Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[O:2]([CH2:9][C:10](=[O:12])[CH3:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CCO>[CH2:17]([O:16][C:14](=[O:15])[C:13](=[O:19])[CH2:11][C:10](=[O:12])[CH2:9][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:18]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)COc1ccccc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)COc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 53.9 %

Procedure:
Sodium (6.74 g, 293 mmol) was added to EtOH at 0° C. The mixture was stirred at 0° C. until the sodium was completely dissolved. Then phenoxy-2-propanone (53 mL, 266 mmol) was added dropwise. The mixture was stirred at 0° C. for 10 minutes and then diethyl oxalate (36 g, 266 mmol) was added. Then the mixture was stirred at room temperature for 16 hours and the solvent was evaporated in vacuo. The residue was dissolved in H2O and the mixture was acidified with a 1M solution of HCl and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by open column chromatography (silica; DCM) to yield 2,4-dioxo-5-phenoxy-pentanoic acid ethyl ester (35.85 g, 54% yield) as an oil.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:14])[C@H:6]([CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)[NH2:7].[C:15]([NH:22][C@H:23]([C:31](O)=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.C(N(CC)CC)C>[CH3:3][O:4][C:5](=[O:14])[C@H:6]([CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)[NH:7][C:31](=[O:32])[C@H:23]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH:22][C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
A slurry of 36.4 g. L-histidine methyl ester dihydrochloride in dichloromethane (1 l.) was cooled to 5° C. and treated with 52 ml. triethylamine. After 10 minutes 40 g. Boc-L-phenylalanine was added followed by 1-hydroxybenzotriazole (30.6 g.), then after another 5 minutes by dicyclohexylcarbodiimide (30.8 g.), and the mixture was stirred at 0° C. for 4 hours and at 20° C. for 90 hours. The mixture was then filtered and the filtered solid was washed with dichloromethane, and the combined organic layers were concentrated and the residue was dissolved in 1 l. ethyl acetate. After 10 minutes of stirring the mixture was filtered and the filtrate was washed with 1N sodium hydroxide (3×150 ml.), brine, dried over magnesium sulfate and concentrated giving 45.9 g. of a colorless solid which was used without additional purification in Step B.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11]C(C=O)=[CH:7][CH:6]=1.[CH3:13][O:14][C:15]([O:18][CH3:19])([CH3:17])C>CO.C(Cl)Cl>[CH3:19][O:18][CH:15]([O:14][CH3:13])[C:17]1[CH:11]=[CH:12][C:5]([O:4][CH2:3][CH2:2][OH:1])=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCCO)cc1
Reactant: COC(C)(C)OC
Solvent: CO
Solvent: ClCCl
Product: COC(OC)c1ccc(OCCO)cc1
Reaction time: 5 h
Yield: 69.9 %

Procedure:
To a solution of 4-hydroxyethoxybenzaldehyde (Bernstein et aL, J. Am. Chem. Soc., 73: 906-912 (1951); 8.5 g, 51.2 mmol), 2,2-dimethoxypropane (30 mL, 244 mmol) in a mixture of methanol (40 mL) and CH2Cl2 (100 mL) was added anhydrous Amberlyst 15 (Aldrich) (1.0 g). The mixture was stirred for 5 hrs, the catalyst was removed by filtration and the filtrate was concentrated to give the crude product contaminated with the starting aldehyde. This material was chromatographed on silica eluting with 1:1 ethyl acetate-hexane. The pure product fractions were pooled and concentrated. Drying under vacuum afforded 7.6 g (70%) of the title compound as a pale yellow, viscous liquid. 1H NMR: d 7.28 (d, J=9 Hz, 2 H), 6.92 (d, J=9 Hz, 2H), 5.31 (s, 1H), 4.86 (t, J=5.5 Hz, 1H), 3.98 (t, J=5 Hz, 2H), 3.71 (q, J=5 Hz, 2H), 3.20 (s, 3H). 13C NMR: d 158.60, 130.19, 127.74, 113.90, 102.46, 69.43, 59.52, 52.27.
Reaction SMILES: N=[C:2]=[NH:3].Cl.Cl.[NH2:6][CH:7]([CH:15]([OH:43])[CH:16]([NH:24][C:25](=[O:42])[C@H:26]([CH:39]([CH3:41])[CH3:40])[NH:27][S:28](=[O:38])(=[O:37])[NH:29][N:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH3:36][N:33]1[CH2:32][CH2:31][N:30]([NH:29][S:28]([NH:27][C@H:26]([C:25]([NH:24][CH:16]([CH:15]([OH:43])[CH:7]([NH:6][C:25](=[O:42])[C@H:26]([CH:39]([CH3:40])[CH3:41])[NH:27][S:28](=[O:37])(=[O:38])[NH:29][N:30]2[CH2:31][CH2:32][N:3]([CH3:2])[CH2:34][CH2:35]2)[CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:42])[CH:39]([CH3:41])[CH3:40])(=[O:37])=[O:38])[CH2:35][CH2:34]1
Reactant: CC(C)[C@H](NS(=O)(=O)NN1CCN(C)CC1)C(=O)NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Reactant: N=C=N
Agent: Cl
Product: CC(C)[C@H](NS(=O)(=O)NN1CCN(C)CC1)C(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)[C@@H](NS(=O)(=O)NN1CCN(C)CC1)C(C)C

