Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[N:4][CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH2:10][O:11][C:12]1[N:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][N:13]=1.[CH3:34][O:35][C:36]1[CH:37]=[C:38]([Sn](CCCC)(CCCC)CCCC)[CH:39]=[CH:40][C:41]=1[O:42][CH3:43].O1CCOCC1>C(OCC)(=O)C.[F-].[K+].[Cu]Cl>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([S:21]([NH:20][C:3]2[C:2]([C:39]3[CH:38]=[CH:37][C:36]([O:35][CH3:34])=[C:41]([O:42][CH3:43])[CH:40]=3)=[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]3[N:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][N:13]=3)[N:6]=[CH:5][N:4]=2)(=[O:23])=[O:22])=[CH:25][CH:26]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CSc1cnc(OCCOc2ncnc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)c2Br)nc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(OC)c(OC)c1
Agent: Cl[Cu]
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(SC)cn2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
A mixture of N-{5-bromo-6-[2-(5-methylthiopyrimidin-2-yloxy)ethoxy]pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide (100 mg), 3,4-dimethoxyphenyltributyltin (220 mg), bis(triphenylphsophine)palladium (II) chloride (26 mg), copper (I) chloride (11 mg), a few crystals of 2,6-di-tert-butylcrezol and dioxane (5 ml) is refluxed for 1.5 hour. After cooling, the reaction solution is diluted with ethyl acetate and aqueous potassium fluoride solution, and the mixture is stirred at room temperature for 30 minutes. The insoluble materials are removed by filtration, and the filtrate is acidified with 10% hydrochloric acid, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and evaporated to remove the solvent. The residue is purified by preparative thin layer chromatography (solvent; chloroform/ethyl acetate=3:1), and recrystallized from ethyl acetate/diisopropyl ether to give 4-tert-butyl-N-{5-(3,4-dimethoxyphenyl)-6-[2-(5-methylthiopyrimidin-2-yloxy)ethoxy]-pyrimidin-4-yl}benzenesulfonamide (82 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[CH3:11][C:12]([OH:15])([CH3:14])[CH3:13]>C(Cl)Cl.CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:12]([O:15][C:8]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=1)=[O:9])([CH3:14])([CH3:13])[CH3:11]
Reactant: O=C(Cl)c1cc(Cl)ccn1
Reactant: CC(C)(C)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1cc(Cl)ccn1
Yield: 49.2 %

Procedure:
A solution of 4-chloro-pyridine-2-carbonyl chloride (150 g, 0.857 mol) in DCM (750 ml) was slowly added to a solution of 2-methyl-propan-2-ol (158.8 g, 2.14 mol) and DMAP (21 g, 0.171 mol) in DCM (750 mL) and pyridine (750 mL). The resultant mixture was stirred at 30° C. overnight. The reaction mixture was concentrated in vacuo and the residue was purified by chromatography to give 4-chloro-pyridine-2-carboxylic acid t-butyl ester (90 g, 49% yield) as a yellow solid. 1H NMR (CDCl3): δ 8.63 (d, J=8.0 Hz, 1H), 8.03 (s, 1H), 7.44 (d, J=8.0 Hz 1H), 1.63 (s, 9H); MS (ESI) m/z: 214 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:13])[C:11]=1[NH2:12])C(OC)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:9]=[C:10]([Cl:13])[C:11]=1[NH2:12]
Reactant: COC(=O)c1cc(Cl)c(N)c(Cl)c1
Solvent: O
Product: Nc1c(Cl)cccc1Cl
Temperature: 250 °C
Reaction time: 3 h
Yield: 76.1 %

Procedure:
0.2 mole=48 g of methyl 3,5-dichloro-4-amino-benzoate were initially introduced into an autoclave together with 250 ml of water. The mixture was heated to 250° C. and stirred at this temperature for 3 hours. Reaction gas formed was continuously let off to maintain a pressure of about 40 bar. The product was recovered by steam distillation. 26.9 g of 2,6-dichloroaniline were obtained, corresponding to a yield of 75.3%.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[C:22](O)=[O:23].N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:22]([C:13]3[CH:14]=[CH:15][C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:12]=3)=[O:23])[CH2:2]1)[CH2:8]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1ccc2ccccc2c1
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc2ccccc2c1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 2-naphthoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.94-2.03 (m, 3H), 2.29-2.40 (m, 4H), 3.40 (s, 2H), 3.51 (s, 4H), 4.43 (s, 1H), 7.54-7.62 (m, 2H), 7.86-8.02 (m, 4H), 8.40 (d, J=1 Hz, 1H); MS (APCI/NH3) m/z 307 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.ON1C2C=CC=CC=2N=N1.[C:22]12([CH2:32][NH2:33])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2.C1(N=C=NC2CCCCC2)CCCCC1>>[Cl:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:33][CH2:32][C:22]12[CH2:31][CH:26]3[CH2:25][CH:24]([CH2:30][CH:28]([CH2:27]3)[CH2:29]1)[CH2:23]2)=[O:6]
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)c1cccc(O)c1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cccc(O)c1Cl

