Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].C(OC(N[C@H](C(O)=O)CC1C=CC(O)=CC=1)=O)(C)(C)C>C(O)CCC>[NH2:1][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4]
Reactant: NCC(O)c1cccc(Cl)c1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Solvent: CCCCO
Product: NC[C@H](O)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 28.7 %

Procedure:
The concentrate (3.38 g) containing 15.0 mmol of 2-amino-1-(3-chlorophenyl)ethanol obtained in the same manner as in Example 295 was added to 20 ml of n-butanol and dissolved at 50° C. The mixture was added with 20 ml of n-butanol containing 2.10 g (7.5 mmol) of N-t-butoxycarbonyl-L-tyrosine (hereinafter briefly referred to as Boc-L-Tyr) with stirring slowly to separate crystals. After cooling to room temperature, the crystals were isolated by filtration to afford 1.95 g (4.31 mmol) of (R)-2-amino-1-(3-chlorophenyl)ethanol.Boc-L-Tyr salt The yield based on the concentrate was 58.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:15]=2)=[O:13])=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:26][C:27]1[CH:28]=[CH:29][C:30]([N:33]2[CH2:38][CH2:37][N:36]([CH2:39][CH3:40])[CH2:35][CH2:34]2)=[N:31][CH:32]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:39]([N:36]1[CH2:35][CH2:34][N:33]([C:30]2[N:31]=[CH:32][C:27]([NH:26][C:4](=[O:5])[C:3]3[CH:7]=[C:8]([NH:11][C:12]([C:14]4[CH:19]=[CH:18][N:17]=[C:16]([N:20]5[CH2:25][CH2:24][O:23][CH2:22][CH2:21]5)[CH:15]=4)=[O:13])[CH:9]=[CH:10][C:2]=3[Cl:1])=[CH:28][CH:29]=2)[CH2:38][CH2:37]1)[CH3:40]
Reactant: CCN1CCN(c2ccc(N)cn2)CC1
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1ccnc(N2CCOCC2)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN(c2ccc(NC(=O)c3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.8 %

Procedure:
2-Chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)benzoic acid (0.162 g) was added to a stirred mixture of 5-amino-2-(4-ethylpiperazin-1-yl)pyridine (0.093 g), diisopropylethylamine (0.232 g), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) (0.176 g) and DMF (10 ml) and the mixture was stirred at ambient temperature for 16 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and evaporated. The residue was triturated under a mixture of isohexane and ethyl acetate. The resultant solid was isolated and dried under vacuum at 40° C. to give the title compound (0.071 g); NMR Spectrum: (DMSOd6) 1.02 (t, 3H), 2.34 (m, 2H), 2.4-2.46 (m, 4H), 3.38-3.42 (m, 4H), 3.5-3.53 (m, 4H), 3.69-3.71 (m, 4H), 6.82 (d, 1H), 7.08 (d, 2H), 7.22 (s, 1H), 7.62 (d, 1H), 7.82-7.98 (m, 3H), 8.28 (d, 1H), 8.39 (s, 1H); Mass Spectrum: M+H+ 550 and 552.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:27])=[CH:4][C:5]([F:26])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([N+:19]([O-:21])=[O:20])=[C:15](F)[CH:16]=3)[C:11](=[O:22])[C:10]([C:23]([OH:25])=[O:24])=[CH:9]2)[CH:7]=1.[NH3:28].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[NH2:28][C:15]1[CH:16]=[C:17]2[C:12]([C:11](=[O:22])[C:10]([C:23]([OH:25])=[O:24])=[CH:9][N:8]2[C:6]2[CH:7]=[C:2]([NH2:1])[C:3]([F:27])=[CH:4][C:5]=2[F:26])=[CH:13][C:14]=1[N+:19]([O-:21])=[O:20]
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc([N+](=O)[O-])c(F)cc32)c(F)cc1F
Reactant: N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc([N+](=O)[O-])c(N)cc32)c(F)cc1F
Temperature: 50 °C
Reaction time: 15 h
Yield: 72 %

