Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH3:29][S:30]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[CH:20][CH:21]=1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccccc1COc1ccc(CCO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccccc1COc1ccc(CCOS(C)(=O)=O)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
Methyl 2-{[4-(2-hydroxyethyl)phenoxy]methyl}benzoate (1.2 g, 4.19 mmol) was dissolved in dichloromethane (20 ml) and the solution was cooled to −20° C. Triethylamine (0.64 g, 6.29 mmol) was added dropwise, and then methylsulfonyl chloride (0.53 g, 4.61 mmol) was added dropwise. The ice bath was removed and the mixture was stirred at room temperature for one hour. Diethyl ether (5 ml) was added and the precipitate was filtered off. The organic phase was washed with 2 portions of brine, dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by preparative HPLC (starting with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). This gave 0.703 g of methyl 2-[(4-{2-[(methylsulfonyl)oxy]ethyl}phenoxy)-methyl]benzoate (yield 46%).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)=[O:14])[CH2:9][C:8]2=[O:20])=[CH:4][CH:3]=1.[I:23][CH3:24]>CC#N.[Al]>[I-:23].[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([N:15]3[CH:19]=[CH:18][N+:17]([CH3:24])=[CH:16]3)=[O:14])[CH2:9][C:8]2=[O:20])=[CH:4][CH:3]=1
Reactant: O=C1CN(C(=O)n2ccnc2)CCN1Cc1ccc(F)cc1
Reactant: CI
Agent: [Al]
Solvent: CC#N
Product: C[n+]1ccn(C(=O)N2CCN(Cc3ccc(F)cc3)C(=O)C2)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-fluorobenzyl)-4-(1H-imidazol-1-ylcarbonyl)piperazin-2-one (2.49 g, 8.2 mmol) in 20 mL of anhydrous MeCN, under an atmosphere of nitrogen, was added iodomethane (2.05 mL, 32.9 mmol). The reaction was covered in aluminum foil and stirred at room temperature overnight. The reaction was concentrated under vacuum, co-evaporated with toluene under vacuum, followed by drying under high vacuum to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.02 (s, 1H), 7.84 (s, 1H), 7.36 (dd, J=8.4, 5.7 Hz, 2H), 7.19 (t, J=8.7 Hz, 2H), 4.56 (s, 2H), 4.23 (s, 2H), 3.91 (s, 3H), 3.77 (bs, 2H), 3.40 (t, J=5.2 Hz, 2H). ES MS (M)=317.
Reaction SMILES: N(C(OC(C)(C)C)=O)CC(N[C@H](C(N[CH2:13][C:14]([NH:16][C@H:17]([C:22]([N:24]1[CH2:38][CH2:37][CH2:36][C@H:25]1[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[O:23])[C@H:18]([CH2:20]C)[CH3:19])=[O:15])=O)C(C)C)=O.Cl.O1CCOCC1.[NH:53]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:54][C:55]([NH:57]CC(O)=O)=[O:56].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH:53]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:54][C:55]([NH:57][CH2:13][C:14]([NH:16][C@H:17]([C:22]([N:24]1[CH2:38][CH2:37][CH2:36][C@H:25]1[C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])=[O:23])[CH:18]([CH3:19])[CH3:20])=[O:15])=[O:56]
Reactant: CC[C@H](C)[C@H](NC(=O)CNC(=O)[C@@H](NC(=O)CNC(=O)OC(C)(C)C)C(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)CNC(=O)CNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1

Procedure:
III (6.0 g, 0.0148 mole) (39) was deblocked with HCl/Dioxane and solvent removed under reduced pressure. The residue was triturated with ether, filtered, washed with ether, then pet. ether and dried. A very hygroscopic material was obtained (4.2 g, 0.0123 mole) which was coupled in DMF with II (2.86 g, 0.0123 mole) in the presence of 10% excess of EDCI (2.60 g) and HOBt (2.07 g). The reaction was worked up as described for I to obtain IV as a white foam in a quantitative yield, no sharp m.p. 54°-62° C. Rf2, 0.42; Rf2, 0.74. Anal. Calcd. for C26H38N4O7 ; C, 60.21; H, 7.38; N, 10.80%. Found: C, 60.0; H, 7.46; N, 10.81%.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22](=[O:24])[CH3:23])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.C(O)(=O)C.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22](=[O:24])[CH3:23])=[CH:11][CH:10]=1
Reactant: CC(=O)c1ccccc1Nc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=O)c1ccccc1Nc1ccc(O)cc1
Yield: 55.9 %

