Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:11][O:10]2)=[CH:4][CH:3]=1.[OH2:12]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([OH:12])[CH2:11][OH:10])=[CH:6][CH:7]=1
Reactant: O
Reactant: Brc1ccc(CC2CO2)cc1
Solvent: C1COCCO1
Product: OCC(O)Cc1ccc(Br)cc1

Procedure:
A mixture of 90 parts of 2-(4-bromophenylmethyl)oxirane, 8 parts of ethanedoic acid, 100 parts of water and 300 parts of 1,4-dioxane is stirred and refluxed overnight. The reaction mixture is evaporated. The residue is dissolved in trichloromethane. The solution is washed with 110 parts of a sodium hydroxide solution 10%, dried, filtered and evaporated. The residue is distilled (bp. 165° C. at 0.6 mm. pressure). The distillate is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding 25 parts of 3-(4-bromophenyl)-1,2-propanediol; mp. 60.6° C.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([S:8][C@@H:9]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([OH:17])[C@H:11]([OH:18])[C@H:10]2[OH:19])[CH:2]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>O>[S:8]([C:3]1[CH:2]=[CH:1][C:6]([NH:7][C:20]([CH3:21])=[O:22])=[CH:5][CH:4]=1)[C@@H:9]1[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([OH:17])[C@H:11]([OH:18])[C@H:10]1[OH:19]
Reactant: Nc1ccc(S[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(S[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reaction time: 0.12 h

Procedure:
To a solution of 1.77 g of p-aminophenyl-1-thio-β-D-glucopyranoside in 10 ml of water was added 0.9 ml of acetic anhydride. The solution was shaken for 7 minutes, then taken to dryness and evaporated with toluene to a residue. This residue was crystallized from ethyl acetate giving 2.0 g of the desired product, mp. 160°-163° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=1.[CH3:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:8][C:6]1[CH:7]=[C:2]([N:23]2[CH:24]=[C:20]([CH3:19])[N:21]=[CH:22]2)[N:3]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:5]=1
Reactant: Cc1c[nH]cn1
Reactant: C[C@H](Nc1nc(Cl)cc(Cl)n1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cn(-c2cc(Cl)nc(N[C@@H](C)c3ccc(F)cc3)n2)cn1
Temperature: 100 °C
Reaction time: 17 h
Yield: 26.7 %

Procedure:
200 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine and 63 mg of 4-methylimidazole were dissolved in 2 ml of dimethylformamide, and 193 mg of potassium carbonate was added thereto, and the mixture was stirred at 100° C. for 17 hours. The reaction solution was diluted with water, and then subjected to extraction with ethyl acetate. The organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 62 mg of the objective compound as a white solid.
Reaction SMILES: P(O)(O)(O)=O.[CH3:6][C:7]1[C:12]([OH:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][CH:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH2:19][CH2:20][CH3:21])[N:8]=1.C(N(CC)CC)C.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37]>>[CH3:14][C:11]1[C:12]([O:13][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:7]([CH3:6])[N:8]=[C:9]([NH:15][CH2:16][CH:17]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:19][CH2:20][CH3:21])[N:10]=1
Reactant: CCCCC(CNc1nc(C)c(O)c(C)n1)c1ccccc1
Reactant: CCOC(=O)Cl
Agent: O=P(O)(O)O
Solvent: CCN(CC)CC
Product: CCCCC(CNc1nc(C)c(OC(=O)OCC)c(C)n1)c1ccccc1