Procedure:
1-(5-Amino-2,4-difluorophenyl)-7-fluoro-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (70 mg) was added to a mixed liquid of 28% aqueous ammonia (85 mg) and pyridine (2 ml), and the mixture was stirred at 50° C. for 15 hours. The reaction mixture was acidified with 3% citric acid (20 ml), and solids formed were collected by filtration. The solids were subjected to azeotropic distillation with ethanol and toluene. Hexane was added to the residue to conduct filtration, thereby obtain the title compound (50 mg) as a yellow powder.
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[O:22][CH2:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[F:31].[C:32]([O:37][CH2:38][CH3:39])(=[O:36])[C:33]#[C:34][CH3:35].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:30][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([F:31])[C:24]=1[CH2:23][O:22][C:16]1[N:15]2[N:14]=[C:34]([CH3:35])[C:33]([C:32]([O:37][CH2:38][CH3:39])=[O:36])=[C:20]2[CH:19]=[C:18]([CH3:21])[CH:17]=1
Reactant: Cc1cc[n+](N)c(OCc2c(F)cccc2F)c1
Reactant: CC#CC(=O)OCC
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cc(C)cc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 33.9 %

Procedure:
1.62 g (3.60 mmol, 1.0 eq.) of 1-amino-2-[(2,6-difluorobenzyl)oxy]-4-methylpyridinium 2,4,6-trimethylbenzenesulphonate from Example 2A were dissolved in 36 ml of DMF, and 0.84 ml (7.19 mmol, 2.0 eq.) of ethyl but-2-ynoate [CAS No: 4341-76-8] were added. 0.994 g (7.19 mmol, 2.0 eq.) of potassium carbonate was added and the mixture was stirred at RT for 1.5 h. Subsequently, the mixture was poured onto 150 ml of water and stirred briefly, and the precipitated solids were filtered off, washed with water and dried. 440 mg of the title compound were obtained (45% of theory, 87%).
Reaction SMILES: C(O[C:6](=[O:30])[CH:7]([CH2:28][CH3:29])[CH2:8][C:9](=[O:27])[C@@H:10]([N:12]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:11])(C)(C)C.C(OC(=O)C(Br)CC)(C)(C)C.C[C:43]([CH:45]([N:47](CC1C=CC=CC=1)[CH2:48][C:49]1C=CC=CC=1)C)=O.NO>>[CH2:45]([N:47]([CH2:48][CH3:49])[C:6](=[O:30])[CH:7]([CH2:28][CH3:29])[CH2:8][C:9](=[O:27])[C@@H:10]([N:12]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:11])[CH3:43]
Reactant: CCC(CC(=O)[C@H](C)N(Cc1ccccc1)Cc1ccccc1)C(=O)OC(C)(C)C
Reactant: CC(=O)C(C)N(Cc1ccccc1)Cc1ccccc1
Agent: CCC(Br)C(=O)OC(C)(C)C
Agent: NO
Product: CCC(CC(=O)[C@H](C)N(Cc1ccccc1)Cc1ccccc1)C(=O)N(CC)CC

Procedure:
Examples 10 and 11 provide a detailed description for the preparation of (5S)-5-(N,N-dibenzylamino)-2-ethyl-4-oxo-hexanoic acid-tert-butyl ester from tert-butyl-2-bromobutyrate and α-(N,N-dibenzylamino)ethyl methyl ketone. This compound is reduced to the corresponding amino alcohol as described in detail above.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Br[CH2:10][CH:11]1[O:15][CH2:14][CH2:13][O:12]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:10][CH:11]1[O:15][CH2:14][CH2:13][O:12]1
Reactant: BrCC1OCCO1
Reactant: Sc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccccc1SCC1OCCO1
Reaction time: 8 h

