20 (m, 2H), 3.21 (s, 3H), 3.52 (m, 8H), 3.72 (m, 4H), 4.17 (q, J=7.1 Hz, 2H), 6.77 (s, 1H), 7.40 (m, 2H), 7.46 (m, 3H). Mass Spectrum (ESI+) m/e=496.2 (M+H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C([O-])(=O)C.[NH4+]>[C:14]([CH:9]1[CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11][C:10]1=[O:13])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CCC(c2ccccc2)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC(=O)C1CC(c2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.3 %

Procedure:
40% Boron trifluoride-acetic acid complex, 5.5 g, was ice-cooled and a mixture of 2 g of 4-phenylcyclohexanone and 2.35 g of acetic anhydride was dropwise added to the complex. After stirring for 30 minutes under ice cooling and at room temperature for 4 hours, 10 ml of saturated ammonium acetate aqueous solution was added to the mixture followed by stirring at 80° C for 1.5 hours. The reaction mixture was extracted with ether and the extract was purified to obtain 1.77 g of 2-acetyl-4-phenylcyclohexanone.
Reaction SMILES: [CH2:1]([CH:4]([CH2:12][CH2:13][CH3:14])[C:5]([NH:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6])[CH2:2][CH3:3].C1(N=C=NC2CCCCC2)CCCCC1.[C:30]([O:49][CH2:50][C@H:51]1[O:55][C@@H:54]([N:56]2[CH:63]=[C:62]([F:64])[C:60](=[O:61])[NH:59][C:57]2=[O:58])[CH2:53][C@@H:52]1O)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:12]([CH:4]([CH2:1][CH2:2][CH3:3])[C:5]([NH:7][CH2:8][C:9]([O:11][C@@H:52]1[C@@H:51]([CH2:50][O:49][C:30]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:55][C@@H:54]([N:56]2[CH:63]=[C:62]([F:64])[C:60](=[O:61])[NH:59][C:57]2=[O:58])[CH2:53]1)=[O:10])=[O:6])[CH2:13][CH3:14]
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)cc1F
Reactant: CCCC(CCC)C(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(CCC)C(=O)NCC(=O)O[C@H]1C[C@H](n2cc(F)c(=O)[nH]c2=O)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 70.8 %

Procedure:
To a suspension in which 0.11 g of N-(2-n-propyl-n-pentanoyl)glycine was suspended in 15 ml of methylene chloride was added 0.11 g of dicyclohexylcarbodiimide under ice-cooling and stirring, and then the mixture was stirred under ice-cooling for one hour. Then, 0.27 g of 2'-deoxy-5'-O-trityl-5-fluorouridine, 70 mg of triethylamine and 34 mg of 4-(N,N-dimethylamino)pyridine were added to the mixture, and the mixture was reacted at room temperature for two days under stirring. Thereafter, the reaction mixture was treated according to the same method as in Reference example 5 to give 0.26 g (Yield: 70%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([O:17][C@@H:18]3[O:44][C@H:43]([CH2:45][O:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[C@@H:35]([O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[C@H:27]([O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C@H:19]3[O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[N:11][NH:12][C:13]=2[CH:14]([CH3:16])[CH3:15])=[C:4]([CH3:53])[CH:3]=1.Br[CH2:55][CH2:56][CH2:57][Cl:58].[OH-].[Na+].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[Cl:58][CH2:57][CH2:56][CH2:55][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([O:17][C@@H:18]3[O:44][C@H:43]([CH2:45][O:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[C@@H:35]([O:36][C:37](=[O:42])[C:38]([CH3:39])([CH3:41])[CH3:40])[C@H:27]([O:28][C:29](=[O:34])[C:30]([CH3:31])([CH3:32])[CH3:33])[C@H:19]3[O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:23])[CH3:24])=[N:11][NH:12][C:13]=2[CH:14]([CH3:16])[CH3:15])=[C:4]([CH3:53])[CH:3]=1
Reactant: Cc1cc(O)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)n[nH]c1C(C)C
Reactant: ClCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1cc(OCCCCl)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)n[nH]c1C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[(4-hydroxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (8.58 g), 1-bromo-3-chloropropane (2.85 mL) and tetra(n-butyl)ammonium bromide (1.86 g) in tetrahydrofuran (43 mL) was added 5 mol/L aqueous sodium hydroxide solution (5.76 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The extract was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in n-hexane (15 mL)-diisopropyl ether (5 mL) under reflux condition. The solution was cooled to room temperature, and n-hexane (25 mL) was added to the solution. The precipitated crystals were collected by filtration, and the crystals were washed with n-hexane and dried under reduced pressure to give the title compound (6.06 g).
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[Si:13]([O:20][C:21]1[CH:26]=[C:25]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[N:24]=[C:23]([S:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[N:22]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].CI>O1CCCC1>[Si:13]([O:20][C:21]1[CH:26]=[C:25]([O:27][Si:28]([C:31]([CH3:33])([CH3:34])[CH3:32])([CH3:29])[CH3:30])[N:24]=[C:23]([S:35][CH:36]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[CH3:1])[N:22]=1)([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(O[Si](C)(C)C(C)(C)C)nc(SCc2ccccn2)n1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(Sc1nc(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)n1)c1ccccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.8 %

