Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9]/[CH:10]=[CH:11]/[C:12]1[NH:20][C:19]2[C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:17][CH:16]=[N:15][C:14]=2[CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:35][CH3:36]>CN(C)C=O.C(OCC)(=O)C>[Si:1]([O:8][CH2:9]/[CH:10]=[CH:11]/[C:12]1[N:20]([CH2:35][CH3:36])[C:19]2[C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:17][CH:16]=[N:15][C:14]=2[CH:13]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CCI
Reactant: CC(C)(C)[Si](C)(C)OC/C=C/c1cc2ncnc(Oc3ccccc3)c2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c(/C=C/CO[Si](C)(C)C(C)(C)C)cc2ncnc(Oc3ccccc3)c21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
6-((1E)-3-{[tert-Butyl(dimethyl)silyl]oxy}-1-propenyl)-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine (100 mg) was dissolved in N,N-dimethylformamide (0.786 mL), cesium carbonate (102.6 mg) was added, and the mixture was stirred at room temperature for 20 min. Iodoethane (0.0231 mL) was added and the mixture was stirred at room temperature for 2 hrs and at 40° C. for 4 hrs. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL) and washed successively with water (30 mL) and saturated brine (30 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→50:50) to give the title compound (79 mg) as an oil.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH:13]=[CH:14][C:15](Cl)=[O:16].[CH3:23][C:24]1[CH:32]=[C:28]([C:29]([OH:31])=[O:30])[C:27]([NH2:33])=[CH:26][CH:25]=1>C(Cl)(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH:13]=[CH:14][C:15]([NH:33][C:27]1[C:28](=[CH:32][C:24]([CH3:23])=[CH:25][CH:26]=1)[C:29]([OH:31])=[O:30])=[O:16]
Reactant: Cc1ccc(N)c(C(=O)O)c1
Reactant: COc1ccc(C=CC(=O)Cl)cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(C=CC(=O)Nc2ccc(C)cc2C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
In a mixture of 3 g of 5-methylanthranilic acid in 30 ml of chloroform is dissolved 3 ml of triethylamine, to this mixture is added a solution of 4.2 g of 3,4-dimethoxycinnamoylchloride in chloroform under cooling. The mixture is stirred at room temperature for 2 hours and then heated under reflux for 2 hours. The reaction mixture is concentrated under a reduced pressure, to the residue is added water and hydrochloric acid is added to make the mixture the weakly acidic. The precipitated crystals are collected by filtration recrystallized from ethanol to obtain 4.8 g of N-(3,4-dimethoxycinnamoyl)-5-methylanthranilic acid as pale yellow needles.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH3:25])=[N:18][CH:19]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:24]([O:23][CH2:22][CH2:21][O:20][C:17]1[N:18]=[CH:19][C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)=[CH:15][CH:16]=1)[CH3:25]
Reactant: CCOCCOc1ccc(C#N)cn1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOCCOc1ccc(-c2nc(=O)c3ccccc3s2)cn1
Yield: 57.3 %

Procedure:
A mixture of methyl thiosalicylate (2.96 g, 17.6 mmol), 5-cyano-2-(2-ethoxy)ethoxypyridine (3.07 g, 16.0 mmol), triethylamine (2.37 ml, 17.0 mmol) and toluene (15 ml) was refluxed under nitrogen atmosphere for 40 hrs. The reaction mixture was concentrated. The residue was subjected to a silica gel column chromatography, eluted with ethyl acetate-hexane (1:1, v/v) and recrystallized from acetone-ethyl acetate-isopropylether to give the titled compound (3.01 g, 57%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[F:9][C:10]1[C:15](B(O)O)=[CH:14][CH:13]=[CH:12][N:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:9][C:10]1[C:15]([C:2]2[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: OB(O)c1cccnc1F
Reactant: O=Cc1cc(Br)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=Cc1cc(-c2cccnc2F)cs1
Temperature: 80 °C
Reaction time: 20 h
Yield: 53.5 %

Procedure:
A suspension of 4-bromothiophene-2-carbaldehyde (10.0 g), 2-fluoro-3-pyridineboronic acid (9.1 g), tetrakis(triphenylphosphine)palladium (0) (3.1 g) and sodium carbonate (13.7 g) in 1,2-dimethoxyethane (100 mL) and water (50 mL) was stirred at 80° C. for 20 hr under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1) to give the title compound as a pale-yellow solid (yield 5.8 g, yield 53%).
