Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][OH:7].[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>>[S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)([O:7][CH2:6][CH2:5][C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([CH3:1])[C:3]=1[N+:11]([O-:13])=[O:12])(=[O:16])=[O:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cccc(CCO)c1[N+](=O)[O-]
Product: Cc1ccc(S(=O)(=O)OCCc2cccc(C)c2[N+](=O)[O-])cc1
Yield: 100 %

Procedure:
3-Methyl-2-nitrophenethyl tosylate was prepared according to the general method as outlined in Preparation 1 starting from 3-methyl-2-nitrophenethyl alcohol (1.06 g, 5.86 mmol) and tosyl chloride (1.34 g, 7 mmol). 2 g product was taken crude to the next step. Yield 100%; 1H NMR (400 MHz, CDCl3) δ 7.68 (d, 2H), 7.29 (m, 3H), 7.17 (t, 2H), 4.23 (t, J=6 Hz, 2H), 2.89 (t, J=6 Hz, 2H), 2.42 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[C:4]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[CH:3]=1.[CH2:19]([O:21][C:22](=[O:29])[CH2:23][C:24](=O)[CH:25]([CH3:27])[CH3:26])[CH3:20]>>[CH2:19]([O:21][C:22]([C:23]1[C:24]([CH:25]([CH3:27])[CH3:26])=[N:9][C:5]2[C:4]([C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=2[CH3:8])=[O:29])[CH3:20]
Reactant: Cc1cc(Cl)cc(C#Cc2ccccc2Cl)c1N
Reactant: CCOC(=O)CC(=O)C(C)C
Product: CCOC(=O)c1c(C(C)C)nc2c(C)cc(Cl)cc2c1Cc1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 10 step B from 4-chloro-2-(2-chloro-phenylethynyl)-6-methyl-phenylamine (400 mg, 1.45 mmol) and 4-methyl-3-oxo-pentanoic acid ethyl ester (0.351 ml, 2.17 mmol). Brown solid. LC-MS (ESI): 416 (M+H)+.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Br[C:6]1[N:10]([C@@H:11]2[O:17][C@H:16]([CH3:18])[C@@H:14]([OH:15])[C@H:12]2[OH:13])[C:9]2[CH:19]=[C:20]([Cl:24])[C:21]([Cl:23])=[CH:22][C:8]=2[N:7]=1>C(Cl)Cl>[Cl:23][C:21]1[C:20]([Cl:24])=[CH:19][C:9]2[N:10]([C@@H:11]3[O:17][C@H:16]([CH3:18])[C@@H:14]([OH:15])[C@H:12]3[OH:13])[C:6]([NH:4][CH:1]([CH3:3])[CH3:2])=[N:7][C:8]=2[CH:22]=1
Reactant: C[C@H]1O[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Reactant: CC(C)N
Solvent: ClCCl
Product: CC(C)Nc1nc2cc(Cl)c(Cl)cc2n1[C@@H]1O[C@H](C)[C@@H](O)[C@H]1O
Yield: 90.4 %

Procedure:
Following General Procedure V, isopropylamine (Aldrich, 3 mL, 34.92 mmol), and 2-bromo-5,6-dichloro-1-(5-deoxy-beta-D-ribofuranosyl)-1H-benzimidazole (200 mg, 0.52 mmol) were reacted for 16 h. Purification on a silica gel column with 1:15 methanol:CH2Cl2 gave 5,6-dichloro-1-(5-deoxy-beta-D-ribofuranosyl)-N-(1-methylethyl)-1H-benzimidazol-2-amine (168 mg, 0.47 mmol, 90%); MS (EI): m/z (rel. intensity) 360 (0.17, M+); 1H NMR (DMSO-d6) δ7.41 (s, 1H, Ar—H), 7.32 (s,1H, Ar—H), 6.63 (d; 1H, NH, J=7.3 Hz), 5.73 (d, 1H, CH, J=6.6 Hz), 5.26 (m, 2H, 2 overlapping OH), 4.33 (m, 1H, CH), 4.01 (m, 1H, CH), 3.91 (m, 1H, CH), 3.81 (m, 1H, CH), 1.37 (d, 3H, CH3, J=6.1 Hz), 1.21 (d, 6H, CH3, J=6.3 Hz).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:41]1[N:42]=[C:43]([NH:46]C=O)[S:44][CH:45]=1)[C:5]([NH:7][CH:8]1[C:39](=[O:40])[N:10]2[C:11]([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[C:12]([CH:15]=[CH:16][C:17]3[N:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:13][S:14][C@H:9]12)=[O:6].Cl.C(=O)(O)[O-].[Na+]>CO.O1CCCC1>[CH3:1][O:2][N:3]=[C:4]([C:41]1[N:42]=[C:43]([NH2:46])[S:44][CH:45]=1)[C:5]([NH:7][CH:8]1[C:39](=[O:40])[N:10]2[C:11]([C:23]([O:25][CH:26]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:24])=[C:12]([CH:15]=[CH:16][C:17]3[N:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3cccnn3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3cccnn3)CS[C@H]12)c1csc(N)n1
Yield: 83.4 %