Procedure:
In a manner similar to that of Example 1, the title compound was prepared from 4.71 g (12 mmol) of 4,6-dimethyl-5-hydroxy-2-phenylhexylaminopyrimidine phosphate salt, triethylamine (16.52 ml, 120 mmol) and ethyl chloroformate (1.7 ml, 18 mmol) to afford 3.8 g of product, mp: 44°-45° C. Mass spectrum m/e=371. NMR (CDCl3) delta: 7.34-7.16 (m, 5H): 5.00 (bs, 1H); 4.36 (q, 6, 3 Hz, 2H): 3.40 (q, 6, 3 Hz, 2H): 2.65, (t, 3 Hz, 2H); 1.74-1.36) (m, 11H). IR (CHCl3): 1761, 1583 cm-1. Anal. Calc'd for C21H29N3O3 : C, 67.90 H, 7.87; N, 11.31. Found: C, 67.95; H, 7.85; N, 11.14.
Reaction SMILES: C(O)(C(F)(F)F)=O.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:30][CH2:29][C:17]3([CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[CH2:16][CH2:15]2)[CH:9]=1>C(Cl)Cl>[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:30][CH2:29][C:17]3([CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:16][CH2:15]2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(c3cccnc3)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cncc(N2CCC3(CCNC3)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TFA (2 ml) was added to a solution of tert-butyl 8-(pyridine-3-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (1.14 mmol, 1.0 eq.) in methylene chloride (6 ml) at 0° C. and the reaction mixture was stirred at 25° C. for 2 h. When the reaction was complete, the solvent was concentrated in vacuo in order to obtain the desired amine (AMN-24).
Reaction SMILES: [NH2:1][O:2][CH2:3][S:4]([C:7]1[CH:8]=[C:9]([OH:14])[C:10](=[CH:12][CH:13]=1)[OH:11])(=[O:6])=[O:5].[NH2:15][C:16]1[S:17][CH:18]=[C:19]([C:21](=O)[C:22]([NH:24][C@@H:25]2[C:32](=[O:33])[N:31]3[C@@H:26]2[S:27][CH2:28][C:29]([CH2:37][S:38][C:39]2[CH:44]=[C:43]([CH3:45])[N:42]4[N:46]=[CH:47][C:48]([C:49]([OH:51])=[O:50])=[C:41]4[N:40]=2)=[C:30]3[C:34]([OH:36])=[O:35])=[O:23])[N:20]=1>>[NH2:15][C:16]1[S:17][CH:18]=[C:19](/[C:21](=[N:1]/[O:2][CH2:3][S:4]([C:7]2[CH:13]=[CH:12][C:10]([OH:11])=[C:9]([OH:14])[CH:8]=2)(=[O:5])=[O:6])/[C:22]([NH:24][C@@H:25]2[C:32](=[O:33])[N:31]3[C@@H:26]2[S:27][CH2:28][C:29]([CH2:37][S:38][C:39]2[CH:44]=[C:43]([CH3:45])[N:42]4[N:46]=[CH:47][C:48]([C:49]([OH:51])=[O:50])=[C:41]4[N:40]=2)=[C:30]3[C:34]([OH:36])=[O:35])=[O:23])[N:20]=1
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=O)c4csc(N)n4)[C@H]3SC2)nc2c(C(=O)O)cnn12
Reactant: NOCS(=O)(=O)c1ccc(O)c(O)c1
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\OCS(=O)(=O)c4ccc(O)c(O)c4)c4csc(N)n4)[C@H]3SC2)nc2c(C(=O)O)cnn12

Procedure:
307 mg of 4-[[(aminooxy)methyl]sulphonyl]pyrocatechol were reacted with 575 mg of (6R,7R)-7-(2-amino-4-thiazoleglyoxylamido)-3-[[(3-carboxy-7-methylpyrazolo[1,5-a]pyrimidin-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid in an analogous manner to the procedure described in Examples 11 or 7. There was obtained (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[(3-carboxy-7-methylpyrazolo[1,5-a]pyrimidin-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a white powder.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CCN(C(C)C)C(C)C>>[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[N:17]1[CH2:18][CH2:19][N:20]([CH2:2][C:3]2[S:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:21][CH2:22]1
Reactant: ClCc1nc2cccnc2s1
Reactant: c1csc(N2CCNCC2)n1
Solvent: CCN(C(C)C)C(C)C
Product: c1cnc2sc(CN3CCN(c4nccs4)CC3)nc2c1