Reaction SMILES: Br[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12][C:4]=2[CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][CH2:7]2.[C:24](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1>[CH3:24][C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12][C:4]=2[CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][CH2:7]2
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCc2cc3c(c(Br)c2CC1)NCCC3
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1c2c(cc3c1NCCC3)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 90 °C
Reaction time: 13 h

Procedure:
To a solution of 460 mg of t-butyl 11-bromo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate in 9 ml of dioxane were added 1.6 ml of a 2 M aqueous potassium carbonate solution under an argon atmosphere, and subsequently 449 mg of trimethylboroxine and 70 mg of tetrakistriphenylphosphine palladium, followed by stirring at 90° C. for 13 hours. The reaction mixture was allowed to cool, filtered, and then concentrated under reduced pressure, the resulting residue was diluted with EtOAc, and the organic layer was washed with water and saturated brine. The solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 380 mg of t-butyl 11-methyl-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:8]([C:18]([F:21])([F:20])[F:19])=[CH:9][C:10](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[N:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[F:22][C:23]([F:37])([F:36])[CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1)[NH2:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C)C=O>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[C:8]([C:18]([F:21])([F:20])[F:19])=[CH:9][C:10](/[CH:13]=[CH:14]/[C:15](=[O:17])[NH:25][CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=3)[C:23]([F:37])([F:36])[F:22])=[N:11][CH:12]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)/C=C/c1cc(C(F)(F)F)c(C(=O)NC2CC2)cn1
Reactant: NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(/C=C/c1cc(C(F)(F)F)c(C(=O)NC2CC2)cn1)NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2E)-3-[5-(Cyclopropylcarbamoyl)-4-(trifluoromethyl)pyridin-2-yl]acrylic acid (61 mg, 0.20 mmol) and 2,2,2-trifluoro-1-[3-trifluoromethylphenyl]ethanamine (46 mg, 0.19 mmol) were initially charged in N,N-dimethylformamide and admixed with HBTU (72 mg, 0.19 mmol) and N-methylmorpholine (57 mg, 0.57 mmol) and stirred at room temperature overnight. Subsequently, the reaction mixture was concentrated under reduced pressure, taken up in ethyl acetate and washed successively with a sodium hydrogencarbonate solution (10% Y) and a saturated sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was chromatographed on a preparative HPLC with water/acetonitrile as the eluent (gradient=43 min from 10% acetonitrile in water to 100% acetonitrile).
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C=O)C.[C:10]1([S:16]([N:19]2[C:31]3[CH:30]=[C:29]([CH:32](O)[CH3:33])[CH:28]=[CH:27][C:26]=3[C:25]3[C:20]2=[CH:21][CH:22]=[CH:23][CH:24]=3)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[C:10]1([S:16]([N:19]2[C:31]3[CH:30]=[C:29]([CH:32]([Cl:3])[CH3:33])[CH:28]=[CH:27][C:26]=3[C:25]3[C:20]2=[CH:21][CH:22]=[CH:23][CH:24]=3)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1ccc2c3ccccc3n(S(=O)(=O)c3ccccc3)c2c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(Cl)c1ccc2c3ccccc3n(S(=O)(=O)c3ccccc3)c2c1

Procedure:
Thionyl chloride (0.26 ml, 3.54 mmol) and catalytically effective amount of DMF were added at room temperature to a solution of 9-benzenesulfonyl-2-(1-hydroxyethyl)carbazole (0.621 g, 1.77 mmol) in methylene chloride, and the mixture was heated under reflux for 1.5 hours. After evaporation of the solvent under reduced pressure, the thus obtained residue was mixed with ethyl acetate and washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution in that order, the organic layer was dried over magnesium sulfate and then the solvent was evaporated under reduced pressure to obtain 9-benzenesulfonyl-2-(1-chloroethyl)carbazole.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=[N:39][N:38]([CH2:41][C:42]3[CH:47]=CC=CC=3Cl)[C:36]=2N=1)(C)(C)C.CN1C=CC(C2CCCN2)=N1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH2:24][CH:23]2[C:47]2[CH:42]=[CH:41][N:38]([CH3:36])[N:39]=2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cn1ccc(C2CCCN2)n1
Product: Cn1ccc(C2CCCN2c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-methyl-3-(pyrrolidin-2-yl)-1H-pyrazole. MS(m/e): 451.4
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:24][C:23]2[C:25](=[O:26])[C:18](=[CH:19][C:20]([C:22]=2OC)=[O:21])[NH:17][C:15](=[O:16])[C:14]([CH3:29])=[CH:13][CH:12]=[CH:11][C@H:10]([O:30][CH3:31])[C@@H:9]([O:32][C:33]([NH2:35])=[O:34])[C:8]([CH3:36])=[CH:7][C@H:6]([CH3:37])[C@@H:5]([OH:38])[C@@H:4]([O:39][CH3:40])[CH2:3]1.[CH3:41][N:42]([CH3:46])[CH2:43][CH2:44][NH2:45].[ClH:47]>C(Cl)Cl.O1CCOCC1>[CH3:1][C@@H:2]1[CH2:24][C:23]2[C:25](=[O:26])[C:18](=[CH:19][C:20]([C:22]=2[NH:45][CH2:44][CH2:43][N:42]([CH3:46])[CH3:41])=[O:21])[NH:17][C:15](=[O:16])[C:14]([CH3:29])=[CH:13][CH:12]=[CH:11][C@H:10]([O:30][CH3:31])[C@@H:9]([O:32][C:33]([NH2:35])=[O:34])[C:8]([CH3:36])=[CH:7][C@H:6]([CH3:37])[C@@H:5]([OH:38])[C@@H:4]([O:39][CH3:40])[CH2:3]1.[ClH:47]
Reactant: COC1=C2C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)C=C(C)[C@H](OC(N)=O)[C@@H](OC)C=CC=C(C)C(=O)NC(=CC1=O)C2=O
Reactant: CN(C)CCN
Agent: COC1=C2C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)/C=C(\C)[C@H](OC(N)=O)[C@@H](OC)/C=C\C=C(/C)C(=O)NC(=CC1=O)C2=O
Agent: CO[C@H]1/C=C\C=C(/C)C(=O)NC2=CC(=O)C(NCCN(C)C)=C(C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)/C=C(\C)[C@@H]1OC(N)=O)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CO[C@H]1C=CC=C(C)C(=O)NC2=CC(=O)C(NCCN(C)C)=C(C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)C=C(C)[C@@H]1OC(N)=O)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of geldanamycin (15 g, 26.75 mmol) (SAIC-Frederick, Lot No. 3155-28-1) and N,N-dimethyl-ethylenediamine (15 mL, 37.83 mmol) (Aldrich, Lot No. HN04216AL) in dry methylene chloride (300 mL) (Mallinckrodt, Lot No. 4881KVJP) was stirred at room temperature for 1 hour and subsequently poured into ice water (500 mL). After the organic layer and aqueous layer became visually separated, the aqueous layer was extracted with methylene chloride (2×100 mL). The combined methylene chloride solution was washed with water (2×100 mL), dried with MgSO4 (Spectrum, Lot No. HJ302), and evaporated in a diaphragm pump. The remaining residue (16.5 g, 26.75 mmol) was dissolved in methylene chloride (130 mL). Dissolved hydrogen chloride (1.1 eq, 29.43 mmol) (Matheson, Lot No. T410242) in dioxane (Aldrich, Lot No. 16619CQ) was added to the solution resulting in immediate precipitation. After stirring for 30 minutes, the solids were collected, rinsed with methylene chloride (50 mL), and air-dried for 18 hours to give the crude hydrochloride salt (17.2 g). A solution of the crude product (17.2 g) in aqueous alcohol (50% v/v, 200 mL) (Aaper Alcohol, Lot. No. 97A28UARAT) was heated to reflux, filtered, and allowed to cool for 30 minutes. After cooling on ice for an additional 30 minutes, the solids were collected, washed with cold anhydrous alcohol (50 mL), and air-dried for 1 hour. The product was dried further at 70° C./0.1 mmHg for 17 hours to give pure target compound. Approximately 13.4 g of 17-Demethoxy-17-[[2(dimethylamino)ethyl]amino]geldanamycin hydrochloride (82%) was isolated as a violet crystalline solid and used in Examples 1 and 2.