Procedure:
To a solution of benzhydryl 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-[2-(3-pyridazinyl)vinyl]-3-cephem-4-carboxylate (syn isomer) (trans isomer) (0.85 g) in methanol (45 ml) and tetrahydrofuran (9 ml) was added conc.hydrochloric acid (0.56 ml) and the mixture was stirred at ambient temperature for 1.5 hours. The resultant solution was adjusted to pH 7.0 with 5% aqueous sodium bicarbonate and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (150 ml). The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuo to give benzhydryl 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[2-(3-pyridazinyl)vinyl]-3-cephem-4-carboxylate (syn isomer) (trans isomer) (0.68 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][N:3]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>>[C:8]([C:7]1[C:2]([N:1]=[CH:12][N:13]([CH3:15])[CH3:14])=[N:3][CH:4]=[N:5][CH:6]=1)#[N:9]
Reactant: N#Cc1cncnc1N
Reactant: COC(OC)N(C)C
Product: CN(C)C=Nc1ncncc1C#N

Procedure:
The title compound was prepared from the reaction of 4-Amino-5-pyrimidinecarbonitrile (Aldrich) with N,N-dimethylformamide dimethyl acetal using the procedure from Example 156B to provide the title compound.
Reaction SMILES: [C:1]([Si:5]([CH3:31])([CH3:30])[O:6][CH2:7][C@@H:8]([C@@H:17]1[C@@H:21]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)[CH2:20][NH:19][CH2:18]1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:32][C:33]1[N:38]=[N:37][CH:36]=[C:35]([C:39](O)=[O:40])[CH:34]=1>>[C:1]([Si:5]([CH3:31])([CH3:30])[O:6][CH2:7][C@@H:8]([C@@H:17]1[C@@H:21]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)[CH2:20][N:19]([C:39]([C:35]2[CH:34]=[C:33]([CH3:32])[N:38]=[N:37][CH:36]=2)=[O:40])[CH2:18]1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)O)cnn1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](Oc1ccc(Cl)cn1)[C@H]1CNC[C@@H]1c1ccc(F)c(F)c1
Product: Cc1cc(C(=O)N2C[C@H]([C@H](CO[Si](C)(C)C(C)(C)C)Oc3ccc(Cl)cn3)[C@@H](c3ccc(F)c(F)c3)C2)cnn1

Procedure:
The titled compound was prepared following a general procedure I for amidation between 2-{(R)-2-(tert-butyl-dimethyl-silanyloxy)-1-[(3R,4S)-4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethoxy}-5-chloro-pyridine and 6-Methyl-pyridazine-4-carboxylic acid . ES-MS m/e: 589.1 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C@@H:11]([OH:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(NCC[C@@H:32](O)[CH2:33][C:34]([O:36][CH2:37][CH3:38])=O)=O)C1C=CC=CC=1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C@@H:11]([O:18][CH:34]1[CH2:33][CH2:32][CH2:38][CH2:37][O:36]1)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C[C@H](O)CCNC(=O)OC(C)(C)C
Reactant: CCOC(=O)C[C@H](O)CCNC(=O)OCc1ccccc1
Product: CCOC(=O)C[C@@H](CCNC(=O)OC(C)(C)C)OC1CCCCO1
Yield: 75 %