Procedure:
According to the carbodiimide coupling procedure of Example 55, the resultant compound of Example 137B was coupled to the resultant compound of Example 138 to give the desired compound.
Reaction SMILES: [CH2:1]([S:3][C:4]1[S:5][C:6]([C:10]#[N:11])=[C:7]([NH2:9])[N:8]=1)[CH3:2].[SH2:12]>>[CH2:1]([S:3][C:4]1[S:5][C:6]([C:10](=[S:12])[NH2:11])=[C:7]([NH2:9])[N:8]=1)[CH3:2]
Reactant: S
Reactant: CCSc1nc(N)c(C#N)s1
Product: CCSc1nc(N)c(C(N)=S)s1
Yield: 49 %

Procedure:
55.5 parts of 2-ethylmercapto-4-amino-5-cyano-thiazole are reacted with 20 parts of hydrogen sulfide as described in Example 1(a). 32.1 parts of 2-ethylmercapto-4-amino-5-thiocarbamoylthiazole (49% of theory) of melting point 180°-183° C. are obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([NH2:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O-])([O-])=O.[K+].[K+].ClC(OCC)=O.B>C1COCC1.O>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C@H:10]([NH:21][CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: NC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: B
Agent: CCOC(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 51.5 %

Procedure:
To a solution of rac-(3S,4R)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylamine (0.54 g, 1.68 mmol) in THF (5 ml) was added a solution of K2CO3 (0.46 g, 3.36 mmol) in H2O (3 ml). After 10 minutes, ethyl chloroformate (0.18 ml, 1.85 mmol) was added and stirring was continued at RT for an additional 2 h. The intermediate carbamate was then extracted with Et2O, dried over Na2SO4 and concentrated under vacuo to give viscous oil. The oil was taken up in THF (5 ml) and a solution of borane in THF (1M) was added (6.7 ml). The reaction mixture was then heated at 65° C. over night, cooled to RT and carefully quenched with conc. HCl (5 ml). The mixture was then heated at 80° C. for 2 h, cooled to RT, concentrated under vacuo, diluted with Et2O (20 ml) and neutralized with an aqueous solution of NaHCO3. The organic phases were dried over Na2SO4 and the product purified by flash chromatography (SiO2, CH2Cl2/MeOH 9:1) to afford 0.29 g (51%) of rac-[(3S,4R)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-amine as a colorless oil. ES-MS m/e: 335.3 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=3[O:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:19]([O-:24])([N+]([O-])=O)=[O:20].[OH-].[Na+].Cl>ClCCl.C(O)(=O)C>[N+:19]([C:8]1[O:9][C:10]2[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:12][C:11]=2[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([O-:24])=[O:20]
Reactant: O=C(O)c1ccc2c(-c3ccccc3)coc2c1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(-c3ccccc3)c([N+](=O)[O-])oc2c1
Reaction time: 70 h