Procedure:
1-[2-(4-Benzyloxyphenylamino)phenyl]ethanone (9 g) in 900 ml of ethanol and 90 ml of acetic acid was hydrogenated in the presence of 1 g of 10% palladium-on-carbon catalyst. The product was isolated and recrystallized from acetonitrile to yield 3.6 g of 1-[2-(4-hydroxyphenylamino)phenyl]ethanone, orange solid, m.p. 168°-169° C.
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C([Li])CCC.[C:22]([Si:26]([CH3:57])([CH3:56])[O:27][C:28]1[CH:55]=[CH:54][C:31]2[C:32]3[CH:41](O)[O:40][C:39]4[C:34](=[CH:35][CH:36]=[C:37]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH:38]=4)[C:33]=3[CH2:51][CH2:52][O:53][C:30]=2[CH:29]=1)([CH3:25])([CH3:24])[CH3:23]>C1COCC1.C1(C)C=CC=CC=1.Cl.CCOC(C)=O>[C:22]([Si:26]([CH3:56])([CH3:57])[O:27][C:28]1[CH:55]=[CH:54][C:31]2[C:32]3[CH:41]([C:2]4[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][N:9]5[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]5)=[CH:4][CH:3]=4)[O:40][C:39]4[C:34](=[CH:35][CH:36]=[C:37]([O:43][Si:44]([C:47]([CH3:48])([CH3:49])[CH3:50])([CH3:45])[CH3:46])[CH:38]=4)[C:33]=3[CH2:51][CH2:52][O:53][C:30]=2[CH:29]=1)([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OC(O)C1=C2CCOc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Reactant: Ic1ccc(OCCN2CCCCC2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OC(c1ccc(OCCN3CCCCC3)cc1)C1=C2CCOc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
1-[2-(4-Iodo-phenoxy)-ethyl]-piperidine(150 mg, 0.453 mmol) was dissolved in THF and cooled to −78° C. To the reaction mixture was then added n-butyl lithium (2M solution in pentane, 226 μl), slowly over 5 min. The reaction mixture was stirred for 1 h at −78° C. In a separate flask, 2,8-bis-(tert-butyl-dimethyl-silyloxy)-11,12-dihydro-5H-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-5-ol (28 mg, 0.053 mmol)) was dissolved in THF (1 mL) and added to the reaction mixture containing the 1-[2-(4-Iodo-phenoxy)-ethyl]-piperidine and n-butyl lithium, slowly over 5 min. The reaction mixture was stirred for additional 1 hr. The reaction mixture was quenched by MeOH (0.5 mL), treated with a saturated solution of ammonium chloride (30 mL) and then diluted with diethyl ether (25 mL). The organic layer was separated and washed with brine (15 mL). The organic layer was dried over anhydrous Na2SO4, filtered and the solvent evaporated to yield a crude oil. The crude oil was diluted with toluene (30 mL) and 1N HCl (6.0 mL) and then stirred for 30 min at room temperature. The reaction mixture was diluted with EtOAc (20 mL) and the organic layer was washed twice with water (20 ml) and with a saturated solution of NaHCO3 (10 ml). The organic layer was separated, dried over anhydrous Na2SO4, filtered and evaporated to yield 1-(2-{4-[2,8-Bis-(tert-butyl-dimethyl-silyloxy)-11,12-dihydro-5H-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-5-yl]-phenoxy}-ethyl)-piperidine as an oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:12][CH:13]=2)[C:8]([NH2:19])=[N:7]1)=[O:5])[CH3:2]>N1C=CC=CC=1>[NH2:19][C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:10]=2)[NH:6][N:7]=1.[CH2:1]([N:3]=[C:4]=[O:5])[CH3:2]
Reactant: CCNC(=O)n1nc(N)c2cc(C(F)(F)F)ccc21
Solvent: c1ccncc1
Product: CCN=C=O
Product: Nc1n[nH]c2ccc(C(F)(F)F)cc12

