Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([CH2:23][OH:24])[CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>>[N:11]1([S:8]([C:5]2[CH:6]=[CH:7][C:2]([N:17]3[CH2:22][CH2:21][CH:20]([CH2:23][OH:24])[CH2:19][CH2:18]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=S(=O)(c1ccc(F)cc1)N1CCCCC1
Reactant: OCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=S(=O)(c1ccc(N2CCC(CO)CC2)cc1)N1CCCCC1

Procedure:
1-[(4-fluorophenyl)sulfonyl]piperidine (0.437 g, 1.8 mmol), 4-piperidinylmethanol (0.230 g, 2 mmol), and ;potassium carbonate (0.262 g, 2 mmol) were heated to 120° C. for 4 hours. The reaction was cooled, and partitioned between ethyl acetate and water. The organic layer was washed with aqueous HCl, and brine. It was dried with sodium sulfate, filtered, and removal of the solvent gave 0.040 g (0.12 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([S:21][C:22](=O)[CH3:23])=[CH:17][CH:16]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[Cl:28][C:29]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])C=1CBr>CCO.O>[C:1]([O:5][C:6](=[O:25])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([S:21][CH2:22][C:23]3[C:29]([Cl:28])=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:37])=[CH:17][CH:16]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1cccc(Cl)c1CBr
Reactant: CC(=O)Sc1ccc(C2CN(CCC(=O)OC(C)(C)C)CCO2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(SCc3c(Cl)cccc3Cl)cc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
A mixture of 3-[2-(4-Acetylsulfanyl-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (0.31 g; 0.85 mmol) and NaOH (37 mg, 0.93 mmol) in EtOH (10 mL) and water (1 mL) was stirred for 30 min at 0° C. Subsequently, 2,6-dichlorobenzyl bromide (0.22 g; 0.93 mmol), dissolved in EtOH (2.5 mL), was added, and the mixture allowed to warm to RT. After 90 min. the mixture was partitioned between EtOAc and 5% aqueous NaHCO3. The layers were separated, and the organic layer was washed with 5% aqueous NaHCO3 and brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2/acetone 95:5) to afford 3-{2-[4-(2,6-dichloro-benzylsulfanyl)-phenyl]-morpholin-4-yl}-propionic acid tert-butyl ester (0.20 g).
Reaction SMILES: [CH2:1]([C@:3]12[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH2:10][CH2:9][C@@H:8]1[CH2:7][C@:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([OH:18])[C@@H:5]([OH:25])[CH2:4]2)[CH3:2].Cl.[N:27]1[CH:32]=[CH:31][C:30]([CH2:33]Cl)=[CH:29][CH:28]=1>>[CH2:1]([C@:3]12[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:33][C:30]4[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=4)=[CH:14][CH:15]=3)[CH2:10][CH2:9][C@@H:8]1[CH2:7][C@:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([OH:18])[C@@H:5]([OH:25])[CH2:4]2)[CH3:2]
Reactant: CC[C@@]12C[C@H](O)[C@](O)(c3ccccc3)C[C@H]1CCc1cc(O)ccc12
Reactant: ClCc1ccncc1
Agent: Cl
Product: CC[C@@]12C[C@H](O)[C@](O)(c3ccccc3)C[C@H]1CCc1cc(OCc3ccncc3)ccc12

Procedure:
The title compound was prepared starting from the title product of Example 16 and 4-picolyl chloride hydrochloride using a procedure analogous to that outlined for Example 2. Product was isolated by flash chromatography eluting with 25% ethyl acetate in methylene chloride. Mass spectrum: m/e 430 (M+1).