Procedure:
A solution of n-butyllithium (11.02 ml, 17.63 mmol, 1.2 equiv., 1.6 M in hexanes) in 60 ml of tetrahydrofuran cooled at -78° C. is treated dropwise with diisopropylamine (1.93 g, 19.10 mmol, 1.3 equiv.) over a two minute period. After stirring for another 10 min, a solution of 4,6-di-(tert-butyldimethylsilyloxy)-2-(2-pyridylmethyl)thio-pyrimidine (6.80 g, 14.69 mmol) in 16 ml of tetrahydrofuran is added dropwise over a 10 min period. The reaction mixture is stirred for 30 min longer and treated dropwise with methyl iodide (2.29 g, 16.16 mmol, 1.1 equiv.) in 6 ml of tetrahydrofuran over a 3 min period. Stirring is facilitated by adding an additional 30 ml of tetrahydrofuran. One hour after the addition of the methyl iodide, the cooling bath is removed and the mixture allowed to warm to room temperature. The contents are then cast into ice water and extracted once with ethyl acetate. The organic layer washed with saturated brine, dried with anhydrous Na2SO4 and concentrated at reduced pressure. A methylene chloride solution of the crude product was treated with silica gel (36 g), concentrated to a free flowing powder and applied to the top of a 350 g silica gel column, packed and eluted with ethyl acetate-hexane (5:95), to obtain 2.23 g (32%) 4,6-di-(tert-butyldimethylsilyloxy)-2-(1-(2-pyridyl)ethyl)thio-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:12].N1C=CC=CC=1.Cl[C:20]([CH2:22][O:23][C:24](=[O:26])[CH3:25])=[O:21]>O1CCCC1>[F:12][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH:1][C:20]([CH2:22][O:23][C:24](=[O:26])[CH3:25])=[O:21])[NH:8][C:7](=[O:11])[CH2:6]2
Reactant: CC(=O)OCC(=O)Cl
Reactant: Nc1cc2c(cc1F)CC(=O)N2
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)Nc1cc2c(cc1F)CC(=O)N2
Temperature: -40 °C
Yield: 70.4 %

Procedure:
6-Amino-5-fluoro-1,3-dihydro-indol-2-one 3d (500 mg, 3.0 mmol) was dissolved in 10 ml of tetrahydrofuran under stirring, and added with 0.4 ml of pyridine to the solution at room temperature. After stirring to mix well, the mixture was cooled down to −40° C. in a dry ice-acetone bath. A solution of acetic acid chlorocarbonylmethyl ester (420 mg, 3.0 mmol) in 10 ml of tetrahydrofuran was added dropwise to the above reaction system. Upon completion of the addition, the dry ice-acetone bath was removed, and the reaction mixture was allowed to warm up to room temperature and stirred overnight. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was filtered. The resulting solid was washed with water for three times and dried to obtain the title compound acetic acid (5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl)-methyl ester 27a (562 mg, yield 70.4%) as a gray solid.
Reaction SMILES: N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[N:24]1[CH2:28][CH2:27][NH:26][C:25]1=[O:29].Br[C:31]1[S:32][C:33]([CH3:36])=[CH:34][CH:35]=1>C(Cl)(Cl)Cl.[Cu](I)I.CO.O1CCOCC1>[CH3:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[N:24]1[CH2:28][CH2:27][N:26]([C:31]2[S:32][C:33]([CH3:36])=[CH:34][CH:35]=2)[C:25]1=[O:29]
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: Cc1ccc(Br)s1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: CO
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(N2CCN(c3cnccc3C)C2=O)s1
Temperature: 110 °C
Yield: 74 %

Procedure:
Copper iodide (16 mg, 0.084 mmol), trans-1,2-diamino cyclohexane (28.8 mg, 0.25 mmol) and potassium phosphate (445 mg, 2.1 mmol) were added to 1,4-Dioxane (10 mL) previously degassed with argon (10 minutes). The reaction mixture was purged with argon for a further 10 minutes, followed by the addition of 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.84 mmol) and 2-bromo-5-methylthiophene (150 mg, 0.84 mmol). The resulting mixture was heated to reflux at 110° C. for 4 hours. The reaction was monitored by TLC (10% MeOH in chloroform). The reaction mixture was filtered through celite and the celitebed was washed with chloroform. The organic layer was dried over Na2SO4 and concentrated. The concentrate was quenched with ice, the precipitate formed was collected and dried to afford 170 mg (74% yield) of 1-(4-methyl-pyridin-3-yl)-3-(5-methyl-thiophen-2-yl)-imidazolidin-2-one.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH3:25][S:26]([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)(=[O:28])=[O:27]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:34]4[CH:35]=[CH:36][C:31]([CH2:30][NH:29][S:26]([CH3:25])(=[O:27])=[O:28])=[CH:32][CH:33]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CS(=O)(=O)NCc1ccc(B(O)O)cc1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4ccc(CNS(C)(=O)=O)cc4)cc32)N=C1N
Temperature: 120 °C
Yield: 16.7 %

Procedure:
Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4-(methylsulfonamidomethyl)phenylboronic acid (24 mg, 0.104 mmol). The mixture was heated at 120° C. under Ar in a microwave reactor for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give N-(4-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzyl)methanesulfonamide (4.26 mg, 17%). 1H-NMR (MeOD): 2.06 (m, 1H), 2.22 (m, 1H), 2.76 (s, 3H), 3.04 (s, 3H), 4.17 (s, 2H), 5.80 (m, 1H), 6.92 (m, 1H), 7.10 (m, 1H), 7.24 (m, 1H), 7.32 (m, 4H), 7.37 (m, 2H), 7.39 (m, 2H), 7.41 (m, 1H).