Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH2:17]([O:24][C:25]([C@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[S:32]([C:35]1[CH:40]=[CH:39][C:38]([N:41]2[CH2:46][CH2:45][C:44](=O)[CH2:43][CH2:42]2)=[CH:37][CH:36]=1)(=[O:34])=[O:33])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25]([C@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[S:32]([C:35]1[CH:36]=[CH:37][C:38]([N:41]2[CH2:46][CH2:45][CH:44]([NH:1][CH2:2][C@H:3]([OH:4])[C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[CH2:43][CH2:42]2)=[CH:39][CH:40]=1)(=[O:33])=[O:34])=[O:26])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1CCN(c2ccc(S(=O)(=O)N3CCC[C@@H]3C(=O)OCc3ccccc3)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(S(=O)(=O)N4CCC[C@@H]4C(=O)OCc4ccccc4)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from N-[5-((1R)-2-Amin o-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide and Reference Example 23, (2R)-1-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid benzyl ester, according to the procedure of Example 1 as a white solid; mp 62-69° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2H), 1.40-1.90 (m, 6H), 2.50-3.20 (m, 5H), 3.75-3.85 (m, 2H), 4.15 (dd, 1H), 4.40-4.50 (m, 1H), 5.19 (s, 2H), 6.80 (d, 1H), 6.92 (d, 3H), 7.15 (d, 1H), 7.40-7.50 (m, 5H), 7.52 (d, 2H); MS (ES) m/z: 673.1.1 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([Cl:9])[CH:3]=1.[OH:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Cl:9])[CH:3]=1)[O:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Fc1cc(Cl)cc(Br)c1
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cc(Br)cc(Oc2cccnc2)c1
Yield: 70 %

