Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([O:34][CH3:35])=[C:26]([CH2:36][C:37]2[S:38][C:39](Br)=[CH:40][CH:41]=2)[CH:25]=1)(=O)C.[C:43]1(B(O)O)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[C@@H:6]1([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([O:34][CH3:35])=[C:26]([CH2:36][C:37]3[S:38][C:39]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[CH:40][CH:41]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: COc1c(Cc2ccc(Br)s2)cc([C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)c2ccccc12
Reactant: OB(O)c1ccccc1
Product: COc1c(Cc2ccc(-c3ccccc3)s2)cc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c2ccccc12

Procedure:
The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methoxynaphthalene and phenylboronic acid were treated in a manner similar to Example 168 to give the desired 1-(β-D-glucopyranosyl)-3-(5-phenyl-2-thienylmethyl)-4-methoxynaphthalene. APCI-Mass m/Z 510 (M+NH4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[C:4]([CH3:28])[CH:3]=1.Cl.[CH3:30][NH:31][CH3:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([N:31]([CH3:32])[CH3:30])=[O:24])=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[C:4]([CH3:28])[CH:3]=1
Reactant: CNC
Reactant: Cc1cc(C(=O)C[C@@H](c2ccc(C(=O)O)cc2)c2ccc(Cl)cc2C)ccn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1cc(C(=O)C[C@@H](c2ccc(C(=O)N(C)C)cc2)c2ccc(Cl)cc2C)ccn1

Procedure:
In analogy to example 207, step 2, 4-[(S)-1-(4-chloro-2-methyl-phenyl)-3-(2-methyl-pyridin-4-yl)-3-oxo-propyl]-benzoic acid (example 282, step 3) was coupled with dimethylamine hydrochloride using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as an off-white foam, MS (ESI+): m/z=421.1 [M+H]+.
Reaction SMILES: C([O-])C1C=CC=CC=1.C([O:16][C:17](=O)[CH:18]=[O:19])C1C=CC=CC=1.[CH2:21]([NH:27][C:28]([NH2:30])=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C(O)(=O)C>[OH:19][CH:18]1[N:27]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:28](=[O:29])[NH:30][C:17]1=[O:16]
Reactant: CCCCCCNC(N)=O
Reactant: O=CC(=O)OCc1ccccc1
Agent: [O-]Cc1ccccc1
Solvent: CC(=O)O
Product: CCCCCCN1C(=O)NC(=O)C1O
Yield: 10.1 %

Procedure:
21.0 g of glyoxylic acid benzyl ester benzyl alcoholate and 10.0 g of N-hexylurea were refluxed in an 80% aqueous solution of acetic acid for 1.5 hours. After cooling, the reaction mixture was evaporated to dryness under reduced pressure. The obtained crude product was purified by column chromatography on silica gel (ethyl acetate:hexane=1:1) and was recrystallized from benzene to give 1.4 g of 5-hydroxy-1-hexylhydantoin (compound 12) in the form of colorless needle crystals.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)=O.CO.[CH2:18]([NH2:20])[CH3:19]>C(Cl)Cl>[CH2:9]([O:8][CH2:7][CH2:6][NH:20][CH2:18][CH3:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CS(=O)(=O)OCCOCc1ccccc1
Reactant: CCN
Solvent: CO
Solvent: ClCCl
Product: CCNCCOCc1ccccc1
Temperature: 110 °C
Yield: 72 %

Procedure:
To 7.0 g (30 mmol) of 2-(benzyloxy)ethyl methanesulfonate, a 75 ml methanol solution of 2M ethylamine was added, and the mixture was heated at 110° C. in a sealed tube for 2 hours. Then, the reaction mixture was returned to room temperature, and then diluted with methylene chloride. The dilution was washed with a saturated aqueous solution of sodium hydride. The washed system was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to obtain 3.85 g (72%) of the captioned compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:21])=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][C:4]=2[N:3]=1.I[CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][P:42](=[O:49])([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45].C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>CN(C=O)C>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][P:42]([O:46][CH2:47][CH3:48])([O:43][CH2:44][CH3:45])=[O:49])=[CH:16][C:15]=3[CH3:21])=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][C:4]=2[N:3]=1
Reactant: CCOP(=O)(CCOCCOCCI)OCC
Reactant: CCOC(=O)CCc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3C)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCCOCCOCCP(=O)(OCC)OCC)cc3C)cc12
Temperature: 60 °C

