Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7](Cl)[CH2:6][CH2:5]2.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:25]2[CH:29]=[CH:28][CH:27]=[N:26]2)[CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)[CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:15][CH:14]=1)[CH2:6][CH2:5]2
Reactant: ClC1CCc2cc(Br)ccc21
Reactant: COC(=O)CC(c1ccc(O)cc1)n1cccn1
Product: COC(=O)CC(c1ccc(OC2CCc3cc(Br)ccc32)cc1)n1cccn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
A mixture of 47.3 (0.16 mmol) and methyl 3-(4-hydroxyphenyl)-3-(1H-pyrazol-1-yl)propanoate 47.4 (obtained by the procedure of Example 58 set forth in US 2006/0004012 which is hereby incorporated by reference) (0.11 mmol) was stirred at 40° C. for 1 hour. After work up and chromatography, 47.5 was obtained in 30% yield. MS ESI (pos.) M/E: 441, 443 (M+H).
Reaction SMILES: [N:1]#[C:2]Br.[O-]Cl.[Na+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[OH:17].[OH-].[Na+]>O1CCCC1.O>[NH2:1][C:2]1[O:17][C:9]2[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=2[N:7]=1
Reactant: N#CBr
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc2ccc([N+](=O)[O-])cc2o1
Reaction time: 24 h
Yield: 71 %

Procedure:
A solution of cyanogen bromide (3.50 g, 33 mmol; caution: highly toxic! Waste disposal: addition of excess NaOCl to a basic aqueous solution of cyanogen bromide) in tetrahydrofuran (3 mL) was added to a solution of 2-amino-5-nitrophenol (4.62 g, 30 mmol) in tetrahydrofuran (20 mL). After stirring for 1 day at r.t, a precipitate had formed which was dissolved by addition of water (5 mL). After stirring further 3 days at r.t., water (10 mL) was added and NaOH was added until the mixture turned basic. The tetrahydrofuran was removed in vacuo and the precipitate formed in the remaining aqueous phase was separated by filtration, washed with water and recrystallized from methanol (100 mL). Upon additional fractional crystallisation of the mother liquor, a total of 3.80 g (21.2 mmol, 71%) of 2-amino-6-nitrobenzoxazole was obtained as a brown solid. LC/ESI-MS: m/z=180 [M+H]+; m/z=178 [M]−H−; R=2.52 min.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:10]=[C:9]([N:11]3[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12]3)[N:8]=[C:7]([NH:18][C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=3)[CH:6]=2)[CH2:2]1.O1[CH2:34][CH2:33][O:32][CH2:31]C1.C(N(C(C)C)C(C)C)C.O1CC(=O)C1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[F:16][C:13]1([F:17])[CH2:14][CH2:15][N:11]([C:9]2[N:8]=[C:7]([NH:18][C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:22]=[CH:21][N:20]=3)[CH:6]=[C:5]([CH:3]3[CH2:2][N:1]([CH:34]4[CH2:31][O:32][CH2:33]4)[CH2:4]3)[CH:10]=2)[CH2:12]1
Reactant: FC1(F)CCN(c2cc(C3CNC3)cc(Nc3cc(C(F)(F)F)ccn3)n2)C1
Reactant: C1COCCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C1COC1
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: FC1(F)CCN(c2cc(C3CN(C4COC4)C3)cc(Nc3cc(C(F)(F)F)ccn3)n2)C1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 3.3 %