Procedure:
Analogously to Example 46, 0.05 mol of 3-amino-5-trifluoromethylindazole and 0.05 mol of ethyl isocyanate in 100 ml of pyridine give 3-amino-5-trifluoromethylindazole-1-carboxylic acid ethylamide (melting point: 131°-132° C; 47% of theory) in 1 hour at 10°-15° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([OH:31])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[O:31][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12
Reactant: Cn1ncc2c(Cl)cc(-c3cccc4[nH]ncc34)nc21
Reactant: COc1ccc(O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2cc(-c3cccc4[nH]ncc34)nc3c2cnn3C)cc1OC
Temperature: 155 °C
Yield: 17.7 %

Procedure:
4-Chloro-6-(1H-indazol-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine 7 (0.040 g, 0.141 mmoles) was dissolved in 2 mL DMF. 3,4-Dimethoxyphenol 8c (0.035 g, 0.281 mmol) was added followed by the addition of potassium carbonate (0.2 g, 1.41 mmol) and the resultant reaction mixture was heated in a microwave at 155° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and filtered. The organic portions were washed with saturated sodium bicarbonate solution followed by brine, dried over anhydrous sodium sulfate, solvent removed and purified to obtain 108 as a white solid (10 mg, 20%). 1H NMR (400 MHz, CDCl3) δ 10.13 (s, 1H), 8.81 (s, 1H), 7.76-7.40 (m, 4H), 7.14-6.87 (m, 2H), 6.87-6.65 (m, 2H), 4.25 (d, J=16.2, 3H), 3.91 (d, J=31.0, 6H) MS (ESI) m/z 402.2 (M+1)+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=NC(C)(C)C.CC1(C)CCCC(C)(C)N1.[Li]CCCC.Cl[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[O:43]1CCCC1>>[C:37]1([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH:1]=[O:43])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: Cc1ccccc1C=NC(C)(C)C
Reactant: C1CCOC1
Reactant: ClCCCCCCCc1ccccc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Product: O=Cc1ccccc1CCCCCCCCc1ccccc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of N-[(2-methylphenyl)methylene]-1,1-dimethylethanamine (11.2 g, 0.064 mol) and 2,2,6,6-tetra-methylpiperidine (0.9 g, 0.0064 mol) in tetrahydrofuran (40 mL) was cooled to -5° C. To this was added n-BuLi (1.6M, 40 mL, 0.064 mol) over 60 min from a syringe pump such that the temperature was maintained below 0° C. The mixture was stirred for 30 min and 1-chloro-7-phenylheptane (11.23 g, 0.053 mol) in tetrahydrofuran (20 mL) quickly added. The reaction mixture was heated at 50°-55° C. for 2 h. The reaction mixture was cooled to 40° C. and quenched by the slow addition of dilute hydrochloric acid (100 mL of acid diluted with 300 mL of water). Hydrolysis was completed by heating the mixture at 50°-60° C. for 2.5 h. The mixture was cooled to ambient temperature and the organic phase separated. The aqueous phase was extracted with hexane (100 mL) and the combined organic extracts washed with water (100 mL). The extracts were dried over magnesium sulphate and after filtering and washing the filter cake with hexane the organic solution was concentrated under vacuum to give 2-(8-phenyloctyl)benzaldehyde as an oil (14.5 g, 69.3% pure by HPLC assay, 87% corrected yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[NH:15]C(=O)C.[N:20](OC(C)(C)C)=O.O>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]2[C:6](=[CH:7][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:10]=2)[NH:15][N:20]=1)=[O:19]
Reactant: COC(=O)Cc1ccc(C(F)(F)F)cc1NC(C)=O
Reactant: CC(C)(C)ON=O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1n[nH]c2cc(C(F)(F)F)ccc12
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2-acetylamino-4-trifluoromethylphenyl)-acetic acid methyl ester (16 g, 0.058 mol) in acetic acid (50 mL) was added dropwise t-butyl nitrite (90%) (7.35 g, 0.063 mol) over a period of 20 min. at 90-95° C. The mixture was then stirred for 0.5 h at 95° C., poured into cold water and stirred for 1 h. The precipitates were collected by filtration and washed with water. The crude material was dissolved in ethyl acetate and dried over sodium sulfate. The solvent was removed in vacuo. This material (13.4 g, 95%) was used without further purification in the next step. A small sample was crystallized from ethyl acetate to yield a white solid, mp 240-242° C. 1H NMR (DMSO-d-6) 8.25 (d, J=8.5 Hz, 1H), 8.04 (s, 1H), 7.58 (d, J=8.5 Hz, 1H), 3.95 (s, 3H). MS (FAB) m/z: 245.1 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]([CH2:17][C:18]([OH:20])=O)[C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[C:25]=1[NH:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]([CH2:17][C:18]([N:26]([CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:25]2[C:35]([CH3:39])=[CH:36][CH:37]=[CH:38][C:24]=2[CH3:23])=[O:20])[C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1cccc(C)c1N(CC(=O)O)C(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)CCCNc1c(C)cccc1C
Product: CCOC(=O)CCCN(C(=O)CN(C(=O)c1ccc(Cl)cc1)c1c(C)cccc1C)c1c(C)cccc1C