Procedure:
To a mixture of 2-bromothiophenol (5 g) and 2-bromomethyl-1,3-dioxolane (2.98 mL) in N,N-dimethylformamide (50 mL) was added potassium carbonate (5.48 g) at room temperature, and the mixture was stirred overnight. The reaction mixture was poured into water, and the mixture was extracted with diethyl ether. The extract washed with water, 1 mol/L sodium hydroxide aqueous solution, water and brine successively, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give (2-bromophenylthiomethyl)-1,3-dioxolane (7.25 g). To a mixture of poly phosphoric acid (20 g) and chlorobenzene (40 mL) was added a solution of (2-bromophenylthiomethyl)-1,3-dioxolene (7.25 g) in chlorobenzene (20 mL), and the mixture was refluxed for 8 hours. The reaction mixture was cooled to room temperature and supernatant solution was collected by decantation. Toluene was added to the residue, and the supernatant was collected by decantation after the mixture was stirred. The supernatant was combined and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution washed with a saturated sodium hydrogencarbonate aqueous solution, water and brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane) to give the title compound (2.27 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]([NH2:22])([CH3:21])[CH3:20].O=CC1C=CC(O)=C(OC)C=1>C(OCC)(=O)C.CCCCCC>[CH:19]([NH:22][C:16](=[O:18])[C@@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])([CH3:21])[CH3:20]
Reactant: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)N
Agent: COc1cc(C=O)ccc1O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)[C@H](NC(=O)OCc1ccccc1)C(C)C

Procedure:
Reaction of N-benzyloxycarbonyl-D-valine with isopropylamine by the method of Example 20, Part A afforded a quantitative yield of N-benzyloxycarbonyl-D-valine isopropylamide of R 0.61 (TLC, ethyl acetate/hexane, 1:1, vanillin spray).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=2[CH3:18])=[CH:6][CH:5]=1)([O-])=O.O.NN>C(O)C.[Pd]>[CH3:18][C:12]1[C:13]([CH3:17])=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=1
Reactant: Cc1cccc(Oc2ccc([N+](=O)[O-])cc2)c1C
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1cccc(Oc2ccc(N)cc2)c1C
Temperature: 90 °C
Reaction time: 1 h
Yield: 105 %

Procedure:
2,3-dimethylphenyl 4-nitrophenyl ether (Intermediate 73, 865 mg) was dissolved in ethanol (10 mL) to give a pale yellow solution. Hydrazine hydrate 50% (0.698 mL, 7.1 mmol) and Pd/C (37.8 mg, 0.36 mmol) were added. The reaction mixture was stirred at 90° C. for 1 hour. The reaction mixture was filtered and the organic phase was evaporated under vacuum to afford the title compound as a pale yellow oil (796 mg).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: COc1ccccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: Brc1ccccn1
Product: COc1ccccc1-c1cccc(-n2cnc(C(=O)c3ccccn3)c2)c1

Procedure:
This compound is prepared by method C using compound 12c and 2-bromopyridine
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][C:14]#[CH:15])[C:6](=[O:16])[C:5]2=[O:17].[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:27](=[O:29])[CH3:28])=[CH:19]1.CNC>CO>[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:27](=[O:29])[CH2:28][C:5]2([OH:17])[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=3)[N:7]([CH2:11][CH2:12][CH2:13][C:14]#[CH:15])[C:6]2=[O:16])=[CH:19]1
Reactant: C#CCCCN1C(=O)C(=O)c2cc(C)ccc21
Reactant: CC(=O)c1c[nH]c2ccccc12
Agent: CNC
Solvent: CO
Product: C#CCCCN1C(=O)C(O)(CC(=O)c2c[nH]c3ccccc23)c2cc(C)ccc21
Temperature: 100 °C

