Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[Br:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:14](=[O:16])[C:13]([N:10]2[CH2:9][CH2:8][CH:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:17])=[CH:30][CH:29]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Br)cc1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.9 %

Procedure:
A mixture of 0.64 g (2.4 mmol) of [4-(4-fluoro-benzyl)piperidin-1-yl]-oxo-acetic acid, 0.34 ml (2.4 mmol) of triethylamine, 0.35 g (2 mmol) of 4-bromo-aniline (Aldrich), 0.91 g (2.4 mmol) of HBTU and 10 ml of dimethylformamide is stirred at room temperature for 24 hours. The reaction mixture is concentrated. Then 30 ml of 8% sodium hydrogencarbonate solution and 30 ml of chloroform is added to the mixture. The organic layer is separated and the water phase is extracted three times with 20 ml of chloroform. The combined organic layers are dried over sodium sulfate, concentrated. The residue is treated with diethylether and the crystals are filtered off to yield 0.36 g (43%) of the title compound. Melting Point: 156-158° C. (diethylether)
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].Cl[CH2:13][C:14]1[CH:24]=[CH:23][C:17]2[N:18]=[C:19]([S:21][CH3:22])[S:20][C:16]=2[CH:15]=1.O>CN(C=O)C>[N:1]1[C:5]2[C:4](=[N:9][CH:8]=[CH:7][CH:6]=2)[N:3]([CH2:13][C:14]2[CH:24]=[CH:23][C:17]3[N:18]=[C:19]([S:21][CH3:22])[S:20][C:16]=3[CH:15]=2)[CH:2]=1
Reactant: c1cnc2[nH]cnc2c1
Reactant: CSc1nc2ccc(CCl)cc2s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc2ccc(Cn3cnc4cccnc43)cc2s1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 41.6 %

Procedure:
To a stirred solution of 4-azabenzimidazole (613 mg, 5.15 mmol) in anhydrous DMF (20 mL) at 0° C. was added in one portion sodium hydride (60% dispersion in mineral oil, 216 mg, 5.41 mmol) and the mixture was stirred at 0° C. for 20 min. The mixture was allowed to warm to rt and stirred for a further 20 min. To the reaction mixture was added a solution of 6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (1.3 g, 5.66 mmol) from Step 4 of Example 36 in DMF (5 mL). The mixture was stirred at rt for 15 h. To the reaction mixture was added water (300 mL) and the mixture was extracted with DCM (3×50 mL). The combined organic layers were washed with brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluting with 100% DCM followed by 1% MeOH in DCM) to afford 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole (670 mg, 41%) as a white solid. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.38 (dd, J=1.3, 4.7 Hz, 1H), 8.11 (dd, J=1.2, 8.0 Hz, 1H), 8.00 (d, J=1.1 Hz, 1H), 7.81 (d, J=8.5 Hz, 1H), 7.46 (dd, J=1.6, 8.4 Hz, 1H), 7.30 (dd, J=4.7, 8.1 Hz, 1H), 5.62 (s, 2H), 2.77 (s, 3H). LCMS (ESI) m/z 313 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:11][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)O)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)c1ccc(CBr)cc1
Yield: 65.3 %

Procedure:
39.7 g (287 mmol) of p-toluylic acid, 51.2 g (287 mmol) of N-bromosuccinimide and 2.8 g (11.5 mmol) of dibenzoyl peroxide were suspended in 350 ml of carbon tetrachloride. Then, the resultant mixture was heated with vigorously stirring to perform a reaction under reflux for 2 hours. After completion of the reaction, the reaction mixture was cooled in ice bath. The deposited crystalline product was collected by filtration, which was then washed with hexane and water, followed by drying. The resultant crystalline product was recrystallized from ethanol to obtain 40.3 g of 4-bromomethylbenzoic acid as a white needle crystal (isolated yield: 65%).
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][CH:6]([NH:24][C:25](=[O:38])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:9]=1.[OH-].[K+].C1COCC1>CO.O>[CH2:17]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH2:7][C@@H:6]([NH:24][C:25](=[O:38])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:5][CH2:4][C:3]([OH:39])=[O:2])=[CH:9]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)CCC(Cc1cn(Cc2ccccc2)c2ccccc12)NC(=O)CCCCCCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)CC[C@@H](Cc1cn(Cc2ccccc2)c2ccccc12)NC(=O)CCCCCCc1ccccc1
Reaction time: 0.67 h
Yield: 63.9 %