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-2-(2,6-dimethylanilino)acetic acid and ethyl 4-(2,6-dimethylanilino)butyrate and suitable processing produces ethyl N-[N-(p-chlorobenzoyl)-2-(2,6-dimethylanilino)acetyl]-4-(2,6-dimethylanilino)butyrate (M.P. 150° to 151°), saponification of which and processing of the reaction product yields N-[N-(p-chlorobenzoyl)-2-(2,6-dimethylanilino)acetyl]-4-(2,6-dimethylanilino) butyric acid (M.P. 214° to 216°).
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[C:2]([CH3:4])=O.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:28][OH:29]>O.CO>[OH:29][N:28]=[C:2]([CH3:4])[CH2:1][C:5]1[C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1
Reactant: COc1cccc(C2=C(CC(C)=O)C(=O)NCCC2)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cccc(C2=C(CC(C)=NO)C(=O)NCCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: The mixture of 7.0 g of 3-acetonyl-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, 3.88 g of potassium carbonate, 3.55 g of hydroxylamine hydrochloride, 5 ml of water and 60 ml of methanol is refluxed for 5 hours and then stirred at room temperature overnight. 80 ml of water are added, the precipitate collected and washed with ethanol and diethyl ether, to yield the 3-(2-hydroxyiminopropyl)-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, melting at 155°-158°.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([Br:18])[N:3]=1.[CH3:19][NH:20][CH2:21][CH2:22][CH2:23]N.O1CCOC[CH2:26]1>>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:6]2[CH:7]=[C:2]([NH:3][CH2:23][CH2:22][CH2:21][NH:20][CH3:19])[CH:26]=[C:4]([Br:18])[CH:5]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: C1COCCO1
Reactant: CNCCCN
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(Br)c2)cc1
Product: CNCCCNc1cc(Br)cc(S(=O)(=O)c2ccc(N)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
0.20 g (0.00051 mol) of 4-(2,6-dibromopyridine-4-sulphonyl)-phenylamine was dissolved in 10 ml of dioxane and treated with 5.1 ml of 3-methylaminopropylamine. The mixture was stirred at room temperature for 2 hrs., the solvent was removed and the residue was chromatographed twice on silica gel, firstly with 20% methanol in dichloromethane and then with 10% methanol in dichloromethane. There was obtained 0.085 g (42%) of N-[3-(4-aminobenzenesulphonyl)-5-bromophenyl]-N'-methylpropane-1,3-diamine as a pale yellow, amorphous solid; MS (ISP): me/e=401, 399 (C15H20BrN4O2S+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: NCCN1CCOCC1
Reactant: CS(=O)c1nc(N)nc(-c2cccs2)c1C#N
Solvent: C1COCCO1
Product: N#Cc1c(NCCN2CCOCC2)nc(N)nc1-c1cccs1

Procedure:
From 2-amino-4-methanesulfinyl-6-thiophen-2-yl-pyrimidine-5-carbonitrile and 4-(2-aminoethyl)morpholine in dioxane. ES-MS m/e (%): 331 (M+H+, 100).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH2:20][CH3:21])[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:10])[CH3:9])[N:7]=1.[NH+]1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O[C:44]1([O:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:49][CH2:48][CH2:47][CH2:46]C1)CCC.C(N(CC)CC)C>C(Cl)Cl>[CH2:51]([O:50][C:44]1([O:1][CH2:2][C:3]2[N:4]([CH2:20][CH3:21])[C:5]([S:11][C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=3)=[C:6]([CH:8]([CH3:9])[CH3:10])[N:7]=2)[CH2:46][CH2:47][CH2:48][CH2:49]1)[CH2:52][CH2:53][CH3:54]
Reactant: CCn1c(CO)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CCCCOC1(OCCCC)CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOC1(OCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2CC)CCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 34 %

