Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:13]=[O:14])=[CH:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=1[S:42](Cl)(=[O:44])=[O:43]>>[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=1[S:42]([N:5]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:2]([CH3:1])[C:3]([CH:13]=[O:14])=[CH:4]1)(=[O:43])=[O:44]
Reactant: Cc1c(C=O)c[nH]c1-c1ccccc1
Reactant: COc1ccc(OC)c(S(=O)(=O)Cl)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(OC)c(S(=O)(=O)n2cc(C=O)c(C)c2-c2ccccc2)c1
Yield: 85.7 %

Procedure:
Using 4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg), sodium hydride (60% in oil, 72 mg), 15-crown-5 (330 mg) and 2,5-dimethoxybenzenesulfonyl chloride (355 mg), a procedure as in Reference Example 219 was performed to give the title compound as a pale-yellow powder (yield 330 mg, 86%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:21])[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=[N:3]1.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[C:32]([F:35])([F:34])[F:33])[C:26](Cl)=[O:27].C(N(CC)CC)C>C(Cl)Cl>[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[C:32]([F:33])([F:34])[F:35])[C:26]([NH:21][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1)=[O:27]
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCCC1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1nccc1-c1cc(NC(=O)c2ccc(C(F)(F)F)c(F)c2)ccc1OCCN1CCCC1
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a solution of 3-(1-methyl-1H-pyrazol-5-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (0.029 g, 0.10 mmol) in CH2Cl2 (1.5 mL) was added 3-fluoro-4-(trifluoromethyl)benzoyl chloride (0.018 mL, 0.12 mmol) and triethylamine (0.018 mL, 0.13 mmol). The reaction was stirred for 1 h, and concentrated and purified by RP-HPLC. Lyophilization afforded a TFA salt as a brown oil (0.042 g, 88%). LCMS m/z (%)=477 (M+H, 100). 1H NMR (400 MHz, DMSO-d6) δ: 10.55 (s, 1H), 8.07-7.95 (m, 3H), 7.88 (dd, J=2.6, 9.0 Hz, 1H), 7.73 (d, J=2.6 Hz, 1H), 7.49 (d, J=1.8 Hz, 1H), 7.27 (d, J=9.0 Hz, 1H), 6.31 (d, J=1.8 Hz, 1H), 4.33-4.29 (m, 2H), 3.69 (s, 3H), 3.58-3.52 (m, 2H), 3.35-3.25 (m, 2H), 2.92-2.81 (m, 2H), 1.95-1.85 (m, 2H), 1.80-1.69 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(O[C:11](=[O:16])[C:12]([Br:15])([F:14])[F:13])C>C1COCC1>[Br:15][C:12]([F:13])([F:14])[C:11]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:16]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Product: CN1CCN(C(=O)C(F)(F)Br)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.2 %

Procedure:
1-Methyl-piperazine (1.23 g; 12.3 mmol; 5 eq.) was added to a solution of bromo-difluoro-acetic acid ethyl ester (500 mg; 2.46 mmol; 1 eq.) in THF (50 mL) and the reaction mixture was stirred at room temperature for 16 hours then concentrated in vacuo. The residue was taken up in EA, washed with water, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (450 mg, 71%) as a yellow oil.
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]1[S:15][CH2:14][CH2:13][S:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:24])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:9][CH2:10][CH:11]1[S:12](=[O:24])[CH2:13][CH2:14][S:15]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(OCC1SCCS1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCC1SCCS1=O)c1ccccc1
Temperature: 0 °C
Yield: 72.1 %

Procedure:
2-Benzoyloxymethyl-1,3-dithiolane (example 12) (5.2 g) was dissolved in dry methylene chloride (200 ml) and cooled to 0° C. in an ice bath. Meta-chloroperbenzoic acid (80%, 4.67 g) in methylene chloride (100 ml) was added slowly while under stirring. The mixture was stirred at room temperature for 1 hour and then poured with into saturated aqueous NaHCO3 solution (100 ml). The organic layer was separated, washed first with saturated NaHCO3 solution (2×100 ml), then with water (100 ml), and finally with brine solution (100 ml), dried over MgSO4 and filtered. The filtrate was evaporated in vacuo and the residue purified by chromatography on silica gel using ethyl acetate as eluant to give 4.0 g (74%) of pure product as a mixture cis- and trans-isomers.
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[CH:7][C:6](CC2C=C3C(=C4C=CC=CC=24)N=CN([C@H]2CCOC[C@@H]2O)C3=O)=CC=1.[Br:32][CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36](Cl)[CH:35]=1>>[Br:32][CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]2[N:8]([CH2:3][CH3:2])[CH:7]=[CH:6][C:35]=12
Reactant: Clc1cc(CBr)ccn1
Reactant: O=c1c2cc(Cc3ccc(CO)nc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Product: CCn1ccc2c(CBr)ccnc21

