Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]([O:11][CH2:12]C)=[O:10])=[CH:5][N:4]=[C:3]1[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][N:4]=[C:3]1[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cnc(CCc2ccccc2OCc2ccccc2)n(C)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)c1cnc(CCc2ccccc2OCc2ccccc2)n(C)c1=O
Yield: 85 %

Procedure:
A mixture of ethyl N1-methyl-2-[2-(2-benzyloxyphenyl)-ethyl]pyrimidin-6(1 H)-one-5-carboxylate (0.5 g) and para-toluene sulphonic acid (30 mg) in methanol was heated under reflux for 18 hours, 150 mg of para-toluene sulphonic acid was added and the mixture heated under reflux for a further 24 hours. The solvent was evaporated to give methyl N1-methyl-2-[2-(2-benzyloxyphenyl)ethyl]-pyrimidin-6(1 H)-one-5-carboxylate (410 mg).
Reaction SMILES: [CH2:1]([CH:3]([C:6](=O)[CH3:7])[CH2:4]O)[CH3:2].[Na].[C:10]([CH2:12][C:13]([NH2:15])=[O:14])#[N:11].C([O-])(=O)C.[NH2+]1CCCCC1>O.C(O)(=O)C>[C:10]([C:12]1[C:13](=[O:14])[NH:15][C:1]([CH3:2])=[C:3]([CH2:6][CH3:7])[CH:4]=1)#[N:11]
Reactant: N#CCC(N)=O
Reactant: CCC(CO)C(C)=O
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: CCc1cc(C#N)c(=O)[nH]c1C
Temperature: 25 °C

Procedure:
Accordingly to the method described in J. Heterocyclic Chem., 24, 351 (1987), a mixture 2-ethyl-3-oxobutanol, sodium salt (37.5 g, 0.275 mol), cyanoacetamide (25.2 g, 0.30 mol), aqueous piperidinium acetate (22 mL) [prepared from glacial acetic acid (4.2 mL), water (10 mL) and piperidine (7.2 mL)] in water (775 ml) was refluxed for four hours. Glacial acetic acid (30 ml) was added cautiously (much foaming) as the product precipitated. Upon cooling to room temperature, the product was collected by filtration, washed with cold water and air dried to yield 22.3 g (50%), m.p. 237°-240° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[NH2:11][OH:12].[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[C:7]([CH:8]=[N:11][OH:12])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: NO
Reactant: O=Cc1cccnc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=Cc1cccnc1Cl
Temperature: 0 °C
Yield: 91.1 %

Procedure:
Combine 2-chloropyridine-3-carboxaldehyde (2.75 g, 0.0195 mol) with hydroxylamine hydrochloride (1.38 g, 0.021 mol) and ice (40 g) in an ethanol/water (15 mL/15 mL) mixture. Add aqueous sodium hydroxide (1.95 g, 0.049 mol, in 5 mL of water) dropwise and stir for 2.5 h near ambient temperature. Adjust the mixture to approx. pH 7.0 with aqueous hydrochloric acid, allowing for product precipitation. Extract with diethyl ether and wash with water and dry over sodium sulfate. Concentrate to obtain the desired crude oxime (2.78 g, 91%) as a white solid. MS(EI): (M)+ 156.3, 158.3 m/z.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.[CH3:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:20])=[CH:17][CH:16]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([CH:21]2[CH2:26][CH2:25][N:24]([C:8]([C:5]3[CH:4]=[C:3]([CH3:11])[C:2]([Br:1])=[CH:7][N:6]=3)=[O:10])[CH2:23][CH2:22]2)=[O:20])=[CH:27][CH:28]=1
Reactant: Cc1cc(C(=O)O)ncc1Br
Reactant: COc1ccc(C(=O)C2CCNCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)C2CCN(C(=O)c3cc(C)c(Br)cn3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.8 %

