Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[N+:13]([O-])=O.[C:16]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+].Cl>O.C1(C)C(C)=CC=CC=1.COCCOCCOC>[C:16]([C:20]1[CH:21]=[CH:22][C:23]([O:26][C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=2[NH2:13])=[CH:24][CH:25]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: CS(=O)(=O)Nc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(C)(C)c1ccc(Oc2ccc(NS(C)(=O)=O)cc2N)cc1
Reaction time: 24 h

Procedure:
N-(4-chloro-3-nitrophenyl)methanesulphonamide (50 g, 0.2 mole), 4-t-butylphenol (33 g, 0.22 mole), potassium carbonate (62.1 g, 0.45 mole) and diglyme (50 ml) were heated and stirred at 165°-170° for 24 hr. The mixture was cooled to 110° and xylene (150 ml) followed by a mixture of 10M-hydrochloric acid (55 ml) and water (130 ml) added.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[S:22]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:11])=[O:12])(=[O:24])=[O:23]
Reactant: COc1ccc(N)c(S(N)(=O)=O)c1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Solvent: c1ccncc1
Product: COc1ccc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
To a solution of 2-amino-5-methoxy-benzenesulfonamide (2.73 g, 13.43 mmol) in pyridine (25 mL), 2,3-dichlorobenzenesulfonyl chloride (3.68 g, 15.0 mmol) was added slowly at 0° C. The reaction mixture was stirred at RT overnight and then concentrated under reduced pressure. The residue was then partitioned between ethyl acetate and 1N HCl. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography using ethyl acetate/hexane (1:1) to afford the title compound (4.8 g, 87%).
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[C:6]([N+:17]([O-:19])=[O:18])[CH:5]=1.[ClH:21]>>[ClH:21].[CH3:16][N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:20])=[O:2])=[CH:5][C:6]=2[N+:17]([O-:19])=[O:18])[CH2:11][CH2:12]1
Reactant: COC(=O)c1ccc(N2CCN(C)CC2)c([N+](=O)[O-])c1
Agent: Cl
Product: CN1CCN(c2ccc(C(=O)O)cc2[N+](=O)[O-])CC1

Procedure:
A solution of 4-(4-methyl-piperazin-1-yl)-3-nitro-benzoic acid methyl ester (1.8 g, 6.4 mmol) in 35 mL of 5N HCl was stirred at 55° C. for 16 h. The reaction mixture was then evaporated to dryness affording the title compound (quantitative) that was used for the next step without any further purification.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:4]1[C@@H:7]([C@@H:8]([CH3:27])[C:9]([C:11]2[S:15][C:14]3=[C:16]([C:19]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)=[O:20])[N:17]=[CH:18][N:13]3[CH:12]=2)=O)[N:6]([C:28]([C:48]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=2)=[O:49])=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:5]1=[O:61])[CH3:3]>C1(C)C=CC=CC=1>[OH:1][C@@H:2]([C@H:4]1[C:5](=[O:61])[N:6]2[C:28]([C:48]([O:50][CH2:51][C:52]3[CH:53]=[CH:54][C:55]([N+:58]([O-:60])=[O:59])=[CH:56][CH:57]=3)=[O:49])=[C:9]([C:11]3[S:15][C:14]4=[C:16]([C:19]([C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[O:20])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:8]([CH3:27])[C@H:7]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1[C@@H](C)C(=O)c1cn2cnc(C(=O)c3cccnc3)c2s1
Solvent: Cc1ccccc1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cccnc5)c4s3)[C@H](C)[C@H]12
Yield: 73.2 %

Procedure:
A solution of 46.9 mg of (3S,4R)-3-[(1R)-1-hydroxy ethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}-1-[4-nitrobenzyloxycarbonyl (triphenylphosphoranylidene)-methyl]azetidin-2-one in 1 ml of toluene was heated under reflux for 3 hr. The solvent was removed by evaporation, and the residue was purified by thin layer chromatography (developed with 10% methanol/methylene chloride) to give 23.1 mg of (4-nitrobenzyl) (1S,5R,6S)-6-[(1R)-1-hydroxyethyl]-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-methylcarbapen-2-em-3-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([O:23]CC)=O)[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[N:27]1([CH2:32][CH2:33][CH2:34][NH2:35])[CH:31]=[CH:30][N:29]=[CH:28]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([NH:35][CH2:34][CH2:33][CH2:32][N:27]4[CH:31]=[CH:30][N:29]=[CH:28]4)=[O:23])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NCCCn1ccnc1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Product: Cn1c(=O)c(C(=O)NCCCn2ccnc2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 32.8 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (10 mg, 0.028 mmol) described in example 92 and [3-(1H-imidazol-1-yl)propyl]amine (48 mg, 0.0384 mmol), was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[3-(1H-imidazol-1-yl)propyl]-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (4 mg, 33% yield), as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.36 (br s, 1 H), 8.59 (s, 1 H), 7.74 (s, 1 H), 7.42 (s, 1 H), 7.18-7.14 (m, 2 H), 7.12 (s, 1 H), 7.05-7.01 (m, 3 H), 4.15 (s, 2 H), 4.11-4.07 (m, 2 H), 3.59 (s, 3 H), 3.51-3.45 (m, 2 H), 2.19-2.12 (m, 2 H); MS m/z 436 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[CH3:14]O>Cl.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH3:11])[C:8]([O:10][CH3:14])=[O:9])=[CH:12][CH:13]=1
Reactant: CC(Oc1ccc(O)cc1)C(=O)O
Reactant: CO
Agent: Cl
Solvent: O
Product: COC(=O)C(C)Oc1ccc(O)cc1
Yield: 99.9 %

