Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([Cl:8])=[O:7].C(N(CC)CC)C.[NH2:21][C:22]1[CH:23]=[C:24]([CH:40]=[CH:41][C:42]=1[Cl:43])[NH:25][C:26]1[C:35]2[C:30](=[CH:31][C:32]([O:38][CH3:39])=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][N:27]=1>C(Cl)Cl>[ClH:8].[Cl:43][C:42]1[CH:41]=[CH:40][C:24]([NH:25][C:26]2[C:35]3[C:30](=[CH:31][C:32]([O:38][CH3:39])=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][N:27]=2)=[CH:23][C:22]=1[NH:21][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc2ncnc(Nc3ccc(Cl)c(N)c3)c2cc1OC
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2cc(Nc3ncnc4cc(OC)c(OC)cc34)ccc2Cl)cc1OC
Product: Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3,4-Dimethoxybenzoyl chloride (200 mg) and triethylamine (0.125 ml) were added to a suspension of 4-(3-amino-4-chloroanilino)-6,7-dimethoxyquinazoline (150 mg) in dry methylene chloride (3 ml) and the mixture was stirred at ambient temperature for 18 hours. The reaction mixture was diluted with methylene chloride and washed with water and brine and evaporated. The residue was triturated with diethyl ether (3×100 ml). The resulting solid was stirred in ethereal hydrogen chloride at ambient temperature for 18 hours and the mixture was evaporated to dryness. The resulting solid was triturated with isohexane and dried under vacuum. The title compound was obtained as a solid (30 mg); NMR: 3.85 (s, 6H), 3.92 (s, 3H), 3.96 (s, 3H), 6.98 (m, 1H), 7.32 (s, 1H), 7.45 (m, 2H), 7.65 (m, 2H), 7.99 (m, 1H), 8.15 (s, 1H), 8.88 (s, 1H), 9.98 (s, 1H), 11.32 (s, 1H); m/s: M+H+ 495, 497.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([C:21]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([BH3-])#N.[Na+]>C(O)C>[CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([CH2:13][N:24]2[CH2:25][CH2:26][C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:22][CH2:23]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccn(Cc2ccccc2)n1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: c1ccc(Cn2ccc(CN3CCC(c4ccccc4)(c4ccccc4)CC3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The product from step (a) (0.17 g) was dissolved in ethanol (3 ml) and a solution of 4,4-diphenylpiperidine (0.118 g) in ethanol (1 ml) added. A solution of sodium cyanoborohydride (1.0 M in tetrahydrofuran, 3.0 ml) was added and the solution stirred at room temperature for 16 hours. Silica gel was added, the solvent removed by evaporation and the crude material purified by chromatography (dichloromethane:methanol, 100:0 to 95:5) to give the product as an oil. Further purification by supercritical fluid chromatography gave the product as a solid (0.010 g), m.p. 167-168° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=1[O:18]C)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.I.Br>C(O)(=O)C>[CH2:1]([C:8]1[CH:13]=[C:12]([C:14]([CH3:16])([CH3:15])[CH3:17])[CH:11]=[CH:10][C:9]=1[OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: COc1ccc(C(C)(C)C)cc1Cc1cccnc1
Agent: Br
Agent: I
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(O)c(Cc2cccnc2)c1
Yield: 34.6 %

