Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:13])[C@:4]([CH2:8][O:9][CH:10]([F:12])[F:11])([CH3:7])[CH:5]=[CH2:6].O.[OH-].[Li+].Cl>O1CCCC1.O>[F:11][CH:10]([F:12])[O:9][CH2:8][C@@:4]([CH3:7])([CH:5]=[CH2:6])[C:3]([OH:13])=[O:2]
Reactant: C=C[C@](C)(COC(F)F)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=C[C@](C)(COC(F)F)C(=O)O
Temperature: 5 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
A solution of (R)-2-difluoromethoxymethyl-2-methyl-but-3-enoic acid methyl ester (159 mg, 0.8 mmol) in tetrahydrofuran (6 mL) was stirred at 5° C. under nitrogen. A solution of lithium hydroxide monohydrate (100 mg, 2.4 mmol) in water (1.5 mL) was added and the reaction mixture was stirred at 5° C. for 1 h and then at room temperature for 20 h. Water was added and the mixture was acidified to pH 2 with hydrochloric acid (2 M) and the mixture was extracted with diethyl ether. The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated to afford the title compound (133 mg, 92%) as a clear oil. 1H NMR (300 MHz, d6-DMSO) 61.24 (s, 3H), 3.80 (d, J=9.4 Hz, 1H), 4.02 (d, J=9.4 Hz, 1H), 5.19 (dd, J=10.6 Hz, 1H), 5.20 (d, J=17.6 Hz, 1H), 5.91 (dd, J=17.6, 10.6 Hz, 1H), 6.68 (t, J=75.6 Hz, 1H), 12.5-13.0 (br s, 1H). LCMS (m/z) 179.1 [M−H], Tr=1.79 min.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:7])[NH:5][CH:6]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:12](Cl)(=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>[N+](C1C=CC=CC=1)([O-])=O>[CH3:1][C:2]1[NH:3][C:4](=[O:7])[NH:5][C:6]=1[C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCC(=O)Cl
Reactant: Cc1c[nH]c(=O)[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCCCC(=O)c1[nH]c(=O)[nH]c1C
Temperature: 75 °C
Reaction time: 5 h
Yield: 31 %

Procedure:
A flask equipped with mechanical stirrer, reflux condenser and nitrogen inlet, was charged with 5.0 g (0.051 mol) of 4-methyl-4-imidazolin-2-one in 40 ml of nitrobenzene and cooled to ice-bath temperature. Aluminum chloride (27.1 g, 0.204 mol) was added portionwise. The reaction was heated to 75° C. and 7.55 g (0.056 mol) of hexanoyl chloride was added dropwise over 1 hour. Heating was continued for an additional 5 hours whereupon all starting material had been consumed as evidenced by tlc analysis (silica gel, methanol/ethyl acetate 1:4, phosphomolybdic acid visualization). The reaction was poured onto 100 ml of ice containing 7.5 g of sodium carbonate dissolved in 25 ml of water. The reaction mixture was stirred rapidly while 100 ml of ether were added. The resulting solids were isolated by filtration to afford after drying 5.2 g of crude ketone. The crude solids were recrystallized from 50 ml of water/ethanol 1:1 to afford 3.1 g (31%) of homogeneous title product; m.p. 221°-223° C.; IR (KBr) cm-1 : 3178 (s), 3153 (s), 3106 (s), 1746 (s), 1714 (s), 1657 (s), 1644 (s), 1611 (s); 1H-NMR (DMSO-d6): 10.17 (s, 2, N--H), 2.5 (m), 2.27 (s, 3), 1.34 (m, 6), 0.86 (t, 3); 13C-NMR (DMSO-d6): 188.5, 152.4, 118.9, 129.4, 38.8, 31.0, 23.4, 22.0, 13.8, 11.7; mass spectrum (70 eV) m/e 196 (parent), 140 (C6H8N2O2, base), 125 (C5H5N2O2).
Reaction SMILES: [Br:1][CH2:2][C:3]([CH2:5][C:6]([NH:8][CH:9]1[C:29](=[O:30])[N:11]2[C:12]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[O:17])=[CH:13][CH2:14][S:15][C@H:10]12)=[O:7])=[O:4].C(O)(=O)C.[N:35]([O-])=[O:36].[Na+]>O1CCCC1.O>[Br:1][CH2:2][C:3]([C:5](=[N:35][OH:36])[C:6]([NH:8][CH:9]1[C:29](=[O:30])[N:11]2[C:12]([C:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=3)=[O:17])=[CH:13][CH2:14][S:15][C@H:10]12)=[O:7])=[O:4]
Reactant: O=N[O-]
Reactant: O=C(CBr)CC(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: O=C(CBr)C(=NO)C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 34.9 %