Procedure:
Into a mixture of 191 g (1 mol) of 2-(4-hydroxyphenoxy)propionic acid, moist (5% of H2O content), and 160 g (5 mol) of methanol there was blown in 0.73 g (0.02 mol) of hydrogen chloride and the mixture was caused to react and purified in a manner similar to that described in example 1. There were obtained 196 g (100%) [content: 99,7%] of methyl 2-(4-hydroxyphenoxy)propionate (chloride value: 34 ppm; organic chlorine: <10 ppm, other impurities: <0,1%, [hydroxyphenoxypropionic acid not detectable]).
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:31])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O1CCOCC1>[CH2:33]([O:32][C:30]([N:27]1[CH2:28][CH2:29][N:24]([C:21]2[CH:22]=[CH:23][C:18]([N:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[NH:8][CH2:9][CH2:10]3)=[CH:19][CH:20]=2)[CH2:25][CH2:26]1)=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CCN(C(=O)OCc4ccccc4)CC3)cc2)c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCN(c2ccc(N3CCNc4ccccc43)cc2)CC1
Reaction time: 0.08 h
Yield: 99.8 %

Procedure:
8.9 g of 4-[4-(4-(benzyloxycarbonyl)piperazin-1-yl)phenyl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester are placed in 220 ml of dichloromethane. 55 ml of a 4N solution of hydrochloric acid in dioxane are slowly added at 0° C. The mixture is stirred for 5 minutes under cold conditions and then it is allowed to return to ambient temperature. The reaction mixture is stirred at ambient temperature for 18 h and is then diluted with dichloromethane. A saturated aqueous sodium carbonate solution is added and then the addition is continued with solid sodium carbonate until a pH=7-8 is reached. The aqueous phase is extracted with dichloromethane. The organic phases are combined, washed with water, dried over sodium sulphate, filtered through a sintered glass filter and concentrated under vacuum. 7.2 g of 4-[4-(3,4-dihydro-2H-quinoxalin-1-yl)phenyl]piperazine-1-carboxylic acid benzyl ester are obtained in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:12]1[O:29][C@H:28]([CH2:30][O:31]C(=O)C)[C@@H:23]([O:24]C(=O)C)[C@H:18]([O:19]C(=O)C)[C@H:13]1[O:14]C(=O)C.[CH2:35]([O:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=O)=[CH:40][CH:39]=1)[CH3:36]>>[Cl:11][C:9]1[CH:10]=[C:2]([Cl:1])[CH:3]=[C:7]2[C:8]=1[C:4]([CH2:42][C:41]1[CH:45]=[CH:46][C:38]([O:37][CH2:35][CH3:36])=[CH:39][CH:40]=1)=[CH:5][N:6]2[C@@H:12]1[O:29][C@H:28]([CH2:30][OH:31])[C@@H:23]([OH:24])[C@H:18]([OH:19])[C@H:13]1[OH:14]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Cl)cc(Cl)cc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCOc1ccc(C(=O)Cl)cc1
Product: CCOc1ccc(Cc2cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3cc(Cl)cc(Cl)c23)cc1