Procedure:
The intended compound (2-b) was prepared in a yield of 75% by a method similar to the process A in EXAMPLE 2, except that ethyl (3R)-5-tert-butoxycarbonylamino-3-hydroxypentanoate (2-a), obtained by the above process B, was used instead of ethyl (3R)-5-benzyloxycarbonylamino-3-hydroxypentanoate (2-a).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][NH2:10].C(N(C(C)C)CC)(C)C.[C:20]1([CH:26]([CH2:30][CH3:31])[C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][NH:10][C:27](=[O:28])[CH:26]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:30][CH3:31]
Reactant: Cc1ccc(F)c(CN)c1
Reactant: CCC(C(=O)Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(C(=O)NCc1cc(C)ccc1F)c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of (2-fluoro-5-methylphenyl)methanamine (1-f, 50 mg, 0.26 mmol, Oakwood Products, Inc., West Columbia, S.C.) and diisopropylethylamine (88 uL, 0.52 mmol) in dichloromethane (1 mL) was treated at room temperature with 2-phenylbutanoyl chloride (1-a, 47 mg, 0.26 mmol). The reaction mixture was stirred for 30 min, partitioned between dichloromethane and 0.1N—NaOH. The aqueous layer was removed and the organic layer washed with 0.1N-HCl. The aqueous layer was removed by filtering through a plastic frit. The organic layer was evaporated in vacuo to give the desired product (1-2); HRMS (M+1)=286.1586.
Reaction SMILES: [Cl:1][C:2](=[CH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:17]([Cl:18])=[C:16]([O:19][CH:20]([F:22])[F:21])[N:15]([CH3:23])[N:14]=2)[C:10]([F:24])=[CH:9][C:8]=1[Cl:25])[C:3](Cl)=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:33][O:34][NH2:35]>C1(C)C=CC=CC=1.O>[CH3:33][O:34][NH:35][C:3](=[O:4])[C:2]([Cl:1])=[CH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:17]([Cl:18])=[C:16]([O:19][CH:20]([F:21])[F:22])[N:15]([CH3:23])[N:14]=2)[C:10]([F:24])=[CH:9][C:8]=1[Cl:25]
Reactant: Cn1nc(-c2cc(C=C(Cl)C(=O)Cl)c(Cl)cc2F)c(Cl)c1OC(F)F
Reactant: CON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CONC(=O)C(Cl)=Cc1cc(-c2nn(C)c(OC(F)F)c2Cl)c(F)cc1Cl
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of 4.5 g (10 mmol) of 2-chloro-3-(2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorophenyl)acryloyl chloride in 25 ml of toluene was treated with 25 ml of water, 14.4 g (0.1 mol) of potassium carbonate and 1.7 g (20 mmol) of methoxyamine hydrochloride. After the mixture had been stirred for 16 hours at approximately 20° C., it was heated for a further 2 hours at 40° C. The reaction mixture was subsequently diluted with 200 ml of toluene and 200 ml of water. The solids were then filtered off. The organic phase was dried over magnesium sulfate and finally concentrated. Yield: 3.1 g.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1>C(O)C>[O:11]=[C:4]1[CH:5]([C:8]([OH:9])=[O:10])[CH2:7][CH2:6][N:13]1[C:14]1[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: Cc1cccc(N)c1
Solvent: CCO
Product: Cc1cccc(N2CCC(C(=O)O)C2=O)c1
Yield: 83.8 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g, 1.47 mmol) and m-toluidine (0.470 mL; 4.41 mmol) in ethanol (3 mL). 2-oxo-1-m-tolylpyrrolidine-3-carboxylic acid 0.270 g (84%) was obtained as a pink film.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][CH2:9][C:10]([C:13]1[CH:17]=[C:16]([NH:18][C:19](=[O:32])[C:20]([CH3:31])([S:22]([CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)(=[O:24])=[O:23])[CH3:21])[O:15][N:14]=1)([CH3:12])[CH3:11].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:11][C:10]([C:13]1[CH:17]=[C:16]([NH:18][C:19](=[O:32])[C:20]([CH3:31])([S:22]([CH:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)(=[O:24])=[O:23])[CH3:21])[O:15][N:14]=1)([CH3:12])[CH2:9][O:8][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(CO)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCC(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Temperature: 25 °C
Yield: 81.2 %