Procedure:
Prepared according to the method of Example 38 using 2-chloro-3-hydroxybenzoic acid (0.39 g), 1-hydroxy benzotriazole (0.31 g), 1-adamantanemethylamine (0.4 ml) and 1,3-dicyclo-hexylcarbodiimide (0.47 g) to yield the title compound as a white solid (0.29 g).
Reaction SMILES: [S:1]1[C:5]2[CH:6]([C:10]([O:12]C)=[O:11])[CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[CH:2]1.O[Li].O>C1COCC1.CO.O>[S:1]1[C:5]2[CH:6]([C:10]([OH:12])=[O:11])[CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)C1CCCc2ncsc21
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCCc2ncsc21
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A mixture of methyl 4,5,6,7-tetrahydrobenzo[d]thiazole-7-carboxylate (1.22 g, 6.11 mmol) and LiOH.H2O (0.39 g, 9.17 mmol) in THF/MeOH/H2O (60 mL, 3:1:1) was stirred at RT for 75 min. The mixture was acidified to pH=3 and extracted with DCM. The comb. org. layers were dried over MgSO4 and conc. in vacuo to provide a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:20])[CH3:19])[CH2:14]3)=[O:12])[S:10][C:3]=12.[OH:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([C:33]([NH:35][CH3:36])=[O:34])=[C:27]([CH3:32])[N:28]2[CH3:31])=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:19][N:18]([CH3:20])[C@@H:15]1[CH2:16][CH2:17][N:13]([C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[O:21][C:22]3[CH:30]=[C:29]4[C:25]([C:26]([C:33]([NH:35][CH3:36])=[O:34])=[C:27]([CH3:32])[N:28]4[CH3:31])=[CH:24][CH:23]=3)[CH:8]=2)=[O:12])[CH2:14]1
Reactant: CNC(=O)c1c(C)n(C)c2cc(O)ccc12
Reactant: CN(C)[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C)n(C)c2cc(Oc3ccnc4cc(C(=O)N5CC[C@@H](N(C)C)C5)sc34)ccc12
Yield: 40.8 %

Procedure:
This material was prepared by the reaction (3R)-1-[(7-chlorothieno[3,2-b]pyridin-2-yl)carbonyl]-N,N-dimethylpyrrolidin-3-amine 27a (0.136 g, 0.44 mmole) with 6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide 16e (0.0649, 0.294 mmole) and Cs2CO3 (0.096 g, 0.29 mmole) in a manner as previously described for example 1 to give a brown colored foam (0.059 g, 17%). 1H NMR (300 MHz, CD3OD) δ 8.40 (1H, d, J=5.46 Hz), 7.84 (1H, d, J=6.59 Hz), 7.76 (1H, d, J=8.67 Hz), 7.29 (1H, d, J=2.07 Hz), 6.95 (1H, dd, J=8.57, 2.17 Hz), 6.62 (1H, d, J=5.65 Hz), 4.06 (1H, m), 3.87 (2H, m), 3.63 (3H, s) 3.03 (2H, m), 2.88 (3H, s), 2.57 (3H, s), 2.37 (3H, s), 2.32 (3H, s), 2.23 (1H, m), 1.95 (1H, m); HRMS (MH+): Calcd: 492.2085. Found: 492.2069.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:23]([OH:24])[C@@H:22]([CH2:25][OH:26])[O:21][C@H:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[C@@H:6]1[O:27][C@H:28]1[O:57][C@H:56]([CH2:58][O:59][C:60](=[O:62])[CH3:61])[C@@H:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C@H:38]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:29]1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:3])[CH3:2].[S:63]([O-])(=[O:66])(=[O:65])[CH3:64]>>[C:1]([O:4][C@H:5]1[C@H:23]([OH:24])[C@@H:22]([CH2:25][O:26][S:63]([CH3:64])(=[O:66])=[O:65])[O:21][C@H:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[C@@H:6]1[O:27][C@H:28]1[O:57][C@H:56]([CH2:58][O:59][C:60](=[O:62])[CH3:61])[C@@H:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C@H:38]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:29]1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)[O-]
Reactant: COC(=O)CCCCCCCCO[C@H]1O[C@H](CO)[C@@H](O)[C@H](OC(C)=O)[C@H]1O[C@H]1O[C@H](COC(C)=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Product: COC(=O)CCCCCCCCO[C@H]1O[C@H](COS(C)(=O)=O)[C@@H](O)[C@H](OC(C)=O)[C@H]1O[C@H]1O[C@H](COC(C)=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Yield: 85.3 %