Procedure:
To a mixture of 5-bromo-4-methylpyridine-2-carboxylic acid (0.400 g, 1.85 mmol, 1.0 eq) and 4-(4-methoxybenzoyl)piperidine hydrochloride (0.474 g, 1.85 mmol, 1.0 eq) was added dimethylformamide (10 mL) followed by triethylamine (0.64 mL, 4.36 mmol, 2.5 eq). HATU (0.774 g, 2.04 mmol, 1.1 eq) was added forming a yellow solution, which was stirred at room temperature for 1 day. The reaction was partitioned between EtOAc (120 mL) and water-NaHCO3 (1:1, 120 mL). The organics were further washed with brine (120 mL), water (120 mL) and brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure. MPLC (0→10% MeOH—CH2Cl2) yielded the title compound (0.693 g, 89%) as a yellow oil; 1H nmr (CDCl3) δ 8.55 (1H, s, pyH-3 or H-6), 7.90 (2H, d, J 9.0 Hz, 2H of C6H4OMe), 7.48 (1H, s, pyH-3 or H-6), 6.91 (2H, d, J 9.0 Hz, 2H of C6H4OMe), 4.64 (1H, m, 1H of BzpipH-2, H-6), 4.01 (1H, m, 1H of BzpipH-2, H-6), 3.83 (3H, s, OCH3), 3.49 (1H, m, BzpipH-4), 3.23 (1H, m, 1H of BzpipH-2, H-6), 3.03 (1H, m, 1H of BzpipH-2, H-6), 2.39 (3H, s, pyCH3), 1.95 (1H, m, 1H of BzpipH-3, H-5), 1.86-1.75 (3H, s, 3H of BzpipH-3, H-5); m/z 417, 419 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH2:11][S:12][CH2:13][CH3:14])=[C:9]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(=O)([O-])[O-].[K+].[K+].C1(N=C=NC2CCCCC2)CCCCC1.[CH2:40]([N:42]1[C:46](=[O:47])[CH:45]=[CH:44][NH:43]1)[CH3:41]>C(O)(CC)(C)C>[Cl:1][C:2]1[C:10]([CH2:11][S:12][CH2:13][CH3:14])=[C:9]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:8]=[CH:7][C:3]=1[C:4]([C:45]1[CH:44]=[N:43][N:42]([CH2:40][CH3:41])[C:46]=1[OH:47])=[O:6]
Reactant: CCSCc1c(S(C)(=O)=O)ccc(C(=O)O)c1Cl
Reactant: CCn1[nH]ccc1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Product: CCSCc1c(S(C)(=O)=O)ccc(C(=O)c2cnn(CC)c2O)c1Cl
Reaction time: 4 h

Procedure:
3 g of 2-chloro-3-ethylthiomethyl-4-methanesulfonylbenzoic acid, 0.72 g of potassium carbonate, 50 ml of t-amyl alcohol, 1.95 g of N,N'-dicyclohexylcarbodiimide and 4.5 g of a 25% t-amyl alcohol solution of 1-ethyl-5-pyrazolone were mixed and heated under stirring for 4 hours at a temperature of from 70° to 80° C. After cooling, the mixture was distilled under reduced pressure, and 200 ml of water was added to the residue. After filtering off the insolubles, the filtrate was washed with chloroform. Hydrochloric acid was added to the aqueous layer, and the mixture was extracted with chloroform. The extract was dried, and the solvent was distilled off to obtain the desired product as a crude product. The crude product was recrystallized from ethanol to obtain 1.88 g of the purified product. (Melting point: 142°-145° C.)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH:6]=1)[CH3:2].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=1>>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[C:9]([O:11][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=2)[CH:8]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH:6]=1)[CH3:2]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: CCOC(=O)c1cc(O)cc(Oc2ccc(C#N)cc2)c1
Product: CCOC(=O)c1cc(OCc2cccc([N+](=O)[O-])c2)cc(Oc2ccc(C#N)cc2)c1
Yield: 80.8 %

Procedure:
Using 1.2 g (4.23 mmol) of 3-(4-cyano phenoxy)-5-hydroxy benzoic acid ethyl ester and 1-bromomethyl-3-nitro-benzene (0.913 g, 4.23 mmol) and following the procedure of Example 42(b) afforded 1.43 g of the required product. 1H NMR (DMSO-d6): δ 1.3 (3H, t), 4.3 (2H, q), 5.4 (2H, s), 7.2 (4H, m), 7.45 (1H, s), 7.72 (1H, t), 7.9 (3H, m), 8.25 (1H, d), 8.35 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]#[N:17])=[N:14][CH:15]=2)=[C:5]([C:18]([F:21])([F:20])[F:19])[CH:4]=1.N>CO.[Ni]>[NH2:17][CH2:16][C:13]1[N:14]=[CH:15][C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[C:18]([F:21])([F:19])[F:20])=[CH:11][CH:12]=1
Reactant: COc1ccc(Nc2ccc(C#N)nc2)c(C(F)(F)F)c1
Agent: [Ni]
Agent: N
Solvent: CO
Product: COc1ccc(Nc2ccc(CN)nc2)c(C(F)(F)F)c1