Procedure:
The title compound was prepared by the procedure described for the synthesis of 6-[(2-chloropyridin-4-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3R)-one in Example 15, substituting 4-(bromomethyl)-1-ethyl-1H-pyrrolo[2,3-b]pyridine for 4-(bromomethyl)-2-chloropyridine. The resultant orange solid gave proton NMR spectra consistent with theory and a mass ion (ES+) of 455.2087 for [M+H]+ [Calc'd for C27H27N4O3, [M+H]+=455.2078]: 1H NMR (400 MHz, d6-DMSO) δ 9.01-8.98 (m, 1H), 8.71 (s, 1H), 8.14-8.08 (m, 2H), 8.01 (s, 1H), 7.75-7.71 (m, 2H), 7.56 (s, 1H), 6.74-6.72 (m, 1H), 6.59 (s, 1H), 5.31 (d, J=5.5 Hz, 1H), 4.80 (s, 2H), 4.63 (br s, 1H), 4.28 (q, J=7.2 Hz, 2H), 4.18-4.15 (m, 1H), 3.99-3.92 (m, 1H), 3.42 (t, J=11.1 Hz, 1H), 3.14 (t, J=10.4 Hz, 1H), 2.26 (br s, 1H), 1.91-1.89 (m, 1H), 1.38 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([S:13][CH3:14])[NH:10][N:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Cl:22])C(=O)C1>>[Cl:22][C:12]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:9][NH:10][C:11]=1[S:13][CH3:14]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CSc1cc(-c2ccc(F)cc2)n[nH]1
Product: CSc1[nH]nc(-c2ccc(F)cc2)c1Cl

Procedure:
Following protocol L, 3-(4-fluoro-phenyl)-5-methylsulfanyl-1H-pyrazole was treated with NCS in to yield the title compound.
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[C:7](Cl)[C:6]([CH:10]([CH3:12])[CH3:11])=[C:5]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH:21]3[O:25][CH2:24][CH2:23][O:22]3)[CH:15]=2)[N:4]=1.[CH2:26]([OH:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([O:33][C:3]1[N:8]=[C:7]([O:22][CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:14][CH:15]=2)[C:6]([CH:10]([CH3:12])[CH3:11])=[C:5]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH:21]3[O:25][CH2:24][CH2:23][O:22]3)[CH:15]=2)[N:4]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1cc(Oc2nc(Cl)nc(Cl)c2C(C)C)cc(C2OCCO2)c1
Reactant: OCc1ccccc1
Agent: [Na]
Product: Cc1cc(Oc2nc(OCc3ccccc3)nc(OCc3ccccc3)c2C(C)C)cc(C2OCCO2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a stirred anhydrous benzyl alcohol (10 ml) under nitrogen atmosphere at room temperature, was added sodium metal (285 mg, 12.41 mmol). After 1 hr., (7) (1.91 g, 5.17 mmol) in anhydrous benzyl alcohol (7 ml) was added. After stirring for overnight at room temperature, the mixture was evaporated in vacuo. The residue was dissolved in dichloromethane, filtered through a celite pad and the pad was washed with dichloromethane. The combined filtrate was then evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:10)) to afford 1.52 g (57%) of a colorless syrup; 1H NMR (200 MHz, CDCl3) δ 1.30 (6H, d, J=7.2 Hz), 2.39 (3H, s), 3.43 (1H, m), 4.02-4.13 (4H, m), 5.12 (2H, s), 5.42 (2H, s), 5.81 (1H, s), 6.92 (1H, s), 7.07 (1H, s), 7.16 (1H, s), 7.20-7.43 (10H, m).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[N:8][OH:9])[CH:2]=1.[CH2:10]([N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])[C:11]#[CH:12]>C(Cl)(Cl)Cl.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[C:11]([CH2:10][N:13]3[CH2:17][CH2:16][CH2:15][C:14]3=[O:18])[O:9][N:8]=2)[CH:2]=1
Reactant: ON=Cc1cccnc1
Reactant: C#CCN1CCCC1=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C1CCCN1Cc1cc(-c2cccnc2)no1
Yield: 35.4 %