Procedure:
To a solution of 4-(azetidin-3-yl)-6-(3,3-difluoropyrrolidin-1-yl)-N-[4-(trifluoromethyl)-2-pyridyl]pyridin-2-amine (1-d, 200 mg, 0.5008 mmol) in 1,4-dioxane (3.0 mL, 35 mmol) and N-ethyldiisopropylamine (0.26 mL, 3.0 equiv., 1.502 mmol) was added 3-oxetanone (219 mg, 6.0 equiv., 3.005 mmol), and the reaction was stirred at 50° C. for 1.5 h. After the reaction was cooled down, sodium triacetoxyborohydride (447 mg, 4.0 equiv., 2.003 mmol) was added in portions. The reaction was stirred at 25° C. overnight. The crude was submitted for HPLC purification to yield 7.5 mg (3.3%) white powder. 1H NMR (400 MHz, DMSO-d6) δ (delta) 9.91 (s, 1H), 8.70 (s, 1H), 8.44 (d, J=5.4 Hz, 1H), 7.14 (d, J=5.3 Hz, 1H), 6.62 (s, 1H), 6.00 (s, 1H), 4.58 (t, J=6.7 Hz, 2H), 4.41 (t, J=5.9 Hz, 2H), 3.85 (t, J=13.2 Hz, 2H), 3.75 (p, J=6.2 Hz, 1H), 3.63 (q, J=6.4, 6.0 Hz, 4H), 3.54 (p, J=7.7, 7.1 Hz, 1H), 3.20 (t, J=6.6 Hz, 2H), 2.58 (td, J=14.5, 7.3 Hz, 2H). LCMS: m/z 456 (M+H).
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH:12]=[O:13].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH3:1][Si:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH2:12][OH:13]
Reactant: C[Si](C)(C)CCOCn1ccnc1C=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C[Si](C)(C)CCOCn1ccnc1CO
Temperature: 0 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
A solution of 1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazole-2-carboxaldehyde (prepared according to procedures described by J. P. Whitten et al., J. Org. Chem., 51 (1986), 1891) (9.95 g, 44.0 mmol) in dry ether (40 ml) was dropped into a suspension of lithium aluminum hydride (0.42 g, 12.0 mmol) in dry ether (40 ml) and stirring was continued for 4 hours at room temperature. Then ice-water was added carefully, and the precipitated aluminum hydroxide was filtered off and washed with ether. The aqueous phase was separated and the organic phase was washed with water, dried over sodium sulfate an evaporated in vacuo to leave an oil (9.0 g) which crystallized spontaneously. Yield: 7.1 g, m.p. 68°-69° C. (from pentane).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][N:31]=1>C(Cl)Cl>[Cl:29][C:30]1[N:31]=[CH:32][C:33]([S:36]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]3)=[CH:4][CH:3]=2)(=[O:38])=[O:37])=[CH:34][CH:35]=1
Reactant: C[C@H]1CN(Cc2ccc(N)cc2)CCN1C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccc(NS(=O)(=O)c3ccc(Cl)nc3)cc2)CCN1C(=O)OC(C)(C)C
Yield: 66 %

Procedure:
D2 (500 mg, 1.64 mmol) and pyridine (1.5 mL) were combined in DCM (5 mL). 2-chloro-pyridine-5-sulfonylchloride (314 mg, 1.48 mmol) in DCM (5 mL) was added dropwise. The solution was stirred over the weekend and the solvent removed. The residue was partitioned between DCM (25 mL) and water (25 mL). The aqueous layer was re-extracted with DCM (25 mL) and the combined organic layers washed with brine (50 mL), dried and concentrated. The crude product was purified by column chromatography. Eluting with 0-50% EtOAc/petroleum ether yielded the product as a yellow foam (470.1 mg), δH (CDCl3, 400 MHz) 1.18 (3H, d), 1.46 (9H, s), 1.97 (1H, m), 2.08 (1H, m), 2.48 (1H, d), 2.68 (1H, d), 3.07 (1H, m), 3.32-3.46 (2H, AB), 3.78 (1H, d), 4.16 (1H, br.s), 7.07 (2H, d), 7.23 (2H, d), 7.39 (1H, d), 7.96 (1H, dd), 8.72 (1H, m). MS (ES+): MH+ 481.2/483.1
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([OH:5])=[O:4].[Cl:12][C:13]1([Cl:19])[CH2:15][CH:14]1[C:16]([NH2:18])=[O:17]>C1(C)C=CC=CC=1>[Cl:12][C:13]1([Cl:19])[CH2:15][CH:14]1[C:16]([NH:18]/[C:2](=[CH:6]\[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])/[C:3]([OH:5])=[O:4])=[O:17]
Reactant: NC(=O)C1CC1(Cl)Cl
Reactant: CCCCCCC(=O)C(=O)O
Solvent: Cc1ccccc1
Product: CCCCC/C=C(\NC(=O)C1CC1(Cl)Cl)C(=O)O
Yield: 6 %