Procedure:
To a solution of ethyl 3-(5-amino-2-(4-hydroxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoate (13) (1.0 equiv.) dissolved in DMF (0.14M) was added a solution of diethyl 2-(2-(2-iodoethoxyl)ethoxy)ethylphosphonate (14): from step 11 above (1.3 equiv.) in DMF (0.7M) and cesium carbonate (4 equiv.). The reaction was stirred at 60° C. After 1.5 hours (or until reaction is complete by LCMS), DCM (2 volume equivalent) was added to the reaction. The solids (inorganic) were filtered, and the filtrate was concentration. The crude product was purified by Combiflash using 0-5% MeOH in DCM to give ethyl 3-(5-amino-2-{2-[4-(2-{2-[2-(diethoxyphosphoryl)ethoxy]ethoxy}ethoxy)-2-methylphenyl]ethyl}benzo[f]1,7-naphthyridin-8-yl)propanoate (15).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[OH:12])=[O:4].[CH3:13][C:14]1[N:15]=[CH:16][S:17][C:18]=1[CH3:19].COC(C)(C)C>C(#N)C>[Br-:1].[OH:12][C:6]1[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][N+:15]1[C:14]([CH3:13])=[C:18]([CH3:19])[S:17][CH:16]=1
Reactant: Cc1ncsc1C
Reactant: O=C(CBr)c1ccc(O)cc1O
Solvent: CC#N
Solvent: COC(C)(C)C
Product: Cc1sc[n+](CC(=O)c2ccc(O)cc2O)c1C
Product: [Br-]
Temperature: 110 °C
Reaction time: 8 h

Procedure:
The neat mixture of 2-bromo-2′,4′-dihydroxyacetophenone (3 g, 13 mmol) and 4,5-dimethylthiazole (1.71 g, 13.3 mmol) was heated at 110° C. for 3 hrs. It was dissolved in acetonitrile (15 mL) and cooled to room temperature. Tert-butyl methyl ether (5 mL) was added and the reaction mixture kept at room temperature overnight. The product crystallized was filtered, washed well with a mixture of acetonitrile and tert-butyl methyl ether (1:1, v/v) and dried. It was recrystallized from a mixture of methanol and a few drops of water. Yield: 2.5 g (50%); mp. 257–260° C. (dec.).
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.Cl.[CH3:22][O:23][C:24]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[CH2:31][NH:30][CH2:29]2)=[O:25].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:22][O:23][C:24]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[CH2:31][N:30]([C:3]1[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[CH:7]([CH3:10])[CH2:8][O:9][C:4]=1[C:5]=34)[CH2:29]2)=[O:25]
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: COC(=O)c1ccc2c(c1)CNC2
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn4c3c1OCC4C)C2
Yield: 20.3 %

Procedure:
142 mg of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 109 mg of 5-methoxycarbonylisoindoline hydrochloride, 228 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 45 mg of the target compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]([CH2:7][C:8]#[CH:9])[C:3]1=[O:10].C(OC(OCC)CN)C.C(Br)C#C>>[CH2:7]([N:4]1[CH:5]=[CH:6][NH:2][C:3]1=[O:10])[C:8]#[CH:9].[CH3:1][N:2]=[C:3]=[O:10]
Reactant: C#CCn1ccn(C)c1=O
Agent: C#CCBr
Agent: CCOC(CN)OCC
Product: C#CCn1cc[nH]c1=O
Product: CN=C=O

Procedure:
The 1,3-dihydro-1-(2-propynyl)-2H-imidazol-2-one intermediates were prepared as outlined in Scheme 2 for the synthesis of 1,3-dihydro-1-methyl-3-(2-propynyl)-2H-imidazol-2-one (X). Aminoacetaldehyde diethyl acetal was reacted with propargylbromide to give a mixture of the tertiary and secondary amines VII and VIII which were separated by chromatography on silica gel. Treatment of VIII with methyl isocyanate gave IX and this was heated in aqueous oxalic acid to give 1-methyl-3-(2-propynyl)-2H-imidazol-2-one (X).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]#[CH:12])=[CH:9][N:8]([C@@H:13]3[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@H:14]3[OH:15])[C:4]=2[N:5]=[CH:6][N:7]=1.[Si]([N:26]=[N+:27]=[N-:28])(C)(C)C.CN(C=O)C>CO.[Cu]I>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[N:26]=[N:27][NH:28][CH:12]=3)=[CH:9][N:8]([C@@H:13]3[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@H:14]3[OH:15])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2ncnc(N)c12
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1ncnc2c1c(-c1c[nH]nn1)cn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 100 °C
Reaction time: 24 h
Yield: 24 %