Procedure:
Analogously to Example 4b, 5-(4-methoxy-2-trifluoromethyl-phenylamino)-pyridine-2-carbonitrile (1.71 mmol) was hydrogenated in a 7N solution of ammonia in methanol (30 mL) with the addition of Raney nickel at ambient temperature. After the catalyst had been filtered off and the solvent distilled off, the crude product thus obtained was further reacted without purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][Li]>C(OCC)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:15])([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: [Li]C
Solvent: CCOCC
Product: CC1(O)CCN(Cc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 82.7 %

Procedure:
A solution of 1-benzyl-4-piperidone (4.9 mL, 26.5 mmol) in anhydrous diethyl ether (50 mL) was cooled to −78° C. and treated with methyllithium (1.4 M, 21 mL, 29 mmol). This mixture was stirred for 2.5 hr at −78° C., then quenched with aqueous brine, and extracted with ethyl acetate (3×100 mL). The combined organics were dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography (CH2Cl2→90:10:1 CH2Cl2/methanol/NH4OH) to yield 4.5 g (83%) of the title compound, ESI-MS m/z: 206 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:12]=1[C:13]#[N:14].[O-]P(OP(OP([O-])([O-])=O)([O-])=O)(=O)[O-].[K+].[K+].[K+].[K+].[K+].C1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:11]([NH:10][C:6]2[C:5]([Cl:9])=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)=[C:12]([CH:15]=1)[C:13]#[N:14]
Reactant: N#Cc1cc(Cl)ccc1N
Reactant: Clc1cc(I)c(Cl)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Solvent: C1COCCO1
Product: N#Cc1cc(Cl)ccc1Nc1cc(Cl)ncc1Cl
Yield: 33 %

Procedure:
To a degassed solution of 2,5-dichloro-4-iodopyridine (4.5 g, 16.43 mmol), 2-amino-5-chlorobenzonitrile (2.507 g, 16.43 mmol) and potassium triphosphate (10.46 g, 49.3 mmol) in 1,4-dioxane (60 ml) stirred under nitrogen at the room temperature was added DPEPhos (0.708 g, 1.314 mmol) and palladium acetate (0.148 g, 0.657 mmol). The reaction mixture was stirred at reflux for 18 hr. The reaction mixture was filtered. The reaction mixture was evaporated. Ether (50 ml) was added and the solid was filtered. 5-chloro-2-[(2,5-dichloro-4-pyridinyl)amino]benzonitrile (1.8 g, 5.43 mmol, 33.0% yield) was isolated as orange solid. 1H NMR (400 MHz, DMSO-d6) ppm 6.63 (s, 1 H) 7.52 (d, J=8.59 Hz, 1 H) 7.81 (dd, J=8.59, 2.53 Hz, 1 H) 8.09 (d, J=2.53 Hz, 1 H) 8.24 (s, 1 H) 9.06 (br. s., 1 H); HPLC Rt=3.53 min, MS (ESI): 298.0, 299.9 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][NH:5][CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:9].[C:18]([CH2:21][N:22]1[CH:30]=[C:28]([CH3:29])[C:26](=[O:27])[NH:25][C:23]1=[O:24])(O)=[O:19].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3](=[O:17])[CH2:4][N:5]([CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH3:9])[C:18](=[O:19])[CH2:21][N:22]1[CH:30]=[C:28]([CH3:29])[C:26](=[O:27])[NH:25][C:23]1=[O:24]
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Reactant: COC(=O)CNCCN(C)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)CN(CCN(C)C(=O)OC(C)(C)C)C(=O)Cn1cc(C)c(=O)[nH]c1=O
Reaction time: 1 h