Procedure:
A mixture of 1.19 g (7.5 mmoles) of 2-ketooctanoic acid, 0.77 g (5.0 mmoles) of 2,2-dichlorocyclopropanecarboxamide, and 5 ml toluene were reacted using the same procedure as in the previous example. The crude product (537 mg) was purified by conversion to the methyl ester (BF3 /CH3OH), preparative TLC (silica gel G, 4:1 hexane-EtOAc) and saponification of the pure Z-methyl ester (0.3M LiOH/CH30H) to give 88 mg of Z-2-(2,2-dichlorocyclopropanecarboxamido)-2-octenoic acid as a partially crystalline gum. ##STR71##
Reaction SMILES: [C:1]1([CH:7]([CH3:12])[CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].C(OCC)(=O)C>S(Cl)(Cl)=O>[CH3:12][CH:7]1[C:1]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9](=[O:11])[CH2:8]1
Reactant: CC(CC(=O)O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1CC(=O)c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
As presented in the following reaction formula, a mixture of 3-phenylbutanoic acid (30 g, 0.18 mol) in thionyl chloride (SOCl2; 100 mL) was refluxed under heating for 2 hours, and then the thionyl chloride was removed. Toluene (200 mL) and aluminum chloride (AlCl3; 24 g, 0.18 mol) were added to the resulting mixture at 0° C., and the reaction mixture was stirred at 0° C. for 0.5 hours, followed by refluxing under heating. After the completion of reaction, the mixture was treated with ice water and then extracted twice with 200 mL of dichloromethane (DCM). The combined organic phase was washed with water (100 mL) and saturated brine (100 mL), and dried and concentrated with magnesium sulfate to give a crude product. The crude product was purified by gel column chromatography (using 100 g of silica gel (product of Merck Co., Ltd.)) using an eluent of pentane (PE):ethyl acetate (20:1 (by volume)) to give 3-methyl-2,3-dihydro-1H-inden-1-one (16 g, yield: 60%) as a brown oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CN(C)C=O.[CH2:20]([N:23]1[C:31]2[CH:30]=[CH:29][N:28]=[C:27]([Cl:32])[C:26]=2[NH:25][C:24]1=[O:33])[CH:21]=[CH2:22]>C(OCC)(=O)C.O>[CH2:20]([N:23]1[C:31]2[CH:30]=[CH:29][N:28]=[C:27]([Cl:32])[C:26]=2[N:25]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:24]1=[O:33])[CH:21]=[CH2:22]
Reactant: C=CCn1c(=O)[nH]c2c(Cl)nccc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCn1c(=O)n(Cc2ccccc2)c2c(Cl)nccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 104.6 %

Procedure:
0.76 g of potassium carbonate and 0.94 g of benzyl bromide were added to a 50 ml N,N-dimethylformamide solution of 1.05 g of 1-allyl-4-chloro-1,3-dihydroimidazo[4,5-c]pyridin-2-one, and the mixture was stirred at room temperature for 14 hours. 300 ml of water and 300 ml of ethyl acetate were added to the solution, and the organic layer was washed three times with 100 ml of water and then with 100 ml of a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure to give 1.57 g of the title compound.
Reaction SMILES: B(O)O.Br[C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O>>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: O=Cc1cccnc1Br
Agent: OBO
Product: O=Cc1cccnc1-c1ccccc1C(F)(F)F

Procedure:
2-(2-(trifluoromethyl)phenyl)nicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromonicotinaldehyde and (2-(trifluoromethyl)phenyl)boronic acid (40 mg, 93.2 mg theoretical, 42.9%). LC-MS m/z 252.2 (M+1).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][CH:6]1[N:24]=[C:25]=[S:26])(=[O:3])[CH3:2].[NH2:27][C:28]1[NH:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1>C1(C)C(C)=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[NH:24][C:25]([NH:27][C:28]1[NH:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1)=[S:26])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1OC(N=C=S)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Nc1nc2ccccc2[nH]1
Solvent: Cc1ccccc1C
Product: CC(=O)OC[C@H]1O[C@@H](NC(=S)Nc2nc3ccccc3[nH]2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 100 °C