Procedure:
1-Bromo-3-chloro-5-fluorobenzene (1.0 g, 4.8 mmol, 1.0 eq), 3-hydroxypyridine (454 mg, 4.77 mmol, 1.00 eq), K2CO3 (792 mg, 5.73 mmol, 1.20 eq) and DMF (15 mL) were added to a microwave vial and microwaved at 200° C. for 30 minutes. The reaction was filtered and concentrated on silica gel (5 g). The silica gel was loaded on top a fresh bed of silica gel and washed with 50% ethyl acetate/hexane. The solvents were removed in vacuo and the crude mixture was purified by flash chromatography on silica gel afforded 950 mg (55%) of the title compound as a golden oil: 1H NMR (400 MHz, CDCl3) δ 8.45-8.44 (m, 2H), 7.58 (dd, J=8.4, 1.5 Hz, 1H), 7.52 (t, J=1.7 Hz, 1H), 7.47 (dd, J=8.5, 4.6 Hz, 1H), 7.25 (t, J=2.1 Hz, 1H), 7.18 (t, J=2.0 Hz, 1H); [M+1]+: 284.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11](=O)/[CH:12]=[CH:13]/N(C)C)[NH:8][CH:7]=1)=[O:5])[CH3:2].Cl.[NH2:19][C:20]([NH2:22])=[NH:21].CC[O-].[Na+]>C(O)C.O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][N:19]=[C:20]([NH2:22])[N:21]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: N=C(N)N
Reactant: CCOC(=O)c1c[nH]c(C(=O)/C=C/N(C)C)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c[nH]c(-c2ccnc(N)n2)c1
Temperature: 110 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
To a suspension of 5-((E)-3-Dimethylamino-acryloyl)-1H-pyrrole-3-carboxylic acid ethyl ester (0.25 g, 1.06 mmol) in 4 mL of ethanol, guanidine hydrochloride (0.121 g, 1.27 mmol) and sodium ethylate (0.086 g, 1.27 mmol) were added. The mixture was heated to 110° C. overnight. Then, a further amount of sodium ethylate (0.086 g, 1.27 mmol) was added to the mixture and heating to 115° C. was prolonged for additional 24 hours. The resulting mixture was cooled at room temperature and diluted with water (2 mL). The solid was isolated by filtration, washed with 10 mL of water, dried in a vacuum oven at 40° C. affording to give 0.197 g (80%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Sn](Cl)(Cl)(Cl)Cl.[CH3:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[CH:18]=1>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([C:18]1[N:19]([N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[C:20]2[C:25]([C:17]=1[CH3:16])=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:5]
Reactant: O=C(Cl)c1ccccc1F
Reactant: Cc1cn(N2C(=O)c3ccccc3C2=O)c2ccccc12
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1c(C(=O)c2ccccc2F)n(N2C(=O)c3ccccc3C2=O)c2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 0.91 ml of 2-fluorobenzoyl chloride in 50 ml of dry DCM was cooled in an ice/salt bath. To the solution was added 0.86 ml (1.9 It g) of tin (IV) chloride. The mixture was stirred at -5° to 0° C. for 10 minutes after which was added 2.0 g of 2-(3-methyl-1H-indol-1-yl)-1H-isoindole-1,3-(2H)dione. The reaction mixture was stirred at 0° C. for 1 hour, allowed to warm to room temperature, cooled again in an ice bath, poured onto ice, extracted twice with ethyl acetate, washed with water, brine, dried (Na2SO4), filtered and concentrated to a green-yellow solid (2.67 g). The solid was chromatographed on silica gel, eluting with 15% acetone/heptane to provide 1.99 g of a solid, which was recrystallized from ethanol, m.p. 197°-199° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Mg].[B:11]([O:22]CCCC)([O:17]CCCC)[O:12]CCCC.[Cl-].[NH4+]>O1CCCC1>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:12][B:11]([OH:22])[OH:17]
Reactant: COc1ccccc1Br
Reactant: CCCCOB(OCCCC)OCCCC
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1OB(O)O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 2-bromoanisole (0.25 ml) dissolved in tetrahydrofuran (5 ml) was added with magnesium (48.6 mg) and stirred at 60° C. for 1 hour to prepare a Grignard reagent. This solution was cooled to −78° C., added with a solution of tributyl borate (0.65 ml) dissolved in tetrahydrofuran (5 ml) and gradually warmed to room temperature with stirring for 20 hours. The reaction mixture was added with saturated aqueous ammonium chloride (10 ml) with ice cooling, stirred for 10 minutes and then extracted twice with ether (10 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain (2-methoxyphenyl)boric acid.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:9]=2[NH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19](OCC)(=[O:25])[C:20](OCC)=[O:21]>>[CH:1]1([N:7]2[C:8]3[C:9](=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=3)[NH:10][C:20](=[O:21])[C:19]2=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1cc(C(F)(F)F)ccc1NC1CCCCC1
Reactant: CCOC(=O)C(=O)OCC
Product: O=c1[nH]c2cc(C(F)(F)F)ccc2n(C2CCCCC2)c1=O

Procedure:
28 g (0.11 mol) of 2-cyclohexylamino-5-trifluoromethylaniline and 322 g (2.2 mol) of diethyl oxalate were refluxed for 2 hours. The reaction mixture was then concentrated, and the crude product was recrystallized from ethanol.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl[CH2:14][CH2:15][O:16][CH2:17][CH2:18]Cl>C(O)C>[CH2:11]([O:10][C:2]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:9])[CH3:12]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClCCOCCCl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.2 %

Procedure:
Sodium (10 g) was dissolved in dry ethanol (300 cm3) and then diethyl malonate (30 g) was added slowly. After stirring for 15 minutes, bis(2-chloroethyl)ether (35 g) was added dropwise. The mixture was heated under reflux for 72 hours and then cooled to room temperature. After filtering the solvent was removed from the reaction mixture under reduced pressure to give the crude product. An initial purification was achieved by chromatography on alumina (activity 4) using ethyl acetate/petroleum ether mixtures as eluants. The pure product (11.3 g) was isolated by distillation under reduced pressure as an oil (b.p. 106°-108° C. at 0.03 mmHg).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([NH:13][C:14](=[O:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Si:21]([CH3:24])([CH3:23])[CH3:22])[CH3:12].[CH3:26][O:27][CH2:28]Cl>C1COCC1>[CH2:11]([N:13]([CH2:26][O:27][CH3:28])[C:14](=[O:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Si:21]([CH3:24])([CH3:23])[CH3:22])[CH3:12]
Reactant: COCCl
Reactant: CCNC(=O)c1ccccc1[Si](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(COC)C(=O)c1ccccc1[Si](C)(C)C
Yield: 49.4 %