Procedure:
To a clean dry Biotage microwave vial equipped with a stir bar was added the 5-methyl-1-(pent-4-yn-1-yl)indoline-2,3-dione (0.015 grams, 0.066 mmol), 1-(1H-indol-3-yl)ethanone (0.19 grams, 0.12 mmol, purchased from Fisher scientific) and 0.2 mL of methanol. 9.0 μL of dimethyl amine (40% by weight in water) was then added and the solution was placed in a Biotage initiator and heated at 100° C. for thirty minutes. The solution was then concentrated and purified on a Teledyne ISCO using hexanes and ethyl acetate. Yield, 20%. 1H-NMR δ 9.15 (bs, 1H), 8.33 (m, 1H), 7.69 (s, 1H), 7.39 (m, 1H) 7.38 (m, 1H), 7.27 (m, 2H), 7.10 (d, 1H), 6.84 (d, 1H), 5.58 (bs, OH), 3.81 (p, 2H), 3.49 (d, 1H), 3.24 (d, 1H) 2.28 (m, 5H), 2.01 (t, 1H), 1.92 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[CH:10]([OH:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:3]=1.[Si:20](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CN=C1.Cl>CN(C)C=O.C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[CH:10]([O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCC(O)/C=C/c1cccc(Br)n1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCCCCC(/C=C/c1cccc(Br)n1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.4 %

Procedure:
A solution of 4 g of 2-bromo-6-[(1E)-(3RS)-3-hydroxy-1undecenyl]-pyridine in 20 ml of dimethylformamide is mixed with 4.1 g of tert-butyldiphenylsilyl chloride and 2.1 g of imidazole and stirred for 15 hours at room temperature. The reaction mixture is poured into 100 ml of diethyl ether, shaken out twice with 20 ml of 1 n hydrochloric acid, 4 times with 20 ml of saturated common salt solution, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with hexane/0-5% ethyl acetate. 5.5 g of 2-bromo-6[(1E)-(3RS)-3-tert-butyldiphenylsilyloxy-1-undecenyl]-pyridine is obtained as oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][C:6]=1[NH2:14].[CH3:15][C:16]1[N:17]=[C:18]([S:21](Cl)(=[O:23])=[O:22])[S:19][CH:20]=1.COC(C)(C)C>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][C:6]=1[NH:14][S:21]([C:18]1[S:19][CH:20]=[C:16]([CH3:15])[N:17]=1)(=[O:23])=[O:22]
Reactant: Cc1csc(S(=O)(=O)Cl)n1
Reactant: COCOc1cc2c(cc1N)CCC2
Solvent: COC(C)(C)C
Solvent: c1ccncc1
Product: COCOc1cc2c(cc1NS(=O)(=O)c1nc(C)cs1)CCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.30 g of 6-(methoxymethoxy)indan-5-amine was dissolved in 33.0 mL of pyridine and 157 mL of a 0.54 M 4-methyl-1,3-thiazole-2-sulfonylchloride/tert-butyl methyl ether solution was added thereto, followed by stirring overnight at room temperature. The reaction liquid was concentrated under reduced pressure, to the residue were added water and ethyl acetate, and the insoluble materials were removed by filtration. After the filtrate was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=73:27 to 60:40) to obtain 4.79 g of N-[6-(methoxymethoxy)-2,3-dihydro-1H-inden-5-yl]-4-methyl-1,3-thiazole-2-sulfonamide.
Reaction SMILES: [C:1](N=NC(Cl)(C)C)(C)(C)[CH3:2].[K].C(OO)(C)(C)C.[C:18]([N:22]=[N:23][C:24]([O:27][O:28][C:29]([CH3:32])(C)C)([CH3:26])[CH3:25])([CH3:21])([CH3:20])[CH3:19].C(N=NC(O)(C)C)(C)(C)C>>[C:18]([N:22]=[N:23][C:24]([O:27][O:28][CH2:29][CH2:32][CH2:1][CH3:2])([CH3:25])[CH3:26])([CH3:19])([CH3:20])[CH3:21]
Reactant: CC(C)(C)N=NC(C)(C)OOC(C)(C)C
Reactant: CC(C)(C)N=NC(C)(C)Cl
Agent: CC(C)(C)N=NC(C)(C)O
Agent: CC(C)(C)OO
Agent: [K]
Product: CCCCOOC(C)(C)N=NC(C)(C)C