Procedure:
The desired compound was prepared by the method of Example 8 from 500 mg (4.09 mmol) of 3-pyridine aldoxime and 1.0 g (2 equivalents) of 1-propargyl pyrrolidin-2-one prepared in Example 7, and purified by separation with silica gel column chromatography using ethyl acetate and then chloroform/methanol (30:1) to obtain 352.2 mg (35.4% yield) of 1-(3-pyridin-3-yl-isoxazol-5-yl-methyl)-pyrrolidin-2-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19](O)=[O:20])=[CH:5]2.[N:22]1([C:27]2[N:32]=[CH:31][C:30]([NH2:33])=[CH:29][N:28]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[N:22]1([C:27]2[N:28]=[CH:29][C:30]([NH:33][C:19]([C:6]3[N:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=4)[C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)=[O:20])=[CH:31][N:32]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: Nc1cnc(N2CCCC2)nc1
Product: O=C(Nc1cnc(N2CCCC2)nc1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1

Procedure:
The process is carried out according to the method described in example 2, using 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (example 1.1) and 2-(pyrrolidin-1-yl)-5-aminopyrimidine (US 20060281772).
Reaction SMILES: C(OC([N:11]1[CH2:17][CH:16]2[N:18]([C:19]([C:21]3[CH:22]=[N:23][C:24]([NH:27][C:28]4[N:29]=[CH:30][C:31]5[CH:36]=[C:35]([C:37](=[O:41])[N:38]([CH3:40])[CH3:39])[N:34]([CH:42]6[CH2:46][CH2:45][CH2:44][CH2:43]6)[C:32]=5[N:33]=4)=[CH:25][CH:26]=3)=[O:20])[CH:13]([CH2:14][CH2:15]2)[CH2:12]1)=O)C1C=CC=CC=1>[Pd]>[CH3:39][N:38]([CH3:40])[C:37]([C:35]1[N:34]([CH:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)[C:32]2[N:33]=[C:28]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([C:19]([N:18]4[CH:16]5[CH2:15][CH2:14][CH:13]4[CH2:12][NH:11][CH2:17]5)=[O:20])=[CH:22][N:23]=3)[N:29]=[CH:30][C:31]=2[CH:36]=1)=[O:41]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4C5CCC4CN(C(=O)OCc4ccccc4)C5)cn3)nc2n1C1CCCC1
Agent: [Pd]
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4C5CCC4CNC5)cn3)nc2n1C1CCCC1
Reaction time: 16 h
Yield: 60.2 %

Procedure:
A suspension of the 8-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-3-carboxylic acid benzyl ester (550 mg, 0.883 mmol) and 10% Pd/C (100 mg, 0.1 eq), in methanol (10 mL) was evacuated and then purged with N2 3 times and then backfilled with hydrogen under balloon pressure and stirred for 16 hr. The reaction mixture was then filtered through a pad of Celite and the filtrate concentrated to a colorless oil. To the oil was added ethyl acetate/heptane and the resulting precipitate triturated which gave 7-cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-8-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide as a white solid (260 mg, 0.532 mmol) in 60% yield. 1H NMR (400 MHz, MeOD) δ ppm 1.68-1.84 (m, 2H) 1.94-2.12 (m, 8H) 2.12-2.18 (m, 1H) 2.45-2.61 (m, 2H) 2.77 (br. s., 2H) 2.93-3.11 (m, 2H) 3.16 (s, 6H) 4.16 (br. s., 1H) 4.64 (br. s., 1H) 4.80 (t, J=8.84 Hz, 1H) 6.64 (s, 1H) 7.92 (dd, J=8.59, 2.53 Hz, 1H) 8.47-8.57 (m, 2H) 8.85 (s, 1H); MS m/z 489.9 (M+H)+.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Br:7][C:8]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:9]=1[O:10][CH:11]1[CH2:15][CH2:14][CH2:13][C:12]1=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Br:7][C:8]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:9]=1[O:10][CH:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[CH2:1]
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCCC1Oc1ccc(Cl)cc1Br
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CCCC1Oc1ccc(Cl)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
To the mixture of methyl triphenylphosphonium bromide (16.0 g, 44.8 mmol) in anhydrous tetrahydrofuran (125 mL) at 0° C. under nitrogen was added portion wise the potassium tert-butoxide (5.0 g, 44.8 mmol). After stirring at 0° C. for 30 minutes, the mixture of 2-(2-bromo-4-chlorophenoxy)cyclopentanone (516B) (10.8 g, 37.3 mmol) in tetrahydrofuran (40 mL) was added slowly. The resulting mixture was stirred at room temperature under nitrogen for 3 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with water, brine, dried with sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5-10% EtOAc in hexanes) to provide 2-bromo-4-chloro-1-(2-methylenecyclopentyloxy)benzene (517) (6.2 g, 58.2%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][NH:22][O:23][CH3:24].N1C=CC=CC=1>S(Cl)(Cl)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([N:22]([O:23][CH3:24])[CH3:21])=[O:19])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(OCc2ccccc2)cc1
Reactant: CNOC
Agent: Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CON(C)C(=O)CCc1ccc(OCc2ccccc2)cc1
Reaction time: 8 h