Procedure:
A 1M THF solution of sodium bis(trimethylsilyl)amide (52.5 mL, 52.5 mmol) was added dropwise over 5 min to a solution of the compound of Example 49 (11.07 g, 50 mmol) in THF (100 mL). The resulting mixture was cooled with a dry ice/acetone bath while neat chloromethyl methyl ether (4.83 g, 60 mmol) was added, maintaining the internal reaction temperature <-70° C. The cold bath was removed and the resulting reaction mixture was allowed to warm for 1 h, then was partitioned between sat aq NaHCO3 and ether. The ether phase was dried (MgSO4), concentrated, and purified by HPLC with 3:17 ethyl acetate/hexanes to afford 6.55 g of the title compound as a colorless oil, a 49% yield.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)#[N:2].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[S:29])=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][NH:12][C:4]([NH:3][C:1]#[N:2])=[N:5][C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)=[S:29])=[CH:23][CH:22]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: N#CNC(=Nc1ccncc1)NCCCCCCO
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: N#CNC(=Nc1ccncc1)NCCCCCCOC(=S)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
N-Cyano-N′-(6-hydroxyhexyl)-N″-4-pyridylguanidine (0.5 g), 4-chlorophenyl isothiocyanate (0.4 g) and diisopropylethylamine (0.32 ml) was mixed in a two-necked flask with a three-way-tap and a septum. The air was exchanged with argon through the three-way-tap. Dry pyridine (10 ml) was added through the septum. The reaction mixture was stirred for 5 days at room temperature.
Reaction SMILES: [Br:1]C1C(C(OC)=O)=NC(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=CN=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[C:31]1[C:32]([C:48]([O:50][CH3:51])=[O:49])=[N:33][C:34]([NH:37][C@@H:38]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40][C@@H:39]2[OH:47])=[CH:35][N:36]=1>>[Br:1][C:35]1[N:36]=[C:31]([C:25]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=2[Cl:23])[C:32]([C:48]([O:50][CH3:51])=[O:49])=[N:33][C:34]=1[NH:37][C@@H:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][C@@H:39]1[OH:47]
Reactant: COC(=O)c1nc(N[C@@H]2c3ccccc3C[C@@H]2O)cnc1-c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1nc(N[C@@H]2c3ccccc3C[C@@H]2O)cnc1Br
Product: COC(=O)c1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(Br)nc1-c1ccc(Cl)cc1Cl

Procedure:
Following the procedure for the preparation of methyl 3-bromo-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylate but substituting methyl 3-(2,4-dichlorophenyl)-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylate and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 2.99–3.04, 3.20–3.25, 3.70, 3.99–4.08, 4.77, 5.59–5.62, 6.11, 7.24–7.38; MS (ESI+) for C21H16BrCl2N3O3 m/z 509 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[NH:13][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][N:10]2[C:20](=[O:29])[C:21]([CH2:23][C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)=[N:22][C:9]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([B:38]2[O:42][C:41]([CH3:44])([CH3:43])[C:40]([CH3:46])([CH3:45])[O:39]2)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH2:1]([C:8]1[C:9]2[N:10]([C:20](=[O:29])[C:21]([CH2:23][C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)([CH2:31][C:32]3[CH:33]=[CH:34][C:35]([B:38]4[O:39][C:40]([CH3:46])([CH3:45])[C:41]([CH3:44])([CH3:43])[O:42]4)=[CH:36][CH:37]=3)[N:22]=2)[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Reactant: O=c1c(Cc2ccco2)nc2c(Cc3ccccc3)[nH]c(-c3ccccc3)cn1-2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CC1(C)OB(c2ccc(CC3(Cc4ccco4)N=C4C(Cc5ccccc5)=NC(c5ccccc5)=CN4C3=O)cc2)OC1(C)C
Temperature: 25 °C