Reaction SMILES: BrC1[O:3][C:4]([CH3:7])=[N:5][N:6]=1.[CH3:8][Si:9]([CH3:16])([CH3:15])[C:10]#[C:11][C:12](=[O:14])[CH3:13].[Cl-].[NH4+].[CH2:19]1COCC1>>[CH3:7][C:4]1[O:3][C:13]([C:12]([OH:14])([C:11]#[C:10][Si:9]([CH3:16])([CH3:15])[CH3:8])[CH3:19])=[N:6][N:5]=1
Reactant: C1CCOC1
Reactant: Cc1nnc(Br)o1
Reactant: CC(=O)C#C[Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1nnc(C(C)(O)C#C[Si](C)(C)C)o1
Temperature: -10 °C

Procedure:
To a solution of isopropylmagnesium chloride lithium chloride complex (1.56 mL of a 1.3M solution in THF, 2.02 mmol) in dry THF (5 mL) at −15° C. under an atmosphere of nitrogen was introduced 2-bromo-5-methyl-1,3,4-oxadiazole (300 mg, 1.84 mmol). The reaction mixture was warmed to −10° C. for 30 minutes. A solution of 4-(trimethylsilyl)but-3-yn-2-one (0.37 ml, 2.21 mmol) in dry THF (5 mL) was added and the reaction mixture warmed to 0° C. for 1 hr. After further warming to RT for 30 minutes, the solution was cooled to 0° C. and saturated aqueous ammonium chloride (5 mL) introduced. The reaction mixture was extracted with DCM (3×10 mL extractions) and the combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash chromatography (Biotage, heptane/EtOAc followed by an EtOAc/MeOH gradient) furnished the title compound as an orange oil: 1H NMR (500 MHz, CDCl3) delta 0.18 (9H, s), 1.95 (3H, s), 2.57 (3H, s), 3.13 (1H, s); LC-MS: m/z=+224.95 (M+H)+.
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[C@H:6]([OH:19])[CH2:5]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:53]([O:57][C:58]([N:60]1[C:64]([CH3:66])([CH3:65])[CH2:63][CH2:62][C@H:61]1[C@H:67]([C:71]1[CH:76]=[CH:75][CH:74]=[C:73]([Cl:77])[CH:72]=1)[C:68](O)=[O:69])=[O:59])([CH3:56])([CH3:55])[CH3:54]>C(Cl)Cl>[Cl:77][C:73]1[CH:72]=[C:71]([C@@H:67]([C@H:61]2[N:60]([C:58]([O:57][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:59])[C:64]([CH3:66])([CH3:65])[CH2:63][CH2:62]2)[C:68]([N:16]2[CH2:15][CH2:14][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[CH2:5][C@@H:6]([OH:19])[C:7]=4[N:8]=[CH:9][N:10]=3)[CH2:18][CH2:17]2)=[O:69])[CH:76]=[CH:75][CH:74]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)O)c2cccc(Cl)c2)CCC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4cccc(Cl)c4)[C@@H]4CCC(C)(C)N4C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
(5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.0661 g, 0.215 mmol), HATU (0.0744 g, 0.196 mmol), and DIEA (d 0.742; 0.0341 mL, 0.196 mmol) were added to a solution of (S)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)-2-(3-chlorophenyl)acetic acid (0.072 g, 0.196 mmol, see Example B, Step 3) in DCM (25 mL). The reaction was stirred overnight at room temperature. The reaction was partitioned between water (20 mL) and DCM (50 mL), and the layers were separated. The organics were washed with water (2×10 mL). The aqueous portion was back extracted with DCM (25 mL), dried (MgSO4), concentrated to an oil and purified by flash chromatography (5% MeOH/DCM) to give (S)-tert-butyl 5-((S)-1-(3-chlorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (0.090 g, 0.154 mmol, 78.7% yield). LC/MS=3.79 minutes, (APCI+) m/z=584 [M+H]+.