Procedure:
To a solution of 5-(1-benzyl-1H-indol-3-yl)-4-(7-phenyl-heptanoylamino)-pentanoic acid methyl ester (48 mg, 0.092 mmol) in MeOH (0.5 mL) was added KOH (100 mg, 1.79 mmol) in water (0.5 mL). THF (1 mL) was added to homogenise the solution and the reaction was complete in 40 min. The solvents were removed and water added. Upon washing with Et2O the aqueous layer was acidified with aqueous HCl and the resultant precipitate filtered. Upon drying the solid was recrystallised from THF/Et2O to afford the title compound (30 mg, 64%), mp 130.4-131.9° C. 13C NMR (DMSO-d6) δ 174.3, 171.8, 142.3, 138.4, 135.9, 128.4, 128.2, 128.2, 127.2, 127.1, 126.8, 125.5, 121.1, 118.9, 118.5, 111.3, 109.9, 48.9, 48.6, 35.5, 35.1, 30.9, 30.7, 30.5, 29.1, 28.5, 28.4, 25.2. ISMS: 511 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[C:12]2[S:16][C:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:14][C:13]=2[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)CCC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[C:12]2[S:16][C:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:14][C:13]=2[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CCNC(=O)Nc1nc2cc(OCc3ccccc3)cc(Br)c2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(OCc3ccccc3)cc(-c3ccccn3)c2s1
Temperature: 100 °C
Yield: 69.6 %

Procedure:
To a stirred solution of viii (110 g, 0.27 mol) in DMF (1.1 L) was added 2-tributylstannyl pyridine (298 g, 0.81 mol). The resulting solution was purged with N2 for 15-20 min followed by addition of Pd(PPh3)4 (25.41 g, 0.022 mol). The resulting reaction mixture was heated to 100° C. under N2 atmosphere for 15-16 h. The reaction was cooled to 40-45° C. and filtered through celite. The celite was washed with DMF (500 mL) and hot EtOAc (1.50 L) and the combined filtrate concentrated at 60-70° C. in vacuo. The residue was purified through silica (20% EtOAc-Hexanes to 100% EtOAc) to obtain ix (76 g, 70%). 1H-NMR (DMSO-d6, 400 MHz): δ 1.08 (t, J=7.20 Hz, 3H), 3.19 (q, J=6.80 Hz, 2H), 5.26 (s, 2H), 6.84 (br s, 1H), 7.32-7.43 (m, 5H), 7.51 (d, J=7.20 Hz, 2H), 7.69 (d, J=2.0 Hz, 1H), 7.95 (m, 1H), 8.25 (m, 1H), 8.78 (m, 1H) and 10.46 (br s, 1H). MS: 405.30 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[N:4]([CH2:12][CH2:13][CH2:14][P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[C:3]1=[O:23].Cl[CH2:25][CH:26]1[CH2:28][CH2:27]1>>[CH:26]1([CH2:25][N:7]2[C:6]3[C:5](=[O:11])[N:4]([CH2:12][CH2:13][CH2:14][P:15](=[O:22])([O:16][CH2:17][CH3:18])[O:19][CH2:20][CH3:21])[C:3](=[O:23])[N:2]([CH3:1])[C:10]=3[N:9]=[CH:8]2)[CH2:28][CH2:27]1
Reactant: CCOP(=O)(CCCn1c(=O)c2[nH]cnc2n(C)c1=O)OCC
Reactant: ClCC1CC1
Product: CCOP(=O)(CCCn1c(=O)c2c(ncn2CC2CC2)n(C)c1=O)OCC

