Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([CH:5](P(OCC)(OCC)=O)[C:6]([O-:8])=[O:7])(C)C.C([Li])CCC.[CH3:22][O:23][CH2:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH2:33][O:34][CH3:35])[CH:29]=[CH:28][C:27]=1[CH:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1.[OH-].[Na+]>O1CCCC1>[CH3:22][O:23][CH2:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH2:33][O:34][CH3:35])[CH:29]=[CH:28][C:27]=1[CH:36]1[CH2:41][CH2:40][C:39](=[CH:5][C:6]([OH:8])=[O:7])[CH2:38][CH2:37]1
Reactant: COCOc1ccc(C2CCC(=O)CC2)c(OCOC)c1
Reactant: CCOP(=O)(OCC)C(C(=O)[O-])[Si](C)(C)C
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCOc1ccc(C2CCC(=CC(=O)O)CC2)c(OCOC)c1
Temperature: 0 °C
Reaction time: 17 h
Yield: 49.2 %

Procedure:
To a round bottomed flask equipped with magnetic stirrer was added trimethylsilyidiethylphosphonoacetate (1.08 ml, 3.83 mmol) and anhydrous tetrahydrofuran (25 ml). The stirred solution was cooled to 0° C. and n-butyl lithium (1.80 ml, 3.83 mmol, 2.2M in cyclohexanes) was added dropwise, via syringe over 5 min. The reaction mixture was allowed to warm slowly to room temperature and stirred for 17 hr. 4-[(2,4-Bis(methoxymethoxy)phenyl)]cyclohexanone (750 mg, 2.55 mmol) was added via syringe as a solution in tetrahydrofuran (25 ml). After 2 hr stirring at room temperature, the reaction mixture was poured into a separating funnel containing aqueous sodium hydroxide solution (10 ml, 10% w/v). After extracting once with diethyl ether (10 ml), the aqueous layer was acidified by adding concentrated hydrochloric acid (10 ml), then extracted with diethyl ether (3×20 ml). The combined organic layers were washed with water (10 ml), dried over magnesium sulfate, filtered and concentrated in vacuo affording the title compound (422 mg, 52%) as an oil. δH(CDCl3) 1.86 (2H, m), 2.00-2.13 (4H, m), 2.42 (2H, m), 3.19 (1H, m), 3.48 (3H, s), 3.51 (3H, s), 5.14 (2H, s), 5.21 (2H, s), 5.71 (1H, s), 6.67 (1H, dd), 6.81 (1H, d), 7.05 (1H, d).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:19])[C:9]([O:15]C(=O)C)=[C:10]([CH3:14])[C:11]=2[CH3:13])[CH:6]([CH3:20])[CH2:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:19])[C:9]([OH:15])=[C:10]([CH3:14])[C:11]=2[CH3:13])[CH:6]([CH3:20])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)C(C)CN2C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)N1CC(C)c2c(C)c(O)c(C)c(C)c21

Procedure:
Deacetylation of 29a was achieved by reaction with potassium carbonate in methanol according to the procedure of Burkalova, et al., Biofizika 1980, 24, 989. Purification of crude material by flash column chromatography on silica gel using a solvent system of ethyl acetate/Skellysolve B (6:4, Rf =0.18) afforded 29b as a white solid, nap 171°-173° C. Spectral data: IR (Nujol) 3500, 1635, 1400, 1210 cm-1 ; 1H NMR (CD3SOCD3): δ 1.05 (d, 3H), 1.90 (br s, 3H), 2.10 (2 partially resolved s, 3H each), 2.15 (br s, 3H), 3.10 (br m, 1H), 3.75 (br m, 1H), 3.85 (br m, 1H), 7.85 (br s, 1H); 13C NMR (CD3 SOCD3): δ 12.34, 12.64, 17.42, 18.10, 23.50, 35.44, 58.25, 117.49, 121.94, 124.93, 133.47, 135.81, 150.41, 168.58; CI-MS: m/z 234 (MH+, base), 172, 154, 136; CI-HRMS: Calcd. for C14H20 NO2 (M+H+) 234.1494, fnd. 234.1494. Anal: calcd. for C14 H19NO2C, 72.07, H, 8.21, N, 6.00, fnd. C, 71.85, H, 8.24, N, 5.92.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH:7]([CH2:11][S:12](Cl)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]1[CH2:28][NH:29][CH2:30][CH2:31][C:22]2=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:16])[CH:7]([CH2:11][S:12]([N:29]1[CH2:30][CH2:31][C:22]2[C:21]3[C:25](=[CH:26][CH:27]=[C:19]([O:18][CH3:17])[CH:20]=3)[NH:24][C:23]=2[CH2:28]1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C(CS(=O)(=O)Cl)C(=O)OC(C)(C)C
Reactant: COc1ccc2[nH]c3c(c2c1)CCNC3
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2[nH]c3c(c2c1)CCN(S(=O)(=O)CC(C(=O)OC(C)(C)C)C(C)C)C3
Reaction time: 0.33 h
Yield: 64.5 %