Reaction SMILES: C[O-:2].[Na+].CO.[N:6]([CH2:13][CH2:14][OH:15])([CH2:10][CH2:11][OH:12])CCO.S([O-])(O[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=O)=O>O>[CH2:20]([O:15][CH2:14][CH2:13][NH:6][CH2:10][CH:11]([OH:12])[OH:2])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: OCCN(CCO)CCO
Reactant: C[O-]
Reactant: CCCCCCCCOS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCCCCOCCNCC(O)O
Temperature: 110 °C

Procedure:
40.3 grams of a 30% (by weight) solution of sodium methylate in methanol (0.224 mole) were added to 100 grams of triethanolamine (0.67 mole), after which the methanol was distilled off by heating to 110° C. 51.6 grams of n-octyl sulfate, Na salt (0.22 mole) were stirred at 20° C. into the solution obtained and the reaction mixture was heated for 4 hours to 200° C. After cooling to 20° C., approx. 160 ml of water were added. Two liquid phases formed. The upper phase was separated off, washed twice with water and dried under a vacuum in a rotary vaporator with gentle heating to approx. 80° C. A brown oily liquid (52 grams) having an amine number of 214 was obtained (the amine number indicates the number of mg of KOH equivalent to 1 gram of the substance).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:20][NH:21][O:22][CH3:23]>C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:21]([O:22][CH3:23])[CH3:20])=[O:7])=[CH:4][CH:3]=1
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
A solution of 4-bromobenzoyl chloride (4.67 g, 21.3 mmol), diisopropylethylamine (3.78 mL, 46.8 mmol), and N,O-dimethylhydroxylamine (2.18 g, 22.3 mmol) in ethyl acetate (100 mL) was heated to 45° C. After 1 h, the reaction mixture was diluted with ethyl acetate (100 mL). The resulting solution was washed sequentially with water and saturated aqueous sodium chloride solution. The collected organic was dried over magnesium sulfate, filtered, and concentrated. Purification by flash column chromatography (hexanes→ethyl acetate in hexanes) provided producted as a tan solid (4.12 g, 79%). LCMS (ESI) m/z: 244.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:6][C:5](=O)[C:4](=O)[CH2:3]1.COP([CH2:16][C:17](=O)[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=O)OC.O.[NH2:25][NH2:26]>>[CH3:20][C:19]([CH3:22])([CH3:21])[CH2:18][C:17]1[N:26]=[N:25][C:4]2[CH2:3][C:2]([CH3:9])([CH3:1])[CH2:6][C:5]=2[CH:16]=1
Reactant: NN
Reactant: COP(=O)(CC(=O)CC(C)(C)C)OC
Reactant: CC1(C)CC(=O)C(=O)C1
Solvent: O
Product: CC(C)(C)Cc1cc2c(nn1)CC(C)(C)C2

Procedure:
off-white solid. MS (ESI): 219.3 (MH+). Prepared from 4,4-dimethyl-cyclopentane-1,2-dione, (4,4-dimethyl-2-oxo-pentyl)-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [O:1]([C:6]1[CH:25]=[CH:24][C:9]([CH2:10][CH:11]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[OH:16])C(O)=O)=[CH:8][CH:7]=1)[C:2]([CH3:5])([CH3:4])[CH3:3].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:33])C=CC=CC=1.C([N:45]([CH2:48]C)CC)C>O1CCCC1>[C:2]([O:1][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][CH:11]2[CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[O:16][C:48](=[O:33])[NH:45]2)=[CH:24][CH:25]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)Oc1ccc(CC(C(=O)O)C(O)c2cccc(Cl)c2)cc1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)Oc1ccc(CC2NC(=O)OC2c2cccc(Cl)c2)cc1

Procedure:
To a solution of (2RS,3RS)-2-(4-tert-butoxylbenzyl)-3-(3-chlorophenyl)-3-hydroxypropanoic acid (4.50 g, 14.3 mmol) in tetrahydrofuran (150 ml) were added diphenylphosphoryl azide (3.39 ml, 15.7 mmol) and triethylamine (3.00 ml, 21.4 mmol), and the mixture was heated under reflux for 1 hr. The reaction solution was allowed to cool and the mixture was evaporated under reduced pressure. To the residue was added water (200 ml), and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give the objective substance (4.01 g, 80%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].O1CCCC1.[H][H]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Cl-].[Ru+2].C(O)C>[CH3:1][O:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C=CCCCC=CCOC
Reactant: [H][H]
Agent: [Ru+2]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCC=CCOC
Reaction time: 6 h

Procedure:
1000 g of 1-methoxy-2,7-octadiene, 500 ml of tetrahydrofuran, 500 ml of ethanol and 2.5 g of tris(triphenylphosphine)ruthenium(II) chloride were placed in a 3 l Büchi autoclave. The temperature was set to 30° C. and the autoclave was pressurized to 30 bar by means of hydrogen. The reaction was followed via the amount of hydrogen taken up and by means of GC analyses. After 6 hours, the reaction was stopped. According to GC analysis, 98% of the 1-methoxy-2,7-octadiene had reacted to form 1-methoxy-2-octene (cis and trans) with a selectivity of 89%. The 1-methoxy-2-octene was separated from solvents and catalyst by distillation.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([O:9][C:10](=[O:21])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][C:14]=1[CH3:20])[CH3:8].[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1Cl)[CH:26]=[O:27]>CN(C=O)C>[CH2:7]([O:9][C:10](=[O:21])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C:30]2[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][C:23]=2[Cl:22])=[CH:15][C:14]=1[CH3:20])[CH3:8]
Reactant: CCOC(=O)COc1ccc(S)cc1C
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Sc2ccc(C=O)cc2Cl)cc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
An oven-dried 500 mL round-bottomed flask was charged with finely powdered K2CO3 (31.8 g, 230 mmol) and anhydrous DMF (104 mL). Next, a solution of compound 10.3 (26.1 g, 115 mmol) and 3,4-dichlorobenzaldehyde (21.0 g, 120 mmol) in anhydrous DMF (52 mL) was added dropwise at 90° C., and the reaction was vigorously stirred at same temperature for 1 h. The reaction mixture was poured into 468 mL of ice-water and extracted with 3×200 mL of AcOEt. The combined organics were sequentially washed with 2×200 mL of water and 100 mL of brine, dried over Na2SO4, and concentrated to a yellow oil, which was then purified by flash chromatography (SiO2 gel 60 N, eluted with 10% AcOEt/hexane—20% AcOEt/hexane). The fractions containing only desired product were combined and concentrated to a slightly yellow oil (34.9 g). 1H NMR (300 MHz) (CDCl3) δ 9.85 (1H, s); 7.81 (1H, d, J=1.5 Hz); 7.50 (1H, dd, J=1.8, 8.1 Hz); 7.37-7.35 (2H, m); 6.80-6.74 (2H, m); 4.71 (2H, s); 4.30 (2H, q, J=7.2 Hz); 2.32 (3H, s); 1.32 (3H, t, J=7.2 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:26]=[CH:25][C:12]3[N:13]([CH3:24])[C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[C:41](O)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>O1CCCC1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]2[N:13]([CH3:24])[C:12]3[CH:25]=[CH:26][C:9]([O:8][C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:41](=[O:48])[C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[CH:7]=4)=[CH:10][C:11]=3[N:15]=2)=[CH:18][CH:19]=1
Reactant: O=C(O)c1ccccc1
Reactant: Cn1c(Nc2ccc(Cl)cc2)nc2cc(Oc3ccnc(N)c3)ccc21
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Solvent: ClCCCl