Procedure:
3-(4-Benzyloxyphenyl) propionic acid prepared in Example S (30 g, 117 mmol) was taken up in 300 mL of thionyl chloride. The reaction was kept under reflux for 5 hours, then cooled and concentrated. The residue was dissolved in 300 mL of CH2Cl2 and treated with N,O-dimethylhydroxyamine hydrochloride (14.1 g, 146 mmol) and 60 mL of pyridine at 0° C. The reaction was stirred overnight. The reaction was quenched with dilute HCl and extracted into EtOAc, and the organic layer was washed with sodium bicarbonate solution and dilute HCl and dried. The organic layer was dried (MgSO4) and concentrated. The residue was used further as crude reaction mixture or purified by flash silica gel column chromatography, eluting with EtOAc:hexane (1:9, then switching to 2:3).
Reaction SMILES: O(CC([N:11]1[CH:15]=[CH:14][CH:13]([C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:12]1)=O)C1C=CC=CC=1.CO>[Pd]>[NH:11]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:12]1
Reactant: COC(=O)c1cccc(C2C=CN(C(=O)COc3ccccc3)C2)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc(C2CCNC2)c1
Reaction time: 5 h

Procedure:
To a solution of methyl 3-[1-(phenoxyacetyl)-2,3-dihydro-1H-pyrrol-3-yl]benzoate (0.5 g, 0.001 mol) in methanol (15 mL, 0.37 mol) was added 10% Pd/C (80 mg), and the resulting suspension was stirred under 1 atm of H, (balloon) for 5 h. The mixture was filtered and the filtrate was concentrated to afford the desired product.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:11][C@H:12]([CH2:17][NH:18][CH:19]([CH3:21])[CH3:20])[CH2:13][C:14](O)=[O:15])[CH:6]=[CH:7][C:8]=1[C:9]#[N:10].C[Si](N[Si](C)(C)C)(C)C>CC#N.O>[Cl:2][C:3]1[CH:4]=[C:5]([NH:11][C@H:12]2[CH2:13][C:14](=[O:15])[N:18]([CH:19]([CH3:21])[CH3:20])[CH2:17]2)[CH:6]=[CH:7][C:8]=1[C:9]#[N:10]
Reactant: CC(C)NC[C@H](CC(=O)O)Nc1ccc(C#N)c(Cl)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: CC#N
Solvent: O
Product: CC(C)N1C[C@@H](Nc2ccc(C#N)c(Cl)c2)CC1=O
Temperature: 60 °C
Reaction time: 15 h
Yield: 49 %

Procedure:
The crude (3S)-3-[(3-chloro-4-cyanophenyl)amino]-4-[(1-methylethyl)amino]butanoic acid hydrochloride was dissolved in MeCN (20 mL) and treated with HMDS (4 mL) and the reaction was stirred at 60° C. for 15 h. After cooled down, the reaction was diluted with H2O and extracted with Et2O (2×). The combined organic extracts were washed with H2O (2×), dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography with 25% EtOAC in hexane grading to 100% EtOAc in hexane to yield the titled product (0.13 g, 49%). LC-MS (ES) m/e 277.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[CH:3]=1.[OH-].[K+].[CH2:12](I)[CH3:13]>C(O)C>[CH2:12]([N:5]1[C:6]([CH3:8])=[CH:7][C:2]([CH3:1])=[CH:3][C:4]1=[O:9])[CH3:13]
Reactant: Cc1cc(C)[nH]c(=O)c1
Reactant: CCI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCn1c(C)cc(C)cc1=O