Procedure:
The above 4,6-dichloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indole and 4-ethoxybenzoyl chloride were treated in a manner similar to Example 3 to give the titled compound, 4,6-dichloro-3-(4-ethoxyphenylmethyl)-1-(β-D-glucopyranosyl)-indole as a colorless powder. APCI-Mass m/Z 499/501 (M+NH4). 1H-NMR (DMSO-d6) δ 1.29 (t, J=7.0 Hz, 3H), 3.15-3.52 (m, 4H), 3.58 (m, 1H), 3.67 (m, 1H), 3.97 (q, J=6.9 Hz, 2H), 4.17 (s, 2H), 4.54 (t, J=5.6 Hz, 1H), 5.10 (d, J=5.3 Hz, 1H), 5.15 (d, J=5.1 Hz, 1H), 5.21 (d, J=5.8 Hz, 1H), 5.45 (d, J=9.0 Hz, 1H), 6.81 (d, J=8.5 Hz, 2H), 7.11 (m, 3H), 7.26 (s, 1H), 7.71 (d, J=1.1 Hz, 1H).
Reaction SMILES: [H-].[Na+].BrCC(OCC(C)C)=O.[CH2:12]([O:16][C:17](=[O:35])[CH2:18][N:19](C(OC(C)(C)C)=O)[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)[CH:13]([CH3:15])[CH3:14]>C1COCC1>[CH2:12]([O:16][C:17](=[O:35])[CH2:18][NH:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)COC(=O)CN(C(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Agent: CC(C)COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)COC(=O)CNc1ccc(Cl)c(Cl)c1

Procedure:
3,4-Dichloroaniline (Aldrich) was treated with di-tert-butyl dicarbonate (Aldrich) using conventional procedures to produce the N-BOC aniline The N-BOC aniline was treated with sodium hydride in THF and then with iso-butyl 2-bromoacetate (from Example AD above) to produce the N-BOC N-(3,4-dichlorophenyl)glycine iso-butyl ester. The BOC group was then removed using General Procedure AN above to afford the title compound. The reaction was monitored by tlc on silica gel (Rf=0.78 in 50% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 50% EtOAc/hexanes as the eluant).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([F:27])[CH:18]=2)=[N:4][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:6][N:7]=1.C(=O)([O-])[O-].[Na+].[Na+].I[CH:35]1[CH2:38][O:37][CH2:36]1>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([F:27])[CH:18]=2)=[N:4][C:5]([CH:35]2[CH2:38][O:37][CH2:36]2)=[CH:6][N:7]=1
Reactant: COC(=O)c1ccc(-c2nc(B3OC(C)(C)C(C)(C)O3)cnc2N)cc1F
Reactant: IC1COC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2nc(C3COC3)cnc2N)cc1F
Temperature: 100 °C
Yield: 11.1 %

Procedure:
To methyl 4-(3-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-yl)-2-fluorobenzoate (150 mg, 0.402 mmol) in DME (6 mL) and sodium carbonate (1.5 mL, 3.0 mmol) was added 3-iodooxetane (370 mg, 2.01 mmol) and PdCl2(dppf)-CH2Cl2 (32.8 mg, 0.042 mmol). The reaction mixture was heated in microwave at 100° C. for 15 min. The reaction mixture was partitioned between ethylacetate and water. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified by prep HPLC to isolate the product (13.5 mg, 11.0%). LCMS (m/z): 304.2 (MH+), 0.61 min.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[S:17][CH3:18])[C:10]([O:12]C)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].C(O)(=O)C>O.C(O)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[S:17][CH3:18])[C:10]([OH:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(SC)c(OC2CCCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CSc1ccc(C(=O)O)cc1OC1CCCC1
Yield: 91.5 %

Procedure:
A solution of methyl 3-cyclopentyloxy-4-(methylthio)benzoate (24.3 g, 91.4 mmol) in water (200 mL) and ethanol (50 mL) containing sodium hydroxide (18.3 g, 460 mmol) is heated under reflux for 3 hours. The solution is then poured into water (750 mL) and 1 N acetic acid is added dropwise with stirring to between pH 5-6. The solid which separates is collected by filtration, washed with water (4×100 mL) and dried giving 3-cyclopentyloxy-4-(methylthio)benzoic acid (21.1 g, 91.7%) as a cream solid m.p. 158-160° C. [Elemental analysis: C,61.5; H,6.31%; calculated: C,61.88; H,6 39%].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].Cl.[CH3:16][NH:17][CH3:18].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N:17]([CH3:18])[CH3:16])=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: CNC
Reactant: COC(=O)c1ccc(F)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N(C)C)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 7 h
Yield: 61 %

Procedure:
To a stirred solution of 4.48 g (22.5 mmol) 4-fluoro-2-nitro-benzoic acid methyl ester (J. Fluorine Chem.; 63; 1-2; (1993); 25-30) and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 7 h at 60° C. in an autoclave and was reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 8a was obtained in 61% yield (3.08 g, 13.7 mmol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@H:8]([OH:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH2:11]([Sn](CCCC)(CCCC)C=C)[CH2:12]CC>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:11]([C:2]1[CH:3]=[C:4]([C@H:8]([OH:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1)=[CH2:12]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: C[C@@H](O)c1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=Cc1cccc([C@@H](C)O)c1
Temperature: 45 °C
Reaction time: 18 h
Yield: 88.9 %