Procedure:
To a suspension of N-[(N-Boc)(N-methyl)-2-aminoethyl]-glycine methyl ester (0.9 g, 0.0037 mol) and DHBT-OH (0.65 g, 0.004 mol) in CH2Cl2 10 ml was added N-1-carboxymethylthymine (0.74 g, 0.04 mol) dissolved in DMF (6 ml). The solution was cooled in an ice bath and DCC (0.905, 0.049 mol) was added. The reaction mixture was stirred for 1 hour and the ice bath was removed. The reaction mixture was left for 16 hours at room temperature. The reaction mixture was filtered and washed twice with 1N KHSO4 (15 ml) and three times with NaHCO3 (15 ml), brine (10 ml) and water (10 ml) and dried with Na2SO4. The product was purified by column chromatography on silica gel with CH2Cl2/MeOH 95:5 eluent. The yield of the title compound was 55%.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[CH:7][C:8]([OH:10])=O)[N:3]=[CH:2]1.S(Cl)(Cl)=O.Cl.Cl.[N:17]1([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:33][C@H:32]([CH2:34][O:35][C:36]4[CH:40]=[CH:39][O:38][N:37]=4)[O:31][C:30]3=[O:41])=[CH:25][C:24]=2[F:42])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)CC)C>ClCCl.CN(C=O)C>[NH:1]1[CH:5]=[C:4]([CH:6]=[CH:7][C:8]([N:20]2[CH2:19][CH2:18][N:17]([C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:33][C@H:32]([CH2:34][O:35][C:36]5[CH:40]=[CH:39][O:38][N:37]=5)[O:31][C:30]4=[O:41])=[CH:25][C:24]=3[F:42])[CH2:22][CH2:21]2)=[O:10])[N:3]=[CH:2]1
Reactant: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCNCC2)c(F)c1
Reactant: O=C(O)C=Cc1c[nH]cn1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(C=Cc1c[nH]cn1)N1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-(4-Imidazolyl)acrylic acid (690 mg, 5 mmol) was suspended in anhydrous dichloromethane (5 ml) under nitrogen, and thionyl chloride (10 ml) and one drop of DMF added. The mixture was stirred at ambient temperature for 18 hours, excess thionyl chloride was evaporated, and the residue azeotroped with dichloromethane (2×50 ml). The acid chloride was suspended in dichloromethane (30 ml), cooled to 4°, and a solution of 3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one dihydrochloride (866 mg, 2 mmol) and triethylamine (2.02 g, 20 mmol) in anhydrous dichloromethane (25 ml) added dropwise. The mixture was stirred for 18 hours at ambient temperature, and insoluble material filtered. The organic layer was treated with water (50 ml), further insoluble material removed, then washed with brine and dried over magnesium sulfate. After evaporation to dryness, the residue was dissolved in ethanol (5 ml) and treated with an excess of ethanol saturated with hydrogen chloride, to precipitate the desired product as a hydrochloride salt (122 mg).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:14]([O:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([F:25])[CH:19]=1)[CH3:15]>CC(C)=O>[CH2:14]([O:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:4][CH2:3][CH2:2][Br:1])=[C:20]([F:25])[CH:19]=1)[CH3:15]
Reactant: CCOC(=O)c1ccc(O)c(F)c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(OCCCBr)c(F)c1
Yield: 71 %