Procedure:
Compound 24 (570 mg, 0.66 mmol) was converted into its methane sulfonyl derivative exactly as described for the preparation of 10 to give 25 (530 mg, 85.3%) as a syrup after chromatography on silica gel using (hexane:ethyl acetate; 3:2) as eluant; ›α!D +76.6° (c 0.57, chloroform). 1H-n.m.r. (CDCl3): δ 5.19(t, 1H, J2,3 =J3,4 10.0 Hz, H-3), 4.90(d, 1H, J1',2' 3.8 Hz, H-1'), 4.82(d, 1H, J1,2 3.8 Hz, H-1), 3.57(s, 3H, OCH3), 3.00(s, 3H, CH3SO2), 2.23 and 2.03(s, 3H each, 2×Ac).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[C:11]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N.[OH-].[Na+]>ClCCl>[C:11]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([N:8]2[CH2:9][CH2:10][C:5]3[CH:4]=[CH:3][O:2][C:6]=3[CH2:7]2)=[O:24])=[CH:26][CH:27]=1)(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1cc2c(o1)CNCC2
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)c1ccc(C(=O)N2CCc3ccoc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.264 g (1.654 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 0.41 g (1.8 mmol) of 4-benzoylbenzoic acid and 0.92 ml (6.6 mmol) of triethylamine in 30 ml of dichloromethane, 0.30 ml (2.0 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. This solution was poured into aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 2/1) to yield the desired product.
Reaction SMILES: [H-].[Na+].[CH:3](=O)[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6].Cl[CH2:13][C:14]([NH:16][C:17]1[CH:18]=[N:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=1)=[O:15].C[O-].[Na+]>CN(C)C=O.O>[C:23]([C:20]1[N:19]=[CH:18][C:17]([NH:16][C:14]([C:13]2[O:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[CH:3]=2)=[O:15])=[CH:22][CH:21]=1)#[N:24]
Reactant: O=Cc1ccccc1O
Reactant: N#Cc1ccc(NC(=O)CCl)cn1
Agent: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(NC(=O)c2cc3ccccc3o2)cn1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (0.184 g, 7.6 mmol) in dry dimethyl formamide (20 mL), a solution of salicylaldehyde (0.947 g, 7.6 mmol) in dry dimethylformamide (20 mL) was added dropwise under stirring. Stirring was continued for 30 minutes, and compound of example 3 (1.5 g, 7.6mmol) was added to the reaction mixture and heated at 80° C. for 2 hours. To this reaction mixture was added a solution of sodium methoxide (0.044 g) and stirred for 1 hour at 80° C. The reaction mixture was cooled, diluted with water and extracted with chloroform (3×100 mL). Chloroform layer was dried over sodium sulfate and concentrated. The crude product was purified using repetitive column chromatography (silica gel, ethyl acetate/petroleum ether followed by chloroform as an eluent) to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:10][CH2:11][CH3:12])=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.Cl.CN(C)CCCN=C=NCC.[C:25]([CH2:27][C:28](O)=[O:29])#[N:26].CN1CCOCC1>C(Cl)Cl>[Br:1][C:2]1[C:3]([NH:10][CH2:11][CH3:12])=[C:4]([NH:9][C:28](=[O:29])[CH2:27][C:25]#[N:26])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: N#CCC(=O)O
Reactant: CCNc1c(Br)cnc(Cl)c1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCNc1c(Br)cnc(Cl)c1NC(=O)CC#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
To a solution of 5-bromo-2-chloro-N4-ethyl-pyridine-3,4-diamine (II, 550 g, 2.21 mol) in CH2Cl2 (5.5 L) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (634.5 g, 3.31 mol), cyanoacetic acid (282 g, 3.31 mol) and N-methylmorpholine (897 g, 8.84 mol). A significant exotherm (˜20° C.) was observed upon the addition of the 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and cyanoacetic acid. After stirring at ambient temperature for 2 h, the solvent was removed under reduced pressure. The resulting reside was extracted with warm EtOAc (40° C., 20 L) and water (40° C., 8 L). The aqueous layer was washed with addition EtOAc (10 L) and the combined organic extracts were washed with water (10 L). The organic extract was concentrated under reduced pressure to a slurry and filtered. The solid was washed with EtOAc and dried to give 534 g (76% yield) of the desired compound (III) as a white crystalline solid. This was used in the next step without further purification. MS (ES+) m/z 317 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][CH2:14]O)=[CH:11][C:10]([CH3:16])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.[K]>CN(C=O)C>[CH2:1]([N:8]1[C:12]([CH2:13][CH2:14][N:23]2[C:19](=[O:29])[C:20]3[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:22]2=[O:24])=[CH:11][C:10]([CH3:16])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1cc(CCO)n(Cc2ccccc2)n1
Agent: [H-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(CCN2C(=O)c3ccccc3C2=O)n(Cc2ccccc2)n1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 5.9 %