Procedure:
The title substance was prepared from 0.015 mol of diethyl [3-(3-methyl-xanthin-1-yl)propyl]phosphonate (Example 42), and 0.017 mol of chloromethylcyclopropane analogously to Example 30 and chromatographed on silica gel (eluent: dichloromethane/methanol 20:1).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([O:18][CH2:19][CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1.C1(=O)[NH:25]C(=O)C2=CC=CC=C12.[K].CN(C)C=O.C1C=CC=CC=1>O>[NH2:25][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([O:18][CH2:19][CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCBr)cc1)OCC
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(OCCN)cc1)OCC
Temperature: 100 °C
Yield: 96.9 %

Procedure:
A mixture of ethyl 3-(4-(2-bromethoxy)phenyl)-2-ethoxypropanoate (3.05 g, 8.8 mmol), potassium phtalimide (2.0 g, 10.8 mmol) and dimethylformamide (20 ml) was heated to 100° C. for 16 h, benzene (200 ml) and water (200 ml) were added and the phases were separated. The organic phase was dried and the solvent evaporated in vacuo. The residue was dissolved in ethanol (60 mL), hydrazine hydrate (1.3 ml) was added and the mixture was refluxed for 2 h, filtered and the solvent evaporated to give 2.4 g (96%) of ethyl 3-(4-(2-aminoethoxy)phenyl)-2-ethoxypropanoate as an oil. Hydrogen oxalate hemihydrate was prepared for characterization by neutralization with oxalic acid in acetone. M.p. 146-148° C. A mixture of dibenzo[b,f]-1,4-thiazepin-11(10H)-thione (2.20 g, 9 mmol; prepared as described in Coll.Czech.Chem.Commun. 48, 1465 (1983), 3-(4-(2-aminoethoxy)phenyl)-2-ethoxypropanoic acid ethyl ester (2.60 g, 8.9 mmol) and 3-methyl-1-butanol (70 ml) was stirred and heated at 150° C. for 16 h. The solvent was evaporated in vacuo, dichloromethane (50 ml) and water (50 ml) were added, the mixture was filtered and the phases were separated. The organic phase was dried (MgSO4) and the solvent was evaporated in vacuo to give a residue which was purified by column chromatography on silica gel eluting with chloroform. This afforded 0.7 g of the starting thione and then 1.7 g (38%) of the title compound as an oil. 1H NMR (250 MHz, CDCl3) δ7.05-7.50 (m, 9 H), 6.85-6.95 (m, 3 H), 5.15 (bs, 1 H), 4.25 (m, 2 H), 4.16 (q, J=7.2 Hz, 2 H), 3.96 (t+m, 3 H), 3.59 (m, 1 H), 3.34 (m, 1 H), 2.95 (d, J=6.4 Hz, 2 H), 1.22 (t, J=7.2 Hz, 3 H), 1.16 (t, J=7.2 Hz, 3 H).
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9]2[N:13]3[CH:14]=[C:15]([O:18][C@H:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[C@@H:22]([NH:29][C:30]([NH:32][C:33]5[N:34]([C:42]6[CH:47]=[CH:46][CH:45]=[C:44]([O:48][CH2:49][CH2:50][OH:51])[CH:43]=6)[N:35]=[C:36]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:37]=5)=[O:31])[CH2:21][CH2:20]4)[CH:16]=[CH:17][C:12]3=[N:11][N:10]=2)[CH2:2]1.CCN(C(C)C)C(C)C.[CH3:61][S:62](Cl)(=[O:64])=[O:63].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH2:2]1[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9]2[N:13]3[CH:14]=[C:15]([O:18][C@H:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[C@@H:22]([NH:29][C:30](=[O:31])[NH:32][C:33]5[N:34]([C:42]6[CH:43]=[C:44]([CH:45]=[CH:46][CH:47]=6)[O:48][CH2:49][CH2:50][O:51][S:62]([CH3:61])(=[O:64])=[O:63])[N:35]=[C:36]([C:38]([CH3:41])([CH3:39])[CH3:40])[CH:37]=5)[CH2:21][CH2:20]4)[CH:16]=[CH:17][C:12]3=[N:11][N:10]=2)[CH2:1]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC56CC6)n4c3)c3ccccc32)n(-c2cccc(OCCO)c2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC56CC6)n4c3)c3ccccc32)n(-c2cccc(OCCOS(C)(=O)=O)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A yellow-orange solution of Intermediate 148f (137 mg, 0.198 mmol), DIPEA (0.10 mL, 0.60 mmol) and methanesulfonyl chloride (45 mg, 0.40 mmol) in DCM (5 mL) was stirred at 0° C. for 30 min, and at RT for 30 min. DIPEA (0.052 mL, 0.30 mmol) and MsCl (23 mg, 0.20 mmol) were added and the solution stirred at RT for 30 min. Water (2 mL) and sat. aq. NaHCO3 solution (2 mL) were added and the mixture shaken. The aqueous was extracted with DCM (5 mL), then the combined organics passed through a hydrophobic frit and concentrated in vacuo to leave the title compound as a yellow solid (100%). LCMS (Method 3): Rt 3.80 min, m/z 769 [MH+].
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][O:8][C:4]=2[N:5]=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.Cl.[CH3:27][O:28][C:29](=[O:36])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH2:35]>CN(C=O)C>[CH3:27][O:28][C:29](=[O:36])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][O:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2occ(-c3ccccc3)c12
Reactant: COC(=O)CCCCCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CCCCCNc1ncnc2occ(-c3ccccc3)c12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Heat 500 mg (2.19 mmol) 4-chloro-5-phenylfuro[2,3-d]pyrimidine, 1.51 ml (8.67 mmol) DIEA and 1 ml DMF to 160° C. and add 787.6 mg (4.34 mmol) 6-aminohexanoic acid methyl ester hydrochloride. After 4 h at 160° C., cool the reaction mixture, add to ice water and extract three times with ethyl acetate. Combine the organic phases and wash with saturated ammonium chloride solution, dry over magnesium sulphate and concentrate under vacuum. Purify the residue by chromatography on silica gel (solvent: cyclohexane/ethyl acetate 10:1→3:1). 470 mg (63.9% of theor.) of the target compound is obtained.
Reaction SMILES: C(OC([N:11]([CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)[CH2:12][CH2:13][CH3:14])=O)C1C=CC=CC=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[CH2:12]([NH:11][CH2:15][CH:16]1[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:20][CH2:21]1)[CH2:13][CH3:14]
Reactant: [H][H]
Reactant: CCCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCNCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 91.9 %