Procedure:
1,3-Dibromopropane (2.2 g, 11.0 mmol), potassium carbon-ate (1.86 g, 13.6 mmol) and potassium iodide (90 mg, 0.5 mmol) were added to 3-fluoro-4-hydroxy-benzoic acid ethyl ester from Example E27 (11.0 g, 5.4 mmol) in acetone (25 ml) and the mixture was heated at reflux for 20 h. The solid was filtered off and washed with EtOAc. The filtrate was concentrated in vacuo and azeotroped with toluene. The residue was purified by flash chromatography on silica gel (eluant; 20% EtOAc:80% hexane) to yield the title compound (1.18 g, 71%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][C:4]([CH3:11])([CH3:10])[C:5]([O:7]CC)=[O:6].[Li+].[OH-].O>CO>[F:1][C:2]([F:12])([F:13])[CH2:3][C:4]([CH3:10])([CH3:11])[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(C)(C)CC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(CC(F)(F)F)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
To a solution of ethyl 4,4,4-trifluoro-2,2-dimethylbutanoate (426 mg, 2.15 mmol) in MeOH (15 mL) was added a solution of LiOH in H2O (2 N, 5.35 mL, 10.75 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was concentrated and the resulting mixture was diluted with DCM and washed with 3 N HCl. The aqueous layer was extracted twice with DCM. The combined organic layers were dried over MgSO4, filtered and concentrated to yield 4,4,4-trifluoro-2,2-dimethylbutanoic acid as a colorless oil (370 mg, 100% yield). 1H NMR (400 MHz, CDCl3) ppm 1.35 (s, 6H), 2.48 (ABqt, J=12 Hz, 2H).
Reaction SMILES: C[Al](C)C.[NH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1.[Si:14]([O:21][CH:22]1[CH2:25][N:24]([CH2:26][C@H:27]([OH:32])[C:28](OC)=[O:29])[CH2:23]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[Si:14]([O:21][CH:22]1[CH2:25][N:24]([CH2:26][C@H:27]([OH:32])[C:28]([NH:5][C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=2)=[O:29])[CH2:23]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: N#Cc1ccc(N)nc1
Reactant: COC(=O)[C@@H](O)CN1CC(O[Si](C)(C)C(C)(C)C)C1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OC1CN(C[C@H](O)C(=O)Nc2ccc(C#N)cn2)C1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Trimethylaluminium (7.95 mL, 15.89 mmol) was added to 6-aminonicotinonitrile (1.646 g, 13.82 mmol) in toluene (50 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes. (S)-Methyl 3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-hydroxypropanoate (Intermediate AD3) (4.0 g, 13.82 mmol) in toluene (20 mL) was added and the resulting solution was allowed to warm to room temperature and then heated at 60° C. for 3 hours. The mixture was cooled to ˜10° C. and quenched by the addition of 20% Rochelle salt solution. It was then diluted with EtOAc (50 mL) and stirred for 2 hours. The organic phase was separated, washed with water and brine, dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography on silica with EtOAc as eluent to afford the product containing some 6-aminonicotinonitrile (4.1 g). This was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]2=[O:27])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH2:13][N:14]=[N+:15]=[N-:16])[N:10]=[CH:9]1.[C:28]([O:32][CH2:33][CH3:34])(=[O:31])[C:29]#[CH:30]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]2=[O:27])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH2:13][N:14]2[CH:30]=[C:29]([C:28]([O:32][CH2:33][CH3:34])=[O:31])[N:16]=[N:15]2)[N:10]=[CH:9]1
Reactant: C#CC(=O)OCC
Reactant: CC(=O)NC[C@H]1CN(c2ccc(-n3cnc(CN=[N+]=[N-])c3)c(F)c2)C(=O)O1
Solvent: CC#N
Product: CCOC(=O)c1cn(Cc2cn(-c3ccc(N4C[C@H](CNC(C)=O)OC4=O)cc3F)cn2)nn1
Yield: 72.9 %

Procedure:
N-[(5S)-3-(3-Fluoro-4-(4-azidomethylimidazol-1-yl)phenyl )-2-oxooxazolidin-5-yl-methyl]acetamide (200 mg, 0.54 mM) and ethyl propiolate (79 mg, 0.81 mM) were dissolved in acetonitrile (10 ml) and heated under reflux for 3 hours. Further ethyl propio late (79 mg) was added, and heting continued for a total of 7 hours. Solvent was evaporated, the residue dissolved in the minimum volume of dichloromethane, and chromatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 10% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the title product (184 mg), containing about 10% of the 5-ethoxycarbonyl isomer.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10](N(OC)C)=[O:11])[CH:5]=[CH:6][CH:7]=1.Br[C:24]1[CH:25]=[N:26][CH:27]=[C:28]([Br:30])[CH:29]=1.C([Mg]Br)(C)C>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([Br:30])[CH:29]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)CC(c1cccc(Br)c1)c1ccccc1C
Reactant: Brc1cncc(Br)c1
Agent: CC(C)[Mg]Br
Product: Cc1ccccc1C(CC(=O)c1cncc(Br)c1)c1cccc(Br)c1

