Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.Br[C:10]1[C:11]([O:26][CH2:27][C:28]2[N:29]([CH2:33][CH3:34])[N:30]=[CH:31][N:32]=2)=[N:12][N:13]2[C:18]=1[CH:17]=[N:16][N:15]=[C:14]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25]>>[CH2:33]([N:29]1[C:28]([CH2:27][O:26][C:11]2[C:10]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)=[C:18]3[N:13]([C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])=[N:15][N:16]=[CH:17]3)[N:12]=2)=[N:32][CH:31]=[N:30]1)[CH3:34]
Reactant: OB(O)c1ccsc1
Reactant: CCn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1Br
Product: CCn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1-c1ccsc1
Yield: 86 %

Procedure:
This was prepared in 86% yield using a similar procedure to that described in Example 18 except using thiophene-3-boronic acid instead of 3-trifluoromethylbenzeneboronic acid and 3-bromo-2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-7-(2-fluorophenyl)pyrazolo[1,5-d][1,2,4]triazine instead of 3-bromo-7-(2-fluorophenyl)-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine. Data for title compound: mp=187-193° C. (CH2Cl2-EtOAc); 1H NMR (400 MHz, CDCl3) δ 1.35 (3H, t, J=7.3 Hz), 4.14 (2H, q, J=7.3 Hz), 5.59 (2H, s), 7.29 (1H, m), 7.40 (1H, td, J=7.6 and 0.8 Hz), 7.48 (1H, s), 7.49 (1H, s), 7.64-7.66 (2H, m), 7.81 (1H, m), 7.90 (1H, s), 9.46 (1H, s); MS (ES+) m/e 422 [MH]+; Anal. Found C, 56.14; H, 3.84; N, 22.75%. C20H16FN7OS.0.3H2O requires C, 56.28; H, 3.92; N, 22.97%.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[CH:17]1[C:22](=[O:23])[CH2:21][CH:20]([CH:24]2[CH2:28][CH2:27][O:26][CH2:25]2)[CH2:19][C:18]1=[O:29].[C:30](Cl)(=[O:32])[CH3:31]>ClCCl>[C:30]([O:23][C:22]1[CH2:21][CH:20]([CH:24]2[CH2:28][CH2:27][O:26][CH2:25]2)[CH2:19][C:18](=[O:29])[C:17]=1[C:10]1[C:11]([CH3:16])=[CH:12][C:13]([CH3:15])=[CH:14][C:9]=1[CH3:8])(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: Cc1cc(C)c(C2C(=O)CC(C3CCOC3)CC2=O)c(C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)CC(C2CCOC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of triethylamine (0.11 ml, 0.79 mmol) in dichloromethane (2 ml) is added dropwise to a chilled (ice-bath) solution of 2-(2,4,6-trimethylphenyl)-5-(tetrahydrofuran-3-yl)cyclohexane-1,3-dione (prepared by a method analogous to that described in Example 2) and acetyl chloride (0.056 ml, 0.79 mmol) in dichloromethane (4.5 ml). Once the addition is complete the cooling bath is removed and the reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with dichloromethane (35 ml) and washed with saturated aqueous sodium bicarbonate solution (20 ml). The organic phase is dried over anhydrous magnesium sulphate, filtered and the filtrate is evaporated in vacuo. The residue is purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and hexane to give 3-oxo-5-(tetrahydrofuran-3-yl)-2-(2,4,6-trimethylphenyl)cyclohex-1-enyl acetate.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[NH:13][C:12](=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.CCN(C(C)C)C(C)C.[CH3:24][O:25][C:26]1[CH:27]=[CH:28][C:29]2[NH:35][C:34](=[O:36])[N:33]([CH:37]3[CH2:42][CH2:41][N:40]([C:43]4[N:48]=[CH:47][N:46]=[C:45]([C:49](O)=[O:50])[CH:44]=4)[CH2:39][CH2:38]3)[CH2:32][CH2:31][C:30]=2[CH:52]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][N:2]([CH2:3][C:4]1[NH:13][C:12](=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[C:49]([C:45]1[CH:44]=[C:43]([N:40]2[CH2:41][CH2:42][CH:37]([N:33]3[CH2:32][CH2:31][C:30]4[CH:52]=[C:26]([O:25][CH3:24])[CH:27]=[CH:28][C:29]=4[NH:35][C:34]3=[O:36])[CH2:38][CH2:39]2)[N:48]=[CH:47][N:46]=1)=[O:50]
Reactant: CNCc1nc2ccccc2c(=O)[nH]1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N(C)Cc4nc5ccccc5c(=O)[nH]4)ncn3)CC1)C(=O)N2
Reaction time: 8 h

Procedure:
2.3 mg (12 μmol) 2-methylaminomethyl-3H-quinazolin-4-one and 1.6 mg (12 μmol) DIPEA were placed in 350 μL DMF. 4.0 mg (10 μmol) of 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetra-hydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid and 1.3 mg (10 μmol) DIPEA in 100 μL DMF were activated with 3.5 mg (11 μmol) TBTU in 50 μL DMF and then added dropwise. The reaction mixture was stirred overnight. 15 μL of an aqueous 2M potassium carbonate solution were added and the mixture was stirred for a further hour. The precipitate formed was allowed to settle and the supernatant solution was pipetted off and concentrated to dryness by rotary evaporation.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:16][F:17])[C@@H:4]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[OH:5].[C:18]([CH2:20][C:21](OCC)=[O:22])#[N:19].C(N(CC)CC)C>C(O)C>[C:18]([CH2:20][C:21]([NH:2][C@H:3]([CH2:16][F:17])[C@H:4]([OH:5])[C:6]1[CH:7]=[CH:8][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:10][CH:11]=1)=[O:22])#[N:19]
Reactant: CS(=O)(=O)c1ccc([C@@H](O)[C@H](N)CF)cc1
Reactant: CCOC(=O)CC#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CS(=O)(=O)c1ccc([C@@H](O)[C@@H](CF)NC(=O)CC#N)cc1

Procedure:
A mixture of (1R,2S )-2-amino-3-fluoro-1-(4-methylsulfonylphenyl)-1-propanol hydrochloride (5.66 g; 20 mmol), absolute ethanol (27 ml), ethyl cyanoacetate (22.62 g; 200 mmol) and triethylamine (3.03 g; 30 mmol) was refluxed for 21 hours.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[C:7]2[C:13]([OH:15])=[O:14].S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[CH2:21]([O:14][C:13]([C:7]1[C:6]2[C:11](=[C:2]([Br:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=[C:9]([CH3:12])[CH:8]=1)=[O:15])[CH3:22]
Reactant: Cc1cc(C(=O)O)c2cccc(Br)c2n1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(C)nc2c(Br)cccc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A stirred mixture of 8-bromo-2-methylquinoline4-carboxylic acid (7.2 g), ethanol (150 ml) and conc. sulfuric acid (3 ml) was boiled for 6 h. After cooling to room temperature solvent was removed at reduced pressure, the residue treated with water and neutralised with solid potassium carbonate. The neutralised mixture was extracted with ethyl acetate, the extracts dried (MgSO4) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel (30% diethyl ether/60-80 petroleum ether) to give the ester (2.5 g). m/z (API+): 294, 296 (MH+).
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]=[N+:14]=[N-:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[CH2:20][N:21](C(C)C)[CH:22](C)C.CNC.C1COCC1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]=[N+:14]=[N-:15])[CH2:10][C@H:9]1[C:16]([N:21]([CH3:22])[CH3:20])=[O:18])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N=[N+]=[N-])C[C@H]1C(=O)O
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)C(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 479.4 %

Procedure:
To a solution of (2S,4S)-1-Boc-4-azidopyrrolidine-2-carboxylic acid (9.5 g, 35 mmol) prepared in Step A in DMF (30□) was added dropwise DIPEA (1.15□, 6.70 mmol), and added dropwise 2M dimethylamine-THF solution (26.3 ml, 52.5 mmol), HOBT (7 g, 52.5 mmol) and EDC (10.2 g, 52.5 mmol) in order. The reaction mixture was stirred at rt for 12 h, and concentrated in vacuo. The residue was diluted with EtOAc, and washed with a saturated NaHCO3 aqueous solution, water and 1N HCl. The organic solution was dried over MgSO4, concentrated in vacuo, and the residue was purified by column chromatography (eluent: EtOAc:Hex=1/2) to give the title compound (9.1 g, 93%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]([CH2:30][CH3:31])[C:12](=[O:29])[CH2:13][CH2:14][CH2:15][NH:16][CH2:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[Cl:28])(=[O:20])=[O:19])=[CH:5][CH:4]=1)#[N:2].[S].[CH2:33](N)[CH2:34][NH2:35]>>[Cl:28][C:22]1[C:23]([Cl:27])=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([CH2:17][NH:16][CH2:15][CH2:14][CH2:13][C:12]([N:11]([CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]2[NH:35][CH2:34][CH2:33][N:2]=2)=[CH:8][CH:7]=1)[CH2:30][CH3:31])=[O:29])(=[O:20])=[O:19]
Reactant: NCCN
Reactant: CCN(CCc1ccc(C#N)cc1)C(=O)CCCNCS(=O)(=O)c1cccc(Cl)c1Cl
Agent: [S]
Product: CCN(CCc1ccc(C2=NCCN2)cc1)C(=O)CCCNCS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Analogously to 13b), 4-[(2,3-dichlorobenzenesulphonyl)methylamino]-N-{2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethyl}-N-ethylbutyramide was prepared from 0.74 g (1.53 mmol) of N-[2-(4-cyanophenyl)ethyl]-4-[(2,3-dichlorobenzenesulphonyl)methylamino]-N-ethylbutyramide, a spatula tip of sulphur and 5 ml of ethylenediamine.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[NH4+].F[P-](F)(F)(F)(F)F.C[N:43](C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH2:43])=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(N)=O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 18 h
Yield: 47.6 %

Procedure:
A mixture of 0.070 g (0.16 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.011 g (0.20 mmole) of ammonium chloride, 0.075 g (0.20 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.068 mL (0.39 mmole) of diisopropylethyl amine and 2.0 mL of dimethylformamide was stirred for 18 hours. The mixture was diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (gradient 100:0-60:40) to give 0.034 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzamide (I-23) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:16]([OH:18])=O)[CH:12]=3)[NH:7][C:6]=2[CH2:5][CH2:4]1.[Cl:20][C:21]1[C:26]([NH2:27])=[CH:25][CH:24]=[CH:23][N:22]=1>>[Cl:20][C:21]1[C:26]([NH:27][C:16]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]2[CH2:5][CH2:4][CH:3]([N:2]([CH3:1])[CH3:19])[CH2:15][C:14]3=2)=[O:18])=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: Nc1cccnc1Cl
Reactant: CN(C)C1CCc2[nH]c3ccc(C(=O)O)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(C(=O)Nc4cccnc4Cl)cc3c2C1
Yield: 9 %

Procedure:
Beginning with 7.4 mg (0.029 mMol) 3-dimethylamino-1,2,3,4-tetrahydro-9H-carbazole-6-carboxylic acid and 2-chloro-3-aminopyridine, 1.2 mg (9%) of the title compound were recovered.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([C:11]1[S:12][CH:13]=[C:14]([C:16]([N:18]2[CH2:23][C:22]3([CH2:28][CH2:27][N:26]([CH2:29][CH2:30][O:31][C:32]4[CH:49]=[CH:48][CH:47]=[CH:46][C:33]=4[CH2:34][CH2:35][O:36][CH2:37][CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])[CH2:25][CH2:24]3)[O:21][CH2:20][CH2:19]2)=[O:17])[N:15]=1)([CH3:10])[CH3:9]>C(Cl)Cl>[CH:8]([C:11]1[S:12][CH:13]=[C:14]([C:16]([N:18]2[CH2:23][C:22]3([CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][C:32]4[CH:49]=[CH:48][CH:47]=[CH:46][C:33]=4[CH2:34][CH2:35][O:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])[CH2:27][CH2:28]3)[O:21][CH2:20][CH2:19]2)=[O:17])[N:15]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCOc4ccccc4CCOCCC(=O)OC(C)(C)C)CC3)C2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCOc4ccccc4CCOCCC(=O)O)CC3)C2)cs1
Reaction time: 16 h

Procedure:
trifluoroacetic acid (2 mL) was added to a stirred solution of tert-butyl 3-(2-(2-(4-(2-s isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethoxy)phenethoxy)propanoate (0.320 g) (example 178 step c) in DCM (5 mL). After 16 h, the solution was evaporated to a gum. The gum was dissolved in acetonitrile (5 mL) and evaporated in vacuo (repeated 3 times). Yield 0.4 g.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([NH2:12])=[O:11])#[CH:2].[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([CH3:21])=[CH:16][N:15]=1.CCN(CC)CC>O1CCOCC1.[Cu]I.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>[Cl:13][C:14]1[N:19]=[C:18]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH2:9][C:10]([NH2:12])=[O:11])[C:17]([CH3:21])=[CH:16][N:15]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: C#Cc1ccccc1CC(N)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1cnc(Cl)nc1C#Cc1ccccc1CC(N)=O
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2-(2-ethynylphenyl)acetamide (I8) (5.40 g, 33.9 mmol), 2,4-dichloro-5-methylpyrimidine (6.63 g, 40.7 mmol) and CuI (0.129 g, 0.678 mmol) in 1,4-dioxane (180 mL) and Et3N (14.2 mL, 101 mmol) was placed under nitrogen. PdCl2(PPh3)2 (0.238 g, 0.339 mmol) was added and the resulting mixture was stirred at 70° C. for 20 minutes, then adsorbed onto silica gel and purified by column chromatography (CombiFlash Rf, 120 g SiO2 Cartridge, 0-5% MeOH in DCM) to give the title compound I9 as a yellow solid (5.01 g, 51%); 1H NMR (300 MHz, d6-DMSO) δ 8.75 (s, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.35-7.52 (m, 4H), 6.97 (brs, 1H), 3.71 (s, 2H), 2.42 (s, 3H). LCMS-B: rt 5.689 min; m/z 286 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:19](O)[CH3:20]>>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][C:10]([O:12][CH2:19][CH3:20])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNc1cccc(Br)c1
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)CNc1cccc(Br)c1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of 21.3 g of 3-bromophenylglycine in 160 cm3 of 6.5N hydrochloric ethanol is heated with stirring for 24 hours at a temperature in the region of 80° C. The reaction medium is filtered and the filter cake is then washed with twice 30 cm3 of ethanol. The filtrate is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. An oil is obtained, which is basified by addition of aqueous sodium carbonate solution. The mixture is extracted with 3 times 100 cm3 of ethyl acetate. The extracts are combined, washed with twice 100 cm3 of aqueous sodium chloride solution, dried over sodium sulfate, filtered and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 4.7 g of ethyl 3-bromophenylglycinate are obtained in the form of a yellow oil. (Rf=0.38 in a 90/5 by volume dichloromethane/methanol mixture, on a Merck 60F254R silica plate).
Reaction SMILES: [OH-:1].[Li+].[CH2:3]([C@H:10]([CH2:22][C:23]([N:25]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:26])=[O:24])[C:11](N1[C@H](C(C)C)COC1=O)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1.O>[CH2:3]([C@H:10]([CH2:22][C:23]([N:25]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:26])=[O:24])[C:11]([OH:12])=[O:1])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)[C@@H]1COC(=O)N1C(=O)[C@@H](CC(=O)N(C)Cc1ccccc1)Cc1ccccc1
Reactant: [OH-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1ccccc1)C(=O)C[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 28.4 %

Procedure:
80 mg (1.89 mmole) of lithium hydroxide were added to a solution of 400 mg (0.95 mmole) of 3-[2(R)-benzyl-4-(N-benzyl-N-methylamino)-4-oxobutyryl]-4(R)-isopropyl-2-oxazolidinone (prepared as described in Preparation 14) in a mixture of 10 ml of tetrahydrofuran and 4 ml of water, and the mixture was stirred at room temperature for 5 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was mixed with methylene chloride. The mixture was then extracted with a 10% w/v aqueous solution of sodium hydroxide. The aqueous layer was adjusted to a pH value of 2.0 by the addition of citric acid and was then extracted with methylene chloride. The methylene chloride extracts were combined, dried over anhydrous magnesium sulfate and concentrated by distillation under reduced pressure, to afford a colorless oil. This oil was triturated with hexane and the powder which deposited was collected by filtration and then recrystallized from diisopropyl ether, to afford 84 mg of the title compound as needles, melting at 119°-121° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:25])[CH:22]([CH3:24])[CH3:23]>C(Cl)Cl>[C:8]1([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])=[CH:7][CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1ccc(-c2ccccc2)cc1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)Nc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a stirring solution of 4-aminobiphenyl (9.53 g, 56.3 mmol) and triethylamine (5.70 g, 56.3 mmol, 7.85 mL) in methylene chloride (60 mL), cooled to 0° C., was added slowly isobutyryl chloride (6.0 g, 56.3 mmol, 5.90 mL). After stirring at 0° C. for 1 h, the mixture was diluted with methylene chloride (120 mL) and washed with 1 N NaOH and saturated brine, then dried (MgSO4), filtered and concnetrated. The residue was washed with ether and dried to provide the title compound as a pale yellow crystalline solid (9.83 g, 73%). 1HNMR (400 MHz, CDCl3/CD3OD) δ7.58 (d, 2H), 7.50 (m, 4H), 7.40-7.25 (m, 3H), 2.55-2.49 (m, 1H), 1.18 (d, 6H).
Reaction SMILES: [OH-].[Na+].Cl.[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([OH:12])=[C:7]([NH2:13])[CH:6]=1.B(O)(O)O.[OH:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](O)=O>C1C=C(Cl)C(Cl)=CC=1>[OH:18][C:19]1[CH:20]=[C:21]([C:22]2[O:12][C:8]3[C:9]([Cl:11])=[CH:10][C:5]([Cl:4])=[CH:6][C:7]=3[N:13]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1cc(Cl)cc(Cl)c1O
Reactant: O=C(O)c1cccc(O)c1
Agent: Cl
Agent: OB(O)O
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Product: Oc1cccc(-c2nc3cc(Cl)cc(Cl)c3o2)c1

Procedure:
178 parts of 45% strength sodium hydroxide solution are added dropwise to a suspension of 460 parts of 93% strength 4,6-dichloro-2-aminophenol hydrochloride in 1,500 parts by volume of dichlorobenzene mixture at 110° to 120°, under a nitrogen atmosphere, 30 parts of boric acid and 276 parts of 3-hydroxy-benzoic acid are added to the resulting clear solution and the water is removed from the system by means of a water separator (about 10 hours). The hot reaction solution is then poured into about 2,500 parts by volume of n-butanol, the hot solution is clarified with fuller's earth and after cooling and, if necessary, further concentrating, about 280 to 290 parts of 2-(3'-hydroxyphenyl) 5,7-dichlorobenzoxazole are obtained, which can be purified further by recrystallisation from chlorobenzene (melting point 233° to 234°). Molecular weight, calculated and confirmed by mass spectrometry at m/e = 280.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[Cl-].[CH3:18][O:19]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([CH:18]=[O:19])[CH2:5][CH2:4]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)C1(c2ccccc2)CCC(C=O)CC1

Procedure:
46 mmol (10.0 g) of 4-dimethylamino-4-phenylcyclohexanone were dissolved in toluene. This solution was added dropwise at 70° C. to a suspension of 138.1 mmol, (47.33 g) methoxymethyl triphenylphosphonium chloride and 138.1 mmol (25.82 g) potassium tert.-butylate. The mixture was stirred for a few more hours at 70° C., hydrolysed with water and extracted using EE. The combined organic phases were washed with saturated NaCl solution, dried over sodium sulphate and concentrated. The resultant brown resin was chromatographed using silica gel. The desired aldehyde is obtained as a cis/trans-mixture.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[F:10].Cl[CH2:12][CH2:13][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[OH:15].CC1(C)CCCC(C)(C)N1>C(#N)C>[F:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][N:2]([CH2:12][CH2:13][CH:14]([OH:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:1]
Reactant: OC(CCCl)c1ccccc1
Reactant: CNCc1ccccc1F
Agent: CC1(C)CCCC(C)(C)N1
Solvent: CC#N
Product: CN(CCC(O)c1ccccc1)Cc1ccccc1F
Temperature: 25 °C
Yield: 59.3 %

Procedure:
A mixture of N-methyl-o-fluorobenzylamine (27.8 g), 3-chloro-1-phenylpropan-1-ol(34.2 g), 2,2,6,6-tetramethylpiperidine (34.4 ml) and acetonitrile (500 ml) was refluxed for 48 h. The mixture was cooled to room temperature, filtered and the solvent removed. The residue was partitioned between chloroform and aqueous sodium bicarbonate. The organic phase was dried and the solvent removed. The residue was disolved in 60°-80° petrol (150 ml) and allowed to crystallise yielding the title compound (32.4 g) which is cyclodehydrohalogenated as in Example 4.
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[C:9]([OH:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=O.P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C>[OH:1][C:2]1[C:10]([OH:11])=[C:9]([OH:12])[CH:8]=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: NC(=O)c1ccc(O)c(O)c1O
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc(O)c(O)c1O
Temperature: 95 °C
Yield: 57 %

Procedure:
Eighteen and five tenths grams of 2,3,4-trihydroxybenzamide were refluxed with 20 ml. of phosphorusoxychloride and 100 ml. of ethyl acetate for 2.5 hours. The volatile constituents were removed in vacuo and the residue poured into 150 ml. of an ice-water mixture. The resulting suspension was heated to 95° C. and then filtered through activated carbon. The filtrate was concentrated to about 50 ml. whereupon 2,3,4-trihydroxybenzonitrile precipitated and was collected by filtration. 2,3,4-Trihydroxybenzonitrile monohydrate thus prepared melted at 172° C. after recrystallization from a methanol-benzene solvent mixture; yield=57%
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[O:14][N:13]=[C:12]([C:15]2[N:16]=[C:17]([CH:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[S:18][CH:19]=2)[CH2:11]1)(=[O:3])[CH3:2].[ClH:33]>O1CCOCC1>[ClH:33].[NH:23]1[CH2:24][CH2:25][CH:20]([C:17]2[S:18][CH:19]=[C:15]([C:12]3[CH2:11][CH:10]([C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[C:1](=[O:3])[CH3:2])[O:14][N:13]=3)[N:16]=2)[CH2:21][CH2:22]1
Reactant: CC(=O)c1ccccc1C1CC(c2csc(C3CCN(C(=O)OC(C)(C)C)CC3)n2)=NO1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)c1ccccc1C1CC(c2csc(C3CCNCC3)n2)=NO1
Temperature: 0 °C

Procedure:
To a solution of tert-butyl 4-{4-[5-(2-acetylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (500 mg) in 1,4-dioxane (5 ml) was added dropwise, at 0° C., a 4 molar solution of hydrogen chloride in 1,4-dioxane (4.2 ml). The reaction mixture was stirred at 0° C. and then gradually warmed to room temperature. After stirring overnight, the solvent and excess hydrogen chloride were removed. This gave 1-(2-{3-[2-(piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}phenyl)ethanone hydrochloride (430 mg).