Procedure:
An argon purged mixture of 7-ethynyltubericidine 2o {compound from example 15} (200 mg, 0.69 mmol), CuI (6.5 mg, 0.03 mmol) and TMSN3 (150 μl, 1.15 mmol) in MeOH (0.2 ml)/DMF (1.8 ml) was stirred 100° C. for 24 h. Volatiles were evaporated under reduced pressure, the residue was twice co-evaporated with MeOH and rest was suspended in MeOH and filtered through celite. Filtrate was co-evaporated with silica and column chromatography on silica afforded title compound 2p as yellowish solid (55 mg, 24%). Compound was recrystallized from water. Mp 286-288° C. [α]D −70 (c 0.217, DMSO). 1H NMR (499.8 MHz, DMSO-d6, t=60° C.): 3.58 (dd, 1H, Jgem=11.9, J5′b,4′=4.2, H-5′b); 3.68 (dd, 1H, Jgem 11.9, J5′a,4′=3.9, H-5′a); 3.93 (ddd, 1H, J4′,5′=4.2, 3.9, J4′,3′=3.6, H-4′); 4.15 (dd, 1H, J3′,2′=5.3, J3′,4′=3.6, H-3′); 4.45 (dd, 1H, J2′,1′=6.0, J2′,3′=5.3, H-2′); 4.93, 5.04 and 5.17 (3×bs, 3×1H, OH-2′,3′,5′); 6.08 (d, 1H, J1′,2′=6.0, H-1′); 7.85 (bs, 2H, NH2); 7.91 (s, 1H, H-6); 8.09 (s, 1H, H-2); 8.23 (s, 1H, H-5-triazole). 13C NMR (125.7 MHz, DMSO-d6, t=60° C.): 61.83 (CH2-5′); 70.54 (CH-3′); 73.72 (CH-2′); 85.15 (CH-4′); 87.41 (CH-1′); 100.16 (C-4a); 105.83 (C-5); 120.80 (CH-6); 126.16 (CH-5-triazole); 141.51 (C-4-triazole); 151.04 (C-7a); 152.35 (CH-2); 158.04 (C-4). MS (ESI) m/z 334 (M+H), 356 (M+Na). HRMS (ESI) for C13H16N7O4 [M+H] calcd: 334.1258. found: 334.1258. Anal. Calcd for C13H15N7O4: C, 46.85; H, 4.54; N, 29.42. Found: C, 47.12; H, 4.82; N, 27.96.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:10])([CH3:9])[CH2:4][S:5]([NH2:8])(=[O:7])=[O:6].[H-].[Na+].Cl[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[CH:21][N:22]=2)[N:19]=1>CN(C=O)C>[CH3:9][C:3]([CH3:10])([CH2:4][S:5](=[O:7])(=[O:6])[NH2:8])[CH2:2][O:1][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[CH:21][N:22]=2)[N:19]=1
Reactant: Clc1ccc2nccn2n1
Reactant: CC(C)(CO)CS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(COc1ccc2nccn2n1)CS(N)(=O)=O
Temperature: 70 °C
Yield: 88 %

Procedure:
To a solution of 3.5 g of 3-hydroxy-2,2-dimethyl-1-propanesulfonamide in 30 ml of DMF was added by portions 0.85 g of sodium hydride (60%, in oil) with stirring. To the mixture were added 3.18 g of 6-chloroimidazo[1,2-b]pyridazine and then 0.85 g of sodium hydride. The reaction solution was heated at 70° C. for 1.5 hours and then at 100° C. for an hour with stirring, and concentrated under reduced pressure. The residue was added into 100 ml of ice-water, extracted with ethyl acetate and tetrahydrofuran (1:1) (100 ml×4), dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was recrystallized from ethanol to obtain 5.18 g of the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][CH:5]=[C:4]([F:12])[C:3]=1B(O)O.C(O)(=[O:18])C.OO>O1CCCC1>[F:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][CH:5]=[C:4]([F:12])[C:3]=1[OH:18]
Reactant: CC(C)Oc1ccc(F)c(B(O)O)c1F
Reactant: CC(=O)O
Agent: OO
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(F)c(O)c1F
Reaction time: 40 h
Yield: 100 %