Procedure:
1.56 g of the compound obtained in Example 3 (b) above was dissolved in 6 ml of acetic acid and 1.2 ml of 57% hydroiodic acid and 1.0 ml of 47% hydrobromic acid were added thereto, followed by heat-refluxing for 30 hours. The mixture was concentrated under reduced pressure, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried, concentrated, and the residue was chromatographed on silica gel column using a mixed solvent of methylene chloride: ethyl acetate (20:1 by volume) as an eluting agent to obtain 510 mg of the title compound having the following properties.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([N:9]([CH2:12][C:13]([OH:15])=O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:28]1([C:31](=[N:33]O)[NH2:32])[CH2:30][CH2:29]1.O>CN(C=O)C>[CH:28]1([C:31]2[N:33]=[C:13]([CH2:12][N:9]3[C:7](=[O:8])[C:5]4=[CH:6][CH:1]=[CH:2][CH:3]=[C:4]4[C:10]3=[O:11])[O:15][N:32]=2)[CH2:30][CH2:29]1
Reactant: NC(=NO)C1CC1
Reactant: O=C(O)CN1C(=O)c2ccccc2C1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1nc(C2CC2)no1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
N-Phthaloylglycine (90.7 g, 442 mmol) was dissolved in portions (because of clumping) in DMF (500 mL). 1,1′-Carbonyldiimidazole (78.9 g, 486 mmrol) was added in portions (attention CO evolution). The resulting suspension was heated at 80° C. for 20 min. and then cooled to rt, then cyclopropanecarboxamidoxime 1 added and then heated at 110° C. for 2 h. The solution was cooled to rt, then poured into water (4 L), stirred for 15 min, filtered, washed with water (400 mL) and (fried. Yield: 104 g (87%). Mp 115° C. m/z 269 (M).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([N:13]2[CH2:17][CH:16]([C:18](Cl)=[O:19])[CH2:15][C:14]2=[O:21])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:24]([NH2:27])[CH2:25][CH3:26]>C1C=CC=CC=1>[CH2:24]([NH:27][C:18]([CH:16]1[CH2:17][N:13]([C:5]2[CH:4]=[C:3]([C:2]([F:23])([F:22])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)[C:14](=[O:21])[CH2:15]1)=[O:19])[CH2:25][CH3:26]
Reactant: O=C(Cl)C1CC(=O)N(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Reactant: CCCN
Solvent: c1ccccc1
Product: CCCNC(=O)C1CC(=O)N(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Yield: 81.1 %

Procedure:
3.59 g (0.01 mole) of the 1-(3,5-bis-trifluoromethylphenyl)-2-oxo-pyrrolidine-4-carboxylic acid chloride, produced according to Example 4, paragraph 1, is dissolved in 400 ml of benzene, and 1.2 g (0.02 mole) of N-n-propylamine is added to the solution. After subsequent processing as described in Example 4 there is obtained 3.1 g (81% of theory) of 1-(3,5-bis-trifluoromethylphenyl)-2-oxo-pyrrolidine-4-carboxylic acid-N-n-propylamide; m.p. 152.5° - 154° C. Analysis for C16H16F6N2O2 (molar weight 382.32):
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](Cl)=[N:11][OH:12])[CH:5]=1.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)#[CH:16].N1C=CC=CC=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[O:12][N:11]=2)[CH:5]=1
Reactant: C#Cc1ccc(C)cc1
Reactant: COC(=O)c1cccc(C(Cl)=NO)c1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(-c2cc(-c3ccc(C)cc3)on2)c1
Temperature: 25 °C

Procedure:
In a 25 ml round flask, 1.9 g (8.9 mmol) of 3-[chloro-(hydroxyimino)-methyl]-benzoic acid methyl ester and 1.03 g (8.9 mmol) of 1-ethynyl-4-methyl-benzene are dissolved in 12 ml of CHCl3 at 0° C. To this solution, 36 μl (0.4 mmol, 0.05 eq.) of pyridine and subsequently 1.24 ml (8.9 mmol) of triethyl amine are added and the mixture is stirred under warming to room temperature for 2 h. Then, the mixture is poured onto water, extracted twice with CH2Cl2, the organic layers are dried with brine and Na2SO4 and then concentrated. Chromatographic purification (250 g SiO2; gradient elution, eluent: hexane/ethyl acetate 95:5→9:1) yields the title compound as a white solid. Mass spectrum: m/z (M+H)+: 294.2
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].Cl[C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][N:17]=1)[C:13]#[N:14]>C1COCC1>[F:3][C:4]([F:8])([F:7])[CH2:5][O:6][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][N:17]=1)[C:13]#[N:14]
Reactant: OCC(F)(F)F
Reactant: N#Cc1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccnc(OCC(F)(F)F)c1
Temperature: 25 °C