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[C@@H:3]1[CH3:18].CCN(C(C)C)C(C)C.[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31]>CC#N>[CH3:28][N:29]([CH3:33])[C:30](=[O:31])[NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[C@@H:3]1[CH3:18]
Reactant: C[C@@H]1[C@H](N)CCCN1C(=O)OCc1ccccc1
Reactant: CN(C)C(=O)Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1[C@H](NC(=O)N(C)C)CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
Commercial (2R,3R)-benzyl 3-amino-2-methylpiperidine-1-carboxylate (323, CAS: 104461-49-7) (900 mg, 3.63 mmol) was dissolved in 30 mL MeCN and stirred at RT. To it were added DIEA (1.89 mL, 10.89 mmol) and then drop-wise dimethylcarbamoyl chloride (1.00 mL, 10.89 mmol). The mixture was stirred for overnight, concentrated on rotavap, diluted with EtOAc, washed with water ×2, dried over MgSO4, concentrated on rotavap, subjected to silica flash column using 0 to 4% MeOH in DCM to give (2R,3R)-benzyl 3-(3,3-dimethylureido)-2-methylpiperidine-1-carboxylate (324). It was dissolved in 100 mL iPrOH, and subjected to hydrogenation at 35 psi on Parr shaker with 10% Pd/C (1.0 g) for overnight. The mixture was filtered through celite, and the filtrate was concentrated in vacuo to afford 1,1-dimethyl-3-((2R,3R)-2-methylpiperidin-3-yl)urea (325) as a thick oil. It was dissolved in 30 mL dry DMF. To it were added 3,5-dichloropyrazine-2-carbonitrile (630 mg, 3.6 mmol) and then DIEA (1.25 mL, 7.2 mmol). The mixture was stirred at RT for overnight. It was diluted with 300 mL EtOAc, washed with water ×3, dried over MgSO4, concentrated on rotavap, and subjected to silica flash column with 0 to 4% MeOH in DCM to isolate 3-((2R,3R)-1-(6-chloro-5-cyanopyrazin-2-yl)-2-methylpiperidin-3-yl)-1,1-dimethylurea (326) (850 mg, 73% overall yield for three steps).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[OH-].[Na+].[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][CH:15]=1)=[O:13].O>CN(C=O)C>[C:22]1([CH2:21][O:20][C:17]2[CH:16]=[CH:15][C:14]([C:12](=[O:13])[CH:11]=[CH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:19][CH:18]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=Cc1ccccn1
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(C=Cc1ccccn1)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.8 %

Procedure:
A sample of a 42.4 g (0.4 mole) of pyridine-2-carboxaldehyde was added to a solution of 83.6 mL of 10% sodium hydroxide and 100 mL of DMF at 10° C. Then a solution of 47.2 g (0.21 mole) of 4-benzyloxyacetophenone in 300 mL of DMF was added slowly over a period of 1 hr to the mixture keeping the temperature of the reaction mixture at 5°-13° C. After 1.5 hr, the reaction mixture was allowed to warm to room temperature. Water was added, and the product precipitated out as a solid. The solid was crystallized from 95% ethanol to give 48.2 g (73% yield) of the title compound as a yellow solid, mp=131°-134° C. An additional 3.3 g (5% yield) of the product was obtained from the mother liquor, mp=131°-134° C.