Procedure:
A solution of 2-chlorosulfonylmethyl-3-methylbutyric acid tert-butyl ester (WO 99/24399) (470 mg) in dichloromethane (10 ml) was added to a mixture of 6-methoxy-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (350 mg) and triethylamine (0.72 ml) in dichloromethane (10 ml) at room temperature under nitrogen. The mixture was stirred for 20 minutes before being evaporated to dryness and the residue chromatographed (SiO2, 1:1 heptane-ethyl acetate) to give the title compound (487 mg, 66%) as a white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:21]1[N:30]=[C:29]([NH2:31])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1>>[C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][NH:19][C:21]3[N:30]=[C:29]([NH2:31])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH2:16][CH2:17]2)(=[O:10])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1nc(Cl)nc2ccccc12
Reactant: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Product: Nc1nc(NCC2CCN(S(=O)(=O)CCc3ccccc3)CC2)nc2ccccc12

Procedure:
EXAMPLE 81 was prepared from C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and 2-chloro-quinazolin-4-yl-amine (2-chloro-quinazolin-4-ylamine was prepared from 2,4-dichloroquinazoline and ammonia in THF at room temperature; N. B. Chapman, G. M. Gibson, F. G. Mann, J. Chem. Soc., 1947, 890–899): MS (m+1)=426.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[N+:24]([O-])([OH:26])=[O:25]>>[N+:24]([C:3]1[C:4](=[O:9])[NH:5][C:6](=[O:8])[NH:7][C:2]=1[CH3:1])([O-:26])=[O:25]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(=O)[nH]c(=O)[nH]1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: Cc1[nH]c(=O)[nH]c(=O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 5 h
Yield: 54 %

Procedure:
50.5 g (0.40 mol) of 6-methyluracil (Merck) are introduced in portions over the course of one hour with stirring at 02 to +5° C. into a solution of 200 ml of 100% nitric acid (fuming) and 50 g of phosphorus pentoxide. When the exothermic reaction is complete, the mixture is stirred at +5° C. for a further 5 hours. The reaction mixture is subsequently poured into 1 kg of ice-water. The resultant precipitate is filtered, washed with water and then dried to constant weight, giving 37 g (54%) of 5-nitro-6-methyluracil, pale-yellow powder, m.p. 281° C. with decomposition.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:10][OH:11])Cl.Cl.[C:13](=NO)(Cl)[C:14]1C=CN=[CH:16][CH:15]=1>>[CH:14]([CH:15]1[O:11][N:10]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[CH2:16]1)=[CH2:13]
Reactant: ON=C(Cl)c1ccccn1
Reactant: ON=C(Cl)c1ccncc1
Agent: Cl
Product: C=CC1CC(c2ccccn2)=NO1