Procedure:
The product from Example 38A (200 mg, 1.1 mmol), 1-(1,3-thiazol-2-yl)piperazine (219 mg, 1.3 mmol), and DIEA (340 μL, 2.1 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.71 (m, 4H) 3.46 (m, 4H) 4.06 (s, 2H) 6.86 (d, J=3.73 Hz, 1H) 7.17 (d, J=3.73 Hz, 1H) 7.56 (dd, J=8.14, 4.75 Hz, 1H) 8.33 (dd, J=8.14, 1.70 Hz, 1H) 8.59 (dd, J=4.58, 1.53 Hz, 1H). (ESI) m/z 318 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[CH:14][C:13](F)=[N:12][C:8]=2[N:9]=[CH:10][N:11]=1.Cl.[CH3:21][NH:22][CH3:23].CCN(CC)CC>CCO>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[CH:14][C:13]([N:22]([CH3:23])[CH3:21])=[N:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: Fc1ccc2c(Nc3cccc(Br)c3)ncnc2n1
Reactant: CNC
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C)c1ccc2c(Nc3cccc(Br)c3)ncnc2n1
Yield: 84 %

Procedure:
Reaction of 4-(3-bromoanilino)-7-fluoropyrido[2,3-d]pyrimidine (see a previous experimental) (0.12 g, 0.38 mmol) with dimethylamine. hydrochloride (92 mg, 1.13 mmol) and Et3N (0.18 mL, 1.32 mmol) in EtOH (15 mL) at 100° C. for 18 h in a pressure vessel, followed by evaporation of the solvent and workup, gives 4-(3-bromoanilino)-7-(dimethylamino)pyrido[2,3-d]pyrimidine (0.11 g, 84%). 1H NMR (DMSO) δ 9.58 (1H, brs), 8.56 (1H, d, J=9.3 Hz) 8.54 (1H, s), 8.18 (1H, t, J=1.9 Hz), 7.84 (dt, Jd=8.0, Hz, J=1.9 Hz), 7.33 (1H, dd, J=8.1, 8.0 Hz) 7.25 (1H, dt, Jd=9.3, Hz, Jt=1.9 Hz), 7.10 (1H, d, J=9.3 Hz), 3.18 (6H, s).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=[O:2].[C:13]1([Mg]Cl)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O1CCCC1>ClCCl>[OH:2][CH:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(O)c2ccccc2)cc1
Reaction time: 0.33 h

Procedure:
To a solution of methyl 4-formylbenzoate (2.83 g, 17.2 mmoles) at −78° C. in 60 mL of dichloromethane is added 10 mL a 2.0 M solution of phenylmagnesium chloride in tetrahydrofuran (20.0 mmoles) over 7 minutes. After stirring for an additional 20 minutes, the reaction was quenched with methanol then with saturated aqueous ammonium chloride. The aqueous layer was acidified with 1N hydrochloric acid and the phases were separated. The organic portion was washed with saturated aqueous sodium bicarbonate, brine and dried over magnesium sulfate. Removal of the volatiles under reduced pressure and purification over silica gel afforded the title ester.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:8][C:9]=1[CH:10]=[O:11])([O-:3])=[O:2].B1([O-])O[O:19]1.O.O.O.O.[Na+]>C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:8][C:9]=1[C:10]([OH:19])=[O:11])([O-:3])=[O:2]
Reactant: [O-]B1OO1
Reactant: O=Cc1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 86.3 %

Procedure:
This aldehyde (454 mg, 2.0 mmol) was dissolved in acetic acid (10 ml) and treated with sodium perborate tetrahydrate (385 mg, 2.5 mmol), the mixture was heated to 50° C. for 48 h then cooled, concentrated to a paste and washed with water (2×50 ml). The residue was dried in a desiccator to afford 3-nitrobiphenyl-4-carboxylic acid as a white solid (420 mg, 87%);
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=2)=[N:5][C:4]([CH2:25][NH2:26])=[N:3]1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1>[CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)[CH:13]=2)=[N:5][C:4]([CH2:25][NH:26][S:28]([CH3:27])(=[O:30])=[O:29])=[N:3]1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1nc(CN)nc1NCCCOc1cccc(CN2CCCCC2)c1
Solvent: c1ccncc1
Product: Cn1nc(CNS(C)(=O)=O)nc1NCCCOc1cccc(CN2CCCCC2)c1
Yield: 23 %