Product: Cn1c(Nc2ccc(Cl)cc2)nc2cc(Oc3ccnc(NC(=O)c4ccccc4)c3)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To [5-(2-amino(4-pyridyloxy))-1-methylbenzimidazol-2-yl] (4-chlorophenyl)amine (1 eq) in tetrahydrofuran added EDC (2 eq) and HOAT (1 eq) and N,N-disopropylethylamine (4 eq) and benzoic acid (1 eq) and the resulting mixture was stirred at ambient temperature for 16 h. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was then dried with sodium sulfate and concentrated and purified by preparative chromatography to give N-[4-({2-[(4-chlorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]benzamide. MS: MH+=470.9.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][NH:6]1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:25]=[C:26]([S:31](Cl)(=[O:33])=[O:32])[CH:27]=[CH:28][C:29]=1[Cl:30].Cl>C(Cl)Cl>[Cl:23][C:24]1[CH:25]=[C:26]([S:31]([N:6]2[CH2:7][CH2:8][C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:5]2[CH2:4][C:3]([O:2][CH3:1])=[O:15])(=[O:32])=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: COC(=O)CC1NCCc2ccccc21
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC1c2ccccc2CCN1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2-(1,2,3,4-Tetrahydroisoquinolin-1-yl)acetic acid methyl ester (7.49 g, 36.5 mmol) was dissolved in DCM (200 ml), and triethylamine (11.7 ml, 83 mmol) was added thereto. The reaction solution was cooled to 0° C., and a solution of 3,4-dichlorobenzenesulfonyl chloride (8.14 g, 33.2 mmol) in DCM (100 ml) was added dropwise. After 3 h, 0.5 M HCl (100 ml) was added. After phase separation, the organic phase was washed with water, dried (sodium sulfate) and concentrated. Purification was carried out by column chromatography on silica gel (heptane/ethyl acetate 4:1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][CH:12]2[CH:19]3[CH:15]([O:16][C:17]([CH3:21])([CH3:20])[O:18]3)[CH:14]([N:22]3[CH:30]=[N:29][C:28]4[C:23]3=[N:24][CH:25]=[N:26][C:27]=4Cl)[O:13]2)[CH:6]=1)=[O:4].C(N(C(C)C)CC)(C)C.[CH3:41][NH:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][CH:12]2[CH:19]3[CH:15]([O:16][C:17]([CH3:21])([CH3:20])[O:18]3)[CH:14]([N:22]3[CH:30]=[N:29][C:28]4[C:23]3=[N:24][CH:25]=[N:26][C:27]=4[N:42]([CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH3:41])[O:13]2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(OCC2OC(n3cnc4c(Cl)ncnc43)C3OC(C)(C)OC23)no1
Reactant: CNCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(OCC2OC(n3cnc4c(N(C)Cc5ccccc5)ncnc43)C3OC(C)(C)OC23)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[6-(6-Chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethoxy]-isoxazole-5-carboxylic acid methyl ester (0.106 g, 0.23 mmol) in tetrahydrofuran (1.2 mL) was added polymer-bound diisopropylethylamine (PS-DIEA; Argonaut Tech., 3.83 mmol/g, 0.190 g, 3 eq), followed by addition of 0.040 mL of N-methyl-N-benzylamine (1.2 eq). The resulting mixture was stirred at room temperature overnight. The PS-DIEA resin was washed three times with dichloromethane and the solution obtained from the washes was concentrated to yield 3-{6-[6-(N-Benzyl-N-methyl-amino)-purin-9-yl]-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethoxy}-isoxazole-5-carboxylic acid methyl ester as yellow oil. This material (0.23 mmol) was dissolved in 1,4-dioxane (1.2 mL) and 0.250 mL of an aqueous 2M lithium hydroxide solution added. The mixture was stirred at room temperature for 4 h. The crude product, isolated after acid workup, was used without further purification in the following step. MW calculated for C25H26N6O7 (MH+): 523, found 523 by LCMS.