Procedure:
4-Nitrobenzyl 7-[2-(2-bromoacetyl)acetamido]-3-cephem-4-carboxylate (8.40 g.) was suspended in a mixture of tetrahydrofuran (150 ml.) and water (30 ml.) To the suspension were added acetic acid (50 ml.) and a solution of sodium nitrite (1.20 g.) in water (15 ml.) under ice-cooling, and stirred at 20° to 22° C. for 1.5 hours. The resultant solution was poured into ice-water (300 ml.) and stirred for 20 minutes. The precipitating substance was collected by filtration, washed with water, dried and then recrystallized from ethyl acetate to give 4-nitrobenzyl 7-[2-(2-bromoacetyl)-2-hydroxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer: 3.1 g.), mp 153° to 162° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][CH:5]=[N:4][C:3]=1[C:7]#[N:8].CO[Na].[NH4+:12].[Cl-]>CO>[CH3:1][C:2]1[O:6][CH:5]=[N:4][C:3]=1[C:7]([NH2:12])=[NH:8]
Reactant: [NH4+]
Reactant: Cc1ocnc1C#N
Agent: CO[Na]
Agent: [Cl-]
Solvent: CO
Product: Cc1ocnc1C(=N)N
Temperature: 35 °C
Reaction time: 3 h

Procedure:
To a solution of 5-methyloxazole-4-carbonitrile AA (0.76 g, 7.0 mmol) in anhydrous MeOH (30 mL) was added MeONa (0.57 g, 10 mmol), after stirred at 35° C. under nitrogen for 3 h, NH4Cl (0.75 g, 14 mmol) was added, refluxed for 2 h. The solvent was removed and the residue was purified by flash chromatography (Biotage, 40 g silica gel, MeOH in DCM 5%˜35%) to afford brown solid AB (587 mg, 67%). 1H NMR (DMSO-d6, 400 MHz) δ ppm: 9.11-9.19 (m, 3H), 8.60 (s, 1H), 2.59 (s, 3H). MS: calc'd (MH+) 126, measured (MH+) 126.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([F:13])[C:5]=1[CH3:14].[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([F:13])[C:5]=1[CH2:14][Br:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c([N+](=O)[O-])ccc(F)c1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c([N+](=O)[O-])ccc(F)c1CBr
Temperature: 85 °C
Reaction time: 6 h
Yield: 54 %

Procedure:
To a suspension of 3-fluoro-2-methyl-6-nitro-benzoic acid methyl ester (6.1 g, 28.6 mmol) and N-bromosuccinimide in 70 mL of CCl4 is added 2,2′-azobisisobutyronitrile at room temperature under nitrogen atmosphere. The reaction mixture is stirred at 85° C. for 6 hours under N2, then cooled to room temperature and filtrated. The filtrate is extracted with CH2Cl2 and washed with aqueous NaHCO3 solution followed by brine, dried over Na2SO4, filtered and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to afford the 2-bromomethyl-3-fluoro-6-nitro-benzoic acid methyl ester (4.48 g, 15.3 mmol, 54%) as yellow oil. 1H-NMR (400 MHz, δ, ppm) CDCl3: 4.01 (s, 3H), 4.53 (d, 2H), 7.31 (dd, 1H), 8.17 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([CH:18]=[O:19])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[CH2:20]([Mg]Cl)[CH3:21]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([CH:18]([OH:19])[CH2:20][CH3:21])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC[Mg]Cl
Reactant: O=Cc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Solvent: ClCCl
Product: CCC(O)c1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-7-carbaldehyde (25 mg, 0.093 mmol) was dissolved in 4 mL of hot dichloromethane. The solution was cooled to room temperature and ethylmagnesium chloride (0.047 mL of 2.0 M in THF, 0.093 mmol) was added. The reaction was stirred at room temperature for 1.5 hours at which point it was quenched via the addition of saturated aqueous ammonium chloride. The mixture was extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, concentrated in vacuo, and purified via flash chromatography (silica, 5-60% ethyl acetate/hexanes) to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 8.80 (d, 1H); 8.52 (d, 1H); 8.21 (d, 1H); 7.73 (dd, 1H); 7.60 (d, 1H); 7.32 (d, 1H); 7.27 (d, 1H); 4.79 (t, 1H); 1.99 (s, 1H); 1.89-1.79 (m, 2H); 0.94 (t, 3H). LRMS (APCI) calc'd for (C17H15ClNO2) [M+H]+, 300.1; found 300.1.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)[N:9]=3)[CH:5]=[CH:4][CH:3]=2)[CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(Br)n2)c1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2)c1