Procedure:
A solution of 1-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-1H-1,2,4-triazole-3-methanamine (0.5 g) and methane sulphonyl chloride (0.16 g) in pyridine (25 ml) was stirred at room temperature for 18 h. The solution was evaporated to give a brown oil which was crystallised from a mixture of ethyl acetate and petroleum ether (b.p. 60°-80°) to give the title compound (0.14 g) as a white powder, m.p. 117°-118°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH2:11][CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)=[CH:8][C:7]=2[CH:22]=1)#[N:2].O[N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=[N:25]1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N:24]1([O:18][C:17]([C:16]2[CH:20]=[CH:21][C:13]([CH2:12][CH2:11][C:9]3[O:10][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:22][C:7]=4[CH:8]=3)=[CH:14][CH:15]=2)=[O:19])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=[N:25]1
Reactant: N#Cc1ccc2oc(CCc3ccc(C(=O)O)cc3)cc2c1
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: N#Cc1ccc2oc(CCc3ccc(C(=O)On4nnc5ccccc54)cc3)cc2c1
Reaction time: 3 h
Yield: 78.5 %

Procedure:
At room temperature, 1 g of 4-[2-(5-cyano-2-benzofuranyl)ethyl]benzoic acid and 578 mg of 1-hydroxybenzotriazole were dissolved in 100 ml of dichloromethane, followed by the addition of 780 mg of 1,3-dicyclohexylcarbodiimide and by subsequent stirring at the same temperature for 3 hours. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using a chloroform/ethanol mixture as an elution solvent, and the thus purified product was crystallized from a benzene/n-hexane mixture. In this way, 1.1 g of 2-[2-[4-[[(1-benzotriazolyl)oxy]carbonyl]phenyl]ethyl]-5-benzofurancarbonitrile was obtained in a powdery form.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:18]([N:20]([CH2:23][CH2:24]Cl)[CH2:21][CH3:22])[CH3:19]>>[ClH:16].[CH2:18]([N:20]([CH2:23][CH3:24])[CH:21]([C:14]1[C:13]([Cl:16])=[CH:12][CH:11]=[C:10]2[C:15]=1[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[N:8][NH:9]2)[CH3:22])[CH3:19]
Reactant: Clc1ccc2[nH]nc(-c3ccccc3)c2c1
Reactant: CCN(CC)CCCl
Agent: Cl
Product: CCN(CC)C(C)c1c(Cl)ccc2[nH]nc(-c3ccccc3)c12
Yield: 140.1 %

Procedure:
By the procedure similar to that described in Example 1, 3-phenyl-5-chloroindazole (4.57 g) and diethylaminoethyl chloride hydrochloride (5.16 g) were treated to obtain 5.1 g of 1-diethylaminoethyl-3-phenyl-5-chloroindazole hydrochloride (m.p. 185°-186° C).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH:11]3[CH2:14][O:13][CH2:12]3)[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[CH3:17][S:18]([C:21]1[C:29]2[C:24](=[CH:25][N:26]=[CH:27][CH:28]=2)[NH:23][N:22]=1)(=[O:20])=[O:19]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH:11]3[CH2:14][O:13][CH2:12]3)[C:7]([CH2:9][N:23]3[C:24]4=[CH:25][N:26]=[CH:27][CH:28]=[C:29]4[C:21]([S:18]([CH3:17])(=[O:19])=[O:20])=[N:22]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1n[nH]c2cnccc12
Reactant: ClCc1nc2cc(Cl)ccc2n1C1COC1
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2C2COC2)c2cnccc12