Procedure:
2-(2-Benzyl-5-methyl-2H-pyrazol-3-yl)-ethanol (848 mg, 3.92 mmol) was dissolved in DMF (21 ml) and cooled to −20° C. followed by the addition of sodium hydride (218 mg, 5.02 mmol). Stirring was continued at rt for 30 minutes. The reaction mixture was again cooled to −20° C. and toluene-4-suofonyl chloride (pTs-Cl, 966 mg, 5.02 mmol) was added. The cooling bath was removed and stirring was continued for 2 h at rt and 30 minutes at 50° C. followed by the addition of potassium phthalimid (1.7 g, 9.2 mmol). Stirring at 50° C. was continued for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was taken up in DCM (30 ml) filtered again and the filtrate was washed with water (30 ml). The phases were separated. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by preparative HPLC to give 80 mg (6%) of 2-[2-(2-benzyl-5-methyl-2H-pyrazol-3-yl)-ethyl]-isoindole-1,3-dione. LC-MS: tR=0.95 min; [M+H]+=346.31.
Reaction SMILES: [C:1]([CH2:3][CH:4]([OH:16])[CH2:5][CH:6]([OH:15])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])#[N:2].CS(O)(=O)=O.CO[C:24](OC)([CH3:26])[CH3:25]>>[C:1]([CH2:3][C@H:4]1[O:16][C:24]([CH3:26])([CH3:25])[O:15][C@@H:6]([CH2:7][C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:5]1)#[N:2]
Reactant: CC(C)(C)OC(=O)CC(O)CC(O)CC#N
Reactant: COC(C)(C)OC
Agent: CS(=O)(=O)O
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CC#N)OC(C)(C)O1
Yield: 70.5 %

Procedure:
Crude [R-(R*,R*)]-1,1-dimethylethyl 6-cyano-3,5-dihydroxyhexanoate (about 150 moles) from Step (2) is diluted with 100 kg of 2,2-dimethoxypropane and acidified with about 1 L of methanesulfonic acid. The reaction is quenched by the addition of aqueous sodium bicarbonate solution and concentrated by vacuum distillation. The residue is diluted with 150 L of hexane, and the layers separated. The organic layer is washed with aqueous sodium bicarbonate solution and cooled to 0° C.±10° C. to crystallize. The product is collected by filtration and washed with cooled hexane, then dried affording 28.5 kg of (4R cis) 1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9](Br)[C:8]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:14][C:7]=2[C:6]=1[OH:21])=[O:4].C([Sn](CCCC)(CCCC)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)CCC>>[CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:14][C:7]=2[C:6]=1[OH:21])=[O:4]
Reactant: COC(=O)c1nc(Br)c2nc(-c3ccccc3)oc2c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Product: COC(=O)c1nc(-c2ccccc2)c2nc(-c3ccccc3)oc2c1O