Procedure:
By substituting an equimolar amount of picolinoyl chloride oxime hydrochloride for the isonicotinoyl chloride oxime hydrochloride employed in the above example, there is obtained the corresponding 2-(5-vinyl-2-isoxazolin-3-yl)pyridine.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][C:29]=1[O:30][C:31](=[O:33])[CH3:32])[CH:8]1[CH2:17][C:16](=O)[C:15]2[C:10](=[CH:11][C:12]([O:23][C:24](=[O:26])[CH3:25])=[CH:13][C:14]=2[O:19][C:20](=[O:22])[CH3:21])[O:9]1)(=[O:3])[CH3:2].[BH4-].[Na+].C(O)(=O)C.C(OC(=O)C)(=O)C>C1COCC1.C(O)C.N1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][C:29]=1[O:30][C:31](=[O:33])[CH3:32])[CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:23][C:24](=[O:26])[CH3:25])=[CH:13][C:14]=2[O:19][C:20](=[O:22])[CH3:21])[O:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(OC(C)=O)c2c(c1)OC(c1ccc(OC(C)=O)c(OC(C)=O)c1)CC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: CC(=O)Oc1cc(OC(C)=O)c2c(c1)OC(c1ccc(OC(C)=O)c(OC(C)=O)c1)CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a stirred solution of 1.0 grams 3',4',5,7-tetraacetoxyflavanone in 50 ml of 50% THF-ethanol was added 100 mg NaBH4. After 30 min., an additional 100 mg NaBH4 was added and stirring continued at room temperature for a total of 1 hour. The mixture was then poured into 200 ml of cold 0.5% acetic acid and extracted three times with 75 ml CHCl3. The combined CHCl3 extracts were dried (NA2SO4) and evaporated to give a thick oil. To the oil was added 6 ml acetic anhydride and 8 ml pyridine and this solution allowed to stand at room temperature overnight. After pouring into 100 ml ice water, the resulting emulsion was extracted with 125 ml chloroform and the chloroform washed with 100 ml ice water, 100 ml cold 3% HCl and 100 ml 0.5% NaHCO3. Drying (Na2SO4) and evaporating the CHCl3 gave an oil which was purified by chromatography on a 2.5 × 4.0 cm column of SILICAR CC-7. The first material to elute with 60% CHCl3 -hexane was 3',4',5,7-tetraacetoxyflavan, which after recrystallization from MeOH, was obtained in an amount of 345 mg (36% yield) mp 143°-4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:11][OH:20])[CH2:9][O:10]2)=[CH:6][CH:7]=1
Reactant: C=C(CO)c1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: OCC1(c2ccc(Cl)cc2)CO1
Yield: 72.2 %

Procedure:
To a solution of the compound prepared in Example 4(c), β-(4-chlorophenyl)-β-methylene ethanol (1.05g) in chloroform (50 mL) add, with cooling, (ice bath) a solution of m-chloroperbenzoic acid (1.2g) in chloroform. Stir the chloroform solution for 4 hr. Wash the chloroform solution, successively, with aqueous 10% NaHSO3 (to remove excess per acid) followed by aqueous NaHCO3 and finally with water. Dry (Na2SO4) the chloroform solution. Remove the chloroform in vacuo to provide the title compound as a colourless oil (0.83 g). Use the title compound without any further purification in the next reaction.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:5]=1[C:6](O)=[O:7])(=O)[CH3:2].O.[NH2:16][NH2:17]>>[CH3:14][O:13][C:10]1[CH:9]=[C:5]2[C:4]([C:1]([CH3:2])=[N:16][NH:17][C:6]2=[O:7])=[CH:12][CH:11]=1
Reactant: NN
Reactant: COc1ccc(C(C)=O)c(C(=O)O)c1
Solvent: O
Product: COc1ccc2c(C)n[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting unpurified 2-acetyl-5-methoxybenzoic acid with hydrazine hydrate.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:12]2[C:13]3[CH:18]=[CH:17][S:16][C:14]=3[CH2:15][C:11]=2[CH:10]=[N:9]1)(=O)=O.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C)C=O>[N:19]([CH2:6][CH2:7][N:8]1[C:12]2[C:13]3[CH:18]=[CH:17][S:16][C:14]=3[CH2:15][C:11]=2[CH:10]=[N:9]1)=[N+:20]=[N-:21]
Reactant: CS(=O)(=O)OCCn1ncc2c1-c1ccsc1C2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCn1ncc2c1-c1ccsc1C2
Temperature: 70 °C
Reaction time: 17 h
Yield: 91.8 %