Procedure:
To a solution of tert-butyl 4-(((benzyloxycarbonyl)(propyl)amino)methyl)piperidine-1-carboxylate (0.280 g, 0.717 mmol) in 7 mls of methanol was added palladium(II) hydroxide (0.200 g, 20 wt % Pd(OH)2 on carbon, Degussa type). This mixture was hydrogenated under a ballon of hydrogen for 1.5 hours, then filtered through GF/F filter paper and the filtrate concentrated. Obtained 0.169 g (92%) of the title compound and used directly without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[N:18]=2)[CH:12]=1)[S:6]([CH3:9])(=[O:8])=[O:7].[C:33](O)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[OH:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][NH:23][C:19]2[N:18]=[C:17]([C:13]3[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=3)[CH2:10][N:5]([S:6]([CH3:9])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2][NH:1][C:33](=[O:40])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:22]=[CH:21][N:20]=2)=[CH:31][CH:30]=1
Reactant: O=C(O)c1ccccc1
Reactant: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Product: CS(=O)(=O)N(CCCNC(=O)c1ccccc1)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Compound 2 was coupled with benzoic acid by procedure K. LC-MS showed the product had the expected M+H+ of 560. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.35 ppm) 8.5 (d, 1H) 8.2 (d, 1H) 8.1 (s, 1H) 8.0 (d, 2H) 7.6 (d, 2H), 7.4 (m, 5H), 7.1 (m, 2H), 6.7 (d, 2H), 4.4 (s, 2H), 3.6 (t, 2H), 3.23 (d, 2H), 2.9 (s, 3H), 2.8 (t, 2H), 1.8 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=2)=[C:9]1[CH:20]=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[BH4-]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([I:19])=[CH:17][CH:18]=2)=[C:9]1[CH2:20][OH:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc(-c2ccc(I)cc2)c1C=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1ccc(-c2ccc(I)cc2)c1CO
Yield: 82.7 %