Procedure:
To the suspension of NaH (2.78 g, 0.11 mole) in THF 100 mL) 2,2,2-trifluoroethanol (10 g, 0.1 mol) was added slowly. The mixture was stirred at RT till it turned clear. A solution of 2-chloro-isonicotinonitrile (13.8 g, 0.1 mol) in THF (100 mL) was slowly added and stirred at reflux for 3 h. After filtration and concentration, the crude oily compound was purified through column chromatography providing pure compound as an oil.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:4].[OH-].[K+]>CO.O>[CH2:14]([O:13][C:11]([N:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C@H:5]1[C:3]([OH:4])=[O:2])=[O:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.2 %

Procedure:
To a stirred solution of (S)-piperidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (8.0g, 28.8 mmol) in MeOH (75 mL ) and water (38 mL ) at 0° C. was added powdered KOH (1.78 g, 31.7 mmol). The reaction mixture was allowed to stir for 16 h at room temperature and then the MeOH was removed in vacuo. The residue was diluted with water and washed DCM. The aqueous layer was acidified with 1.0-M HCl and extracted with ethyl acetate three times. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound as pale yellow oil (7.6 g, 100%): 1H NMR (400 MHz, CD3OD) δ 1.36–1.61 (2H, m), 1.70–1.85 (3H, m), 2.28–2.40 (1H, m), 3.05–3.26 (1H, m), 4.06–4.14 (1H, m), 4.89–5.26 (4H, m), 7.37–7.48 (5H, m); 13C NMR (100 MHz, CD3OD) δ 20.5, 20.6 (CH2), 24.6, 24.7 (CH2), 26.6 (CH2), 41.8, 41.9 (CH2), 54.5, 54.7 (CH), 67.2, 67.3 (CH2), 127.6 (CH), 127.9 (CH), 128.4 (CH), 136.9 (C), 173.4 (CO).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.C1(N=C=NC2CCCCC2)CCCCC1.[OH:25][C:26]1[C:27]([N+:36]([O-:38])=[O:37])=[C:28]([CH3:35])[CH:29]=[CH:30][C:31]=1C(O)=O.ClCCl>CN(C=O)C>[CH3:1][O:2][C:3](=[O:9])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:31]1[CH:30]=[CH:29][C:28]([CH3:35])=[C:27]([N+:36]([O-:38])=[O:37])[C:26]=1[OH:25]
Reactant: Cc1ccc(C(=O)O)c(O)c1[N+](=O)[O-]
Reactant: COC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1c1ccc(C)c([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
16.5 g of L-proline methyl ester and 27.2 g of N,N'-dicyclohexylcarbodiimide were successively added to an ice-cooled and constantly stirred solution of 25.2 g of 3-hydroxy-2-nitro-p-toluic acid dissolved in a mixture consisting of 480 ml of dichloromethane and 43 ml of N,N'-dimethylformamide. The whole mixture was stirred at ice-cooled temperature for 1 hour and then at room temperature for 1 hour. After the reaction, the separated crystalline precipitate was filtered off, and the filtrate was washed with 10% aqueous hydrochloric acid, 5% aqueous solution of sodium hydrogen carbonate and 5% aqueous solution of sodium carbonate. The layer of 5% aqueous solution of sodium carbonate was acidified with hydrochloric acid and extracted with chloroform. The chloroform layer was dehydrated and concentrated. The residue was recrystallized from 50% ethanol, and there was obtained 32.7 g of 1-(3-hydroxy-2-nitro-p-toluyl)-L-proline methyl ester as yellow-colored prismatic crystal having a melting point of 111° to 113.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([CH3:21])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1.[CH2:23](O)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]C.C([Sn](=O)CCCC)CCC>CO>[CH2:1]([O:2][C:3](=[O:22])[CH:4]([CH3:21])[CH2:5][C:6]1[CH:7]=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]([OH:16])=[C:10]([C:12]([CH3:14])([CH3:13])[CH3:15])[CH:11]=1)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23]
Reactant: COC(=O)C(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CCCCCCCCCCCCO
Agent: CCCC[Sn](=O)CCCC
Solvent: CO
Product: CCCCCCCCCCCCOC(=O)C(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 100 °C