Reaction SMILES: [CH3:1][C:2]1([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]1([C:9]([O:11][CH3:12])=[O:10])[CH2:3][CH2:4][C:5](=[O:8])[CH2:6][CH2:7]1
Reactant: COC(=O)C1(C)C=CC(=O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C1(C)CCC(=O)CC1
Yield: 95.4 %

Procedure:
Methyl 1-methyl-4-oxo-2-cyclohexenecarboxylate [J. Am. Chem. Soc., 101, 6996 (1979)] (100 g) was dissolved in ethyl acetate (600 ml), 10% Pd-C (5 g) was added, and catalytic reduction was carried out at room temperature and 1 atomosphere. About 14 liters of hydrogen was absorged in about 2 hours. The catalyst was filtered off, and the filtrate was concentrated and distilled under reduced pressure to give methyl 1-methyl-4-oxocyclohexanecarboxylate (96.5 g, 95.4%, b.p. 82°-84° C./0.5 mmHg).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[H-].[Na+].[CH3:18]I.O>CN(C)C=O>[CH3:18][O:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CO)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 105.6 %

Procedure:
To a solution of tert-butyl (R)-3-hydroxymethylpiperidine-1-carboxylate (11.50 g, 53.7 mmol) in N,N-dimethylformamide (110 ml) was added sodium hydride (3.22 g, 80.6 mmol) under ice-cooling, and the mixture was stirred at room temperature for 20 min. To the reaction mixture was added methyl iodide (4.35 ml, 69.9 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give tert-butyl (R)-3-methoxymethylpiperidine-1-carboxylate (13.00 g, yield 100%).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH3:8][C:9]1[O:13][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:11][C:10]=1[CH2:20][O:21][C:22]1[CH:42]=[CH:41][C:25]([CH2:26][N:27]2[C:39]3[CH:38]=[CH:37][CH:36]=[C:35]([OH:40])[C:34]=3[C:33]3[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:24][C:23]=1[O:43][CH3:44].Br[C@H:46]([CH2:52][CH3:53])[C:47]([O:49][CH2:50][CH3:51])=[O:48]>O>[CH3:44][O:43][C:23]1[CH:24]=[C:25]([CH:41]=[CH:42][C:22]=1[O:21][CH2:20][C:10]1[N:11]=[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:13][C:9]=1[CH3:8])[CH2:26][N:27]1[C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([O:40][C@@H:46]([CH2:52][CH3:53])[C:47]([O:49][CH2:50][CH3:51])=[O:48])[C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2
Reactant: COc1cc(Cn2c3ccccc3c3c(O)cccc32)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: CCOC(=O)[C@H](Br)CC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H](CC)Oc1cccc2c1c1ccccc1n2Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
41 mg of sodium hydride (60%) was added to N,N-dimethylformamide (2.5 mL) solution of 500 mg of 9-{4-[(5-methyl-2-phenyloxazole-4-yl)methoxy]-3-methoxybenzyl}-9H-carbazole-4-ol while being cooled in an ice bath, and stirred at room temperature for 1 hour. Thereafter, 239 mg of ethyl (R)-2-bromobutyrate was added thereto dropwise at −5° C., and was stirred for 30 minutes. Water was added to the reaction mixture, and extracted twice with ethyl acetate. The combined extract was washed with brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo, the residue was purified by NH silica gel chromatography (ethyl acetate:n-hexane=1:4), and 650 mg of the subject compound was prepared. Optical purity 95% ee (HPLC).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:4](=[O:18])[N:3]=1.[H-].[Na+].[C:21](=O)([O:29]C1C=CC=CC=1)[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1.CCOC(C)=O>[C:23]1([O:22][C:21](=[O:29])[NH:1][C:2]2[C:7]([F:8])=[CH:6][N:5]([S:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)(=[O:10])=[O:11])[C:4](=[O:18])[N:3]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1nc(=O)n(S(=O)(=O)c2ccccc2)cc1F
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1nc(=O)n(S(=O)(=O)c2ccccc2)cc1F)Oc1ccccc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 24.3 %

Procedure:
To a suspension of 4-amino-1-benzenesulfonyl-5-fluoro-1H-pyrimidin-2-one (0.20 g, 0.74 mmol) in anhydrous THF (3 mL) was added NaH (0.044 g of 60 wt % suspension in mineral oil, 1.11 mmol) at 0° C. After gas evolution had subsided, the mixture was transferred via cannula to an ice-cold mixture of diphenyl carbonate (1.5 g, 7.4 mmol) in anhydrous THF (5 mL) and stirred for 6 h. The reaction was diluted with EtOAc (25 mL) and the resulting solution was washed with satd aq NH4Cl (15 mL) and brine (15 mL). The organic phase was dried over Na2SO4, filtered, and the solvent evaporated. The residue was purified by precipitation from MeOH and Et2O to give (1-benzenesulfonyl-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)carbamic acid phenyl ester as a light brown solid (0.070 g, 24%): mp 182-185° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.95 (m, 2H), 7.87 (d, J=7.0 Hz, 1H), 7.71 (d, J=7.5 Hz, 1H), 7.61 (t, J=7.7 Hz, 2H), 7.33 (t, J=7.9 Hz, 2H), 7.15 (d, J=7.3 Hz, 1H), 7.06 (d, J=7.6 Hz, 2H); ESIMS m/z 390 ([M+H]+), 388 ([M−H]−).