Procedure:
To a solution of 2,6-difluoro-3-isopropoxy-phenylboronic acid (10.0 g, 0.046 mol) in tetrahydrofuran (160 mL) was added glacial acetic acid (60 mL). The resulting mixture was cooled to 0° C. before hydrogen peroxide (50% aqueous solution, 8 mL) was added. The resulting mixture was allowed to come to room temperature and stirred for 40 h. The mixture was evaporated and the residue was dissolved in ethyl acetate, washed with hydrochloric acid (0.5N), water and brine. The organic phase was dried, filtered and evaporated which afforded 2,6-difluoro-3-isopropoxy-phenol (8.70 g, 100%) as a brown oil.
Reaction SMILES: [N:1]1[C:10]2[N:9]3[CH2:11][CH2:12][O:13][CH2:14][CH:8]3[CH2:7][NH:6][C:5]=2[CH:4]=[N:3][C:2]=1[C:15]1[C:23]2[C:18](=[C:19]([O:24][CH3:25])[CH:20]=[CH:21][CH:22]=2)[N:17](C(OC(C)(C)C)=O)[CH:16]=1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34].[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[NH:17][CH:16]=[C:15]2[C:2]1[N:3]=[CH:4][C:5]2[NH:6][CH2:7][CH:8]3[CH2:14][O:13][CH2:12][CH2:11][N:9]3[C:10]=2[N:1]=1
Reactant: COc1cccc2c(-c3ncc4c(n3)N3CCOCC3CN4)cn(C(=O)OC(C)(C)C)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc2c(-c3ncc4c(n3)N3CCOCC3CN4)c[nH]c12

Procedure:
A TFA salt of the title compound was prepared in a manner similar to EXAMPLE 8 using tert-butyl 3-(5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)-7-methoxy-1H-indole-1-carboxylate (60 mg, 0.137 mmol) in CH2Cl2 and TFA. 1H NMR (400 MHz, DMSO-d6) δ 2.92-3.05 (m, 1H), 3.27-3.30 (m, 1H), 3.53-3.66 (m, 1H), 3.76-3.90 (m, 1H), 3.91-3.98 (m, 5H), 3.97-4.06 (m, 1H), 4.08-4.18 (m, 1H), 4.68-4.84 (m, 1H), 6.33-6.45 (br s, 1H), 6.79-6.87 (m, 1H), 7.09-7.20 (m, 1H), 7.38-7.46 (m, 1H), 7.80-7.89 (m, 1H), 8.15-8.23 (m, 1H), 12.18-12.29 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C18H19N5O2S, 338.15. found 338.4.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](O)=[O:6].S(Cl)([Cl:14])=O.CN(C=O)C>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([Cl:14])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(C(=O)O)cc1I
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Cl)cc1I

Procedure:
3-Iodo-4-methylbenzoic acid (9.84 g) was dissolved in THF (50 ml) and thionyl chloride (4 ml) and DMF (0.05 ml) were added. The mixture was heated under ref lux for 3 hrs. The reaction mixture was concentrated under reduced pressure to give 3-iodo-4-methylbenzoyl chloride (10.18 g) as a brown powder. Then, by the reaction in the same manner as in Example 26-i), the title compound (3.47 g) was obtained from a solution of 3-iodo-4-methylbenzoyl chloride (4.00 g) and methylamine in THF (2M, 30 ml) as colorless powder crystals
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([CH2:27][C:28]3[S:29][C:30]([C:33]4[O:34][CH:35]=[CH:36][CH:37]=4)=[CH:31][N:32]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:38][O:39]C(=O)C)(=O)C.C[O-].[Na+].C(O)(=O)C>CO>[O:34]1[CH:35]=[CH:36][CH:37]=[C:33]1[C:30]1[S:29][C:28]([CH2:27][C:21]2[CH:20]=[C:19]([C@H:8]3[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:38][OH:39])[O:7]3)[CH:24]=[CH:23][C:22]=2[C:25]#[N:26])=[N:32][CH:31]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C#N)c(Cc3ncc(-c4ccco4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ncc(-c2ccco2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 20285.7 %