Procedure:
Prepared from 4-bromo-7-hydroxy-2-phenyl-oxazolo[4,5-c]pyridine-6-carboxylic acid methyl ester, example 3a, and tributylphenyltin under conditions analogous to example 3b. MS: (+) m/z 347.1 (M+1).
Reaction SMILES: [F:1][CH2:2][CH2:3][C@@H:4]1[C@@H:12]([O:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:11]([CH3:18])[O:10][C:9](=[O:19])[C@@H:8]([NH:20][C:21](=[O:31])[C:22]2[C:27]([OH:28])=[C:26]([O:29][CH3:30])[CH:25]=[CH:24][N:23]=2)[CH2:7][CH2:6][CH2:5]1.C([O-])([O-])=O.[K+].[K+].[C:38]([O:41][CH2:42]Br)(=[O:40])[CH3:39]>CC(C)=O>[C:38]([O:41][CH2:42][O:28][C:27]1[C:22]([C:21](=[O:31])[NH:20][C@H:8]2[CH2:7][CH2:6][CH2:5][C@H:4]([CH2:3][CH2:2][F:1])[C@@H:12]([O:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:11]([CH3:18])[O:10][C:9]2=[O:19])=[N:23][CH:24]=[CH:25][C:26]=1[O:29][CH3:30])(=[O:40])[CH3:39]
Reactant: CC(=O)OCBr
Reactant: COc1ccnc(C(=O)N[C@H]2CCC[C@H](CCF)[C@@H](OCC(C)C)[C@H](C)OC2=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccnc(C(=O)N[C@H]2CCC[C@H](CCF)[C@@H](OCC(C)C)[C@H](C)OC2=O)c1OCOC(C)=O
Temperature: 50 °C
Reaction time: 16 h
Yield: 77.2 %

Procedure:
To a solution of N-((3S,7R,8R,9S)-7-(2-fluoroethyl)-8-isobutoxy-9-methyl-2-oxooxonan-3-yl)-3-hydroxy-4-methoxypicolinamide (97 mg, 0.220 mmol) in anhydrous acetone (2.2 mL) were added powdered K2CO3 (60.9 mg, 0.440 mmol) and bromomethyl acetate (32.4 μl, 0.330 mmol). The resulting mixture was heated to 50° C. and stirred vigorously for 16 h, then filtered through a plug of Celite®, concentrated, and purified by column chromatography on SiO2 (5→50% acetone/hexanes) to provide the title compound as a sticky solid (87 mg, 77%): 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J=8.1 Hz, 1H), 8.28 (d, J=5.4 Hz, 1H), 6.95 (d, J=5.4 Hz, 1H), 5.74 (s, 2H), 4.90 (dq, J=9.1, 6.4 Hz, 1H), 4.58 (ddt, J=9.4, 5.9, 4.6 Hz, 2H), 4.50-4.39 (m, 1H), 3.91 (s, 3H), 3.45 (dd, J=8.4, 6.6 Hz, 1H), 3.26 (dd, J=8.4, 6.4 Hz, 1H), 3.14-3.02 (m, 1H), 2.36 (dt, J=12.9, 6.7 Hz, 1H), 2.07 (s, 3H), 2.06-1.98 (m, 1H), 1.84 (dp, J=13.4, 6.7 Hz, 1H), 1.78-1.60 (m, 4H), 1.57 (s, 1H), 1.42 (d, J=6.4 Hz, 3H), 1.39-1.29 (m, 1H), 1.10 (dd, J=14.3, 5.7 Hz, 1H), 0.92 (d, J=6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 170.35, 167.84, 160.52, 157.81, 143.31, 141.51, 140.02, 107.14, 87.11, 81.42, 81.36, 79.73, 77.78, 72.81, 53.74, 49.43, 37.34, 37.30, 31.13, 29.17, 28.98, 26.73, 26.26, 18.44, 17.02, 16.98, 16.74, 15.69; HRMS-ESI (m/z) ([M+Na]+) calcd for C25H37FN2O8Na, 535.2426, found 535.2423.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C@@H:14](/[CH:15]=[CH:16]/[C:17](=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH2:12][C:11]1=[O:24].O[C@@H](CCCCC)/C=C/[C@H]1CCC(=O)N1CCSCCCC(O)=O.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.Cl>C1(C)C=CC=CC=1.CO>[CH3:1][O:2][C:3](=[O:25])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:11](=[O:24])[CH2:12][CH2:13][C@@H:14]1/[CH:15]=[CH:16]/[C@@H:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCC(=O)/C=C/[C@H]1CCC(=O)N1CCCCOCC(=O)OC
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: CCCCC[C@H](O)/C=C/[C@H]1CCC(=O)N1CCSCCCC(=O)O
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCC[C@H](O)/C=C/[C@H]1CCC(=O)N1CCCCOCC(=O)OC
Temperature: -26 °C
Reaction time: 7 h

