Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)[C:6]=2[CH:20]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:32](B(O)O)=[CH:31][CH:30]=[N:29]2)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[C:32]([C:2]3[CH:3]=[CH:4][C:5]4[N:9]=[CH:8][N:7]([C:10]5[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=5)[C:6]=4[CH:20]=3)=[CH:31][CH:30]=[N:29]2)=[CH:26][CH:27]=1
Reactant: OB(O)c1ccnn1-c1ccc(Cl)cc1
Reactant: FC(F)(F)c1ccc(-n2cnc3ccc(Br)cc32)cc1
Product: FC(F)(F)c1ccc(-n2cnc3ccc(-c4ccnn4-c4ccc(Cl)cc4)cc32)cc1

Procedure:
The title compound, light brown solid (37 mg, 29%), MS (ISP) m/z=439.4 [(M+H)+], mp 196° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-(4-trifluoromethyl-phenyl)-1H-benzo[d]imidazole (intermediate I) (100 mg, 293 μmol) and 1-(4-chloro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate D) (71.7 mg, 322 μmol).
Reaction SMILES: [C:1]([C:9]1[CH:18]=[CH:17][C:12]([O:13][CH2:14][CH2:15][NH2:16])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([S:21][C:22](Cl)=[O:23])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:19]([S:21][C:22](=[O:23])[NH:16][CH2:15][CH2:14][O:13][C:12]1[CH:11]=[CH:10][C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:17]=1)[CH3:20]
Reactant: NCCOc1ccc(C(=O)c2ccccc2)cc1
Reactant: CCSC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCSC(=O)NCCOc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
6.4 g of 2-(p-benzoylphenoxy)ethylamine and 17.2 g of chlorothioformic acid S-ethyl ester are dissolved in 230 ml of acetone, 22.2 g of potassium carbonate are added to the solution. The mixture is heated under reflux for 6 hours. After cooling to room temperature, the mixture is filtered, the residue is washed with acetone and the filtrate is evaporated in vacuo. The residue is suspended in hot ether and filtered. The residue is then washed with ether and the filtrate is evaporated in vacuo. Recrystallization of the residue from ether yields 2-(p-benzoylphenoxy)ethylthiocarbamic acid S-ethyl ester, m.p.--90°-92° C. Recrystallization of the mother liquor yields a further 1 g of product.
Reaction SMILES: Cl[CH2:2][S:3][C:4]#[N:5].[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[S:12])=[CH:9][CH:8]=1.O>CO>[S:3]([CH2:2][O:13][C:11](=[S:12])[C:10]1[CH:14]=[CH:15][C:7]([Cl:6])=[CH:8][CH:9]=1)[C:4]#[N:5]
Reactant: N#CSCCl
Reactant: OC(=S)c1ccc(Cl)cc1
Solvent: CO
Solvent: O
Product: N#CSCOC(=S)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
16 g (0.15 mol) of chloromethyl thiocyanate were added dropwise to 31.5 g (0.15 mol) of the K salt of 4-chlorothiobenzoic acid in 200 ml of methanol at 0°-10° and the mixture was then first warmed to room temperature and then to 50°-60°, until the reaction had taken place. The cooled mixture was poured onto 1 liter of cold water, whilst stirring vigorously, and the precipitate was filtered off and dried. Light pink-coloured crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.CC([O-])=O.[Na+].[NH2:21][OH:22].Cl>CCO>[Br:1][C:2]1[CH:3]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:5]([OH:11])=[C:6]([C:8](=[N:21][OH:22])[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Br)cc(C(C)(C)C)c1O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=NO)c1cc(Br)cc(C(C)(C)C)c1O