Procedure:
A 0.75 g of 2-(1,4-dihydrothieno[2′,3′:4,5]cyclopenta[1,2-c]pyrazol-1-yl)ethyl methanesulfonate was dissolved in 10 ml of dimethylformamide, 0.47 g of sodium azide was added, and the mixture was stirred at 70° C. for 17 hours. After cooling, the reaction solution was poured into ice water and extracted with ether. The organic layers were combined, washed with brine and then dried with anhydrous magnesium sulfate. After removal of the drying agent, the solvent was concentrated under a reduced pressure to give 0.56 g of 1-(2-azidoethyl)-1,4-dihydrothieno[2′,3′:4,5]cyclopenta[1,2-c]pyrazole.
Reaction SMILES: [Na].[CH2:2]([N:8]1[C:17](=[O:18])[C:16]2[NH:15][CH:14]=[N:13][C:12]=2[N:11]([CH3:19])[C:9]1=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl[CH2:21][P:22](=[O:25])([CH3:24])[CH3:23]>>[CH2:2]([N:8]1[C:17](=[O:18])[C:16]2[N:15]([CH2:21][P:22](=[O:25])([CH3:24])[CH3:23])[CH:14]=[N:13][C:12]=2[N:11]([CH3:19])[C:9]1=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: CP(C)(=O)CCl
Agent: [Na]
Product: CCCCCCn1c(=O)c2c(ncn2CP(C)(C)=O)n(C)c1=O

Procedure:
The title substance was prepared from 26 g (0.1 mol) of 1-hexyl-3-methylxanthine sodium salt and chloromethyldimethylphosphine oxide analogously to Example 59 and crystallized from hexane.
Reaction SMILES: [CH:1]1([O:5][C:6]2[N:14]=[C:13]3[C:9]([N:10]=[C:11]([O:21][CH3:22])[N:12]3[CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)=[C:8]([NH2:23])[N:7]=2)[CH2:4][CH2:3][CH2:2]1.Br[C:25]1N(C2CCCCO2)C2C(N=1)=C(N)N=C(OC1CCCC1)N=2>>[CH:1]1([O:5][C:6]2[N:14]=[C:13]3[C:9]([N:10]=[C:11]([O:21][CH3:22])[N:12]3[CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)=[C:8]([NH2:23])[N:7]=2)[CH2:2][CH2:25][CH2:3][CH2:4]1
Reactant: COc1nc2c(N)nc(OC3CCC3)nc2n1C1CCCCO1
Reactant: Nc1nc(OC2CCCC2)nc2c1nc(Br)n2C1CCCCO1
Product: COc1nc2c(N)nc(OC3CCCC3)nc2n1C1CCCCO1

Procedure:
Prepared similarly to Intermediate 57 from 8-bromo-2-(cyclopentyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([C@H:19]1[C:27]2[C:22](=[C:23]([C:28]3[N:32]=[C:31]([C:33]4[S:34][C:35]([C:44]([F:47])([F:46])[F:45])=[C:36]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH:37]=4)[O:30][N:29]=3)[CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1)C(=O)OC(C)(C)C)(C(C)(C)C)(C)C.Cl.CCOCC>C(Cl)Cl>[C:38]1([C:36]2[CH:37]=[C:33]([C:31]3[O:30][N:29]=[C:28]([C:23]4[CH:24]=[CH:25][CH:26]=[C:27]5[C:22]=4[CH2:21][CH2:20][C@H:19]5[NH:11][CH2:10][CH2:9][OH:8])[N:32]=3)[S:34][C:35]=2[C:44]([F:46])([F:47])[F:45])[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CC(C)(C)OC(=O)N(CCO[Si](C)(C)C(C)(C)C)[C@@H]1CCc2c(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)cccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: OCCN[C@@H]1CCc2c(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)cccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 65 %