Procedure:
A solution of the {4-[(R)-2-Oxo-5-((E)-3-oxo-oct-1-enyl)-pyrrolidin-1-yl]-butoxy}-acetic acid methyl ester prepared as in Example 1 (250 mg, 0.71 mmol) in 10 mL of anhydrous toluene was added dropwise to a −26° C. solution of (R)-2-methyl-CBS-oxazaborolidine (Aldrich, 1 M in toluene, 0.35 mL) and borane-methyl sulfide complex (10 M, 0.07 mL). The reaction was stirred under nitrogen for 7 hours at −26° C. and then a solution of hydrochloric acid in methanol (2 M, 1-2 mL) was added. The solution was warmed to room temperature and the solvents were removed via reduced pressure. The crude residue was purified via silica gel chromatography yielding 11 mg of {4-[(R)-2-((E)-(S)-3-hydroxy-oct-1-enyl)-5-oxo-pyrrolidin-1-yl]-butoxy}-acetic acid methyl ester as an oil. This was taken directly on to the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.ON1C2C=CC=CC=2N=N1.Cl.[CH3:23][NH:24][O:25][CH3:26].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([N:24]([O:25][CH3:26])[CH3:23])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)Cc1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of 3-chlorophenylacetic acid (5.00 g, 29.3 mmol), 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide HCl (6.18 9, 32.2 mmol), and 1-hydroxybenzotriazole (HOBt; 4.00 9, 29.3 mmol) in dichloromethane (DCM; 40 mL) was stirred at room temperature for about 10 minutes. The solution was cooled to about 0° C. To it were added N,O-dimethylhydroxylamine HCl (2.86 g, 29.0 mmol) and diisopropylethylamine (DIEA; 3.80 g, 29.3 mmol). The reaction mixture was warmed to room temperature and stirred for about 5 hours. The solution was diluted with 100 mL of DCM and washed with saturated NaHCO3 aqueous solution (2 times), iN HCl aqueous solution (2 times) and brine (2 times), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The liquid obtained was purified by column chromatography on silica eluting with EtOAc/hexane 1:1. The title compound was obtained as colorless liquid. Yield: 5.60 g, 89%. Rf=0.44 (silica, EtOAc/hexane 1:1). 1H NMR (300 MHz, CDCl3) 7.18-7.34 (m, 4H), 3.76 (S, 2H), 3.66 (S, 3H), 3.22 (S, 3H).
Reaction SMILES: I[CH2:2][CH:3]=[CH2:4].[CH3:5][N:6]([CH3:18])[C:7]1[CH:8]=[C:9]([F:17])[C:10]([N+:14]([O-:16])=[O:15])=[C:11]([OH:13])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CCOCC.O>[CH2:2]([O:13][C:11]1[CH:12]=[C:7]([N:6]([CH3:18])[CH3:5])[CH:8]=[C:9]([F:17])[C:10]=1[N+:14]([O-:16])=[O:15])[CH:3]=[CH2:4]
Reactant: C=CCI
Reactant: CN(C)c1cc(O)c([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: C=CCOc1cc(N(C)C)cc(F)c1[N+](=O)[O-]
Yield: 85.8 %

Procedure:
3-Iodo-1-Propene (0.30 mL, 3.3 mmol) was added to 5-Dimethylamino-3-fluoro-2-nitro-phenol (0.592 g, 2.96 mmol) and Potassium carbonate (1.1 g, 7.9 mmol) in Dimethyl sulfoxide (15 mL) and the reaction was stirred under an atmosphere of Nitrogen for 45 m. The mixture was diluted with ether (120 mL) and water (50 mL), the layers separated and the aq. back extracted with 25 mL ether. The combined organics were washed with water (60 mL) and brine (60 mL). After drying over sodium sulfate, the solution was conc. in vacuo and the residue chromatographed (ISCO, 52 g SiO2, 0-50% EtOAc:Hex) to afford (3-Allyloxy-5-fluoro-4-nitro-phenyl)-dimethyl-amine as a yellow solid (0.61 g, 86%). 1H-NMR (CDCl3): 6.01 (m, 2H), 5.90 (s, 1H), 5.46 (d, 1H, J=17.2 Hz), 5.32 (d, 1H, J=10.6 Hz), 4.63 (m, 2H), 3.03 (s, 6H); 19F-NMR (CDCl3): −119.