Procedure:
Bis(triphenylphosphine)palladium(II) dichloride (360 mg, 0.512 mmol) was added to a degassed solution of (R)-1-(3-bromo-phenyl)-ethanol (1.03 g, 5.123 mmol) and tributyl(vinyl)tin (1.8 ml, 6.15 mmol) in toluene (10 ml) under N2 and the reaction was stirred at 45° C. for 18 h. Tributyl(vinyl)tin (2.56 mmol, 750 uL) and bis(triphenylphosphine)palladium(II) dichloride (0.256 mmol, 180 mg) were added and stirring was continued for 18 h. The reaction was cooled and the solvent evaporated to afford a residue which was absorbed onto SiO2. Purification by SiO2 (3:11-hexane/ethyl acetate) afforded 13a as a yellow oil (675 mg, 89%). 1H NMR (300 MHz, CDCl3) δ7.49 (1H, s), 7.33 (3H, m), 6.75 (1H, dd, J=17.6, 10.9 Hz), 5.80 (1H, d, J=17.6 Hz), 5.28 (1H, d, J=10.7 Hz), 4.93 (1H, m), 1.81 (1H, d, J=3.1 Hz), 1.52 (3H, d, J=6.5 Hz).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:11]=[C:4]2[N:3]=1.CN(C)C=O.[CH:23]([NH:26][CH:27]([CH3:29])[CH3:28])([CH3:25])[CH3:24]>>[CH:23]([N:26]([CH:27]([CH3:29])[CH3:28])[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:11]=[C:4]2[N:3]=1)([CH3:25])[CH3:24]
Reactant: Cc1cc(Cl)nc2nc(N3CCOCC3)nn12
Reactant: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: Cc1cc(N(C(C)C)C(C)C)nc2nc(N3CCOCC3)nn12
Reaction time: 24 h

Procedure:
To a solution of 2.54 g (0.01 mole) of 5-chloro-7-methyl-2-morpholino-1,2,4-triazolo[1,5-a]pyrimidine in 10 ml of dimethylformamide 2.02 g (0.02 mole≈2.8 ml) of diisopropylamine are added, and the reaction mixture is boiled for 24 hours under stirring. The solution thus obtained is evaporated to dryness in vacuo and the residue is recrystallized from 20 ml of water.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][N:3]=1.C([Li])CCC.[CH2:12]([Sn:16]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])Cl)[CH2:13][CH2:14][CH3:15].C([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][C:2]1[CH:6]=[C:5]([Sn:16]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:12][CH2:13][CH2:14][CH3:15])[S:4][N:3]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1ccsn1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(C)ns1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of 3-methylisothiazole (100 mg, 1.0 mmol) in anhydrous THF (2.0 mL) was added n-butyllithium (0.693 mL, 1.1 mmol) dropwise. After stirring for 60 minutes at −78° C., a solution of tributylchlorostannane (0.326 mL, 1.210 mmol) in anhydrous THF (0.5 mL) was added to the reaction mixture. The reaction mixture was stirred for 30 minutes at −78° C. and then allowed to warm to RT over a 2 to 3 hour period. Saturated aq NaHCO3 was added and the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and evaporated in vacuo. The residue was purified by silica gel chromatography (Flash 60 column) eluting with hexane/EtOAc (9:1) to give the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 0.86-0.94 (m, 9H), 1.05-1.21 (m, 6H), 1.26-1.38 (m, 6H), 1.44-1.65 (m, 6H), 2.56 (s, 3H), 6.97-7.04 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:17][C:18]1[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:21]=[C:20]([N:28]2[CH2:35][CH:34]3[CH:30]([CH2:31][NH:32][CH2:33]3)[CH2:29]2)[CH:19]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:6]([C:7]([N:32]2[CH2:33][CH:34]3[CH:30]([CH2:29][N:28]([C:20]4[CH:19]=[C:18]([CH3:17])[N:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[N:21]=4)[CH2:35]3)[CH2:31]2)=[O:9])[CH:10]=1
Reactant: Cc1cc(N2CC3CNCC3C2)nc(C(F)(F)F)n1
Reactant: O=C(O)c1cc(F)ccc1-c1ncccn1
Product: Cc1cc(N2CC3CN(C(=O)c4cc(F)ccc4-c4ncccn4)CC3C2)nc(C(F)(F)F)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 13 and Intermediate 31. MS (ESI): mass calculated for C23H20F4N6O, 472.45; m/z found 473.2 [M+H]+.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:23])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[CH:6][C:5]=1[O:24][CH3:25].[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[OH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:23])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=2)=[CH:6][C:5]=1[O:24][CH3:25]
Reactant: COC(=O)c1ccc(NC(=O)Cc2cccc(C(F)(F)F)c2)cc1OC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: COc1cc(NC(=O)Cc2cccc(C(F)(F)F)c2)ccc1CO
Temperature: -20 °C
Reaction time: 2 h