Procedure:
A mixture of 1-(5-bromo-3-(tert-butyl)-2-hydroxyphenyl)ethanone (0.5 g, 1.8 mmol), NaOAc (246 mg, 3.0 mmol) and NH2OH.HCl (187 mg, 2.7 mmol) in EtOH (10 mL) was heated at reflux for 3 h, concentrated and the obtained solid was washed with water to give compound P8a (0.5 g, 97%) as solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][C:14](O)([C:16]([F:19])([F:18])[F:17])[N:13]=[C:12]2[C:21]2[CH:29]=[CH:28][C:24]3[O:25][CH2:26][O:27][C:23]=3[CH:22]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:13]=[C:12]2[C:21]2[CH:29]=[CH:28][C:24]3[O:25][CH2:26][O:27][C:23]=3[CH:22]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccc3c(c2)OCO3)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccc3c(c2)OCO3)cc1
Yield: 79 %

Procedure:
A mixture of 5-[1-[4-(methylsulfonyl)phenyl]-4-hydroxy-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]-1,3-benzodioxole from Step 2 (1.26 g, 2.9 mmol) and p-toluenesulfonic acid monohydrate (200 mg) in toluene (50 mL) was heated to reflux for 72 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude residue was redissolved in methylene chloride and washed with water, aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration and concentration in vacuo, the crude mixture (1.34 g) was purified by chromatography on silica gel using toluene/ethyl acetate 1/1 to give pure 5-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]-1,3-benzodioxole (940 mg, 80%) as a white solid: mp (DSC) 165° C. Anal Calc'd. for C18H13N2SO4F3: C, 52.68, H, 3.19, N, 6.83. Found: C, 53.05, H, 3.19, N, 6.65.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH:22]([CH2:23][C:24]4[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=4)[O:27][CH2:28][C:29]([O:31]CC)=[O:30])[CH2:21][CH2:20][O:19]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:38]>C(O)C>[C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH:22]([CH2:23][C:24]4[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=4)[O:27][CH2:28][C:29]([O-:31])=[O:30])[CH2:21][CH2:20][O:19]3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+:38]
Reactant: CCOC(=O)COc1cccc(CC2CCOC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])COc1cccc(CC2CCOC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 4 h

Procedure:
To a solution of ethyl [3-[[2-(4,5-diphenyloxazol-2-yl)tetrahydrofuran-3-yl]methyl]phenoxy]acetate (560 mg) in ethanol (20 ml) was added 1N-NaOH solution (1.2 ml). After being stirred for 4 hours at the same temperature, the solvent was removed in vacuo to give sodium [3-[[2-(4,5-diphenyloxazol-2-yl)tetrahydrofuran-3-yl]methyl]phenoxy]-acetate (0.46 g) FABMS (m/z): 478 (M+ +1) IR (Nujol): 3400, 1600 cm-1NMR (DMSO-d6, δ): 1.6-3.0 (5H, m), 3.8-4.2 (4H, m), 4.68 (1/3H, d, J=7.0 Hz), 5.13 (2/3H, d, J=8.0 Hz), 6.6-6.8 (3H, m), 7.0 (1H, t, J=8 Hz), 7.2-7.8 (10H, m)
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[CH3:27][N:28]1[C:32]([CH3:33])=[CH:31][C:30]([C:34](O)=[O:35])=[N:29]1>>[CH3:27][N:28]1[C:32]([CH3:33])=[CH:31][C:30]([C:34]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][N:12]([C:8]4[CH:7]=[CH:6][CH:5]=[C:4]5[C:9]=4[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]5)[CH2:17][CH2:16]3)[CH:21]=2)=[O:35])=[N:29]1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: Cc1cc(C(=O)O)nn1C
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)c5cc(C)n(C)n5)c4)CC3)cccc2n1
Yield: 35 %