Procedure:
To a solution of 8-benzyl-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazin-3(7H)-one, 2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, potassium carbonate and potassium iodide (33 mg, 0.20 mmol) is added. The reaction mixture is stirred at room temperature and is heated to 40° C. until HPLC shows the completion of the reaction.
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=1)[CH2:3][C:4]#[CH:5].[N:12]([CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[N+:13]=[N-:14]>>[ClH:1].[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([CH2:15][N:12]2[CH:5]=[C:4]([CH2:3][CH2:2][C:6]3[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=3)[N:14]=[N:13]2)=[CH:17]1
Reactant: C#CCCc1c[nH]c(N)n1
Reactant: [N-]=[N+]=NCc1c[nH]c2ccccc12
Agent: Cl
Product: Nc1nc(CCc2cn(Cc3c[nH]c4ccccc34)nn2)c[nH]1
Yield: 58.3 %

Procedure:
4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.073 g, 0.429 mmol) was reacted with 3-azidomethyl-indole (0.089 g, 0.515 mmol) following the general procedure for click reactions outlined above to produce 4-{2-[1-(1H-Indol-3-ylmethyl)-1H-[1,2,3]triazol-4-yl]-ethyl}-1Himidazol-2-ylamine hydrochloride (0.086 g, 58%) as a yellow oil, 1H NMR (300 MHz, CD3OD) δ 8.11 (s, 1H), δ 7.84 (m, 2H), δ 7.41 (m, 2H), δ 7.06 (d, 1H), δ 5.66 (s, 2H), δ 3.04 (t, 2H), δ 2.85 (t, 2H) ppm; 13C (75 MHz, CD3OD) δ 147.5, 144.9, 144.8, 134.7, 131.9, 127.2, 127.1, 127.1, 125.8, 125.3, 124.4, 109.5, 49.9, 23.6, 23.2 ppm; HRMS (ESI) calcd for C17H19N7 (M+) 321.1701. Found 321.1704.
Reaction SMILES: [CH3:1][C:2]1([CH2:8][OH:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOCC>[CH3:1][C:2]1([CH:8]=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: CC1(CO)CCOCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: CC1(C=O)CCOCC1
Reaction time: 1.17 h
Yield: 68.5 %

Procedure:
To a solution of (4-methyl-tetrahydro-pyran-4-yl)-methanol (1.5 g, 11.5 mmol) in CH2Cl2 was added a suspension of Dess-Martin periodinane (5.8 g, 14 mmol) in CH2Cl2 (30 mL). After 70 min, the heterogenous mixture was diluted with Et2O (100 mL), stirred for 10 min, treated with 1 N HaOH (10 mL), and stirred for another 10 min. The mixture was filtered, and the filtrate was concentrated. The residue was purified by chromatography (Et2O/CH2Cl2) to give the title compound (1.01 g, 68%) as a colorless volatile oil. The spectral data matched that reported in PCT Intl. Pat. Appl. Publ. No. WO 2006/001752.
Reaction SMILES: Cl[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=2[F:15])[C:6](=[O:16])[N:5]([CH3:17])[C:4](=[O:18])[CH:3]=1.CN.FC1C=C(I)C=C[C:23]=1[N:29]1C(=O)C=C(NC)N(C)C1=O>CO>[F:15][C:9]1[CH:10]=[C:11]([I:14])[CH:12]=[CH:13][C:8]=1[N:7]1[C:2]([NH:29][CH3:23])=[CH:3][C:4](=[O:18])[N:5]([CH3:17])[C:6]1=[O:16]
Reactant: Cn1c(=O)cc(Cl)n(-c2ccc(I)cc2F)c1=O
Reactant: CNc1cc(=O)n(-c2ccc(I)cc2F)c(=O)n1C
Agent: CN
Solvent: CO
Product: CNc1cc(=O)n(C)c(=O)n1-c1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.9 %