Procedure:
30.6 g (0.1 mol) of methyl-2-methyl-3-(3',5'-di-tert.-butyl-4'-hydroxyphenyl)-propionate and 18.6 g (0.1 mol) of 1-dodecanol are placed in a 4-necked glass flask and heated to 100° C., then 0.25 g=1 mol % of dibutyltin oxide is added and the mixture is heated further to 180° C., with methanol being split off. The reaction mixture is maintained at 180° C. for 6 hours.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[CH2:9]([Mg]Br)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:1][C:2]1[CH:7]=[C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:5]([Br:8])=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:9]([C:2]1[CH:7]=[CH:6][C:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:4][CH:3]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCC[Mg]Br
Reactant: Brc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCCCCCCCCCc1cc(Br)c(CCCCCCCCCC)cc1Br
Product: CCCCCCCCCCc1ccc(CCCCCCCCCC)cc1

Procedure:
2,5-Dibromo-1,4-didecylbenzene is prepared from 1,4-dibromobenzene in two steps according to literature procedures: decylmagnesium bromide is coupled to 1,4 dibromobenzene using PdCl2(dppf) to yield 1,4-didecylbenzene, which is subsequently treated with bromine to afford 2,5-dibromo-1,4-didecylbenzene.
Reaction SMILES: [OH-].[Na+].[O:3]=[CH:4][C@@H:5]([C@H:7]([C@@H]([C@@H](CO)O)O)O)[OH:6].[Na+].[Cl-].C([C:22]1([O:31][C@H:30]([CH2:32][OH:33])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]1[NH2:25])[OH:23])(=O)C(C)O>O>[C:4]([NH:25][C@@H:24]1[C@@H:26]([OH:27])[C@H:28]([OH:29])[C@@H:30]([CH2:32][OH:33])[O:31][CH:22]1[OH:23])(=[O:3])[CH:5]([CH3:7])[OH:6]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(O)C(=O)C1(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1N
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(O)C(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
30 g of liquid product as described in example 2 was dissolved in 120 g of water. The pH of the solution was adjusted to 6 with 50% NaOH solution. Finally 60 g of maltodextrin (with a dextrose equivalent of 10) and 30 g of NaCl were dissolved in the solution. The viscous liquid obtained was then spray-dried to get a powder flavour ingredient containing N lactoyl glucosamine.
Reaction SMILES: [C:1]1([C:7]2[CH:17]=[N:16][C:10]3[O:11][CH2:12][C:13](=[O:15])[NH:14][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Br:18][C:17]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][C:9]2[NH:14][C:13](=[O:15])[CH2:12][O:11][C:10]=2[N:16]=1
Reactant: O=C1COc2ncc(-c3ccccc3)cc2N1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1COc2nc(Br)c(-c3ccccc3)cc2N1
Temperature: 80 °C
Yield: 90.5 %

Procedure:
In a 10 ml microwave vial was 7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (50 mg, 0.221 mmol) and N-bromosuccinimide (78.6 mg, 0.441 mmol) in dimethylformamide (1 ml). The reaction mixture was heated to 80° C. under microwave irradiation for 30 minutes. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (10 ml). The organic solution was washed with water (2×10 ml) and brine (2×10 ml). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified via Biotage chromatography (gradient 0% to 5% methanol in dichloromethane) to give the title compound as a yellow solid (61 mg, 90%). 1H NMR (500 MHz, CD3OD) δ 7.48-7.32 (5H, m), 7.12 (1H, s), 4.82 (2H, s).
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([CH3:10])[NH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:18][CH2:19][OH:20]>CC#N.C(Cl)Cl>[CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([CH3:10])[N:4]([CH2:18][CH2:19][OH:20])[N:3]=1
Reactant: Cc1n[nH]c(C)c1[N+](=O)[O-]
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1nn(CCO)c(C)c1[N+](=O)[O-]
Temperature: 90 °C