Procedure:
To 10 ml of anhydrous xylene were added 390 mg (1 mmol) of 2,3,4,6-tetra-O-acetyl-D-glucopyranosyl isothiocyanate and 135 mg (1 mmol) of 2-aminobenzimidazole (MW 133) and the mixture was heated at 100° C. for 1 hour and allowed to cool to room temperature. Crystals formed were filtered off and recrystallized from methanol to give colourless needles melting between 162° and 165° C. (uncorrected). Yield: 245 mg (47%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@@H:14](O)[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[N:9]=2)=[CH:4][CH:3]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](/[CH:13]=[CH:14]/[C:15]([F:18])([F:16])[F:17])[C:11](=[O:20])[N:10]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@@H](O)C(F)(F)F)c1=O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(/C=C/C(F)(F)F)c1=O
Reaction time: 12 h

Procedure:
At RT, 280 mg (0.74 mmol) of the compound of Example 7A together with 108 mg (0.89 mmol) of 4-N,N-dimethylaminopyridine were initially charged in 5.3 ml of pyridine, 0.31 ml (1.84 mmol) of trifluoromethanesulphonic anhydride were added a little at a time and the mixture was stirred for 12 h. The pyridine was then removed on a rotary evaporator. The residue was taken up in acetonitrile and 1 N hydrochloric acid and purified by preparative HLPC [Method 9]. This gave 230 mg (86% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>C1C=CC=CC=1>[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc(C(=O)O)c1C
Solvent: c1ccccc1
Product: Cc1cccc(C(=O)Cl)c1C
Yield: 91.6 %

Procedure:
2,3-dimethylbenzoic acid (35.0 g, 233 mmol) was heated to reflux temperature, in dry benzene (80 ml) containing thionyl chloride (45.0 g, 378 mmol) for five hours. The mixture was cooled, filtered and evaporated under reduced pressure to give 2,3-dimethylbenzoyl chloride (36.0 g, 92%) as an oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([NH:12][C:13]2([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=3)[CH2:15][CH2:14]2)=[O:11])[CH2:3][CH2:2]1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:30]Cl.CCN(C(C)C)C(C)C>C(#N)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:30][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([NH:12][C:13]2([C:16]3[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=3)[CH2:14][CH2:15]2)=[O:11])[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cccc4c3NCC4)CC2)cc1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1ccc(C2(NC(=O)c3cccc4c3N(Cc3ccc(Cl)c(Cl)c3)CC4)CC2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Methyl 4-{1-[(2,3-dihydro-1H-indol-7-ylcarbonyl)amino]cyclopropyl}benzoate (110 mg, 0.327 mmol) was dissolved in acetonitrile (1.3 ml). 3,4-dichlorobenzyl chloride (136 ul. 0.981 mmol), DIPEA (171 ul, 0.981 mmol) and a crystal of TBAI were added. The mixture stirred at 70° C. for 2 h. The solvent was removed. Purification on silica gel.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH:21]=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[C:25]([F:28])([F:27])[F:26]>[F-].[Cs+].Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[C@@H:21]([OH:22])[C:25]([F:28])([F:27])[F:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C=O
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Product: CC(C)(C)OC(=O)N1CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1[C@@H](O)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.7 %