Procedure:
Acetic anhydride (24 uL, 0.26 mmol) and a catalytic amount of DMAP are added in sequence to a solution of N-[3-(2-hydroxy-1,1-dimethyl-ethyl)-isoxazol-5-yl]-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionamide (80.0 mg, 0.21 mmol) and pyridine (21 uL, 0.26 mmol) in anhydrous DCM (2.1 mL). The solution is stirred at room temperature until complete consumption of starting material. After removal of the solvent under reduced pressure, the crude is purified by silica gel column chromatography to afford 71 mg of acetic acid 2-methyl-2-{5-[2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionylamino]-isoxazol-3-yl}-propyl ester. Yield: 80%; m/z 417 [M+H].
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5](O)[C:6]2[S:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:2].P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:5]1[C:6]2[S:11][CH:10]=[CH:9][C:7]=2[N:8]=[C:3]([CH2:1][CH3:2])[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1nc(O)c2sccc2n1
Product: CCc1nc(Cl)c2sccc2n1

Procedure:
2-Ethyl-4-hydroxythieno[3,2-d]pyrimidine (0.6725 g, 0.00373M) was refluxed with phosphorus oxychloride (20 ml) for 2 hours. The reaction mixture was cooled, concentrated under vacuum, the residue dissolved in methylene chloride, poured over ice and water and basified with ammonia. The layers were separated and the aqueous layer extracted with ether. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated under vacuum to obtain the product, 0.65 g, as a tan solid, m.p. 46°-48° C. the structure of which was confirmed by NMR.
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH2:26][O:27][CH2:28][C:29]4[N:30]=[N:31][N:32](CCF)[CH:33]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[C:10](=[O:11])[C:8]2=[O:9])=[CH:4][CH:3]=1.[F:39][CH2:40]N=[N+]=[N-]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH2:26][O:27][CH2:28][C:29]4[N:30]=[N:31][N:32]([CH2:40][F:39])[CH:33]=4)(=[O:19])=[O:20])=[CH:15][CH:16]=3)[C:10](=[O:11])[C:8]2=[O:9])=[CH:37][CH:38]=1
Reactant: [N-]=[N+]=NCF
Reactant: O=C1C(=O)N(Cc2ccc(F)cc2)c2ccc(S(=O)(=O)N3CCC[C@H]3COCc3cn(CCF)nn3)cc21
Product: O=C1C(=O)N(Cc2ccc(F)cc2)c2ccc(S(=O)(=O)N3CCC[C@H]3COCc3cn(CF)nn3)cc21

Procedure:
is prepared according to the procedure for compound 12, with the exception that fluoromethylazide is used in place of the 2-fluoroethylazide.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][CH:6]1Br)(=[O:3])[CH3:2].[CH3:20][C:21]1[S:22][C:23]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:24]=2[N:25]=1>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][C@H:6]1[O:30][C:27]1[CH:28]=[CH:29][C:23]2[S:22][C:21]([CH3:20])=[N:25][C:24]=2[CH:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)CSC(Br)[C@@H]1OC(C)=O
Reactant: Cc1nc2cc(O)ccc2s1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc2sc(C)nc2c1
Yield: 6 %

Procedure:
By carrying out the process in a manner similar to example 7, starting from 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide and 2-methyl-5-hydroxybenzothiazole, the desired product is obtained in the form of white crystals with a yield of 6%.
Reaction SMILES: [C:1]1(=[O:16])[N:5]([N:6]2[CH:10]=[CH:9][CH:8]=[CH:7]2)[C:4](=[O:11])[C:3]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]12.[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].O>ClC(Cl)C>[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([C:7]1[N:6]([N:5]2[C:4](=[O:11])[C:3]3=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]3[C:1]2=[O:16])[CH:10]=[CH:9][CH:8]=1)=[O:21]
Reactant: O=C(Cl)c1ccccc1F
Reactant: O=C1c2ccccc2C(=O)N1n1cccc1
Solvent: CC(Cl)Cl
Solvent: O
Product: O=C(c1ccccc1F)c1cccn1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.1 %