Procedure:
To a 6:5 mixture (75.7 g) of 6-chloro-1-(2-fluoro-4-iodophenyl)-3-methyl-1H-pyrimidine-2,4-dione 65 and 6-chloro-3-(2-fluoro-4-iodophenyl)-1-methyl-1H-pyrimidine-2,4-dione 66 obtained in Step 3 were added methanol (227 ml) and 40% solution (152 ml) of methylamine in methanol, and the mixture was stirred at room temperature for 2.5 hrs. The reaction mixture was concentrated under reduced pressure, and toluene(150 ml) and water (150 ml) were added to the residue, and the mixture was stirred under heating at reflux for 30 min. After allowing to return to room temperature, the crystals were collected by filtration and dried to give a 6:5 mixture (59.6 g, yield 79.9%) of 1-(2-fluoro-4-iodophenyl)-3-methyl-6-methylamino-1H-pyrimidine-2,4-dione 67 and 3-(2-fluoro-4-iodophenyl)-1-methyl-6-methylamino-1H-pyrimidine-2,4-dione 68 as pale-yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([OH:16])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:17][CH3:18])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:19])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.I[CH2:32][C:33]([OH:35])=[O:34]>O>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:32][C:33]([OH:35])=[O:34])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:17][CH3:18])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:19])[CH:5]=1
Reactant: CCC12CCC(=O)C=C1c1c(cc(O)c(Cl)c1Cl)C2
Reactant: O=C(O)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2
Temperature: 50 °C

Procedure:
5,6-Dichloro-9a-ethyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one, (Example 1, Step C) (15 gm., 0.048 mole), potassium carbonate (13.3 gm., 0.096 mole), dimethylformamide (100 ml.) and iodoacetic acid (10.6 gm., 0.057 mole) is stirred at room temperature for 24 hours. The reaction mixture is poured into water (150 ml.), stirred, warmed to 50° C., filtered and the filtrate acidified with 6 N hydrochloric acid to obtain [(5,6-dichloro-9a-ethyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetic acid, which after recrystallization from acetic acid, melts at 237° C.-238° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([OH:9])=[CH:4][N:3]=1.[H-].[Na+].C1N=CN([C:17](N2C=NC=C2)=[O:18])C=1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[O:9][C:17](=[O:18])[NH:8][C:6]=2[N:7]=1
Reactant: Nc1ncc(O)c(N)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc2oc(=O)[nH]c2n1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
2,4-Diamino-pyrimidin-5-ol (500 mg, 3.97 mmol) [prepared according to the method of Hull. J. Chem. Soc. 1956, 2033-2035] was suspended in DMF (10 mL). To this was added consecutively NaH (86.7 mg, 3.77 mmol) and CDI (707 mg, 4.36 mmol), and the reaction mixture was heated with vigorous stirring at 60° C. for 3 h. The mixture was cooled to ambient temperature, and then quenched with water (25 mL). The solvent and water were removed via rotary evaporation, and the residue was then triturated in water (5 mL). The solid was then collected by filtration and dried, affording 230 mg (38%): 1H NMR (400 MHz, d6-DMSO) δ 11.90 (br s, 1H), 7.72 (br s, 1H), 6.72 (s, 2H); Analysis calc'd for C5H4N4O2.0.2H2O: C, 38.56; H, 2.85; N, 35.98. Found: C, 39.01; H, 2.71; N, 35.58; [M+H]+ m/z 153.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[O:5]=[C:6]1[NH:14][CH:13]=[N:12][C:11]2[N:10]([CH2:15][CH2:16][C:17]([O:19]CC)=O)[CH:9]=[N:8][C:7]1=2.C(#N)C>CCOCC>[O:5]=[C:6]1[NH:14][CH:13]=[N:12][C:11]2[N:10]([CH2:15][CH2:16][C:17]([NH:3][CH2:2][CH2:1][NH2:4])=[O:19])[CH:9]=[N:8][C:7]1=2
Reactant: NCCN
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Solvent: CCOCC
Solvent: CC#N
Product: NCCNC(=O)CCn1cnc2c(=O)[nH]cnc21
Yield: 92 %