Procedure:
A solution of 2 g of 3-phenyl-6-benzofurancarboxylic acid in 100 ml of dichloromethane and 20 drops of acetic acid is treated with 3.0 g of dinitrogen tetroxide. The mixture is stirred for about 70 hours then evaporated to provide a residue. The residue is treated with cold 5% sodium hydroxide solution until solution occurs. The solution is acidified with 6N hydrochloric acid and the yellow solid is collected and recrystallized from ethanol to provide 2-nitro-3-phenyl-6-benzofurancarboxylic acid, m.p. 244°-247° C.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][CH:22]1[CH2:27][NH:26][CH2:25][CH2:24][N:23]1[C:28]1[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:26]2[CH2:25][CH2:24][N:23]([C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)[CH:22]([CH3:21])[CH2:27]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Reactant: Cc1cccc(N2CCNCC2C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CCCN3CCN(c4cccc(C)c4)C(C)C3)nn2C(C)(C)C)cc1

Procedure:
71 mg (66%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (60 mg, 0.222 mmol), 2-methyl-1-rn-tolylpiperazine (42 mg, 0.222 mmol), DIPEA (0.06 mL, 0.333 rnmol) and NaBH(OAc)3 (141 mg, 0.666 mmol).
Reaction SMILES: C([NH+](CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O-:37])=[O:36])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1.C(N(CC)CC)C.[CH:45]1[C:50]([F:51])=[C:49]([F:52])[C:48](OC(C(F)(F)F)=O)=[C:47]([F:60])[C:46]=1[F:61]>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][C:45]2[C:50]([F:51])=[C:49]([F:52])[CH:48]=[C:47]([F:60])[C:46]=2[F:61])=[O:36])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:12][CH:11]=1
Reactant: O=C(Oc1c(F)c(F)cc(F)c1F)C(F)(F)F
Reactant: COc1ccc(C(NCCCCCC(=O)[O-])(c2ccccc2)c2ccccc2)cc1
Agent: CC[NH+](CC)CC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(NCCCCCC(=O)Oc2c(F)c(F)cc(F)c2F)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
The acid 6 obtained as described above (2.2 g, 4.4 mmol) was dissolved in anhydrous CH2Cl2 and treated with 1 ml of triethylamine followed by 0.8 ml of 2,3,5,6-tetrafluorophenyltrifluoroacetate. After being kept at room temperature for 30 min, the reaction was concentrated to an oil (crude 7), which then was re-suspended in 20% ethyl acetate/80%hexane and applied to a silica gel column. Elution with 15% ethyl acetate/85% hexane and concentration of the pure product fractions afforded 2.0 g (82%) of the TFP ester (7) as a colorless, viscous oil.
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].Br[CH2:23][CH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[CH2:30][CH2:29][CH2:28]2.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:23][CH2:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[CH2:30][CH2:29][CH2:28]3)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: BrCCc1ccc2c(c1)CCC2
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCN(CCc2ccc3c(c2)CCC3)C1

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.6 g--see Preparation 8), 5-(2-bromoethyl)indane (0.49 g--see Preparation 14), anhydrous potassium carbonate (0.6 g) and acetonitrile (20 ml) was heated under reflux for 1.25 hours. The mixture was partitioned between 10% aqueous potassium carbonate (10 ml) and dichloromethane (50 ml), the layers were separated and the aqueous layer extracted with dichloromethane (3×100 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 6%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield 0.29 g.
Reaction SMILES: [CH:1]1([O:5][C:6]2[CH:7]=[C:8]([N:14]3[CH2:19][CH2:18][NH:17][C@@H:16]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH2:15]3)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:4][CH2:3][CH2:2]1.[N:28]1[CH:33]=[CH:32][CH:31]=[N:30][C:29]=1[CH2:34][C:35](O)=[O:36]>>[CH:1]1([O:5][C:6]2[CH:7]=[C:8]([N:14]3[CH2:19][CH2:18][N:17]([C:35](=[O:36])[CH2:34][C:29]4[N:30]=[CH:31][CH:32]=[CH:33][N:28]=4)[C@@H:16]([CH2:20][C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)[CH2:15]3)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:2][CH2:3][CH2:4]1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccc(F)cc3)C2)cc1OC1CCC1
Reactant: O=C(O)Cc1ncccn1
Product: COc1ccc(N2CCN(C(=O)Cc3ncccn3)[C@@H](Cc3ccc(F)cc3)C2)cc1OC1CCC1
Yield: 81 %