Procedure:
The title compound was prepared in analogy to Example 2-1 by using 5-chloro-2-chloromethyl-1-oxetan-3-yl-1H-benzoimidazole and 3-methanesulfonyl-1H-pyrazolo[3,4-c]pyridine instead of 5-chloro-2-chloromethyl-1-((S)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-1H-benzoimidazole and 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[N:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Si:14]([O:13][CH:10]1[CH2:9][CH2:8][N:7]([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)[CH2:12][CH2:11]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cn1ccnc1N1CCC(O)CC1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cn1ccnc1N1CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(1-Methyl-1H-imidazol-2-yl)piperidin-4-ol (0.200 g, 1.10 mmol), tert-Butyldimethylsilyl chloride (0.333 g, 2.21 mmol), 4-Dimethylaminopyridine (30 mg, 0.2 mmol), 1H-Imidazole (225 mg, 3.31 mmol) and DCM (6.0 mL, 94 mmol) was stirred at ambient temperature for 1 h. The reaction mixture was diluted with DCM to ≈60 mL, washed with sat. NaHCO3 solution, water, and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel [Isco Combiflash, 2.5 g loading column/12 g column, eluting with DCM→5% MeOH in DCM]. Fractions containing the title compound were combined and dried in vacuo overnight, giving the title compound as yellow oil. 1H NMR (400 MHz, CDCl3): δ=6.77 (d, J=1.2 Hz, 1H), 6.65 (d, J=1.4 Hz, 1H), 3.85 (tt, J=8.0, 3.8 Hz, 1H), 3.47 (s, 3H), 3.28-3.21 (m, 2H), 2.91 (br ddd, J=12.0, 9.0, 3.0 Hz, 2H), 1.92-1.84 (m, 2H), 1.73-1.64 (m, 2H), 0.90 (s, 9H), 0.07 (s, 6H). MS (ES+): m/z=296.29 (100) [MH+]. HPLC: tR=3.22 min (verypolar—5 min, ZQ3). UV: λmax≈240 nm.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.[CH3:11][N:12]([CH3:17])[C:13](=[O:16])[CH2:14]Cl.C(=O)(O)[O-].[Na+].O1CCCC1>CO>[CH3:11][N:12]([CH3:17])[C:13](=[O:16])[CH2:14][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1
Reactant: CNCCc1ccncc1
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(CCc1ccncc1)CC(=O)N(C)C

Procedure:
4-[2-(methylamino)ethyl]pyridine (34.4 g) and 29.18 g of chloroacetic acid-dimethylamide are dissolved in 200 ml of methanol. After the addition of 20 g of sodium bicarbonate the mixture is refluxed for 5 hours with stirring. For working up the mixture is combined with 1000 ml of tetrahydrofuran, decanted off from the precipitated salts and the solution is filtered through active charcoal. After the limination of the solvent, N,N-dimethyl-2-[methyl-(2-pyridine-4-yl-ethyl)-amino]-acetamide is obtained as a crude product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:11][C:12]2[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=2)[CH:5]=[CH:4][CH:3]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]([O:10][C:28]2[CH:29]=[CH:30][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)=[O:9])=[C:6]([NH:11][C:12]2[N:13]=[C:14]([O:20][CH3:21])[CH:15]=[C:16]([O:18][CH3:19])[N:17]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OC)nc(Nc2cccc(Cl)c2C(=O)O)n1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1cc(OC)nc(Nc2cccc(Cl)c2C(=O)Oc2ccc([N+](=O)[O-])cc2)n1