Procedure:
A mixture of 4,6-dimethyl2(1H)-pyridone (2.46 g., 0.02 moles), potassium hydroxide (1.58 g., 0.024 moles) and ethyl iodide (6.24 g., 0.04 moles) in 50 ml. ethanol is heated at reflux for 3 hours. The ethanol is removed under vacuum leaving a solid residue which is extracted with methylene chloride. The methylene chloride extracts are washed with 2.5 N sodium hydroxide, water, a saturated salt solution, and dried over sodium sulfate. Evaporation of the dried extracts affords 1-ethyl-4,6-dimethyl-2(1H)-pyridone as a pale yellow oil (1.5 g., 48%) which shows a single spot on thin layer chromatography.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:16]4[CH:17]=[N:18][CH:19]=[N:20][CH:21]=4)=[CH:9][CH:10]=3)[C:5]3([CH2:25][O:24][C:23]([NH2:26])=[N:22]3)[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.I[CH2:39][CH2:40][CH3:41]>O>[CH2:39]([O:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:16]4[CH:17]=[N:18][CH:19]=[N:20][CH:21]=4)=[CH:9][CH:10]=3)[C:5]3([CH2:25][O:24][C:23]([NH2:26])=[N:22]3)[C:4]=2[CH:3]=1)[CH2:40][CH3:41]
Reactant: CCCI
Reactant: NC1=NC2(CO1)c1cc(O)ccc1Oc1ccc(-c3cncnc3)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccc2c(c1)C1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A glass vial was charged with 2′-hydroxy-7′-(5-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine (prepared as described in Example 2; 53.68 mg, 155 μmol), cesium carbonate (75.7 mg, 232 μmol), DMF (0.62 mL), and 1-iodopropane (16.6 μl, 170 μmol). The mixture was stirred at RT for 18 h, then poured into water (10 mL) and extracted with EtOAc (3×7 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on silica gel (eluting with 0-80% of a 90:10:1 DCM/MeOH/NH4OH solution in DCM) to give 2′-(1-propyloxy)-7′-(5-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine as a white solid. MS m/z=389.2 [M+H]+. Calc'd for C22H21N4O3: 389.2.
Reaction SMILES: [CH:1]1[C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=O)=[CH:5][CH:4]=[C:3]([Cl:12])[CH:2]=1.[NH2:13][C:14]1[CH:19]=[CH:18][N:17]([CH2:20][CH:21]([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])[C:16](=[O:28])[N:15]=1.Cl.C(N=C=NCCCN(C)C)C.O>CN(C)C=O>[Cl:12][C:3]1[CH:2]=[CH:1][C:6](/[CH:7]=[CH:8]/[C:9]([NH:13][C:14]2[CH:19]=[CH:18][N:17]([CH2:20][CH:21]([O:22][CH2:23][CH3:24])[O:25][CH2:26][CH3:27])[C:16](=[O:28])[N:15]=2)=[O:11])=[CH:5][CH:4]=1
Reactant: CCOC(Cn1ccc(N)nc1=O)OCC
Reactant: O=C(O)/C=C/c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(Cn1ccc(NC(=O)/C=C/c2ccc(Cl)cc2)nc1=O)OCC
Temperature: 70 °C
Reaction time: 5 h
Yield: 68 %

Procedure:
P-chloro cinnamic acid (1.84 g, 10 mM), 4-amino-1-(2,2-diethoxyethyl)-1H-pyrimidin-2-one (b, 3.00 g, 15 mM), 1-hydroxybenztriazolemonohydrate (2.30 g, 15 mM) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (2.90 g, 15 mM) were suspended in N,N-dimethylformamide (20 mL) and stirred at 70° C. for 5 hours. After the reaction mixture was cooled to room temperature, water (20 mL) was added and stirred at room temperature. The crystal precipitated from the reaction mixture was filtered to afford 2.48 g of the desired compound (E)-3-(4-chlorophenyl)-N-[1-(2,2-diethoxyethyl)-2-oxo-1,2-dihydropyrimidin-4-yl]-acrylamide (c) (yield 68%, colorless crystal).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH2:15])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[Cl:16][C:17]1[C:18]([OH:28])=[C:19]([S:24](Cl)(=[O:26])=[O:25])[CH:20]=[C:21]([Cl:23])[CH:22]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([NH:15][S:24]([C:19]2[CH:20]=[C:21]([Cl:23])[CH:22]=[C:17]([Cl:16])[C:18]=2[OH:28])(=[O:25])=[O:26])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NS(=O)(=O)c2cc(Cl)cc(Cl)c2O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.4 %