Procedure:
The title compound was prepared from 6′-bromo-4-methyl-6-(4-trifluoromethylphenyl)-[2,2′]bipyridinyl (example E.96) (0.393 g, 1.0 mmol) and commercially available 3-(tert-butylsulfamoyl)-benzeneboronic acid (0.283 g, 1.1 mmol) according to the general procedure VI. Obtained as a white solid (0.500 g, 95%). MS (ISP) 526.3 [(M+H)+].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.CN(C)C=O.[CH2:14]([O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1Cl)[CH3:15]>O>[CH2:14]([O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[O:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH3:15]
Reactant: OCc1cccnc1
Reactant: CCOC(=O)c1cccnc1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccnc1OCc1cccnc1
Reaction time: 0.5 h

Procedure:
To a solution of Pyridin-3-yl-methanol (0.59 grams, 5.4 mmole) in dimethylformamide (20 ml) sodium hydride (0.259 grams, 6.5 mmole) was added and stirred for 30 minutes. 2-Chloro-nicotinic acid ethyl ester (1.0 grams, 5.4 mmole) was added via syringe and stirred at room temperature over night. The mixture was diluted with water (150 ml) and extracted by diethyl ether and ethyl acetate. The combined extracts were washed with 1N NaOH, water and brine, dried over Na2SO4, filtered, and concentrated to an oil (1.3 g). MW 258.28; MS (m/e) 259 (M++1).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([CH:14]=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([CH2:14][OH:15])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=CC1(c2ccc(F)nc2)CCOCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCC1(c2ccc(F)nc2)CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To an ice cooled solution of 4-(6-fluoropyridin-3-yl)tetrahydro-2H-pyran-4-carbaldehyde (560 mg, 2.68 mmol) in methanol (18 mL) was added sodium borohydride (91 mg, 2.41 mmol). The reaction solution was stirred at ambient temperature for 30 min. The solvent was removed under vacuum. The residue was diluted with ethyl acetate, and was washed with water, brine, dried over sodium sulfate, filtered and concentrated to give (4-(6-fluoropyridin-3-yl)tetrahydro-2H-pyran-4-yl)methanol (550 mg, 2.60 mmol, 97%) as brown color oil. LCMS (m/z): 212 (MH+), 0.42 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.Br[CH2:13][CH2:14][CH2:15]CBr.C(O[K])(C)(C)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[C:6]1([CH2:15][CH2:14][CH2:13]1)[CH2:5]2
Reactant: BrCCCCBr
Reactant: O=C1CCc2cc(Br)ccc21
Agent: CC(C)(C)O[K]
Solvent: Cc1ccccc1
Product: O=C1c2ccc(Br)cc2CC12CCC2
Temperature: 130 °C

Procedure:
100 mg of 5-bromo-1-oxoindane was dissolved in 10 ml of toluene, 0.3 ml of 1,4-dibromobutan and 132 mg of tert-butoxypotassium were added, and the mixture was stirred all night by heating at 130° C. under reflux. The reaction solution was cooled down to room temperature, the solvents were distilled outunder reduced pressure and the residues were separated and purified by silicagel chromatography (ethyl acetate/hexane=1/2) to obtain 71 mg of the above compound as a yellow oily matter.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][OH:8].CC(C)([O-])C.[K+].Cl[C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1>C1COCC1>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1
Reactant: CN1CCC[C@H]1CO
Reactant: Clc1cnccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCC[C@H]1COc1cnccn1
Reaction time: 0.17 h