Procedure:
To (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-(5-(4-phenyl-5-(trifluoromethyl)thiophen-2-yl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamate INT-63 (0.108 g, 0.16 mmol) dissolved in DCM (1.5 mL) was added 2N HCl in ether (1.45 mL, 2.9 mmol). The solution was stirred at room temperature for 12 h. The solvent was removed under a stream of nitrogen and the product dried under vacuum to afford 0.052 g (65%) of (R)-2-(4-(5-(4-phenyl-5-(trifluoromethyl)thiophen-2-yl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ylamino) ethanol 67 as the HCl salt. LCMS-ESI (m/z): calcd for C24H20F3N3O2S: 471.5; found 472.1 [M+H]+, tR=7.43 min (Method 2). 1H NMR (400 MHz, CDCl3) δ 9.62 (s, 1H), 8.19 (d, J=7.6, 1H), 8.03 (d, J=7.5, 1H), 7.87 (t, J=1.5, 1H), 7.53-7.40 (m, 6H), 4.86 (d, J=4.8, 1H), 3.88 (s, 2H), 3.74-3.50 (m, 1H), 3.41 (ddd, J=13.3, 9.4, 4.4, 1H), 3.06 (m, 1H), 2.98 (m, 1H), 2.67-2.42 (m, 2H). 13C NMR (100 MHz, DMSO) δ 169.22, 168.07, 145.68, 144.75, 139.39, 135.43, 132.42, 129.42, 129.37, 129.25, 128.69, 128.27, 127.62, 126.41, 123.16, 122.37, 120.47, 61.10, 56.63, 46.54, 31.66, 27.80.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]([CH2:16][C:17]([N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])[C:10](=[O:15])[CH2:11][N:12]=[C:13]=[O:14])[CH:6]=[CH:7][CH:8]=1.[OH:27][CH:28]([C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33])[CH3:29]>O1CCCC1>[OH:27][CH:28]([C:30]1[CH:31]=[C:32]([NH:33][C:13](=[O:14])[NH:12][CH2:11][C:10]([N:9]([CH2:16][C:17]([N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:15])[CH:34]=[CH:35][CH:36]=1)[CH3:29]
Reactant: COc1cccc(N(CC(=O)N(C)c2ccccc2)C(=O)CN=C=O)c1
Reactant: CC(O)c1cccc(N)c1
Solvent: C1CCOC1
Product: COc1cccc(N(CC(=O)N(C)c2ccccc2)C(=O)CNC(=O)Nc2cccc(C(C)O)c2)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 43.2 %

Procedure:
2-[N-(3-Methoxyphenyl)isocyanatoacetamido]-N-methyl-N-phenylacetamide (3 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of 3-(1-hydroxyethyl)aniline (1.1 g) in anhydrous tetrahydrofuran (20 cc). The solution obtained is stirred for 16 hours at a temperature in the region of 20° C. and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residual oil is purified by chromatography on silica (0.063-0.2 mm) (150 g) contained in a column 2.5 cm in diameter) [eluent: dichloromethane/methanol (98:2 by volume)], collecting 20-cc fractions. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallisation in diisopropyl ether, (RS)-2-[2-{3-[3-(1-hydroxyethyl)phenyl]ureido}-N-(3-methoxyphenyl)acetamido]-N-methyl-N-phenylacetamide (1.7 g), m.p. 115° C., is thereby obtained.
Reaction SMILES: [CH3:1][C:2]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[Li+].[OH-].Cl>O1CCOCC1>[CH3:1][C:2]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)CCCOc1cccc(C)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cccc(OCCCC(=O)O)c1C
Temperature: 60 °C
Yield: 102.2 %

Procedure:
A mixture of ethyl 4-(2,3-dimethylphenoxy)butanoate (22.28 g, 94 mmol), 4 N LiOH (94 mL, 377 mmol) in dioxane (50 mL) was heated at 60° C. for 4 h. After cooling to room temperature, the mixture was adjusted to pH 2-3 with 3 N HCl, and extracted with EtOAc (2×10 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford the title compound (20 g, 100% yield). LCMS, [M−H]+=207.1. 1H NMR (400 MHz, CDCl3) δ 7.02 (dd, J=8.2, 7.5 Hz, 1H), 6.76 (d, J=7.5 Hz, 1H), 6.67 (d, J=8.2 Hz, 1H), 3.99 (t, J=6.0 Hz, 2H), 2.60 (t, J=7.3 Hz, 2H), 2.25 (s, 3H), 2.18-2.09 (m, 2H), 2.12 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[CH3:14][C:15](OC(C)=O)=O>>[CH3:14][C:15]1[NH:13][S:10](=[O:12])(=[O:11])[C:3]2[CH:4]=[C:5]([Br:9])[CH:6]=[C:7]([Br:8])[C:2]=2[N:1]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1c(Br)cc(Br)cc1S(N)(=O)=O
Product: CC1=Nc2c(Br)cc(Br)cc2S(=O)(=O)N1