Procedure:
Crude 2-t-butylazo-2-butylperoxypropane was prepared by reacting 2-t-butylazo-2-chloropropane with an aqueous solution of the potassium salt of t-butyl hydroperoxide according to the method described in MacLeay, Lange and Sheppard application Ser. No. 426,411 filed Dec. 19, 1973, (which is incorporated herein by reference). The resultant product contained approximately 75% 2-t-butylazo -2-t-butylperoxypropane and 25% 2-t-butylazo-2-hydroxy-propane (which has been marketed as "LUCEL 3").
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].Br[C:9]1[N:10]=[CH:11][C:12]([C:22]([OH:24])=[O:23])=[N:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1.Cl>CN(C=O)C.O>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]2[N:13]=[C:12]([C:22]([OH:24])=[O:23])[CH:11]=[N:10][C:9]=2[O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[CH:20][CH:19]=1
Reactant: O=C(O)c1cnc(Br)c(-c2ccc(Cl)cc2)n1
Reactant: OCC1CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.3 %

Procedure:
Cyclopropylmethanol (1.54 g, 1.73 ml, 21.3 mmol) was diluted in dried DMF (15 mL); sodium hydride (512 mg, 21.3 mmol) was added in portions and the reaction mixture was stirred at room temperature for 15 minutes. The resulting solution was added slowly at <5° C. to a solution of 5-bromo-6-(4-chlorophenyl)pyrazine-2-carboxylic acid (CAN 960247-80-7; 3.040 g, 9.7 mmol) in dried DMF (15 mL). The reaction mixture was stirred at room temperature for 30 minutes; water was added and the mixture was acidified with 1M HCl solution to pH=2. The mixture was extracted with ethyl acetate; organic phases were combined, dried with MgSO4 and concentrated in vacuo. The crude did still contain starting material and was dissolved again in 15 mL DMF; a solution of cyclopropylmethanol (1.05 g, 1.18 ml, 14.5 mmol) and sodium hydride (582 mg, 14.5 mmol) in 15 mL DMF was added and the mixture was stirred at room temperature for 3 hours. Water was added and the reaction mixture was acidified with 1M HCl solution to pH 2; the product precipitated to give 2.55 g (86%) of the title compound as light yellow solid; MS (ESI) 303.2 (M−H)−.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH3:30][N:31]([CH3:42])[CH2:32][CH2:33][O:34][C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=1)[NH2:38]>CC(O)C.Cl.C(Cl)Cl>[CH3:30][N:31]([CH3:42])[CH2:32][CH2:33][O:34][C:35]1[CH:36]=[C:37]([NH:38][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:17]4[CH:18]=[C:19]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH:20]=[CH:21][CH:22]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)[CH:39]=[CH:40][CH:41]=1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)C(F)(F)F
Reactant: CN(C)CCOc1cccc(N)c1
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: CN(C)CCOc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)C(F)(F)F)c4)nn4ccccc34)n2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a suspension of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide (150 mg, 0.36 mmol) (see Example 1, Step C) in i-PrOH (4 mL) were added 3-{[2-(dimethylamino)ethyl]oxy}aniline (80 mg, 0.45 mmol) and 12 N HCl (3 drops). The reaction was stirred overnight at 80° C. The crude reaction mixture was diluted with DCM and extracted with saturated aqueous NaHCO3. The organic layer was dried over Na2SO4, filtered, and purified by column chromatography to generate the title compound in 84% yield. 1H NMR (400 MHz, d6-DMSO): δ 11.4 (bs, 1H), 9.58 (s, 1H), 8.85 (d, J=7.0 Hz, 1H), 8.50 (d, J=9.0 Hz, 1H), 8.28 (d, J=5.3 Hz, 1H), 8.00 (s, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.45-7.57 (m, 4H), 7.28 (d, J=9.4 Hz, 1H), 7.10-7.15 (m, 2H), 6.51-6.56 (m, 2H), 4.00 (t, J=5.7 Hz, 2H), 2.7 (bs, 2H), 2.35 (s, 6H). ES-LC/MS m/z=562 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[N+]([O-])([O-])=O.[Ag+:14]>O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[Ag:14]
Reactant: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: c1ccc2[nH]nnc2c1
Solvent: O
Product: [Ag]