Procedure:
To a solution of the peracetylate 59 (208 mg, 0.35 mmol) in MeOH (10 mL) was added NaOMe (25 wt. % in MeOH, 0.2 mL). The reaction mixture was stirred at ambient temperature for 3 h. Acetic acid was added to neutralize the reaction mixture and concentrated in vacuo. The residue was redissolved in MeOH and further purified by prep HPLC (C18) to provide the titled compound (106 mg, 71 mmol) as a white solid.
Reaction SMILES: CC([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH2:26])[O:22][C:21]3=[O:27])=[CH:16][C:15]=2[F:28])[CH2:10][CH2:9]1)=[O:7])(C)C.N1C=CC=CC=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>C(Cl)Cl>[C:35]([NH:26][CH2:25][C@@H:23]1[O:22][C:21](=[O:27])[N:20]([C:17]2[CH:18]=[CH:19][C:14]([CH:11]3[CH2:10][CH2:9][N:8]([C:6]([OH:5])=[O:7])[CH2:13][CH2:12]3)=[C:15]([F:28])[CH:16]=2)[CH2:24]1)(=[O:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N3C[C@H](CN)OC3=O)cc2F)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(C(=O)O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (S)-(-)-4-[4-[5-(aminomethyl)-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (EXAMPLE 20, Step 8, 9.45 g) in dry methylene chloride (96 mL) under N2 is treated with pyridine (5.82 mL) and acetic anhydride (3.40 mL), and the resulting mixture is stirred at ambient temperature for four hours, diluted with methylene chloride (25 mL), washed with water (25 mL), saturated aqueous sodium bicarbonate (25 mL) and saline (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which is then chromatographed on silica gel (230-400 mesh, 350 g), eluting with a gradient of methanol/chloroform (2.5/97.5-7.5/92.5). Pooling and concentration of those fractions with an Rf =0.51 by TLC (methanol/chloroform, 10/90) gives the title compound, mp 144-146° C.
Reaction SMILES: [OH:1][C:2]([C@@H:4]1[CH:19]=[C:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][CH:11]=3)[N:6]([CH3:7])[CH2:5]1)=[O:3].C(O)(C(F)(F)F)=O.[Br:28]Br>O1CCOCC1.C(Cl)(Cl)Cl>[Br:28][C:11]1[NH:12][C:13]2[C:20]3[C:10]=1[CH2:9][C@@H:8]1[C:18](=[CH:19][C@@H:4]([C:2]([OH:1])=[O:3])[CH2:5][N:6]1[CH3:7])[C:17]=3[CH:16]=[CH:15][CH:14]=2
Reactant: CN1C[C@H](C(=O)O)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: BrBr
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CN1C[C@H](C(=O)O)C=C2c3cccc4[nH]c(Br)c(c34)C[C@H]21
Temperature: 5 °C

Procedure:
Lysergic acid (8.05 g, 30 mmol) is suspended in dioxane and is treated with dropwise addition of TFA (exothermic). Bromine (1.54 ml, 30 mmol, 1.0 eq.) in chloroform is added dropwise. The reaction is cooled to 5° C. and product crystallizes. (6aR,9R)-5-Bromo-7-methyl-4,6,6a,7,8,9-hexahydro-indolo[4,3-fg]quinoline-9-carboxylic acid is isolated by filtration and re-crystallised from diethylether. Rf=0.5, 10% MeOH:DCM, M+H+=346, 348, m.p.>245 (decomposition).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C(O)(=O)C.C(O)(=O)C.[NH2:13][C:14]1([C:20]([O:22][CH2:23][CH:24](OCN2C=NC3C(=O)NC(N)=NC2=3)[CH2:25][O:26]C(C2(N)CCCCC2)=O)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.[OH-].[NH4+]>O>[C:1]([OH:4])(=[O:3])[CH3:2].[NH2:13][C:14]1([C:20]([O:22][CH2:23][CH2:24][CH2:25][OH:26])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Nc1nc2c(ncn2COC(COC(=O)C2(N)CCCCC2)COC(=O)C2(N)CCCCC2)c(=O)[nH]1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: NC1(C(=O)OCCCO)CCCCC1
Reaction time: 7 h