Procedure:
A solution of 6(400 mg, 1.0 mmol) in anhydrous THF (12 mL) under argon was cooled to −20 to −25° C. and LiBH4 (55 mg, 2.5 mmol) was added in portions. The reaction was monitored by TLC (silica, hexanes/ethyl acetate (4:1)), and when no starting material was detected (20-25 min), the reaction was quenched with cold water (30 mL). The aqueous layer was extracted with CH2Cl2 and the organic layer was dried (Na2SO4), concentrated, and purified by flash column chromatography [silica, hexanes/ethyl acetate containing 1% Et3N (3:1)] yielding a gum (330 mg, 82%). 1H NMR δ 1.62 (s, 9H), 3.61 (br, 1H), 4.66 (d, J=7.2 Hz, 2H), 6.25 (d, J=3.6 Hz, 1H), 7.18 (d, J=8.1 Hz, 2H), 7.22 (d, J=3.6 Hz, 1H), 7.71 (d, J=8.1 Hz, 2H); 13C NMR δ 27.8, 55.3, 84.7, 92.4, 111.2, 121.3, 127.9, 130.0, 130.4, 134.1, 137.5, 149.8; FAB-MS obsd 399.0336, calcd 399.0331 (C16H18INO3).
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=O)[NH:14][C:12]2=[O:13])[CH:8]=[CH:7]1)(=[O:3])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>N1C=CC=CC=1>[C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[S:21])[NH:14][C:12]2=[O:13])[CH:8]=[CH:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H]1C=C[C@H](n2cc(C)c(=O)[nH]c2=O)O1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: CC(=O)OC[C@@H]1C=C[C@H](n2cc(C)c(=S)[nH]c2=O)O1

Procedure:
MS: m/z 266 (C12H14N2O6, M+), 141 (C7H9O3, sugar group), 126 (C5H6N2O2, base+H). The 1-(5-O-acetyl-2,3-dideoxy-β-D-glycero-pent-2-enofuranosyl)-thymine is dissolved in 25 mL of absolute pyridine and refluxed for 48 hours with 2 g of phosphorus pentasulfide. After cooling, the solution is decanted from the insolubles and evaporated to dryness under vacuum. The resulting residue is fractionated by column chromatography on Kieselgel 40 with chloroform as eluent. From the fractions containing the product, 265 mg of 1-(5-O-acetyl-2,3-dideoxy-β-D-glycero-pent-2-enofuranosyl)-4-thiothymine is obtained after recrystallization from methanol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]([CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=O)[C:11]2([CH3:21])[CH3:20])[CH:8]=[N:7][CH:6]=1)=[O:4].S(F)(F)(F)[F:23].[FH:27]>>[CH3:1][O:2][C:3]([C:5]1[N:9]([CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([F:23])([F:27])[C:11]2([CH3:21])[CH3:20])[CH:8]=[N:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cncn1C1c2ccccc2C(=O)C1(C)C
Reactant: FS(F)(F)F
Reactant: F
Product: COC(=O)c1cncn1C1c2ccccc2C(F)(F)C1(C)C
Yield: 68.4 %