Procedure:
A stirred solution of 2-amino-3,5-dibromobenzenesulfonamide (see compound 125) (660 mg; 2 mmol) was refluxed in Ac2O (25 ml; 265 mmol) over night. The reaction mixture was poured onto ice and filtered. The isolated solid was washed with Et2O. M.p. 287-289° C.
Reaction SMILES: CC([O:4][C@@H:5]1[C@@H:10]([O:11]C(C)=O)[C@@H:9]([O:15]C(C)=O)[C@@H:8]2[NH:19][C:20]([C:22]3[C:27]([C@H:7]2[CH2:6]1)=[CH:26][C:25]1[O:28][CH2:29][O:30][C:24]=1[CH:23]=3)=[O:21])=O.C(=O)([O-])[O-].[K+].[K+]>CO>[CH:26]1[C:27]2[C:7]3=[CH:6][C@H:5]([OH:4])[C@@H:10]([OH:11])[C@@H:9]([OH:15])[C@@H:8]3[NH:19][C:20](=[O:21])[C:22]=2[CH:23]=[C:24]2[O:30][CH2:29][O:28][C:25]=12
Reactant: CC(=O)O[C@H]1[C@@H]2NC(=O)c3cc4c(cc3[C@H]2C[C@H](OC(C)=O)[C@H]1OC(C)=O)OCO4
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C1N[C@@H]2C(=C[C@H](O)[C@@H](O)[C@H]2O)c2cc3c(cc21)OCO3
Yield: 91 %

Procedure:
This compound is produced as follows. 2,3,4-triacetoxy-7-deoxy-trans-dihydro narciclasine (13, 0.14 g) is saponified in 9:1 aqueous methanol and with potassium carbonate (0.003 g), and is conducted as described above for obtaining alcohol 2c to yield triol 1e as a colorless solid; 89 mg (91% yield); mp>300° C. (dec.).
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:45])[CH2:5][CH:6]([CH2:26][O:27][C:28](=[O:44])[C@H:29]([CH:41]([CH3:43])[CH3:42])[NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:7][O:8][C:9](=[O:25])[C@H:10]([CH:22]([CH3:24])[CH3:23])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].[I-:46].[Na+]>C(#N)C>[I:46][CH2:2][O:3][C:4](=[O:45])[CH2:5][CH:6]([CH2:26][O:27][C:28](=[O:44])[C@H:29]([CH:41]([CH3:43])[CH3:42])[NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:7][O:8][C:9](=[O:25])[C@H:10]([CH:22]([CH3:24])[CH3:23])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: [I-]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(=O)OCCl
Agent: [Na+]
Solvent: CC#N
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(=O)OCI