Procedure:
To a solution of 3,5-dimethyl-4-nitro-1H-pyrazole (500 mg, 3.52 mmol) in MeCN (5 mL), Cs2CO3 (1.26 g, 3.87 mmol) and 2-bromoethanol (0.3 mL, 4.21 mmol) was added. The resulting mixture was refluxed (90° C.) for 3 h, then the reaction mixture was allowed to reach rt. The mixture was diluted with DCM, filtered, the filter cake rinsed with DCM and the filtrate concentrated in vacuo. The residue was partitionned between water and EtOAc, the org. layer was separated and the aq. layer was extracted with EtOAc (1×). The combined org. layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to yield 2-(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)ethanol as a white solid. LC-MS conditions A: tR=0.53 min, [M+H]+=186.39.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][N:4]=1.[CH3:11][S:12]([C:15]1[CH:41]=[CH:40][C:18]([CH2:19][NH:20][C:21]([C:23]2[C:28](=[O:29])[C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]([F:38])[F:37])[CH:31]=3)=[C:26]([CH3:39])[NH:25][CH:24]=2)=[O:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13]>>[CH3:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([CH2:19][NH:20][C:21]([C:23]2[C:28](=[O:29])[C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]([F:37])[F:38])[CH:31]=3)=[C:26]([CH3:39])[N:25]([CH2:2][C:3]3[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][N:4]=3)[CH:24]=2)=[O:22])=[CH:40][CH:41]=1)(=[O:14])=[O:13]
Reactant: N#Cc1ccc(CBr)nc1
Reactant: Cc1[nH]cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)c1-c1cccc(C(F)F)c1
Product: Cc1c(-c2cccc(C(F)F)c2)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cn1Cc1ccc(C#N)cn1

Procedure:
Example 40 is prepared as described for example 2.1, substituting benzyl bromide with 6-bromomethyl-nicotinonitrile and substituting preparation 5 with preparation 39a. ESI mass spectrum: [M+H]+=563; Retention time HPLC: 0.99 min (Z018_S04).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.Cl[CH2:10][CH2:11][N:12]([CH2:35][CH2:36]Cl)[C:13]1[CH:33]=[C:32]([Cl:34])[C:16]2[O:17][C:18]3[C:27]([CH3:28])=[CH:26][C:25]([C:29]([OH:31])=[O:30])=[CH:24][C:19]=3[S:20](=[O:23])(=[O:22])[CH2:21][C:15]=2[CH:14]=1.[CH3:38]O>>[CH3:38][O:31][C:29]([C:25]1[CH:26]=[C:27]([CH3:28])[C:18]2[O:17][C:16]3[C:32]([Cl:34])=[CH:33][C:13]([N:12]4[CH2:11][CH2:10][N:1]([CH2:2][C:3]5[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=5)[CH2:36][CH2:35]4)=[CH:14][C:15]=3[CH2:21][S:20](=[O:23])(=[O:22])[C:19]=2[CH:24]=1)=[O:30]
Reactant: CO
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N(CCCl)CCCl)cc1CS2(=O)=O
Reactant: NCc1cccnc1
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(Cc4cccnc4)CC3)cc(Cl)c1O2
Temperature: 70 °C

Procedure:
3-Aminomethyl-pyridine (0.66 mL, 6.25 mmol) was added to a solution of Example 102j (0.6 g, 1.25 mmol) in methanol (10 mL), followed by addition of n-tetrabutylammonium iodide (0.010 g, 0.027 mmol) in an atmosphere of nitrogen and sealed in a pressure reactor vessel at 110° C. for 6 h. The reaction mixture was brought to room temperature, concentrated, treated with methanolic HCl solution, and refluxed at 70° C. for 6 h. It was concentrated, treated with water, aqueous sodium bicarbonate solution to neutral pH and the solid that separated was washed with water dried, and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound as a white solid. Yield: 0.160 g, (25%); 1H NMR (DMSO-d6): δ 2.70 (s, 3H, CH3), 3.20-3.60 (m, 8H, 4CH2), 3.65 (s, 2H, CH2), 3.90 (s, 3H, OCH3), 5.10 (s, 2H, CH2), 7.05 (s, 1H, Ar), 7.20 (s, 1H, Ar), 7.40 (t, 1H, Ar), 7.75 (d, 1H, Ar), 8.10 (s, 1H, Ar), 8.20 (s, 1H, Ar), 8.50 (d, 1H, Ar), 8.55 (s, 1H, Ar); MS: m/e (CI+) 528 (M+1).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][N:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=[O:15])[N:5]=1)(=[O:3])[NH2:2].[CH3:17]C1N=CC=C2C=NNC=12>>[C:1]([C:4]1[C:12]2[C:7](=[C:8]([CH3:17])[N:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=[O:15])[N:5]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1nn(CC(=O)O)c2cnccc12
Reactant: Cc1nccc2cn[nH]c12
Product: Cc1nccc2c(C(N)=O)nn(CC(=O)O)c12