Procedure:
1.500 g (25.0 mmol) of ethylenediamine was stirred at room temperature with 250 mg (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) for one hour. The solution was treated with 4 ml acetonitrile and 20 ml of ether with stirring. Upon filtration and washing with ether, this yielded 245 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-(2-aminoethyl)propanamide (AIT-0058) as a slightly yellow solid. Yield: 92%.
Reaction SMILES: [N+]([O-])(O)=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH2:15])=[NH:14])=[CH:8][CH:7]=1.[OH-].[Na+].CO[CH2:20][CH2:21]O>>[CH3:10][C:9]1[NH:12][CH:13]=[C:20]([CH3:21])[C:8]=1[C:7]1[CH:6]=[CH:11][N:15]=[C:13]([NH:12][C:9]2[CH:8]=[CH:7][C:6]([F:5])=[CH:11][CH:10]=2)[N:14]=1
Reactant: COCCO
Reactant: N=C(N)Nc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Product: Cc1c[nH]c(C)c1-c1ccnc(Nc2ccc(F)cc2)n1
Yield: 62 %

Procedure:
To a mixture of 3-dimethylamino-1-(2,4-dimethyl-1H-pyrrol-3-yl)-propenone (1 mmol, 0.19 g) and 4-fluorophenyl guanidine nitrate (2 mmol, 0.44 g) in 2-methoxyethanol (5 mL) was added NaOH (40 mg). The reaction mixture was heated at 100–120° C. under N2 for 6 h. The solvent was evaporated to dryness and the residue was purified by flash chromatography (1:2 EtOAc/PE). Recrystallisation from EtOAc/PE afforded the title compound (174 mg, 62%) as brown crystals. 1H-NMR (CDCl3) δ: 2.21 (s, 3H, CH3), 2.43 (s, 3H, CH3), 6.33 (s, 1H, pyrrolyl-H), 6.73 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.00 (m, 2H, Ph-H), 7.79 (m, 2H, Ph-H), 8.28 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 9.16 (s, 1H, NH), 10.59 (s, 1H, NH).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH2:18](Cl)[C:19](=[CH2:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1)[C:19](=[CH2:18])[CH3:21]
Reactant: C=C(C)CCl
Reactant: COC(=O)C(c1ccc(O)cc1)C1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)COc1ccc(C(C(=O)OC)C2CCCC2)cc1

Procedure:
10 g (0.043 mol) of methyl 2-(4-hydroxyphenyl)-2-cyclopentyl-acetate are dissolved in 200 ml of dimethylformamide and 4.1 g (0.043 mol) of methallyl chloride and 5.9 (0.043 mol) of potassium carbonate are added with stirring. The mixture is allowed to react overnight at 100° C. After cooling, the solvent is evaporated in vacuo, the residue is taken up in 200 ml of dichloromethane, the solution is washed twice with 100 ml of water, the organic phase is dried using sodium sulphate and the product from evaporation in vacuo is purified by column chromatography (silica gel 60, eluent: toluene/ethyl acetate=100:5).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:7][CH2:6][C:5](=[CH:8][CH2:9][N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][C:13]([NH2:20])=[N:14][C:15]=3Cl)[CH2:4][O:3]1.C(N(CC)CC)C>[Pd].C(OCC)(=O)C>[NH2:20][C:13]1[N:12]=[C:11]2[C:16]([N:17]=[CH:18][N:10]2[CH2:9][CH2:8][CH:5]2[CH2:6][O:7][C:2]([CH3:21])([CH3:1])[O:3][CH2:4]2)=[CH:15][N:14]=1
Reactant: CC1(C)OCC(=CCn2cnc3c(Cl)nc(N)nc32)CO1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1(C)OCC(CCn2cnc3cnc(N)nc32)CO1
Reaction time: 18 h
Yield: 74.5 %

Procedure:
A mixture of 2,2-dimethyl-5-[2-(2-amino-6-chloropurin-9-yl)]ethylidene-1,3-dioxane (0.45 g), 5% palladium on carbon (0.225 g) and triethylamine (0.22 ml) in ethyl acetate (22.5 ml) was hydrogenated at 50° C. for 18 hours at 50 p.s.i. The catalyst was removed by filtration and the filter washed with ethyl acetate. The combined filtrate and wash were concentrated under reduced pressure to give a gum which was purified by silica gel chromatography (eluted with dichloromethane/methanol 99:1 increasing to 97:3) to give the title compound (300 mg, 74% yield).