Procedure:
To aldehyde 51C (2.10 g, 6.38 mmol) was added trimethyl(trifluoromethyl)silane (800 μL, 6.57 mmol) and cesium fluoride (dried under high vacuum at 130° C. for 12 h) (10.0 mg, 0.0658 mmol). The reaction was stirred at rt for 24 h then heated to 50° C. for 5 h. After cooling to rt, 4 N HCl (ca. 10 mL) was added and the reaction was stirred overnight. The brown aqueous solution was decanted and the waxy yellow solid was dried under high vacuum overnight then recrystallized from hexane to provide (2R,3R)-3-(tert-butyl-dimethyl-silanyloxy)-2-[(1R)-(2,2,2-trifluoro-1-hydroxy-ethyl)]-pyrrolidine-1-carboxylic acid tert-butyl ester (66A) (1.19 g) as a white solid. The mother liquor was concentrated and purified via flash chromatography eluting with 5-20% ethyl acetate/hexane to provide (2R,3R)-3-(tert-butyl-dimethyl-silanyloxy)-2-[(1S)-(2,2,2-trifluoro-1-hydroxy-ethyl)]-pyrrolidine-1-carboxylic acid tert-butyl ester (66B) (192 mg) as an oil and a mixture of 66A and starting material 51C (306 mg). The latter mixture was recrystallized from hexane to provide additional 66A (100 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[CH3:17][S:18]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](O)=O)(=[O:20])=[O:19]>>[CH3:17][S:18]([C:21]1[CH:22]=[C:23]([C:24]2[O:14][C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:15][N:16]=2)[CH:27]=[CH:28][CH:29]=1)(=[O:19])=[O:20]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2cccc(S(C)(=O)=O)c2)o1
Yield: 13 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 3-(methylsulfonyl)-benzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=50:30:20 to 20:60:20, 44 mg, 13%) which was obtained as a white solid. MS: m/e=382.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:4]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[N:3]=1.O.Cl[C:27]([O:29][CH3:30])=[O:28].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:21]1([CH3:24])[CH:22]=[CH:23][C:18]([S:15]([O:14][C:4]2[N:3]=[C:2]([NH:1][C:27]([O:29][CH3:30])=[O:28])[N+:7]([O-:8])=[C:6]([NH:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=2)(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: COC(=O)Nc1cc(OS(=O)(=O)c2ccc(C)cc2)nc(N)[n+]1[O-]
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)Nc1cc(OS(=O)(=O)c2ccc(C)cc2)nc(NC(=O)OC)[n+]1[O-]
Reaction time: 0.17 h