Procedure:
To a solution of 2-amino-indan-2-carboxylic acid ethyl ester (3.14 g, 15.3 mmol) and 3,5-dichloro-2-hydroxy-benzenesulfonyl chloride (1 g, 3.82 mmol) in anhydrous DCM (dichloromethane, 20 mL) is added DIPEA (631 μL, 3.82 mmol). The resulting solution is stirred at RT for 1 hour. The reaction solution is diluted in DCM (50 mL) and washed with water (1×5 mL) and brine (2×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by HPLC to give a pure product (30) as white solid (450 mg, 27%).
Reaction SMILES: C([O:8][CH2:9][N:10]1[C:25](=[O:26])[C:24]2[C:23]3[C:22]4[C:17](=[C:18]([O:27]CC5C=CC=CC=5)[CH:19]=[CH:20][CH:21]=4)[NH:16][C:15]=3[C:14]3[N:35]([C@:50]4([C:70](=[O:72])[CH3:71])[O:58][C@H:57]([CH2:59][OH:60])[C@@:55]([C:61](=[O:63])[CH3:62])([OH:56])[C@:53]([C:64](=[O:66])[CH3:65])([OH:54])[C@@:51]4([C:67](=[O:69])[CH3:68])[OH:52])[C:36]4[C:37]([O:42]CC5C=CC=CC=5)=[CH:38][CH:39]=[CH:40][C:41]=4[C:13]=3[C:12]=2[C:11]1=[O:73])C1C=CC=CC=1.C(OCC)(=O)C>[C].[Pd].C(O)C>[OH:42][C:37]1[C:36]2[N:35]([C@:50]3([C:70](=[O:72])[CH3:71])[O:58][C@H:57]([CH2:59][OH:60])[C@@:55]([C:61](=[O:63])[CH3:62])([OH:56])[C@:53]([C:64](=[O:66])[CH3:65])([OH:54])[C@@:51]3([C:67](=[O:69])[CH3:68])[OH:52])[C:14]3[C:15]4[NH:16][C:17]5[C:22](=[CH:21][CH:20]=[CH:19][C:18]=5[OH:27])[C:23]=4[C:24]4[C:25](=[O:26])[N:10]([CH2:9][OH:8])[C:11](=[O:73])[C:12]=4[C:13]=3[C:41]=2[CH:40]=[CH:39][CH:38]=1
Reactant: CC(=O)[C@@]1(O)[C@](O)(C(C)=O)[C@](C(C)=O)(n2c3c(OCc4ccccc4)cccc3c3c4c(c5c6cccc(OCc7ccccc7)c6[nH]c5c32)C(=O)N(COCc2ccccc2)C4=O)O[C@H](CO)[C@]1(O)C(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)[C@@]1(O)[C@](O)(C(C)=O)[C@](C(C)=O)(n2c3c(O)cccc3c3c4c(c5c6cccc(O)c6[nH]c5c32)C(=O)N(CO)C4=O)O[C@H](CO)[C@]1(O)C(C)=O
Yield: 57.7 %

Procedure:
To 4.5 mg of 6-benzyloxymethyl-1,11-dibenzyloxy-12,13-dihydro-13-(tetraacetyl-β-D-glucopyranosyl)-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H )-dione were added 1.5 ml of ethyl acetate and 9 ml of ethanol to make a solution, and the solution was subjected to hydrogenation reaction in the presence of palladium-carbon catalyst (two medical spoonsful) for 3 hours. After the reaction, the palladium-carbon was removed by filtration and washed with methanol and tetrahydrofuran. The filtrate and the washings were concentrated under reduced pressure, the residue was subjected to thin layer chromatography (Kiesel gel 60; developed with chloroform-methanol =19:1), and the desired product was scraped and extracted with methanol to give 12,13-dihydro-1,11-dihydroxy-6-hydroxymethyl-13-(tetraacetyl-β-D-glucopyranosyl)-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (yield: 57.7%).