Procedure:
Prepared by the method outlined for Example 189 using (S)-1-(3-cyclobutoxy-4-methoxyphenyl)-3-(4-fluorobenzyl)piperazine and 2-(pyrimidin-2-yl)acetic acid as starting materials. Product was obtained as a colorless solid (81%). LC/MS 3.59 min, [M+1]+ 491.
Reaction SMILES: C(OC(=O)N[C@@H](CC1C=CC=CC=1)[C@@H](O)[CH2:10][C@H:11]([C:13](=O)[NH:14]CCC(C)(C)C)[CH3:12])(C)(C)C.C(N)C(C)C.[CH:36]([O:39][C:40]1[CH:41]=[C:42]([CH:61]=[C:62]([N:64]2[CH2:68][CH2:67][CH2:66][C:65]2=[O:69])[CH:63]=1)[C:43]([NH:45][C@H:46]([C@@H:54]1[CH2:58][C@@H:57]([CH3:59])[C:56](=[O:60])[O:55]1)[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:44])([CH3:38])[CH3:37]>>[CH2:47]([C@H:46]([NH:45][C:43](=[O:44])[C:42]1[CH:61]=[C:62]([N:64]2[CH2:68][CH2:67][CH2:66][C:65]2=[O:69])[CH:63]=[C:40]([O:39][CH:36]([CH3:37])[CH3:38])[CH:41]=1)[C@@H:54]([OH:55])[CH2:58][C@H:57]([C:56](=[O:60])[NH:14][CH2:13][CH:11]([CH3:12])[CH3:10])[CH3:59])[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: CC(C)Oc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H]2C[C@@H](C)C(=O)O2)cc(N2CCCC2=O)c1
Reactant: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NCCC(C)(C)C
Solvent: CC(C)CN
Product: CC(C)CNC(=O)[C@H](C)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(OC(C)C)cc(N2CCCC2=O)c1

Procedure:
Prepared in an analogous manner to D1 from isobutylamine and 3-isopropoxy-N-[(S)-1-((2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl)-2-phenylethyl]-5-(2-oxopyrrolidin-1-yl)benzamide (D49).
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([O:7][C:8](=[O:13])[C:9]([CH2:11]O)=[CH2:10])[CH3:6].O>CCOCC>[CH2:5]([O:7][C:8](=[O:13])[C:9]([CH2:11][Br:2])=[CH2:10])[CH3:6]
Reactant: BrP(Br)Br
Reactant: C=C(CO)C(=O)OCC
Solvent: CCOCC
Solvent: O
Product: C=C(CBr)C(=O)OCC
Reaction time: 3 h
Yield: 123.1 %