Procedure:
This compound is prepared in a manner analogous to that of Example 1, Step G, using equimolar amounts of 6-chloro-2-(4,6-dimethoxypyrimidin-2-ylamino)benzoic acid, 4-nitrophenol, and dicyclohexylcarbodiimide in methylene chloride to yield 4-nitrophenyl 6-chloro-2-(4,6-dimethoxypyrimidin-2-ylamino)benzoate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:34])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH:22]([C:24]3[CH:29]=[CH:28][C:27]([S:30](=[O:33])(=[O:32])[NH2:31])=[CH:26][CH:25]=3)[CH3:23])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:35]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[CH2:36][CH2:37][CH3:38]>>[CH2:35]([N:39]1[CH2:44][CH2:43][N:42]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:34])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH:22]([C:24]4[CH:29]=[CH:28][C:27]([S:30](=[O:32])(=[O:33])[NH2:31])=[CH:26][CH:25]=4)[CH3:23])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:41][CH2:40]1)[CH2:36][CH2:37][CH3:38]
Reactant: CC(NS(=O)(=O)c1ccc(NC(=O)Nc2cccc(C#N)c2)cc1)c1ccc(S(N)(=O)=O)cc1
Reactant: CCCCN1CCNCC1
Product: CCCCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NC(C)c4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 8 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(1-(4-sulfamoylphenyl)ethyl)benzenesulfonamide following procedure C and using 2 equivalents of n-butylpiperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [CH2:1]([N:8]([CH3:29])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:25])([CH2:23][OH:24])[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:11][C:10]=1[N+:26]([O-:28])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[N-]>C(Cl)Cl>[CH2:1]([N:8]([CH3:29])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:25])([CH2:23][O:24][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:16]([N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)=[O:17])=[CH:11][C:10]=1[N+:26]([O-:28])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)c1ccc(C(C)(CO)C(=O)N2CCCC2)cc1[N+](=O)[O-]
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: ClCCl
Product: CCOC(=O)COCC(C)(C(=O)N1CCCC1)c1ccc(N(C)Cc2ccccc2)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
A solution of 8.0 g (20 mmol) of 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-hydroxy-1-pyrrolidino-propan-1-one and 5 ml (48 mmol) of ethyl diazoacetate in 50 ml of methylene chloride is mixed with 2.0 ml of boron trifluoride-diethylether complex (16 mmol) at room temperature and refluxed for 14 hours. After cooling, the reaction solution is stirred into ice water and the organic phase is separated off. The aqueous phase is extracted three times with methylene chloride, the combined organic phases are washed with saline solution, dried over sodium sulphate and concentrated by evaporation. The residue is dissolved in ethyl acetate and purified on silica gel, extracting initially with petroleum ether, then with petroleum ether/ethyl acetate (1:1). The uniform fractions are combined and concentrated by evaporation.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:37]=[CH:36][CH:35]=[CH:34][C:7]=1[C:8]([C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[S:17]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=O)(=[O:19])=[O:18])=[O:9]>C1C=CC=CC=1>[Cl:5][C:6]1[CH:37]=[CH:36][CH:35]=[CH:34][C:7]=1[C:8]([C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[S:17]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([Cl:3])=[O:33])(=[O:19])=[O:18])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCCCCCCCCNS(=O)(=O)c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Solvent: c1ccccc1
Product: O=C(Cl)CCCCCCCCCCNS(=O)(=O)c1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
19 g of redistilled thionyl chloride are added to 10.3 g of 11-[2-(2-chlorobenzoyl)-4-chlorobenzenesulphonamido]undecanoic acid in 130 ml of anhydrous benzene. After refluxing for 2 hours, the reaction medium is evaporated to dryness under vacuum and it gives a colourless oil which is used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][N:3]=1.[C-:10]#[N:11].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:10]#[N:11])=[CH:4][N:3]=1
Reactant: [C-]#N
Reactant: BrCc1ccc(Br)nc1
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 29.2 %

Procedure:
The 476 g of crude 2-bromo-5-bromomethylpyridine from step 4 was dissolved in 4000 mL of dimethylformamide (DMF)/water (7:1) and treated with 168 g (2.58 mol) of potassium cyanide. The reaction was allowed to stir at ambient temperature for 72 h, concentrated in vacuo, and partitioned between ethyl acetate and water; the organic layer was washed with water, washed with brine, dried (MgSO4), and reconcentrated in vacuo to provide the crude nitrile. Purification by silica gel chromatography (Waters Prep-500A) using ethyl acetate/hexane (25:75) gave 109 g (32% from 2-bromo-5-picoline) of 2-bromo-5-cyanomethylpyridine as a yellowish orange solid: mp 55.5°-57.5° C.; NMR (CDCl3) δ 3.74 (s, 2H), 7.54 (d, J=8 Hz, 1H), 7.59 (dd, J=8 and 2 HZ, 1H), 8.35 (d, J=2 Hz, 1H); MS (FAB) m/e (rel intensity) 199 (85), 197 (100).