Procedure:
To a solution of 2-hydroxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-ethyl-1H-imidazole (19) (345 mg, 1 mmol) prepared in accordance with the method as described in WO 96/10019 (EXAMPLE 25) and p-toluenesulfonic acid pyridinium (264 mg, 1.05 mmol) in methylene chloride (5 ml) was added 1,1-dibutoxycyclohexane (2.14 g, 10.0 mmol), and stirred at room temperature for 20 hours. A drop of triethylamine was added to the reaction mixture , and the mixture was filtered to remove the precipitated insoluble matter. The filtrate was concentrated under reduced pressure. Hexane was added to the residue, and the mixture was filtered to remove the insoluble matter. The filtrate was purified by chromatography on an alumina column (eluate: toluene) to give the compound 20 (165 mg, 34%). Rf 0.41 (Al2O3 60, Type E, toluene).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:17][C:18]1[S:22][C:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[N:20][C:19]=1[CH3:30]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15][CH2:17][C:18]2[S:22][C:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[N:20][C:19]=2[CH3:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1CCl
Product: Cc1nc(-c2ccc(Cl)cc2)sc1COCC1CN(C(=O)OC(C)(C)C)CCO1
Yield: 69 %

Procedure:
Using 4-(tert-butoxycarbonyl)morpholin-2-ylmethanol (217 mg, 1.00 mmol) and 5-chloromethyl-2-(4-chlorophenyl)-4-methylthiazole (258 mg, 1.00 mmol), the same procedure was followed as in Step 5a of Example 5 to give 303 mg (69%) of the desired compound as a yellow oil.
Reaction SMILES: O.Cl.C[O:4][CH:5](OC)[CH2:6][CH2:7][CH2:8][NH:9][C:10]1[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH:20](OC)[O:21]C)[N:13]=[C:12]([NH:25][CH2:26][CH2:27][CH2:28][CH:29]([O:32]C)OC)[N:11]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:32][CH:29]1[CH2:28][CH2:27][CH2:26][N:25]1[C:12]1[N:13]=[C:14]([N:16]2[CH2:17][CH2:18][CH2:19][CH:20]2[OH:21])[N:15]=[C:10]([N:9]2[CH2:8][CH2:7][CH2:6][CH:5]2[OH:4])[N:11]=1
Reactant: COC(CCCNc1nc(NCCCC(OC)OC)nc(NCCCC(OC)OC)n1)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: OC1CCCN1c1nc(N2CCCC2O)nc(N2CCCC2O)n1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Water (50 ml) containing 37 weight % hydrochloric acid (6 ml) was added in one portion to a stirred solution of the tris-(4,4-dimethoxybutylamino)-1,3,5-triazine of Example 1 (6.0 g; 0.0127 mole) in acetone (50 ml) under nitrogen. The reaction mixture was stirred at room temperature for four days and thereafter neutralized with solid potassium carbonate. The solution was then transferred to a separatory funnel and extracted with ethyl acetate (2×150 ml). The organic layer was separated, dried over anhydrous sodium sulfate and the volatiles were removed under reduced pressure to give 2,4,6-tris-(2-hydroxypyrrolidin-1-yl)-1,3,5-triazine as a solid (2.7 g; 64% isolated yield). The structure of the product was confirmed from the 1H NMR spectrum which exhibited the characteristic absorption for the --NCHO- group at (δ) 5.6 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12]C(=O)[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]2[CH2:21][C:22]2[O:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[CH:9]([NH:10][C:14](=[O:15])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:21][C:22]2[O:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC(c2ccc(F)cc2)C1Cc1ccc(C(F)(F)F)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(C(F)(F)F)o1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.7 %

Procedure:
To 1,1-dimethylethyl (4RS,5SR)-5-(4-fluorophenyl)-2-oxo-4-((5-(trifluoromethyl)-2-furanyl)methyl)-1,3-oxazolidine-3-carboxylate (1.91 g, 4.45 mmol) in methanol (10.7 ml) was added a methanol solution (10.7 ml, 5.35 mmol) of 0.5N sodium hydroxide under ice-cooling and the mixture was stirred at room temperature for 10 min. Water (50 ml) was added to the reaction solution and the mixture was extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (1.79 g, 100%).