Procedure:
A silver benzotriazole emulsion was prepared as follows: 28 g of gelatin and 13.2 g of benzotriazole were dissolved in 3,000 ml of water. The resulting solution was stirred at 40° C., while a solution of 17 g of silver nitrate dissolved in 100 ml of water was added to the solution in the course of 2 minutes.
Reaction SMILES: [S:1]1[C:5]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[N:4][N:3]=[N:2]1.[CH3:14][N:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16](Cl)=[O:17]>>[S:1]1[C:5]([NH:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][C:16](=[O:17])[N:15]([CH3:14])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:11][CH:12]=2)=[N:4][N:3]=[N:2]1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1ccc(Nc2nnns2)cc1
Product: CN(C(=O)Oc1ccc(Nc2nnns2)cc1)c1ccccc1

Procedure:
The title product was prepared from 4-(1,2,3,4-thiatriazol-5-ylamino)phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (10%, light brown solid material). HPLC-MS: m/z=328.0 (M+1); Rt: 3.69 min, purity 81%.
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].[NH2:14][C@H:15]([C:17]([N:19]([C:24]1[CH:28]=[CH:27][S:26][CH:25]=1)[CH2:20][C:21]([OH:23])=[O:22])=[O:18])[CH3:16].C([BH3-])#N.[Na+]>>[C:3]([CH:2]([NH:14][C@H:15]([C:17]([N:19]([C:24]1[CH:28]=[CH:27][S:26][CH:25]=1)[CH2:20][C:21]([OH:23])=[O:22])=[O:18])[CH3:16])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:5])=[O:4]
Reactant: C[C@H](N)C(=O)N(CC(=O)O)c1ccsc1
Reactant: O=C(O)C(=O)CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@H](NC(CCc1ccccc1)C(=O)O)C(=O)N(CC(=O)O)c1ccsc1

Procedure:
2-Oxo-4-phenylbutyric acid and L-alanyl-N-(3-thienyl)glycine are condensed in the presence of sodium cyanoborohydride to yield N-(1-carboxy-3-phenylpropyl)-L-alanyl-N-(3-thienyl)glycine.
Reaction SMILES: BrCCBr.[CH3:5][O:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][Br:15])=[CH:10][CH:9]=1.S([C:27]#[N:28])(C1C=CC(C)=CC=1)(=O)=O>C1COCC1.[Zn].Cl[Si](C)(C)C>[CH3:5][O:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][Br:15])=[C:10]([C:27]#[N:28])[CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: COC(=O)c1ccc(CBr)c(C#N)c1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 44.6 %

Procedure:
A suspension of zinc dust (792 mg, 12.12 mmol) and 1,2-dibromoethane (44 μL, 0.51 mmol) in THF (3 mL) was stirred at 70° C. for 10 minutes. The mixture was cooled to room temperature and chlorotrimethylsilane (45 μL, 0.36 mmol) was added. The mixture was cooled to 0° C. and a solution of methyl-4(bromomethyl)benzoate (2.314 g, 10.10 mmol) in THF (11 mL) was added at 0° C. over 2 hours and then stirred for an additional 2 hours at 0° C. The reaction mixture was cooled to −78° C. and a solution of tosyl cyanide (1.556 g, 8.59 mmol) in THF (11 mL) was added and the resultant mixture stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, diluted with CH2Cl2 (100 mL) and saturated aqueous NaHCO3 (15 mL) and filtered. The phases were separated and the aqueous layer was extracted with CH2Cl2 (3×50 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel (Hexanes/EtOAc, 10:1) afforded the desired nitrile (973 mg) as a 16:1 mixture (desired product/side product).