Procedure:
The title compound was prepared in 35% yield according to the general procedure for the preparation of the amides (Method C) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 1,5-dimethyl-1H-pyrazole-3-carboxylic acid.
Reaction SMILES: C[O:2][C:3]1C=C(C2C=CC3N=CN=CC=3N=2)C=C[C:8]=1OC.[NH2:21][C:22]1[N:23]=[C:24]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH:43]2[C:48](=[O:57])[NH:49][C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[CH:51]=2)[C:25]2[N:31]=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH3:41])[CH:33]=3)[CH:29]=[CH:28][C:26]=2[N:27]=1.N.CNC>>[C:3]([NH:21][C:22]1[N:23]=[C:24]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH:43]2[C:48](=[O:57])[NH:49][C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[CH:51]=2)[C:25]2[N:31]=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH3:41])[CH:33]=3)[CH:29]=[CH:28][C:26]=2[N:27]=1)(=[O:2])[CH3:8]
Reactant: COc1ccc(-c2ccc3ncncc3n2)cc1OC
Reactant: COc1ccc(-c2ccc3nc(N)nc(N4CCNCC4C(=O)Nc4cccc(C)c4)c3n2)cc1OC
Agent: CNC
Agent: N
Product: COc1ccc(-c2ccc3nc(NC(C)=O)nc(N4CCNCC4C(=O)Nc4cccc(C)c4)c3n2)cc1OC

Procedure:
2-acetamido-4-[(N-3-methyl-phenylcarbamoyl)-piperazin-1-yl]-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine was synthesized from 2-chloro-4-(4-[3-methylphenyl)amino]carbonyl]piperazin-1-yl)-6-(3,4-dimethoxyphenyl)pyrido[3,2-d]pyrimidine. In a first step, 2-amino-4-[(N-3-methyl-phenylcarbamoyl)-piperazin-1-yl]-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine was synthesized according to the procedure mentioned for examples 15, using ammonia (instead of dimethylamine). Subsequent acetylation yielded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21](I)[N:20]=[CH:19]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:24][C:25]1[N:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21]([C:28]4[CH:27]=[N:26][C:25]([NH2:24])=[N:30][CH:29]=4)[N:20]=[CH:19]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1cc(-c2cccc(Cl)c2)nc(-n2cnc(I)c2)n1
Product: Nc1ncc(-c2cn(-c3nc(-c4cccc(Cl)c4)cc(C(F)(F)F)n3)cn2)cn1

Procedure:
The title compound was prepared from 4-(3-chloro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (example E.72) (0.45 g, 1.0 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.26 g, 1.2 mmol) according to the general procedure VI. Obtained as a yellow solid (0.27 g, 65%). MS (ISP) 418.1 [(M+H)+]; mp 281° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH2:16])=[N:11][CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB(C2C=CC([C:29]([OH:31])=[O:30])=CC=2)O1>>[NH2:16][C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][C:13]([C:29]([OH:31])=[O:30])=[CH:12][N:11]=1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Reactant: Nc1ncc(Br)cc1OCc1ccccc1
Product: Nc1ncc(C(=O)O)cc1OCc1ccccc1

Procedure:
6-Amino-5-benzyloxy-nicotinic acid was prepared according to procedure 3 from 3-benzyloxy-5-bromo-pyridin-2-ylamine and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid. MS m/z 321 (M+1).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH:12]([CH3:14])[CH3:13])=[N:7]2.[NH2:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[S:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1>>[CH:12]([C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:15][C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1)([CH3:14])[CH3:13]
Reactant: CC(C)c1ccc2c(Cl)ccnc2n1
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Product: Cc1ccc(Sc2ccc(O)cc2)c(Nc2ccnc3nc(C(C)C)ccc23)c1