Procedure:
A solution of (S)-1-methyl-2-pyrrolidinemethanol (1.15 g) in THF (45 mL) was treated with potassium tert-butoxide (1.2 g). After 10 min, chloropyrazine was added and the reaction stirred for 1.5 h. The reaction was quenched with 5N HCl (4 mL) and the solvent evaporated. The residue was suspended in water and extracted with ether. The aqueous fraction was made basic and extracted with CHCl3. The extracts were dried, the solvent evaporated, and the residue purified by radial chromatography eluting with 20%-EtOH-2%-NH4OH-CHCl3 to give (S)-2-(1-methyl-2-pyrrolidinylmethoxy)pyrazine (1.1). The HCl salt crystallized from EtOAc as a white solid, m.p. 121-122° C. (Compound 28).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.[NH2:51][C:52]1[C:61]2[C:56](=[CH:57][CH:58]=[C:59]([O:62][Si:63]([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64])[CH:60]=2)[CH:55]=[CH:54][CH:53]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:10][CH2:11][S:12][CH3:13])[C:14]([NH:51][C:52]1[C:61]2[C:56](=[CH:57][CH:58]=[C:59]([O:62][Si:63]([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:64])[CH3:65])[CH:60]=2)[CH:55]=[CH:54][CH:53]=1)=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cccc(N)c2c1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccc2ccc(O[Si](C)(C)C(C)(C)C)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To (R)-N-(tert-butoxycarbonyl)methionine (27.3 g, 109 mmol) in dry CH2Cl2 (45 mL) at 0° C., under argon, were added PYBOP (57 g, 109 mmol), 1-amino-7-(tert-butyldimethylsilyloxy)naphthalene hydrochloride, as described above in Step C above (13.6 g, 44 mmol), and N,N-diisopropylethylamine (26.7 mL, 153 mmol). The reaction mixture was allowed to warm to ambient temperature and was stirred for 4 hours, then partitioned between 10% aqueous citric acid (400 mL) and CH2Cl2 (1 L). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of hexane—10% to 25% EtOAc to yield the titled product.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[C:21]1([N:27]2[CH:31]=[C:30]([C:32](O)=[O:33])[CH:29]=[N:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:32]([C:30]3[CH:29]=[N:28][N:27]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:31]=3)=[O:33])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C(O)c1cnn(-c2ccccc2)c1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cnn(-c2ccccc2)c1

Procedure:
Phenyl-1H-pyrazole-4-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate D and 1-phenyl-1H-pyrazole-4-carboxylic acid. MS calcd. for C26H20ClN4O2 [(M+H)+] 455.1, obsd. 455.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.C[O-].[Na+].CN(C)C=O.Br[C:29]([CH3:35])([CH3:34])[C:30]([O:32][CH3:33])=[O:31]>O.C1(C)C=CC=CC=1>[CH3:33][O:32][C:30](=[O:31])[C:29]([CH3:35])([CH3:34])[N:11]1[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][C:6]=2[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8][CH2:9][C:10]1=[O:12]
Reactant: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: COC(=O)C(C)(C)Br
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)N1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Reaction time: 6 h

Procedure:
A mixture of 0.1 mole of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one and 0.11 mole of sodium methoxide in about 200 ml. of dimethylformamide is heated at about 95° C. for about 20 minutes. To the mixture is added a solution of 0.11 mole of methyl 2-bromo-2-methylpropionate in about 200 ml. of toluene over a period of about 1 hour at about 95° C., and heating is continued for an additional period of about 6 hours. The reaction mixture is then evaporated in vacuo and the residue thus obtained is stirred with about 500 ml. of water. The resulting suspension is filtered and the solids thus obtained are crystallized from a suitable organic solvent such as ether, methanol, methylene chloride, methylene chloride-methanol and the like to obtain 7-chloro-2,3-dihydro-α,α-dimethyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-acetic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:13]2[N:14]=[N:15][S:16][C:17]=2[CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[N:11][OH:12])[CH:5]=[CH:6][C:7]=1[F:8].C1N=CN([C:35](N2C=NC=C2)=[O:36])C=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:35](=[O:36])[O:12][N:11]=[C:10]2[C:13]2[N:14]=[N:15][S:16][C:17]=2[CH2:18][O:19][Si:20]([CH:24]([CH3:26])[CH3:25])([CH:27]([CH3:29])[CH3:28])[CH:21]([CH3:22])[CH3:23])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)[Si](OCc1snnc1C(=NO)Nc1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)[Si](OCc1snnc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Temperature: 70 °C
Yield: 99.2 %

Procedure:
Into a round bottom flask was added N-(3-chloro-4-fluorophenyl)-N′-hydroxy-5-[(triisopropylsilyl)oxy]methyl-1,2,3-thiadiazole-4-carboximidamide (85.0 mg, 0.185 mmol), anhydrous THF (1.1 mL), and N,N-carbonyldiimidazole (55 mg, 0.34 mmol). The reaction was heated to 70° C. for 2.5 h. The reaction was concentrated in vacuo and the crude purified by flash chromatography to give the desired product (89 mg, 99%). MF═C20H26ClFN4O3SSi; LCMS calculated for C20H27ClFN4O3SSi (M+H)+: m/z=485.2.
Reaction SMILES: [CH3:1][N:2]1[C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][CH:4]=[N:3]1.Br[C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([Cl:24])[CH:18]=1>COCCOC.CO>[Cl:24][C:19]1[CH:18]=[C:17]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:23]=[CH:22][C:20]=1[NH2:21]
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: Nc1ccc(Br)cc1Cl
Solvent: CO
Solvent: COCCOC
Product: Cn1nccc1-c1ccc(N)c(Cl)c1
Yield: 74 %