Procedure:
To a mixture of N-phthalimidopyrrole (10 g, 47 mmole) and fused zinc chloride (10 g, 73 mmole) in 80 ml dichloroethane was added o-fluorobenzoyl chloride (7.5 g, 47 mmole). The reaction mixture was stirred at ambient temperature for twenty hours and at 80° for one hour. Thereafter, it was cooled, poured into water and extracted with dichloromethane. The organic extract was washed with water and with saturated sodium chloride solution, and dried over magnesium sulfate. The solution was filtered and evaporated to an oil which yielded a solid upon trituration with ethanol (yield 11 g, m.p. 180°-190°). This material was purified by column chromatography (silica gel, dichloromethane) to give 3 g solid. This material was recrystallized from isopropanol to give 2.6 g (17%) crystals, m.p. 202°-203°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11]2)[CH:5]=[C:4]([Cl:16])[N:3]=1.[Cl:17]N1C(=O)CCC1=O.CN(C)C=O>C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11]2)[C:5]([Cl:17])=[C:4]([Cl:16])[N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1nc(Cl)cc(NCC2(CO)CCC2)n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1nc(Cl)c(Cl)c(NCC2(CO)CCC2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 54.1 %

Procedure:
To 2-amino-6-chloro-4-[[(1-hydroxymethyl-1-cyclobutyl)methyl]amino]pyrimidine (0.24 g, 2.0 mmol) were added N-chlorosuccinimide (0.27 g, 2.0 mmol) and dimethylformamide (1.5 ml), and the mixture was stirred at room temperature for 2 days. Ethyl acetate was added and the mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to give colorless prism crystals (0.3 g, 54.2%), m.p. 179-181° C. (acetone).
Reaction SMILES: [Cl:1][C:2]([F:15])([F:14])[C:3]1([C:10]([Cl:13])([F:12])[F:11])[O:7][CH:6]([CH2:8][OH:9])[CH2:5][O:4]1.[O-:16][C:17]#[N:18].[Na+].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:13][C:10]([F:11])([F:12])[C:3]1([C:2]([Cl:1])([F:14])[F:15])[O:7][CH:6]([CH2:8][O:9][C:17](=[O:16])[NH2:18])[CH2:5][O:4]1
Reactant: N#C[O-]
Reactant: OCC1COC(C(F)(F)Cl)(C(F)(F)Cl)O1
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)OCC1COC(C(F)(F)Cl)(C(F)(F)Cl)O1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A sample of 15 grams of 2,2-bis(chlorodifluoromethyl)-4-hydroxymethyl-1,3-dioxolane (0.055 mols) is dissolved in 75 ml methylene chloride and 7.16 grams of sodium cyanate (0.11 mols) is added. Trifluoroacetic acid, 12.6 grams, (0.11 mols) is added dropwise with stirring at 23°-33° C. The temperature is then raised to 40° C. and stirring continued for 18 hours. The product is filtered and the filtrate washed with water until neutral. Vacuum stripping gives a quantitative yield of crude products which solidified partly. Filtration and recrystallization from a mixture of benzene-hexane and once from cyclohexane yields 2,2-bis(chlorodifluoromethyl)-4-carbamoyloxymethyl-1,3-dioxolane (m.p. 56°-57° C.)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([O:14][CH2:15][CH3:16])[CH:8]=1)[CH3:2].Cl[CH2:19][C:20]1[C:21]([CH3:36])=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[CH:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:19][C:20]2[C:21]([CH3:36])=[N:22][C:23]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=3)=[CH:24][CH:25]=2)=[C:9]([O:14][CH2:15][CH3:16])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1ccc(O)c(OCC)c1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Product: CCOC(=O)CCc1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c(OCC)c1

Procedure:
In analogy to the procedures described in examples 8A] and 31B], 3-(3-ethoxy-4-hydroxy-phenyl)-propionic acid ethyl ester [Eur. Pat. Appl. (1996), EP 710659/A1] was reacted with 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example 1N]) to give 3-{3-ethoxy-4-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-phenyl}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: Br[C:2]([CH3:15])([CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][Br:13])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].C([OH:20])C>COCCOC>[Br:13][CH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[C:2]([OH:20])([CH3:15])[CH3:14])=[CH:6][CH:7]=1
Reactant: CCO
Reactant: CC(C)(Br)C(=O)c1ccc(CCBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: CC(C)(O)C(=O)c1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5.0 g, 0.105 mol) of 2-bromo-1-[4-(2-bromo-ethyl)-phenyl]-2-methyl-propan-1-one, 0.60 g (0.015 mol) of sodium hydroxide, 100 ml of ethanol and 50 ml of 1,2-dimethoxyethane is stirred at room temperature overnight. The reaction mixture is concentrated and the crude product is dissolved in ethyl acetate. The solution is washed with distilled water, dried over sodium sulfate and concentrated to give 3.4 g of 1-[4-(2-bromoethyl)phenyl]-2-hydroxy-2-methylpropan-1-one.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=2)[CH:9]=[CH:8]1)[CH3:6])[CH3:2].[F:18][C:19]([F:40])([F:39])[CH2:20][N:21]1[C:25]([CH2:26]O)=[CH:24][C:23]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)=[N:22]1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:26][C:25]3[N:21]([CH2:20][C:19]([F:39])([F:18])[F:40])[N:22]=[C:23]([C:28]4[CH:33]=[CH:32][C:31]([O:34][C:35]([F:37])([F:38])[F:36])=[CH:30][CH:29]=4)[CH:24]=3)[CH:14]=2)[CH:9]=[CH:8]1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)n1ccc2ccc(O)cc21
Reactant: OCc1cc(-c2ccc(OC(F)(F)F)cc2)nn1CC(F)(F)F
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(C)n1ccc2ccc(OCc3cc(-c4ccc(OC(F)(F)F)cc4)nn3CC(F)(F)F)cc21