Procedure:
In analogy to example 74, step 5, from 3-(3-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 98, step 4) and 3,5-dibromopyridine (CAS RN: [625-92-3]) using i-propylmagnesium bromide instead of n-butyllithium was prepared the title compound as a white solid, MS (ESI+): m/z=457.9738 ([M+H]+, 1Br).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])=[CH:9][CH:8]=1.[CH2:22]=O>C(O)(=O)C>[Cl:6][C:7]1[CH:8]=[C:9]2[C:10]([CH2:13][CH2:14][N:15]([C:16](=[O:21])[C:17]([F:19])([F:20])[F:18])[CH2:22]2)=[CH:11][CH:12]=1
Reactant: C=O
Reactant: O=C(NCCc1ccc(Cl)cc1)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(N1CCc2ccc(Cl)cc2C1)C(F)(F)F
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To a mixture of concentrated sulfuric acid (40 mL) and acetic acid (60 mL), N-[2-(4-chlorophenyl)ethyl]-2,2,2-trifluoroacetamide (14.2 g) and paraformaldehyde (2.79 g) were added sequentially and stirred overnight under an argon atmosphere. The reaction mixture was added to ice-cold water, extracted with ethyl acetate, and then washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 7-chloro-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline (13.7 g) as a light-yellow solid.
Reaction SMILES: [C:1]([N:5]1[CH2:8][CH:7]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[C:23]([Cl:25])[C:22]([Cl:26])=[CH:21][C:20]=3[O:27]C)=[O:16])[CH2:11][CH2:10]2)[CH2:6]1)(=[O:4])[CH:2]=[CH2:3].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:26][C:22]1[C:23]([Cl:25])=[CH:24][C:19]([CH2:18][NH:17][C:15]([CH:12]2[CH2:11][CH2:10][N:9]([CH:7]3[CH2:8][N:5]([C:1](=[O:4])[CH:2]=[CH2:3])[CH2:6]3)[CH2:14][CH2:13]2)=[O:16])=[C:20]([OH:27])[CH:21]=1
Reactant: C=CC(=O)N1CC(N2CCC(C(=O)NCc3cc(Cl)c(Cl)cc3OC)CC2)C1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CC(=O)N1CC(N2CCC(C(=O)NCc3cc(Cl)c(Cl)cc3O)CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.6 %

Procedure:
To a solution of 1-(1-acryloylazetidin-3-yl)-N-(4,5-dichloro-2-methoxybenzyl)piperidine-4-carboxamide (150 mg, 0.35 mmol) in DCM (15 mL) at −60° C., BBr3 (0.6 g, 2.4 mmol) was added dropwise. The resulting mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was poured into ice-water, basified with saturated NaHCO3 solution to adjust the pH to 8-9, and then extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=20:1) to afford the desired product (34 mg, 24% yield). 1H NMR (400 MHz, DMSO-d6) δ: 10.34 (s, 1H), 8.2-8.25 (m, 1H), 7.2 (s, 1H), 7.0 (s, 1H), 6.91 (s, 1H), 6.33-6.27 (m, 1H), 6.12-6.07 (dd, J=2.4, 12.4 Hz, 1H), 5.68-5.65 (dd, J=2.4, 10.4 Hz, 1H), 4.24-4.20 (m, 1H), 4.17-4.14 (m, 2H), 4.14-3.99 (m, 1H), 3.94-3.90 (m, 1H), 3.73-3.70 (m, 1H), 3.10 (s, 1H), 2.84-2.80 (m, 2H), 2.22 (m, 1H), 1.80 (s, 2H), 1.73-1.71 (m, 2H), 1.63-1.57 (m, 2H). ESI-MS m/z: 412.2[M+H]+.
Reaction SMILES: [O:1]([C:3]1[CH2:4][C:5]([S:12]([C:15]2([CH2:23][CH2:24][Cl:25])[CH:20]=[CH:19][CH:18]=[C:17]([O:21]C)[CH2:16]2)(=[O:14])=[O:13])([CH2:9][CH2:10][Cl:11])[CH:6]=[CH:7][CH:8]=1)C.B(Br)(Br)Br.[Na+].[Cl-]>C(Cl)Cl>[OH:1][C:3]1[CH2:4][C:5]([S:12]([C:15]2([CH2:23][CH2:24][Cl:25])[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH2:16]2)(=[O:14])=[O:13])([CH2:9][CH2:10][Cl:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COC1=CC=CC(CCCl)(S(=O)(=O)C2(CCCl)C=CC=C(OC)C2)C1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(C1(CCCl)C=CC=C(O)C1)C1(CCCl)C=CC=C(O)C1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To 6 (8.95 mmol, 2.1 g) in dry DCM (50 cm3) was added IM BBr3 (27 mmol, 27 cm3) in DCM at 0° C. The solution was allowed to reach 20° C. over night, poured into ice water (100 cm3) and stirred for 1.5 h. The aqueous layer was saturated with NaCl and extracted with DCM. The combined organic layers were dried over MgSO4. Filtration and removal of the solvent gave 7 as a white solid An analytical sample was obtained by recrystallisation from DCM (mp: 107.6° C.).