Procedure:
3,3-bis (N-CBz-L-valyloxymethyl)-propionic acid chloromethyl ester (900 mg, 1.38 mmole) was dissolved in acetonitrile (5 ml). Sodium iodide (289 mg, 1.93 mmole) was added to the solution. After reaction at 70° C. for 3 hr, the reaction mixture was filtered and the residue was dissolved in methylene chloride (5 ml) and refiltered. The solution was dried and gave the titled product. 800 mg.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]=[CH:6][N:5]([C:8]2[N:9]=[CH:10][C:11]([O:24][CH3:25])=[C:12]3[C:16]([C:17](=[O:23])[C:18]([O:20]CC)=[O:19])=[CH:15][NH:14][C:13]=23)[N:4]=1.C([O-])([O-])=O.[K+].[K+].Cl>CO.O>[OH:1][CH2:2][C:3]1[N:7]=[CH:6][N:5]([C:8]2[N:9]=[CH:10][C:11]([O:24][CH3:25])=[C:12]3[C:16]([C:17](=[O:23])[C:18]([OH:20])=[O:19])=[CH:15][NH:14][C:13]=23)[N:4]=1
Reactant: CCOC(=O)C(=O)c1c[nH]c2c(-n3cnc(CO)n3)ncc(OC)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cnc(-n2cnc(CO)n2)c2[nH]cc(C(=O)C(=O)O)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-(7-(3-(hydroxymethyl)-1H-1,2,4-triazol-1-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate (70 mg, 0.203 mmol) and K2CO3 (56.0 mg, 0.405 mmol) were dissolved in MeOH (2 mL) and water (2.000 mL). The mixture was stirred at room temperature overnight, and neutralized with 1N HCl to pH 3. All solvents were removed under vacuum to give 2-(7-(3-(hydroxymethyl)-1H-1,2,4-triazol-1-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid. LCMS: m/z 318.2 (M+H)+, 1.04 min (method 8).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:16]C)=[CH:9][CH:10]=3)[C:5]3([CH2:22][O:21][CH2:20][C:19](=[O:23])[NH:18]3)[C:4]=2[CH:3]=1.B(Br)(Br)Br>C(Cl)Cl.O>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([OH:16])=[CH:9][CH:10]=3)[C@:5]3([CH2:22][O:21][CH2:20][C:19](=[O:23])[NH:18]3)[C:4]=2[CH:3]=1
Reactant: COc1ccc2c(c1)C1(COCC(=O)N1)c1cc(Br)ccc1O2
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C1COC[C@@]2(N1)c1cc(O)ccc1Oc1ccc(Br)cc12
Temperature: -78 °C
Reaction time: 2 h

Procedure:
In a 25-mL flask, the 2′-bromo-7′-methoxyspiro[morpholine-3,9′-xanthen]-5-one (0.094 g, 0.250 mmol) was dissolved in DCM (5 mL). The solution was cooled to −78° C., and a solution of boron tribromide (1.0 M, 0.750 mL, 0.750 mmol) in DCM was added. The mixture was warmed to 0° C. and held at that temperature for 2 h. The reaction was diluted with water (20 mL) and the aqueous phase was extracted with 3% MeOH/DCM (3×25 mL). The organics were combined, washed with dilute brine (5 mL), dried over sodium sulfate, and concentrated. The residue was purified by chromatography (70:30:1 EtOAc/hexane/MeOH) to afford (R)-2′-bromo-7′-hydroxyspiro[morpholine-3,9′-xanthen]-5-one.
Reaction SMILES: [NH:1]=[C:2]1[CH:7]=[CH:6][C:5]([O:12][CH3:13])([S:8][CH2:9][CH2:10][CH3:11])[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:3]1[NH:21][C:22]([NH:24][C:25]([O:27][CH3:28])=[O:26])=[S:23].[OH-].[Na+].[CH3:31]I>CC(C)=O.O>[NH:1]=[C:2]1[CH:7]=[CH:6][C:5]([O:12][CH3:13])([S:8][CH2:9][CH2:10][CH3:11])[C:4]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:3]1[NH:21][C:22](=[N:24][C:25]([O:27][CH3:28])=[O:26])[S:23][CH3:31]
Reactant: CCCSC1(OC)C=CC(=N)C(NC(=S)NC(=O)OC)=C1Cc1ccccc1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCCSC1(OC)C=CC(=N)C(NC(=NC(=O)OC)SC)=C1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53 %

Procedure:
To a suspension of 1-imino-(4-methoxy)phenylmethyl-2-(3-carbomethoxythioureido)-4-propylthiobenzene (4.18 g; 0.01 mole) in acetone (60 ml) and water (20 ml) there is added 50% aqueous sodium hydroxide (0.08 g; 0.01 mole). The solution that forms within 10 min. is stirred at room temperature for 50 min. and to it there is added methyl iodide (1.42 g; 0.01 mole). The suspension that forms is stirred at room temperature for 1 hr. and is vacuum filtered. The filter cake is air dried to afford 1-imino-(4-methoxy)phenylmethyl-2-(3-carbomethoxy-S-methylisothioureido)-4-propylthiobenzene (2.3 g; 53%), m.p. 90-92.