Procedure:
Phosphorus tribromide (17.16 g, 63.41 mmol) was added to a stirred solution of the compound of example 30 (17.92 g, 138.1 mmol) in dry ether (132 mL) at −10° C. The temperature was allowed to rise to 20° C. and stirring was continued for 3 h. Water (80 mL) was then added at −10° C. and the mixture was extracted with hexane (3×45 mL). The organic extracts were washed with saturated sodium chloride solution (2×45 mL) and dried with anhydrous MgSO4. Evaporation of solvent under vacuum gave 15.07 g (yield 56.6%) of the crude product, which was used directly in the next reaction without any further purification. 1H NMR (CDCl3, 400 MHz) δ 6.25 (s, 1H), 5.88 (s, 1H), 4.2 (q, 2H), 4.11 (s, 2H), 1.25 (t, 3H); 13C NMR (CDCl3, 400 MHz) 166.7, 140.1, 125.3, 61.1, 53.9, 14.4.
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:14]=[CH:13][C:9](C(O)=O)=[CH:8][CH:7]=2)[CH2:5][CH2:4]1)#[N:2].C1(P([N:29]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>C(O)(C)(C)C>[NH2:29][C:9]1[CH:13]=[CH:14][C:6]([C:3]2([C:1]#[N:2])[CH2:5][CH2:4]2)=[CH:7][CH:8]=1
Reactant: N#CC1(c2ccc(C(=O)O)cc2)CC1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: N#CC1(c2ccc(N)cc2)CC1
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
750 mg (4 mmol) of 4-(1-cyano-cyclopropyl)-benzoic acid (Example 110b) in 20 ml of tert-butanol are stirred in presence of 0.86 ml (4 mmol) diphenylphosphoryl azide (DPPA, Fluka, Buchs, Switzerland) and 0.59 ml (4 mmol) triethylamine at 95° C. for 3 h. Are added 0.43 ml (2 mmol) DPPA and 0.29 ml (2 mmol) triethylamine and the reaction mixture is stirred at 95° C. for 30 min. The reaction mixture is evaporated to dryness and then is taken in EtOAc and washed with H2O, dried over Na2SO4, filtered and evaporated. The solid is separated by flash chromatography (CH2Cl2-MeOH 99:1). The purified compound is treated in 5 ml 4 M HCl in dioxane at rt for 2 h. The crude deprotected product is purified by flash chromatography (CH2Cl2-MeOH 98:2). The product is triturated in MeOH to give the title compound. Analytical HPLC: tret=3.68 minutes (Grad 2).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[C:9]2[C:10](=[O:15])[O:11][C:12](=O)[NH:13][C:8]=2[CH:7]=[C:6]([CH3:16])[CH:5]=1>CO>[NH2:13][C:8]1[CH:7]=[C:6]([CH3:16])[CH:5]=[C:4]([CH3:3])[C:9]=1[C:10]([O:11][CH3:12])=[O:15]
Reactant: Cc1cc(C)c2c(=O)oc(=O)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1c(C)cc(C)cc1N
Temperature: 60 °C
Yield: 86 %

Procedure:
To a stirred solution of sodium hydroxide (0.013 g, 0.33 mM) in methanol (1.7 mL) was added 5,7-dimethyl-2H-3,1-benzoxazine-2,4(1H)-dione (0.67 g, 3.5 mM). The mixture was heated to 60° C. and maintained at that temperature for 45 min during which vigorous gas evolution ensued and all solids dissolved completely. The solution was cooled and concentrated using a rotary evaporator. The residue was dissolved in ethyl acetate, and the ethyl acetate solution was washed with water, dried (Na2SO4), filtered and concentrated to provide the title compound (0.54 g, 86%) as a tan solid; MS(CI); 180 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11]([O:13][C:14](=[O:20])[CH:15](Br)[CH2:16][CH2:17][CH3:18])[CH3:12].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:11]([O:13][C:14](=[O:20])[CH:15]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8])[CH2:16][CH2:17][CH3:18])[CH3:12]
Reactant: CCCC(Br)C(=O)OCC
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(Oc1ccc(Cl)cc1C=O)C(=O)OCC
Temperature: 140 °C
Yield: 84.3 %

Procedure:
A mixture of 5-chloro-2-hydroxy-benzaldehyde (15 g, 0.1 mol), 2-bromo-pentanoic acid ethyl ester (27 g, 0.13 mol) and K2CO3 (27 g, 0.2 mol) in DMF (100 mL) was heated at 140° C. for 1 h. After cooled to room temperature, the mixture was poured into water and the water phase was extracted with EtOAc thrice. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column to give the title compound as a colorless oil (24 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:8](Cl)(Cl)Cl)[NH:5][C:6]=1[Cl:7].ClC1C(Cl)=NC(=C(Cl)Cl)[N:14]=1.Cl.N>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([C:8]#[N:14])[NH:5][C:6]=1[Cl:7]
Reactant: Clc1nc(C(Cl)(Cl)Cl)[nH]c1Cl
Reactant: ClC1=NC(=C(Cl)Cl)N=C1Cl
Agent: Cl
Agent: N
Solvent: CCO
Product: N#Cc1nc(Cl)c(Cl)[nH]1
Yield: 90 %