Procedure:
2-((2-Amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy)-1,3-propanediyl bis-(1-amino-cyclohexane-carboxylate) tris acetate, 98 mg (lyophilized sample contained 3.0 equivalents of acetic acid by NMR), 0.143 mmol (=a total of 0.43 mmol of acetic acid) is dissolved in de-ionized water, 0.4 mL, and 38 μL of a 0.015M ammonium hydroxide solution (=0.57 mmol) is added. The mixture is left at room temperature for 7 hrs., the vial is placed in a oil bath maintained at 48°-50° C. and left in the oil bath for 22 hrs. The sample is injected in two equal lots onto a preparative reverse phase HPLC column (YMC-Pack, ODS-AM DM-33-5, 20×250 mm; YMC Inc.). Separation is achieved with a solvent system of 15% methanol/85% 0.1M ammonium acetate buffered to pH 4 with acetic acid, flow rate: 9.5 mL/min and the detector set to 256 nm. The peak representing the mono ester is collected. The solvent is removed under high vacuum to about 2 mL and the residue is lyophilized three times from water containing acetic acid (0.1%) to remove the buffer. Excess acetic acid is then removed by drying at room temperature under high vacuum for 42 hrs. 30 mg (0.068 mmol=48%) of 2-(2-amino-1,6-dihydro-6-oxo purin-9-yl)methoxy)-3-hydroxy-1-propanyl (1-amino-cyclohexane-carboxylate) acetate, identical by HPLC and NMR with the product of Example 4B, is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[C:14]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:13]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[NH2:26][NH2:27]>O1CCOCC1>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([NH:26][NH2:27])[N:15]=[C:14]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:13]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CCOc1cc(Cl)nc(N2CCOCC2)n1)C(=O)OC(C)(C)C
Reactant: NN
Solvent: C1COCCO1
Product: CN(CCOc1cc(NN)nc(N2CCOCC2)n1)C(=O)OC(C)(C)C

Procedure:
[2-(6-chloro-2-morpholin-4-yl-pyrimidin-4-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester (5.6 g) was dissolved in dioxane (100 mL) and hydrazine (6 mL) was added. The solution was heated to reflux for one hour, at which point the solvent was evaporated. The solid was dissolved in dichloromethane (200 mL) and washed with 10% sodium carbonate (10 mL). The organic layer was dried over magnesium sulfate and evaporated to give [2-(6-hydrazino-2-morpholin-4-yl-pyrimidin-4-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester, which was used without purification in the next reaction.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:9])=[C:5]([CH3:7])[N:6]=1.C(N(CC)CC)C.[Br:26][CH2:27][CH2:28][CH2:29][C:30](Cl)=[O:31]>O1CCCC1.ClCCl>[Br:26][CH2:27][CH2:28][CH2:29][C:30]([NH:1][C:2]1[S:3][C:4]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:9])=[C:5]([CH3:7])[N:6]=1)=[O:31]
Reactant: Cc1nc(N)sc1C(=O)NCc1ccc(F)cc1
Reactant: O=C(Cl)CCCBr
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(NC(=O)CCCBr)sc1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of 2-amino-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide (5.60 g, 22.0 mmol) and triethylamine (2.61 g, 26.0 mmol) in anhydrous tetrahydrofuran (250 mL) was added 4-bromobutanoyl chloride (4.99 g, 26.0 mmol) in anhydrous dichloromethane (10 mL) dropwise at 0° C. The reaction mixture was stirred at ambient temperature for 2 hours, then diluted with dichloromethane (200 mL) and washed with saturated aqueous sodium bicarbonate solution (2×150 mL), and brine (150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrate in vacuo to afford the title compound as a yellow oil in 92% yield (8.00 g): 1H NMR (300 MHz, CDCl3) δ 8.61 (br s, 1H), 7.32-7.22 (m, 2H), 7.05-6.94 (m, 2H), 6.14 (t, J=5.6 Hz, 1H), 4.53 (d, J=5.6 Hz, 2H), 3.45 (t, J=6.7 Hz, 2H), 2.65 (t, J=6.7 Hz, 2H), 2.58 (s, 3H), 2.23 (quintet, J=6.7 Hz, 2H); MS (ES+) m/z 413.1 (M+1), 415.1 (M+1).