Procedure:
Prepared using Method C (Preparation 85) using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 4-bromo-2-chloroaniline in DME/MeOH 2/1 for 10 minutes at 150° C. under microwave irradiation. Purified using silica gel column chromatography eluting with 20% hexane in ethyl acetate to afford the title compound as a white powder (77 mg, 74%). 1H-NMR (500 MHz, CDCl3): δ 3.86 (s, 3H), 4.26 (s, br, 2H), 6.22 (d, J=2 Hz, 1H), 6.81 (d, J=8.3 Hz, 1H), 7.1 (dd, J=2 Hz, 8.3 Hz. Hz, 1H), 7.31 (d, J=2.0 Hz, 1H), 7.48 (d, J=2 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[O:13][CH3:14].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26].C(C1C=CC(C=O)=CC=1)(C)C.O=P(Cl)(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:28]=[CH:29][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:32]=3)[O:24][C:25]=2[CH3:26])=[CH:8][C:7]=1[O:13][CH3:14]
Reactant: Cc1oc(-c2ccc(C(C)C)cc2)nc1CCl
Reactant: CCO[C@@H](Cc1ccc(O)cc1OC)C(=O)OC
Agent: CC(C)c1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccc(C(C)C)cc3)oc2C)cc1OC)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 f], (2S)-2-ethoxy-3-(4-hydroxy-2-methoxy-phenyl)-propionic acid methyl ester (example 24 c]) was reacted with 4-chloromethyl-2-(4-isopropyl-phenyl)-5-methyl-oxazole (prepared from 4-isopropyl-benzaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 5 a] and 2 b]) in the presence of cesium carbonate and potassium iodide to yield (S)-2-ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-propionic acid methyl ester as orange liquid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=1.[Cl:22][C:23]1[N:28]=[CH:27][C:26]([C:29]([C:31]2[N:32]([CH3:36])[CH:33]=[N:34][CH:35]=2)=[O:30])=[CH:25][CH:24]=1>>[Cl:21][C:16]1[CH:15]=[C:14]([C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:29]([C:26]4[CH:27]=[N:28][C:23]([Cl:22])=[CH:24][CH:25]=4)([C:31]4[N:32]([CH3:36])[CH:33]=[N:34][CH:35]=4)[OH:30])[CH:3]=3)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=2)[CH:19]=[C:18]([Cl:20])[CH:17]=1
Reactant: COc1cc(-c2cc(Cl)cc(Cl)c2)c2cc(Br)ccc2n1
Reactant: Cn1cncc1C(=O)c1ccc(Cl)nc1
Product: COc1cc(-c2cc(Cl)cc(Cl)c2)c2cc(C(O)(c3ccc(Cl)nc3)c3cncn3C)ccc2n1
Yield: 39.4 %

Procedure:
Following the same procedure as described in example 1E, 6-bromo-4-(3,5-dichloro-phenyl)-2-methoxy-quinoline (1.88 g, 4.91 mmol) and (6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methanone (0.94 g, 4.27 mmol) generated the title compound of 16C as a yellow solid (0.885 g, 39.5% yield).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][OH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].O>C(Cl)Cl>[CH3:18][S:19]([O:9][CH2:8][C@@H:7]([NH:10][C:11]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:17])[CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)(=[O:21])=[O:20]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1CCCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)CC1CCCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-tert-butyl 1-cyclopentyl-3-hydroxypropan-2-ylcarbamate in CH2Cl2 (30 mL) Et3N (3.2 mL, 24.3 mmol) was added. The reaction mixture was cooled to 0° C. followed by dropwise addition of MsCl (1.1 g, 9.7 mmol) in CH2Cl2 (10 mL). After stirring for an additional 2 h, water (30 mL) was added and the mixture was extracted with CH2Cl2 (2×30 mL). The organic layers were washed with saturated aqueous brine, dried over MgSO4, and evaporated to give crude (S)-2-(tert-butoxycarbonylamino)-3-cyclopentylpropyl methanesulfonate that was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 4.59 (brs, 1H), 4.27 (dd, J=10, 3.2 Hz, 1H), 4.17 (dd, J=10, 4 Hz, 1H), 3.86 (m, 1H), 3.02 (s, 3H), 1.81 (m, 3H), 1.60 (m, 3H), 1.50 (m, 3H), 1.46 (s, 9H), 1.09 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1B(O)O>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:23]2[CH:22]=[CH:21][C:20]([F:19])=[CH:25][C:24]=2[F:26])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2F)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) and 2,4-difluorobenzene boronic acid according to the general procedure B. Obtained as a yellow solid (3.26 g).