Procedure:
2-Methoxy-4-[2-(3-trifluoromethylphenyl)acetylamino]benzoic acid methyl ester (2.0 g, 5.4 mmol) was dissolved in dry DCM (100 mL) under nitrogen and cooled to −20° C. Diisobutylaluminum hydride (1.2 M in toluene, 18.9 mmol, 16 mL) was dropwise added over 40min. The reaction mixture was heated to 20° C. and stirred at this temperature for 2 hr. After dilution with DCM (100 mL) the reaction mixture was quenched by dropwise addition of water (10 mL) at 20-25° C. The mixture was filtered after 16 hr and the organic phase was dried (magnesium sulphate), filtered and concentrated in vacuo to give crude N-(4-hydroxymethyl-3-methoxyphenyl)-2-(3-trifluoromethylphenyl)acetamide that was purified by column chromatography on silica (30 g) using heptane and ethyl acetate (3:2) as eluent.
Reaction SMILES: C([Li])CCC.Br[C:7]1[N:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][CH:8]=1.[C:15]([N:19]=[C:20]=[O:21])([CH3:18])([CH3:17])[CH3:16].[NH4+].[Cl-]>C1COCC1>[C:15]([NH:19][C:20]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([O:13][CH3:14])[N:12]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)N=C=O
Reactant: COc1cccc(Br)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cccc(C(=O)NC(C)(C)C)n1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 84.8 %

Procedure:
n-Butyllithium (18.25 mmole) was added dropwise to a cooled solution of 6-bromo-2-methoxypyridine (3.12 g, 16.6 mmole, prepared from 2,6-dibromopyridine (Aldrich) according to Comins and Killpack, J. Org. Chem., 55:69-73 (1990)) in 40 mL of THF at -78° C., the resulting orange solution was stirred for 20 minutes at -78° C., and t-butylisocyanate (26.3 mmole) was added with a syringe. The mixture was stirred for 30 minutes at -78° C., warmed to room temperature, then saturated NH4Cl (20 mL) was added. The layers were separated, and the aqueous layer was extracted with methylene chloride (2×20 mL). The combined organic layers were dried over MgSO4 and concentrated, and the residue was chromatographed on silica gel, eluting with 10% to 25% ethyl acetate in hexane, to provide 2.93 g of the title compound as an oil. MS: 209 (M+H)+ ; 1H NMR (CDCl3) δ: 7.85-7.68 (m, 3H), 6.87 (d, J=8 Hz, 1H), 3.96 (s, 3H), 1.49 (s, 9H).
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:10]([CH2:11][OH:12])[O:9][C@H:8]2[C@H:4]([N:5]=[C:6]([N:13]([CH2:21][CH2:22][F:23])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[S:7]2)[C@H:3]1[OH:24].[C:25]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[Si:29]([O:12][CH2:11][C@H:10]1[O:9][C@H:8]2[C@H:4]([N:5]=[C:6]([N:13]([CH2:21][CH2:22][F:23])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18])[S:7]2)[C@@H:3]([OH:24])[C@@H:2]1[OH:1])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)N(CCF)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CCF)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 6 h
Yield: 47.6 %

Procedure:
To a solution of tert-butyl (3aR,5R,6S,7R,7aR)-6,7-dihydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(2-fluoroethyl)carbamate (16 g, 43.7 mmol) in dichloromethane (100 mL) was added tert-butylchlorodimethylsilane (7.6 g, 50.7 mmol), 4-dimethylaminopyridine (530 mg, 4.34 mmol) and triethylamine (6.6 g, 65 mmol). After stirred for 6 h at room temperature, the resulting mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column, eluting with 20% petroleum in ethyl acetate to give compound 69 as pale yellow oil (10 g, 48%). (ES, m/z) [M+H]+ 481.0; 1H NMR (300 MHz, CDCl3) δ 6.17-6.19 (d, J=6.3 Hz, 1H), 4.42-4.74 (m, 3H), 3.52-4.26 (m, 7H), 1.56 (s, 9H), 0.92 (s, 9H), 0.10 (s, 6H).