Procedure:
In analogy to the procedure described for example 3 c], [rac]-2-(6-hydroxy-indol-1-yl)-propionic acid ethyl ester (J. E. D. Barton, D. Cartwright, C. J. Mathews, Brit. UK Pat. Appl. (1992), GB 2253848 A1) was reacted with [2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-methanol (example 15 b]) in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give [rac]-2-{6-[2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-propionic acid ethyl ester as colorless oil.
Reaction SMILES: [N:1]1([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][N:19]=[C:18]([NH2:22])[CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:26]1[S:27][C:28]([C:31]#[N:32])=[CH:29][N:30]=1>>[N:1]1([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][N:19]=[C:18]([NH:22][C:26]4[S:27][C:28]([C:31]#[N:32])=[CH:29][N:30]=4)[CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: N#Cc1cnc(Cl)s1
Reactant: Nc1cc(N2CCN(C(=O)CN3CCOCC3)CC2)ncn1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cnc(Nc2cc(N3CCN(C(=O)CN4CCOCC4)CC3)ncn2)s1

Procedure:
42-3 (0.36 g, 1.18 mmol), sodium hydride (0.094 g, 2.35 mmol) and 2-chloro-1,3-thiazole-5-carbonitrile 2-2 (0.17 g, 1.18 mmol) were treated as in Scheme 4 above. The reaction was cooled, quenched with methanol and water, evaporated to dryness and partitioned between methylene chloride, methanol and water. The organic layers were evaporated to dryness and purified on a C18 preparative hplc column and isolated via lyophilization to afford 42-4. Hi-Res MS: calc: 415.1659 found: 415.1638. 1H-NMR (CD3OD): 8.44(s, 1H); 8.01(s, 1H); 6.20(s, 1H); 4.36(s, 2H); 4.05(br s, 2H); 3.88(br s, 2H); 3.82(m, 2H); 3.76(m, 2H); 3.71(m, 2H); 3.56(m, 4H); 3.25(br s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:26]3[N:27]=[C:28]([NH:31][CH:32]([CH3:34])[CH3:33])[S:29][CH:30]=3)[CH:15]=2)[CH2:10][CH:9]1[C:35]([OH:37])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:38]([O:40][C:41]([C:43]1([NH2:48])[CH2:45][CH:44]1[CH:46]=[CH2:47])=[O:42])[CH3:39]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:26]3[N:27]=[C:28]([NH:31][CH:32]([CH3:33])[CH3:34])[S:29][CH:30]=3)[CH:15]=2)[CH2:10][CH:9]1[C:35](=[O:37])[NH:48][C:43]1([C:41]([O:40][CH2:38][CH3:39])=[O:42])[CH2:45][CH:44]1[CH:46]=[CH2:47])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2c(OC3CC(C(=O)O)N(C(=O)OC(C)(C)C)C3)cc(-c3csc(NC(C)C)n3)nc2c1
Reactant: C=CC1CC1(N)C(=O)OCC
Product: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3csc(NC(C)C)n3)nc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C)C(=O)OCC
Yield: 81 %

Procedure:
Compound 133 (300 mg, 0.56 mmol) was reacted with 1-amino-2-vinyl-cyclopropanecarboxylic acid ethyl ester (130 mg, 0.84 mmol) as described in Example 11 which gave the title compound (302 mg, 80%).