Procedure:
150 g of methyl 2-amino-6-[(p-tolylsulfonyl)oxy]-4-pyrimidinecarbamate-3-oxide are suspended in 2 l of methylene chloride and 2 l of water while stirring. After cooling to 0°-5°, 50 ml of methyl chloroformate are added thereto. After stirring vigorously for about 10 minutes, the mixture is adjusted to a pH of 7-7.5 with about 150 g of sodium bicarbonate. The mixture is subsequently stirred at 0°-5° for a further 3 hours. The organic phase is separated and the aqueous phase is extracted with 1 l of methylene chloride. The combined organic phases are washed twice with 1 l of water each time, dried over sodium sulphate and evaporated in vacuo. There is obtained crude dimethyl 6-[(p-tolylsulfonyl)oxy]-2,4-pyrimidinedicarbamate-3-oxide which is used in the next step (a pure product of melting point 178°-180° can be obtained by digestion with ethyl acetate).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH3:4][C:5]1[C:6]([S:19][C:20]2[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=2)=[CH:7][C:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[C:13]=2[CH:14]=1.O>C1COCC1>[CH2:1]([NH:3][C:24](=[O:25])[C:23]1[CH:22]=[CH:21][C:20]([S:19][C:6]2[C:5]([CH3:4])=[CH:14][C:13]3[C:12]([CH3:15])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:18])([CH3:17])[C:8]=3[CH:7]=2)=[CH:28][CH:27]=1)[CH3:2]
Reactant: CCN
Reactant: Cc1cc2c(cc1Sc1ccc(C(=O)Cl)cc1)C(C)(C)CCC2(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(Sc2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
640 μl (8 mmol) of a 70% solution of ethylamine and 20 ml of THF were introduced into a round-bottomed flask. A solution of 735 mg (2 mmol) of 4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoyl chloride dissolved in 30 ml of THF was added dropwise and the mixture was stirred at room temperature for three hours. The reaction medium was poured into water, extracted with ethyl acetate, the organic phase decanted off, dried over magnesium sulfate and evaporated.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8](=[O:21])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[O:17][CH:18]=[CH:19][CH:20]=1.[C:22](=O)([O-])[O-:23].[Na+].[Na+]>CN(C)C=O>[CH3:6][O:7][C:8](=[O:21])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[O:17][C:18]([CH:22]=[O:23])=[CH:19][CH:20]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)CCCCCCCc1ccco1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)CCCCCCCc1ccc(C=O)o1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
6.13 g of phosphorous oxychloride were added, while stirring, to 2.93 g of dimethyl formamide at 5°-10° C for 5 minutes. The mixture was kept at 0°-5° C for 40 minutes and then heated to room temperature. Immediately, and with vigorous stirring, 8.96 g of 8-(2-furyl)-octanoic acid methyl ester were added, whereupon the mixture was cooled to 5°-10° C in an ice-salt bath during 1 hour. After further 1 hour at room temperature, 40 g of ice were added, whereupon the mixture was neutralized with 10 g of sodium carbonate. The two phases were then separated, and the aqueous phase was extracted with ether. The combined organic phases were dried and then distilled. Boiling point 144° C at 0.2 mm Hg.
Reaction SMILES: C([O:8][C:9]1[C:14]2[N:15]=[C:16]([CH3:19])[N:17]([CH3:18])[C:13]=2[CH:12]=[C:11]([N:20]([CH3:24])[C:21](=[O:23])[CH3:22])[CH:10]=1)C1C=CC=CC=1.[I-].O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:16][N:17]([CH2:18][C:10]1[C:11]([N:20]([CH3:24])[C:21](=[O:23])[CH3:22])=[CH:12][C:13]2[N:17]([CH3:18])[C:16]([CH3:19])=[N:15][C:14]=2[C:9]=1[OH:8])[CH3:13]
Reactant: CC(=O)N(C)c1cc(OCc2ccccc2)c2nc(C)n(C)c2c1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)N(C)c1cc2c(nc(C)n2C)c(O)c1CN(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
A suspension of 4.7 g (18.9 mmol) N-(7-benzyloxy-2,3-dimethy-3H-benzimidazol-5-yl)-N-methyl-acetamide in dry dichloromethane (200 ml) was treated with 4.5 g (24.6 mmol) N,N-dimethylmethylenimmonium iodide and the reaction was stirred overnight at room temperature. The reaction mixture was poured into water, neutralized with sat. sodium bicarbonate solution and extracted with dichloromethane (2×20 ml). The organic layers were dried over magnesium sulphate and concentrated in vacuo. The residue afforded 2.2 g (41%) of the title compound as a white solid. m.p. 181°-184° C.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:19][CH2:20][CH2:21][CH2:22]I>CCCCCCC.CCOC(C)=O>[Cl:19][CH2:20][CH2:21][CH2:22][N:6]1[C:5]2[CH:11]=[CH:12][C:2]([CH3:1])=[CH:3][C:4]=2[O:9][CH2:8][C:7]1=[O:10]
Reactant: Cc1ccc2c(c1)OCC(=O)N2
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)OCC(=O)N2CCCCl
Yield: 78.6 %

Procedure:
7-Methyl-4H-benzo[1,4]oxazin-3-one (81MF2246a) (1.42 g, 8.7 mmol), Cs2CO3 (4.24 g, 13.0 mmol) and 3-chloro-1-iodopropane (1.95 g, 9.5 mmol) were mixed according to GP6. CC (SiO2; Heptane/EtOAc 10:1-5) gave the title compound (81MF2246b) (1.64 g, 79%). 1H NMR (CDCl3) δ 6.98-6.81 (m, 3H), 4.59 (s, 2H), 4.06-4.03 (m, 2H), 3.63-3.60 (m, 2H), 2.26 (s, 2H), 2.20-2.15 (m, 2H); 13C NMR (CDCl3) δ 164.8, 145.8, 134.3, 123.9, 118.1, 114.9, 68.0, 42.8, 39.4, 30.5, 21.0