Reaction SMILES: C([O:5][C:6](=[O:42])[C@@H:7]([NH:28][S:29]([C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]2[NH:22][CH2:23][CH2:24][CH2:25][N:26]=2)=[CH:11][CH:10]=1)(C)(C)C>FC(F)(F)C(O)=O.O>[C:32]1([S:29]([NH:28][C@@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]3[NH:26][CH2:25][CH2:24][CH2:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]([OH:42])=[O:5])(=[O:31])=[O:30])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCCN2)cc1)NS(=O)(=O)c1cccc2ccccc12
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCCOc1ccc(C[C@H](NS(=O)(=O)c2cccc3ccccc23)C(=O)O)cc1)NC1=NCCCN1
Reaction time: 2 h

Procedure:
31 mg of (2S)-2-(naphthalene-1-sulfonylamino)-3-{4-[3-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-propoxy]-phenyl}-propionic acid tert-butyl ester were dissolved in trifluoroacetic acid/water (95/5) and stirred for 2 hours. The solvent was removed in vacuo, and the residue was dissolved in acetic acid/water and lyophilized. Yield 19.7 mg. MS (ES+): m/e=539.3 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:22])[CH2:10][CH2:11][CH2:12][N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(=O)([O-])O.[Na+]>ClCCl>[CH3:30][S:31]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:22])[CH2:10][CH2:11][CH2:12][N:13]([C:14]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:20])[CH3:21])=[CH:5][CH:4]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: CN(CCCC(=O)c1ccc(CO)cc1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCCC(=O)c1ccc(COS(C)(=O)=O)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.1 %

Procedure:
The compound (651 mg, 2.12 mmol) obtained in Example 78a was dissolved in dichloromethane (20 mL), triethylamine (0.590 mL, 4.24 mmol) and methanesulfonyl chloride (0.245 mL, 3.18 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The resulting organic layer was dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a crude 4-{4-[(tert-butoxycarbonyl)(methyl)amino]butanoyl}benzyl methanesulfonate (851 mg) as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[CH:9][N:10]([CH3:11])[C:6]=2[N:5]=[C:4]2[NH:12][C:13](=[O:23])[N:14]([C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=3[F:22])[C:3]=12.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:34]1([S:37](Cl)(=[O:39])=[O:38])[CH2:36][CH2:35]1>C1COCC1>[Cl:1][C:2]1[CH:7]2[N:8]=[CH:9][N:10]([CH3:11])[CH:6]2[N:5]=[C:4]2[N:12]([S:37]([CH:34]3[CH2:36][CH2:35]3)(=[O:39])=[O:38])[C:13](=[O:23])[N:14]([C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=3[F:22])[C:3]=12
Reactant: Cn1cnc2c(Cl)c3c(nc21)[nH]c(=O)n3-c1ccc(I)cc1F
Reactant: O=S(=O)(Cl)C1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1C=NC2C(Cl)=c3c(n(S(=O)(=O)C4CC4)c(=O)n3-c3ccc(I)cc3F)=NC21
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 8-chloro-1-(2-fluoro-4-iodophenyl)-5-methyl-3,5-dihydrodiimidazo[4,5-b:4′,5′-e]pyridin-2(1H)-one (200 mg, 0.36 mmol) in THF (6 ml) at −78° C. is added LiHMDS (0.54 ml, 1 M in THF, 0.54 mmol). The reaction mixture is stirred at −78° C. for 10 min and cyclopropylsulfonyl chloride (100 mg, 0.72 mmol) is added to the mixture. The reaction is slowly warmed to room temperature and stirred at the temperature for 3 h. The reaction is quenched with saturated aqueous NH4Cl solution (10 ml) and extracted with EtOAc (2×10 ml). The combined organic solution is washed with brine (10 ml), dried over MgSO4 and concentrated. Silica gel chromatography yields the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C([O-])(=O)C.[Na+].[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1>O.O1CCCC1.CCOCC>[CH3:2][O:3][N:4]=[CH:15][C:14]1[CH:17]=[CH:18][C:11]([F:10])=[CH:12][CH:13]=1
Reactant: CON
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CON=Cc1ccc(F)cc1
Temperature: 22 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
A solution of O-methyl-hydroxylamine, hydrochloride (13.4 g, 0.16 mol) in a mixture of water (150 ml) and tetrahydrofuran (50 ml) was treated with sodium acetate (11.2 g, 0.136 mol) followed by 4-fluorobenzaldehyde (11.57 g, 93.2 mmol) and the resulting mixture was stirred at 22° C. for 4 hours. The reaction mixture was then diluted with ether, washed with brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure gave 14.3 g of the crude title material as a clear oil which was used as such for the next step. Distillation of an aliquot in vacuo gave a clear oil; bp 45-50° C./0.5 torr. 1H NMR 400 MHz (CDCl3) δ (ppm): 3.99 (3H, s), 7.09 (2H, m), 7.6 (2H, m), 8.06 (1H, s).