Procedure:
25.4 g (0.1 mol) of 4,5-dichloro-2-trichloromethyl-imidazole prepared by treating 4,5-dichloro-2-dichloromethylene-imidazole with dry HCl at -20° to +600° C., were introduced in small portions into 200 ml of ethanol saturated with ammonia, whilst cooling with ice and stirring vigorously. The mixture was stirred for a further 30 minutes at 50° C., the constituents which had not dissolved were then filtered off and the filtrate was evaporated under reduced pressure. The combined residues were dissolved in hot water. On acidifying the solution with dilute hydrochloric acid, the reaction product precipited out. This was filtered off, washed with water and dried. In this way 14.6 g (90% of theory) of 4,5-dichloro-2-cyano-imidazole were obtained and after recrystallisation from toluene this had a melting point of 187°-189° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.OC1C2N=NNC=2C=CC=1.[ClH:28].[C:29]([C:33]1[N:38]=[C:37]([N:39]2[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][CH2:47][CH2:48][NH:49][CH3:50])[CH2:41][CH2:40]2)[CH:36]=[C:35]([CH:51]2[CH2:54][CH2:53][CH2:52]2)[N:34]=1)([CH3:32])([CH3:31])[CH3:30].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[ClH:28].[C:29]([C:33]1[N:38]=[C:37]([N:39]2[CH2:40][CH2:41][N:42]([CH2:45][CH2:46][CH2:47][CH2:48][N:49]([CH3:50])[C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[CH2:43][CH2:44]2)[CH:36]=[C:35]([CH:51]2[CH2:54][CH2:53][CH2:52]2)[N:34]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CNCCCCN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1
Reactant: O=C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(CCCCN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1)C(=O)c1ccc(F)cc1
Reaction time: 16 h
Yield: 41.8 %

Procedure:
0.5 g of 4-fluorobenzoic acid (3.57 mmol) and 1.27 g of triethylamine (12.57 mmol) were dissolved in 40 ml of dimethylformamide. 0.5 g of hydroxybenzotriazole (HOBt, 3.7 mmol), 1.3 g of {4-[4-(2-tert-Butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-butyl}-methyl-amine hydrochloride (2.77 mmol), and 0.75 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDCl, 3.91 mmol) were added at room temperature, and the reaction mixture was stirred for 16 h. The reaction mixture was partitioned between water and ethyl acetate, the organic phase dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using dichloromethane-methanol (2%). The residue was re-dissolved in isopropanol, treated with 4 N hydrochloric acid in dioxan. The precipitate was collected by filtration and dried to yield 0.6 g of the title compound as a white solid.
Reaction SMILES: I[CH:2](I)[CH3:3].C(=O)([O-])[O-].[K+].[K+].[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[C:20]([F:23])[C:21]=1[F:22])[N:18]=[C:17]([SH:24])[C:16]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:15]2[OH:30]>CN(C)C=O>[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[C:20]([F:23])[C:21]=1[F:22])[N:18]1[CH:2]([CH3:3])[S:24][C:17]1=[C:16]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:15]2=[O:30]
Reactant: CC(I)I
Reactant: CCOC(=O)c1c(S)nc2c(F)c(F)c(F)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2n(c3c(F)c(F)c(F)cc3c1=O)C(C)S2
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
To 25 ml of N,N-dimethylformamide were added 12 g of diiodoethane and 8.3 g of potassium carbonate, a solution of 6.07 g of the compound obtained in Example 4 dissolved in 60 ml of N,N-dimethylformamide was gradually dropped thereinto, and the mixture was stirred for 30 minutes at the same temperature. N,N-Dimethylformamide was evaporated therefrom in vacuo, the residue was dissolved in a mixture of chloroform and methanol (2:1), washed with water, dried over magnesium sulfate, the solvent was evaporated therefrom, and the crystals separated out therefrom were washed with ether to give 3.35 g of ethyl 6,7,8-trifluoro-1-methyl-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate.