Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][C:20]([I:22])=[CH:21][C:16]=2[C:15](=[O:23])[N:14]([C@@H:24]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH3:25])[C@@H:13]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=2[O:40]CC=C)[C:12]1=[O:44])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CO>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:1]([O:5][C:6](=[O:45])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][C:20]([I:22])=[CH:21][C:16]=2[C:15](=[O:23])[N:14]([C@@H:24]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH3:25])[C@@H:13]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=2[OH:40])[C:12]1=[O:44])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCOc1cc(Cl)ccc1[C@H]1C(=O)N(CCCCC(=O)OC(C)(C)C)c2ccc(I)cc2C(=O)N1[C@H](C)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](c1ccc(Cl)cc1)N1C(=O)c2cc(I)ccc2N(CCCCC(=O)OC(C)(C)C)C(=O)[C@@H]1c1ccc(Cl)cc1O
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
5-[(3S)-3-(2-Allyloxy-4-chlorophenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-7-iodo-2,5-dioxo-1,4-benzodiazepin-1-yl]valeric acid tert-butyl ester (224 mg, 0.29 mmol) and dichloro bis(triphenylphosphine)palladium (II) (10 mg, 0.015 mmol) were dissolved at room temperature in THF (5 mL). Sodium borohydride (11 mg, 0.29 mmol) was added and the reaction was stirred under argon for 30 minutes. Methanol (10 mL) was added and the reaction was stirred for 15 additional minutes. The solvent was evaporated under vacuum and the residue was purified by column chromatography (AcOEt/Hexanes, 1:2) to give 200 mg of the title compound contaminated with 5-[(3S)-3-(2-Allyloxy-4-chlorophenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-2,5-dioxo-1,4-benzodiazepin-1-yl]valeric acid tert-butyl ester. This mixture was carried out to the next step without further purification.
Reaction SMILES: Br.Br[CH2:3][CH2:4][C:5]1[C:10](=[O:11])[N:9]2[CH2:12][CH2:13][S:14][C:8]2=[N:7][C:6]=1[CH3:15].[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C:24](=[N:31][OH:32])[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(=O)([O-])O.[Na+]>CC(C)CC(=O)C>[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C:24](=[N:31][OH:32])[N:25]1[CH2:30][CH2:29][N:28]([CH2:3][CH2:4][C:5]2[C:10](=[O:11])[N:9]3[CH2:12][CH2:13][S:14][C:8]3=[N:7][C:6]=2[CH3:15])[CH2:27][CH2:26]1
Reactant: Cc1nc2n(c(=O)c1CCBr)CCS2
Reactant: ON=C(c1ccc(F)cc1F)N1CCNCC1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: Cc1nc2n(c(=O)c1CCN1CCN(C(=NO)c3ccc(F)cc3F)CC1)CCS2
Reaction time: 20 h
Yield: 50.5 %

Procedure:
A mixture of 8 parts of 6-(2-bromoethyl)-2,3-dihydro-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one monohydrobromide, 4.8 parts of 1-[(2,4-difluorophenyl)(hydroxyimino)methyl]piperazine, 8 parts of sodium hydrogen carbonate and 180 parts of 4-methyl-2-pentanone was stirred for 20 hours at reflux temperature. The reaction mixture was filtered while hot and the filtrate was evaporated in vacuo. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was concentrated in vacuo. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 4.4 parts (50.5%) of 6-[2-[4-[(2,4-difluorophenyl)-(hydroxyimino)methyl]-1-piperazinyl]ethyl]-2,3-dihydro-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (int. 13).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][CH3:22])=[CH:16][CH:17]=4)[CH2:12][CH2:11]3)=[CH:4][C:3]=2[O:2]1.Cl.[CH3:24][OH:25]>>[OH:25][C:24]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][CH3:22])[CH:14]=2)[CH:10]([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)[CH2:11]1
Reactant: CCCOc1ccc2c(c1)CCC2c1ccc2c(c1)OCO2
Reactant: CO
Agent: Cl
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1O)CC2c1ccc2c(c1)OCO2
Yield: 94 %

Procedure:
To a solution of (1RS, 3RS)-3-[(2-methoxymethoxy)-4-methoxyphenyl)]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane (0.075 g, 0.16 mmol) in methanol (5 ml) was added 4-5 drops of 6M-HCl and the mixture refluxed for 1.5 h under argon. The solvent was removed in vacuo and the product partitioned between EtOAc and water. The organic extract was washed with water then sat. aq. NaHCO3 solution and finally brine. After drying (MgSO4 anhydrous) filtration and evaporation gave the title compound (0.064 g, 94%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1O)([O-:3])=[O:2].S([O-])([O-])=[O:12].[Na+].[Na+]>>[CH:9]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=1
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: O=S([O-])[O-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(O)cc1

Procedure:
The pH of the aqueous distillation residue can be adjusted by addition of acid or alkali. According to a preferred procedure, the slightly acid organic solution containing the nitrophenol isomers is neutralised by means of an aqueous solution of sodium sulphite the solvent followed by the o-nitrophenol are then removed to leave a slightly alkaline aqueous distillation residue of p-nitrophenol, to which a suitable amount of acid is added to adjust the pH. The acid may be a strong inorganic acid such as sulphuric acid or phosphoric acid or an organic acid such as acetic acid. The pH is preferably adjusted to 5.8 to 6.1 but in practice, it is very particularly recommended to adjust the pH of the aqueous solution of para-nitrophenol to pH 6.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:43]=[CH:42][C:12]([O:13][CH2:14][C@@H:15]([OH:41])[CH2:16][N:17]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([NH:33][CH:34]3[S:38][C:37](=[O:39])[NH:36][C:35]3=[O:40])=[CH:29][CH:28]=2)C(=O)OC(C)(C)C)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][C@@H:15]([OH:41])[CH2:16][NH:17][CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([NH:33][CH:34]3[S:38][C:37](=[O:39])[NH:36][C:35]3=[O:40])=[CH:31][CH:32]=2)=[CH:42][CH:43]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(NC2SC(=O)NC2=O)cc1)C[C@H](O)COc1ccc(OCc2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC(=O)C(Nc2ccc(CCNC[C@H](O)COc3ccc(OCc4ccccc4)cc3)cc2)S1
Yield: 58 %

Procedure:
This compound was prepared from tert-butyl (2S)-3-[4-(benzyloxy)phenoxy]-2-hydroxypropyl{4-[(2,4-dioxo-1,3-thiazolidin-5-yl)amino]phenethyl}carbamate and trifluoroacetic acid in substantially the same manner as described in example 1, step e, with one modification, the product was isolated as the free base and recrystallized from methanol, tetrahydrofuran, hexanes to give a yellow foam solid (58% yield): mp 152° C.; MS m/e 508 (M+H)+; 1H NMR (DMSO-d6 300 MHz) δ2.68 (m, 2H), 2.81 (m, 1H), 2.88 (m, 4H), 3.85 (m, 2H), 4.00 (m, 1H), 5.02 (s, 2H), 5.45 (br, 1H), 5.99 (d, 1H), 6.59 (d, 2H), 6.66 (d, 1H), 6.84 (d, 2H), 6.86 (m, 2H) 6.92 (m, 2H), 7.28 (m, 5H), 8.80 (br, 1 H);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[NH:24][C:25]([NH:27][CH:28]1[CH2:30][CH2:29]1)=[O:26])[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([C:16]([OH:18])=O)[CH:14]=2)[N:9]=[CH:8][CH:7]=1.[NH2:31][CH2:32][CH:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.CN([PH+](N(C)C)N(C)C)C>CN(C)C=O.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[NH:24][C:25]([NH:27][CH:28]1[CH2:29][CH2:30]1)=[O:26])[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([C:16]([NH:31][CH2:32][CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)=[O:18])[CH:14]=2)[N:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)c2cc1C(=O)O
Agent: CN(C)[PH+](N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)c2cc1C(=O)NCC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
4-(3-Chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylic acid) (171 mg, 0.40 mmol) was dissolved in dimethylformamide (4 ml) under a nitrogen atmosphere, and then tert-butyl 4-aminomethyl-1-piperidinecarboxylate (171 mg, 0.80 mmol), triethylamine (0.2 ml) and 1H-1,2,3-benzotriazol-1-yloxy)(tri(dimethylamino))phosphonium hexafluorophosphate (265 mg, 0.60 mmol) were added in that order at room temperature, and the mixture was stirred overnight. The reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was suspended in ethyl acetate and diluted with hexane, and the crystals were filtered out and blow-dried to obtain the title compound (249 mg, quantitative) as white crystals.
Reaction SMILES: F[C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[CH2:23]([N:27]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=1)[C:28]([C:30]1[C:34]([Cl:35])=[C:33]([CH3:36])[NH:32][N:31]=1)=[O:29])[CH2:24][CH2:25][CH3:26]>>[CH2:23]([N:27]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=1)[C:28]([C:30]1[C:34]([Cl:35])=[C:33]([CH3:36])[N:32]([C:2]2[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])=[CH:4][C:3]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:31]=1)=[O:29])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCN(Cc1ccc(Cl)c(Cl)c1)C(=O)c1n[nH]c(C)c1Cl
Reactant: CCOC(=O)c1cc(C(=O)OCc2ccccc2)ccc1F
Product: CCCCN(Cc1ccc(Cl)c(Cl)c1)C(=O)c1nn(-c2ccc(C(=O)OCc3ccccc3)cc2C(=O)OCC)c(C)c1Cl
Yield: 78328.7 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 1E, 1-benzyl 3-ethyl 4-fluoroisophthalate (Intermediate 91B, 270 mg, 0.89 mmol) and N-butyl-4-chloro-N-(3,4-dichlorobenzyl)-5-methyl-1H-pyrazole-3-carboxamide (Intermediate 179B, 502 mg, 1.34 mmol) were converted to the title compound (458 g, 78%). 1H NMR (CDCl3, mixture of amide rotamers) δ 8.68 (dd, J=19.3, 1.9 Hz, 1H), 8.33 (dt, J=7.9, 2.0 Hz, 1H), 7.54-7.34 (m, 8H), 7.24-7.07 (m, 1H), 5.43 (d, J=3.1 Hz, 2H), 4.79-4.63 (m, 2H), 4.19 (q, J=7.3 Hz, 1H), 3.94 (q, J=7.2 Hz, 1H), 3.48-3.33 (m, 2H), 2.16 (d, J=6.6 Hz, 3H), 1.68-1.46 (m, 2H), 1.41-1.31 (m, 1H), 1.25-1.14 (m, 2.5H), 1.09 (t, J=7.2 Hz, 1.5H), 0.96-0.88 (m, 1.5H), 0.79 (t, J=7.4 Hz, 1.5H); MS(ESI+) m/z 656.0 (M+H)+.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:18]([O:25][C:26](=[O:30])[CH2:27][CH2:28][NH2:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.Cl>C(Cl)Cl.O>[CH2:18]([O:25][C:26](=[O:30])[CH2:27][CH2:28][NH:29][C:3](=[O:4])[CH:2]([Br:1])[CH3:6])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCC(=O)OCc1ccccc1
Reactant: CC(Br)C(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Br)C(=O)NCCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
53.65 g (313 mmol) of 2-bromopropionic acid chloride is added in drops at 0° C. to 100 g (285 mmol) of β-alanine-benzyl ester-p-toluenesulfonic acid salt and 31.67 g (313 mmol) of triethylamine in 400 ml of methylene chloride. The temperature is not allowed to exceed 5° C. After addition is completed, it is stirred for 1 hour at 0° C., then for 2 hours at room temperature. 500 ml of ice water is added, and the water phase is set at pH 2 with 10% aqueous hydrochloric acid. The organic phase is separated, washed once each with 300 ml of 5% aqueous hydrochloric acid, 300 ml of 5% aqueous soda solution and 400 ml of water. The organic phase is dried on magnesium sulfate and evaporated to dryness in a vacuum. The residue recrystallizes from diisopropyl ether.
Reaction SMILES: [CH3:1][Si:2]([CH3:22])([CH3:21])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:18]=[C:17]([CH2:19][OH:20])[CH:16]=[CH:15][CH:14]=2)=[N:8]1.C(N(CC)C(C)C)(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)(Cl)Cl>[CH3:32][S:33]([O:20][CH2:19][C:17]1[N:18]=[C:13]([NH:12][C:9]2[CH:10]=[CH:11][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:22])([CH3:21])[CH3:1])[N:8]=2)[CH:14]=[CH:15][CH:16]=1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc(Nc2cccc(CO)n2)n1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ccc(Nc2cccc(COS(C)(=O)=O)n2)n1
Reaction time: 1 h

Procedure:
To a mixture of 10 mg of (6-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyridin-2-yl)methanol, 27 μl of N,N-diisopropylethylamine and 1 ml of chloroform was added 7.3 μl of methanesulfonyl chloride at room temperature followed by stirring for 1 hour. The reaction mixture was washed with brine, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was then concentrated in vacuo to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12]=C)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[O:14]=[O+][O-].CSC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12]=[O:14])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: C=Cc1ccc(Cl)cc1C(=O)OC
Reactant: O=[O+][O-]
Solvent: CSC
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)ccc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
Into a solution of methyl 5-chloro-2-vinylbenzoate (16.3 g, 82.89 mmol) in dry DCM (250 mL) was bubbled O3 at −78° C. over a 30 minute period. Next, nitrogen gas was bubbled into the solution until it turned colorless. Dimethylsulfane (10.3 g, 165.79 mmol) was added dropwise. The resulting mixture was warmed to RT, stirred for 2 hours, and concentrated. The crude product was purified by silica gel column chromatography eluting with petroleum ether and ethyl acetate (PE/EtOAc=40:1) to give the title compound as a white solid (10 g, 60%). 1H NMR (400 MHz, CDCl3) δ ppm 10.52 (s, 1H), 7.89 (d, J=2.0 Hz, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.55 (dd, J=8.0 Hz and 2.0 Hz, 1H), 3.93 (s, 3H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][NH:6][CH2:5]2.[CH3:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:24][C@@H:25]([CH3:30])[C:26]([F:29])([F:28])[F:27])=[C:19]([CH:23]=1)[C:20](O)=[O:21])(=[O:14])=[O:13]>>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:20]([C:19]1[CH:23]=[C:15]([S:12]([CH3:11])(=[O:13])=[O:14])[CH:16]=[CH:17][C:18]=1[O:24][C@@H:25]([CH3:30])[C:26]([F:28])([F:29])[F:27])=[O:21])[CH2:5]2
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: Ic1ccc2c(c1)CNC2
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccc(I)cc2C1)C(F)(F)F

Procedure:
Prepared in analogy to Example 1 from 5-Iodo-2,3-dihydro-1H-isoindole (example A38(a)) and 5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (example B3). Off white solid. MS (m/e): 539.1 (M+, 100%).
Reaction SMILES: [CH2:1]([N:8]1[C:12](Br)=[C:11]([N+:14]([O-:16])=[O:15])[C:10]([Br:17])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([NH2:20])[CH3:19]>>[CH2:1]([N:8]1[C:12]([NH:20][CH2:18][CH3:19])=[C:11]([N+:14]([O-:16])=[O:15])[C:10]([Br:17])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1c(Br)nn(Cc2ccccc2)c1Br
Reactant: CCN
Product: CCNc1c([N+](=O)[O-])c(Br)nn1Cc1ccccc1
Yield: 89 %

Procedure:
3.61 (10 mmoles) of 1-benzyl-3,5-dibromo-4-nitropyrazole are heated at 60° C. in 120 ml of a 30-percent aqueous ethylamine solution for 1 hour. After cooling, the product separates in the form of colorless crystals with a melting point of 122° C. 2.88 g (89 percent of theory) of 1-benzyl-3-bromo-5-ethylamino-4-nitropyrazole are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([S:19](F)(=[O:21])=[O:20])[N:13]=1>>[Cl:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([Cl:10])[C:3]=1[NH:4][S:19]([C:14]1[N:13]=[C:12]([CH3:11])[CH:17]=[C:16]([CH3:18])[N:15]=1)(=[O:20])=[O:21]
Reactant: Cc1cc(C)nc(S(=O)(=O)F)n1
Reactant: Cc1ccc(Cl)c(N)c1Cl
Product: Cc1cc(C)nc(S(=O)(=O)Nc2c(Cl)ccc(C)c2Cl)n1

Procedure:
This material was prepared from 2,6-dichloro-3-methylaniline and 4,6-dimethyl-2-pyrimidinesulfonyl fluoride following the general procedure described in Example 2. The desired product was isolated as a solid, m.p. 234°-235°. NMR (90 MHZ) D6 -Acetone: δ 7.4 (d, 2H), 7.3 (s, 1H), 2.5 (s, 6H) and 2.3 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)([CH2:14][CH2:15]OS(C)(=O)=O)[O:11][CH2:10][C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:41]([N:44]([C:46]1([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)[CH3:45])(=[O:43])[CH3:42].C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.C(Cl)Cl.CCOCC.O>[OH2:11].[ClH:27].[C:41]([N:44]([C:46]1([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:47][CH2:48][N:49]([CH2:15][CH2:14][C:12]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)[CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9](=[O:29])[CH2:10][O:11]2)[CH2:50][CH2:51]1)[CH3:45])(=[O:43])[CH3:42]
Reactant: CC(=O)N(C)C1(c2ccccc2)CCNCC1
Reactant: CS(=O)(=O)OCCC1(c2ccc(Cl)c(Cl)c2)CN(Cc2ccccc2)C(=O)CO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CC(=O)N(C)C1(c2ccccc2)CCN(CCC2(c3ccc(Cl)c(Cl)c3)CN(Cc3ccccc3)C(=O)CO2)CC1
Temperature: 90 °C
Yield: 79.6 %

Procedure:
A mixture of 1.1 g of the compound obtained in step B of EXAMPLE 14, 1.85 g of 4-(acetyl-N-methylamino)-4-phenylpiperidine p-toluenesulfonate and 1.3 g of K2CO3 in 3 ml of DMF is heated at 80-100° C. for 2 hours. After cooling to RT, the reaction mixture is poured into water and extracted with ether, the organic phase is washed with water and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using a DCM/MeOH mixture (from 100/1; v/v to 100/4; v/v) as the eluent. The product obtained is dissolved in DCM, a saturated solution of hydrochloric acid in ether is added until the pH is 1, and the precipitate formed is wrung tio give 0.62 g of the expected product. M.p.=148-150° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:44][O:45][C:46]1[C:51]2[N:52]=[C:53]([NH2:55])[O:54][C:50]=2[C:49]([CH:56]2[CH2:61][CH2:60][O:59][CH2:58][CH2:57]2)=[CH:48][CH:47]=1>C1COCC1.O1CCOCC1.CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:55][C:53]1[O:54][C:50]2[C:49]([CH:56]3[CH2:57][CH2:58][O:59][CH2:60][CH2:61]3)=[CH:48][CH:47]=[C:46]([O:45][CH3:44])[C:51]=2[N:52]=1)=[O:7]
Reactant: O=C(O)c1ccnc(Br)c1
Reactant: COc1ccc(C2CCOCC2)c2oc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C2CCOCC2)c2oc(NC(=O)c3ccnc(Br)c3)nc12
Reaction time: 5 h
Yield: 84.4 %

Procedure:
To a stirred solution of 106 mg (0.52 mmol) 2-bromo-isonicotinic acid in 5 ml THF were added 230 mg (0.60 mmol) HATU and 0.10 ml (0.60 mmol) N-ethyldiisopropyl-amine and stirring continued at room temperature for 5 h. A solution of 100 mg (0.40 mmol) 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzooxazol-2-ylamine in 5 ml dioxane and 1 ml DMF was then added and stirring continued at 40° C. for 72 h. The reaction mixture was then poured into 100 ml water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (dichoromethane then methanol/dichloromethane 20/80) followed by trituration in ether afforded 146 mg (84%) 2-bromo-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzooxazol-2-yl]-isonicotinamide as a white crystalline solid. ES-MS m/e (%): 434 (M{81Br}+H+, 95), 432 (M{79Br}+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[N:4][C:3]=1[C:15]([NH2:17])=[O:16].[CH:18](N)=O>>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][N:6]1[C:2]2[N:1]=[CH:18][NH:17][C:15](=[O:16])[C:3]=2[N:4]=[N:5]1
Reactant: NC=O
Reactant: NC(=O)c1nnn(Cc2ccccc2F)c1N
Product: O=c1[nH]cnc2c1nnn2Cc1ccccc1F
Temperature: 0 °C

Procedure:
70,5 g (0.3 mol) of 5-amino-1-(2-fluorobenzyl)-1H-1,2,3-triazole-4-carboxamide and 339 g (300 ml; 7.53 mol) of formamide are heated at a gentle boil for 2 hours. The reaction solution is then allowed to cool to approximately 100° and poured onto 2 l of ice-water. The precipitated product is filtered off with suction and washed with water. Drying at 100° yields 3-(2-fluorobenzyl)-3H,6H,7H-1,2,3-triazolo[4,5-d]pyrimidin-7-one having a melting point of 215°-218°.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C1(C)C(C)=CC=CC=1>[CH2:20]([NH:19][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[C:1]1([NH:7][C:8]([N:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)Nc1ccccc1
Agent: CCCCCCCCNCCCCCCCC
Solvent: Cc1ccccc1C
Product: CCCCCCCCN(CCCCCCCC)C(=O)Nc1ccccc1

Procedure:
Phenylurea and dioctylamine were heated in xylene, with vigorous stirring, under various conditions. Samples were withdrawn from the mixture after specific reaction times, the solvent was evaporated from each of the samples at 65° C. in vacuo and the residue was taken up in CDCl3, in which phenylurea is virtually insoluble and in which N-phenyl-N',N'-dioctylurea and dioctylamine on the other hand are completely soluble. The precipitated phenylurea was filtered off and a 1H-NMR spectrum of the filtrate was prepared. The particular molar ratio of dioctylamine to the N-phenyl-N',N'-dioctylurea formed was determined by integrating the signals from the --N--CH2 protons of the dioctylamine (2.75 ppm) and the N-phenyl-N',N'-dioctylurea formed (3.28 ppm), from which was derived the degree of conversion.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@@H:8]([C:20](=[O:37])[NH:21][C@@H:22]([C:34](=[S:36])[NH2:35])[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:6][NH:7][C@H:8]([CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[C:20]([NH:21][C@@H:22]([C:34](=[S:36])[NH2:35])[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)=[O:37]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)N[C@H](Cc1ccc2ccccc2c1)C(N)=S
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N[C@H](Cc1ccc2ccccc2c1)C(N)=S
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
N-Methyl-N-((1R)-2-(2-naphthyl)-1-((1R)-2-(2-naphthyl)-1-thiocarbamoylethylcarbamoyl)ethyl)carbamic acid tert-butylester (0.25 g; 0.462 mmol) was dissolved in methylene chloride (1.5 ml) and trifluoroacetic acid (1.5 ml) was added. The reaction mixture was stirred 1 h at RT. The solvent was removed in vacuo and the residue was dissolved in methylene chloride (5 ml) and washed with aqueous sodium hydrogencarbonate (5 ml). The organic phase was dried (Magnesium sulfate) and the solvent was removed in vacuo to afford 0.201 g of (2R)-2-methylamino-3-(2-naphthyl)-N-((1R)-2-(2-naphthyl)-1-thiocarbamoylethyl)propionamide.