Procedure:
The product from Example 8b (100 mg, 0.435 mmol) was reacted with the product from Example 4c (105 mg, 0.435 mmol) for 18 h following the procedure from Example 1g producing the crude title compound that was purified by HPLC with TFA giving the trifluoroacetic acid salt (90 mg, 47%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (d, J=6.62 Hz, 6H), 2.13-2.30 (m, 1H), 2.33 (s, 3H), 2.89 (d, J=6.99 Hz, 2H), 6.29 (d, J=6.99 Hz, 1H), 6.73 (d, J=8.46 Hz, 2H), 7.00 (d, J=8.09 Hz, 1H), 7.13-7.34 (m, 4H), 7.81 (d, J=8.46 Hz, 1H), 8.43 (d, J=6.99 Hz, 1H), 9.03 (d, J=8.46 Hz, 1H), 10.99 (br. s., 1H), 14.36 (br. s., 1H); MS ESI+ m/z 416 (M+H)+; ESI− m/z 414 (M−H)−.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[CH:27][CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:3]=1.[OH:38][C:39]1[CH:40]=[C:41]([NH:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH:42]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:44]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[OH:38][C:39]1[CH:40]=[C:41]([NH:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH:42]=[C:43]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[CH:27][CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:3]=2)[CH:44]=1
Reactant: C[C@H](Nc1ncnc2c1c(Br)cn2COCC[Si](C)(C)C)c1nn2cccc2c(=O)n1-c1ccccc1
Reactant: CC1(C)OB(c2cc(O)cc(NS(C)(=O)=O)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C[C@H](Nc1ncnc2c1c(-c1cc(O)cc(NS(C)(=O)=O)c1)cn2COCC[Si](C)(C)C)c1nn2cccc2c(=O)n1-c1ccccc1
Yield: 83.2 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (160 mg, 0.28 mmol) was treated with N-(3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (220 mg, 0.70 mmol), sodium carbonate (86.3 mg, 0.81 mmols) and bis(triphenylphosphine)palladium(II) dichloride (81.8 mg, 0.1 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 80%, hexane-ethyl acetate) to give 160 mg (79% yield) of the title compound. Purity 94%.
Reaction SMILES: [Cl:1]Cl.[CH2:3]([N:5]1[CH:9]=[N:8][C:7]([OH:10])=[N:6]1)[CH3:4].C(N(CC)CC)C>C(O)C>[CH2:3]([N:5]1[C:9]([Cl:1])=[N:8][C:7]([OH:10])=[N:6]1)[CH3:4]
Reactant: CCn1cnc(O)n1
Reactant: ClCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCn1nc(O)nc1Cl
Reaction time: 2 h

Procedure:
71.5 g of chlorine is passed into a solution of 75.5 g of 1-ethyl-3-hydroxy-1,2,4-triazole and 185 ml of triethylamine in 800 ml of absolute ethanol. The exothermic reaction is kept at 20° to 30°C while cooling. Triethylamine hydrochloride is precipitated. The batch is further stirred for 2 hours after the chlorine has been passed in. Triethylamine hydrochloride is filtered off and the filtrate concentrated. The residue is dissolved in 500 ml of ether and 500 ml of water. The phases are separated and the aqueous phase is extracted 3 times with 300 ml of ether each time. The ethereal extracts are dried over sodium sulphate. The drying agent is filtered off and the filtrate concentrated. The residue is recrystallised from a mixture of 400 ml of xylene and 250 ml of ligroin and dried in vacuo. Yield: 28.7 g (29 % of theory); m.p. 108°-110°C.
Reaction SMILES: [CH3:1][OH:2].[CH2:3]([N:8]([C:14]([O:16][CH2:17][C:18]#[CH:19])=[O:15])[C:9](=[O:13])[C:10](Cl)=[O:11])[C:4]([CH3:7])([CH3:6])[CH3:5].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:3]([N:8]([C:14]([O:16][CH2:17][C:18]#[CH:19])=[O:15])[C:9](=[O:13])[C:10]([O:2][CH3:1])=[O:11])[C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: C#CCOC(=O)N(CC(C)(C)C)C(=O)C(=O)Cl
Reactant: CO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C#CCOC(=O)N(CC(C)(C)C)C(=O)C(=O)OC
Yield: 97.9 %

Procedure:
0.64 g (0.02 mole) of methanol are added to 5.35 g (0.02 mole) of 97% pure N-neopentyl-N-2-propinyloxycarbonyloxamic acid chloride in 50 ml of toluene, and 2.02 g (0.02 mole) of triethylamine are then added dropwise, while cooling with ice. After the precipitate has been filtered off, the filtrate is washed with water, dried over sodium sulphate and freed from the solvent under a high vacuum. 5 g (98% of theory) of methyl N-neopentyl-N-2-propinyloxycarbonyl-oxamate of refractive index nD20 =1.4634 are obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1([OH:17])[CH2:16][CH2:15][C:10]2(OCC[O:11]2)[CH2:9][CH2:8]1.Cl>C1COCC1>[OH:17][C:7]1([C:2]2[N:1]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:16][CH2:15][C:10](=[O:11])[CH2:9][CH2:8]1
Reactant: OC1(c2ncccn2)CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCC(O)(c2ncccn2)CC1
Reaction time: 48 h
Yield: 49.3 %

Procedure:
To the product from step A (190 mmol, 44 g) in THF (200 mL) was added HCl solution (300 mmol, 100 mL). The reaction was stirred over 2 days after which the reaction was washed using diethyl ether. The aqueous layer was then quenched using NaOH (50%) to obtain a pH of 11. The aqueous layer was extracted using EtOAc (6×300 mL). The organic layers were combined and dried over MgSO4 and concentrated in vacuo. The reaction was purified via flash chromatography to afford the desired ketone (18 g, 49%). MS (M+H)+ 193.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8](F)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16].[CH3:19][O:20][C:21]([C:23]1[N:24]=[CH:25][NH:26][CH:27]=1)=[O:22]>O1CCCC1.CS(C)=O>[CH3:19][O:20][C:21]([C:23]1[N:24]=[CH:25][N:26]([C:8]2[CH:9]=[C:4]([C:3]([O:2][CH3:1])=[O:18])[C:5]([N+:15]([O-:17])=[O:16])=[CH:6][C:7]=2[C:11]([F:14])([F:13])[F:12])[CH:27]=1)=[O:22]
Reactant: COC(=O)c1c[nH]cn1
Reactant: COC(=O)c1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COC(=O)c1cn(-c2cc(C(=O)OC)c([N+](=O)[O-])cc2C(F)(F)F)cn1
Temperature: 25 °C
Yield: 80.2 %

Procedure:
A solution of 5-fluoro-2-nitro-4-trifluoromethyl-benzoic acid methyl ester (1 g, 3.74 mmol) and 1H-imidazole-4-carboxylic acid methyl ester (0.53 g, 4.12 mmol) in 10 ml of tetrahydrofuran and 2 ml of DMSO is heated to reflux for 90 hours. The solution is allowed to 5 cool to room temperature and evaporated. The residue is crystallized from dichloromethane and hexane to give 1.12 g (3 mmol, 80%) of 1-(5-methoxycarbonyl-4-nitro-2-trifluoromethyl-phenyl) -1H-imidazole-4-carboxylic acid methyl ester, m.p. 136 -138° C., ES-MS: m/z 374 [M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.[CH3:8][N:9]1[CH2:12][CH2:11][C:10]1=[O:13].[C:14](=O)([O:18]CC)[O:15][CH2:16][CH3:17]>O1CCCC1>[CH2:16]([O:15][C:14]([CH:11]1[CH2:12][N:9]([CH3:8])[C:10]1=[O:13])=[O:18])[CH3:17]
Reactant: CN1CCC1=O
Reactant: CCOC(=O)OCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1CN(C)C1=O
Reaction time: 0.42 h

Procedure:
Into tetrahydrofuran (20 ml) containing diisopropylamine (1.82 ml) is added 15% n-butyllithium-hexane (7.5 ml), and the mixture is stirred for 25 minutes. To this solution are added 1-methyl-2-azetidinone dropwise at -70° C. and after 20 minutes, diethyl carbonate (1.33 ml). After 2.5 hours stirring, reaction mixture is quenched with 10% hydrochloric acid (15 ml) and extracted with ethyl acetate. The solvent is evaporated to give 1-methyl-2-oxoazetidine-3-carboxylic acid ethyl ester (476 mg). Colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:17][OH:18])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CC(C)=[O:21].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([OH:21])=[O:18])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: OCc1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a stirred solution of (1-(4-fluorophenyl)-1H-indazol-5-yl)methanol (0.45 g, 1.9 mmol) in acetone (10 mL) was added Jones' reagent (3 mL) dropwise at 0° C. The reaction mixture was stirred at rt for 1 hr and concentrated under reduced pressure. Water was added to the residue and the solid that separates out was filtered, washed with water and dried to give 1-(4-fluorophenyl)-1H-indazole-5-carboxylic acid (0.43 g, 1.7 mmol, 89% yield) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([NH2:8])=[CH:4][C:5]([NH2:7])=[O:6].N.[CH3:12]NN.Cl>O.C(O)C>[CH3:12][N:8]1[C:3]([C:2]([F:10])([F:9])[F:1])=[CH:4][C:5]([OH:6])=[N:7]1
Reactant: CNN
Reactant: NC(=O)C=C(N)C(F)(F)F
Agent: Cl
Agent: N
Solvent: O
Solvent: CCO
Product: Cn1nc(O)cc1C(F)(F)F
Temperature: 30 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
30.82 g (0.2 mol) of 4,4,4-trifluoro-3-amino-2-butenamide (prepared by addition of 2 equivalents of ammonia to the corresponding alkenoic ester) was added to 10.1 g (0.22 mol) of methylhydrazine at room temperature. A slight exotherm raised the temperature to 30° C. The mixture was stirred for 1 hr. at which time the mixture became semi-solid; 10 ml. of ethanol was added to improve stirring. After another 1.5 hr., 7 ml. of ethanol was added, again to aid in stirring the mixture. After a total of 24 hr., the mixture was taken up in 25 ml. of water, the pH was adjusted to 6.5-7.0 with conc. hydrochloric acid (17 ml.), and the precipitated product was collected by filtration and dried to obtain 21.37 g (65.3%) of product m.p. 129°-131° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([B:15]2[O:19][C:18]([CH3:21])([CH3:20])[C:17]([CH3:23])([CH3:22])[O:16]2)=[CH:11][CH:10]=1)(=O)=O.[NH2:24][C@@H:25]([CH3:35])[C@@H:26]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[OH:27].C(OCC)(=O)C>CN(C)C=O>[CH3:21][C:18]1([CH3:20])[C:17]([CH3:22])([CH3:23])[O:16][B:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][NH:24][C@@H:25]([CH3:35])[C@@H:26]([C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=3)[OH:27])=[CH:14][CH:13]=2)[O:19]1
Reactant: CC1(C)OB(c2ccc(OCCOS(C)(=O)=O)cc2)OC1(C)C
Reactant: C[C@H](N)[C@H](O)c1ccc(O)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](NCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)[C@H](O)c1ccc(O)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 16.6 %

Procedure:
A mixture of 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl methanesulfonate (1.20 g) and 4-((1R,2S)-2-amino-1-hydroxypropyl)phenol (1.76 g) in N,N-dimethylformamide (20 mL) was stirred at 80° C. for 5 hrs. Ethyl acetate was added to the reaction mixture. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:n-hexane/ethyl acetate=1/1, methylene chloride/methanol=9/1) to afford the title compound (0.24 g).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])=[CH:22][CH:21]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)=[O:32])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ncc(N)n3)n2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccc(F)cc1
Product: CC(=O)c1csc(Cn2ncc(NC(=O)c3ncoc3-c3ccc(F)cc3)n2)n1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(4-fluoro-phenyl)-oxazole-4-carboxylic acid.