Procedure:
was prepared using the same procedure as for the preparation of 2-(3-carbamoyl-1H-pyrazolo[3,4-c]pyridin-1-yl)acetic acid starting from 7-methyl-1H-pyrazolo[3,4-c]pyridine (Scheme A26). MS (LC-MS): 235 [M+H]+, tR (HPLC conditions k): 0.6 min.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(Cl)Cl.C(N(CC)CC)C.[C:15](N=[N+]=[N-])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>O>[C:15]([CH:3]=[CH:2][CH2:1][NH2:4])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: C=CCN
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C=CCN
Temperature: 25 °C
Reaction time: 16.5 h

Procedure:
A mixture of 3.00 ml of allylamine, 30 ml of CH2Cl2, 5.85 ml of triethylamine and 5.81 ml of BOC-azide is prepared at 0° C. and stirred at 25° C. for 16.5 hours while protected from moisture. It is then treated with 2 ml of water for 20 minutes, evaporated, treated with ethyl acetate, extracted successively with water, aqueous pH 2 phosphate buffer, water, aqueous K2HPO4 and brine, dried with MgSO4, filtered and evaporated to afford 5.54 g of product, m.p. 37° C.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1O.CI>CC(C)=O>[Br:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[O:4][CH3:1]
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Cl)cc1Br
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(Cl)cc1Br
Temperature: 25 °C

Procedure:
A mixture of K2CO3 (68 g, 0.5 mol), 2-bromo-4-chlorophenol (50 g, 0.24 mol) and MeI (42.6 g, 0.3 mol) in acetone (1000 mL) was heated to reflux for 5 h and then cooled to room temperature. The solid was filtered off and washed with dichloromethane (100 mL×3). The combined filtrate was concentrated to dryness. The residue was diluted with diethyl ether (500 mL) and washed with 1N HCl (100 mL×2), H2O (100 mL×2) and brine (200 mL). The separated organic layer was dried over Na2SO4 and concentrated to give 2-bromo-4-chloroanisole 4a as light yellow liquid. 1H NMR (CDCl3): δ 7.52 (d, J=2.8 Hz, 1H), 7.24 (q, J1=8.8 Hz, J2=2.8 Hz, 1H), 6.81 (d, J=8.8 Hz, 1H), 3.86 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][CH2:14][C:15]1[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=1.C(N1C=CN=C1)([N:25]1C=CN=C1)=O.[OH-].[NH4+]>CN(C=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][CH2:14][C:15]1[S:16][C:17]([C:20]([NH2:25])=[O:22])=[CH:18][N:19]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1onc(-c2ccccn2)c1CCc1ncc(C(=O)O)s1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccn2)c1CCc1ncc(C(N)=O)s1
Temperature: 60 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To a solution of 2-[2-(5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (73 mg, 0.23 mmol) in DMF (3 mL) was added 1,1′-carbonyldiimidazole (45 mg, 0.28 mmol). The resulting reaction mixture was stirred for 1 h at 60° C. and then treated with an ammonium hydroxide solution (357 μL, 2.3 mmol) and stirred overnight at room temperature. The reaction mixture was then evaporated. Purification by chromatography (silica, 0 to 10% methanol in dichloromethane) afforded the title compound (51 mg, 70%) as an off white solid. MS: m/e=315.0 [M+H]+.