Procedure:
A mixture of 11.4 g of 1-(2,2-dimethyl-3-oxo-indan-1-yl)-5-imidazolecarboxylic acid methyl ester, 43 g of sulfur tetrafluoride and 160 g of hydrogen fluoride is heated for 24 hours to +50° C. in an acid-resistant autoclave. The pressure is about 7 bars. The unreacted hydrogen fluoride is removed and the residue is taken up with methylene chloride. The organic phase is neutralized with sodium bicarbonate, washed with water, dried with sodium sulfate and concentrated to dryness. Chromatography of the residue at a silica gel column with a diethyl ether/hexane mixture (3:1 by volume) affords 8.4 g of 1-(2,2-dimethyl-3,3-difluoro-indan-1-yl)-5-imidazolecarboxylic acid methyl ester, mp. 96°-97° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[Cl:10][C:11]1[C:16](B(O)O)=[CH:15][C:14]([CH3:20])=[CH:13][N:12]=1.O.C(=O)([O-])[O-].[Na+].[Na+].COCCOC.O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:10][C:11]1[C:16]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=2)=[CH:15][C:14]([CH3:20])=[CH:13][N:12]=1
Reactant: Cc1nc(N)nc(Cl)n1
Reactant: Cc1cnc(Cl)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cnc(Cl)c(-c2nc(C)nc(N)n2)c1
Temperature: 90 °C
Yield: 44.6 %

Procedure:
A glass microwave reaction vessel was charged with 4-chloro-6-methyl-1,3,5-triazin-2-amine (0.350 g, 2 mmol), 2-chloro-5-methylpyridin-3-ylboronic acid (combi-blocks catalog number BB-3511) (0.6 g, 3 mmol), sodium carbonate, monohydrate, crystal (J. T. Baker catalog number 3600-01) (0.450 g, 7 mmol), tetrakis(triphenylphosphine)palladium (0) (Strem chemicals catalog number 46-Z150) (0.3 g, 0.2 mmol). Degassed 1,2-dimethoxyethane (Aldrich catalog #255527) (11 mL, 109 mmol) and water (1 mL, 2 mmol) were added to the mixture. The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 90° C. for 30 min. The mixture was filtered through Celite® (diatomaceous earth) and washed with ethyl acetate. The crude product was adsorbed onto a plug of silica gel and chromatographed through a RediSep®, Teledyne ISCO, Lincoln, Nebr., pre-packed silica gel column (40 g), eluting with a gradient of 5% to 10% 2 M NH3/MeOH in dichloromethane, to provide 4-(2-chloro-5-methylpyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.210 g, 36% yield).
Reaction SMILES: [F:1][C:2]1[C:24]([S:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])[CH2:28][CH2:27]2)=[CH:23][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.C(O)(C(F)(F)F)=[O:38].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[F:1][C:2]1[C:24]([S:25]([CH:26]2[CH2:31][CH2:30][N:29]([C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])[CH2:28][CH2:27]2)=[O:38])=[CH:23][C:5]2[C:6]3[N:10]([CH:9]=[C:8]([C:14]4[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=4)[N:7]=3)[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(SC4CCN(C(C)(C)CO)CC4)c(F)cc2OCC3)n(C(C)C)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2cc(S(=O)C4CCN(C(C)(C)CO)CC4)c(F)cc2OCC3)n(C(C)C)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
To an ice-cooled solution of 2-{4-[8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}-2-methylpropan-1-ol from Example 8 (148 mg, 0.287 mmol) in DCM (10 mL) was added TFA (67 μL, 0.863 mmol) followed by a solution of m-CPBA (55 mg, 0.316 mmol) in DCM (2 mL). The resulting mixture was stirred for 30 min at 0° C. then volatiles were removed under reduced pressure. The crude material was purified by column chromatography (C18, gradient 10-40% MeOH in 0.5% TFA/H2O) affording 212 as a white solid (135 mg, 88%). LCMS: RT 2.58 min [M+H]+ 531.1. 1H NMR (DMSO, 400 MHz): δ 8.69 (1H, d, J=7.99 Hz), 7.91 (1H, s), 7.13 (1H, d, J=10.67 Hz), 5.67-5.56 (1H, m), 4.65-4.50 (4H, m), 4.20 (1H, t, J=5.39 Hz), 3.20 (2H, d, J=5.03 Hz), 3.09-2.97 (2H, m), 2.84-2.73 (1H, m), 2.25 (3H, s), 2.21-2.07 (2H, m), 1.90-1.82 (1H, m), 1.56-1.38 (9H, m), 0.88 (6H, s)