Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:11])(=O)=O)=CC=1.[CH2:21]([O:28][C:29](=[O:61])[N:30]([C@@H:36]([CH2:56][CH2:57][CH2:58][CH:59]=[O:60])[CH2:37][O:38][Si:39]([C:52]([CH3:55])([CH3:54])[CH3:53])([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCOCC>CC(O)C.C1COCC1>[CH2:21]([O:28][C:29](=[O:61])[N:30]([C@@H:36]([CH2:56][CH2:57][CH:58]([F:11])[CH:59]=[O:60])[CH2:37][O:38][Si:39]([C:52]([CH3:53])([CH3:54])[CH3:55])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[CH2:31][CH2:32][CH:33]([CH3:34])[CH3:35])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)CCN(C(=O)OCc1ccccc1)[C@@H](CCCC=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)CCN(C(=O)OCc1ccccc1)[C@@H](CCC(F)C=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: -20 °C
Reaction time: 24 h

Procedure:
Racemic 5-benzyl-2-2,3-trimethylimidazolidin-4-one dichloroacetic acid (109 mg, 0.314 mmol) and N-fluorobenzenesulfonimide (593 mg, 1.88 mmol) were dissolved in 10% i-PrOH-THF (3.75 mL). The reaction mixture was cooled to −20° C., and the compound from Step 7 (900 mg, 1.57 mmol) in 1.25 mL of 10% i-PrOH-THF was added. The reaction mixture was stirred at −20° C. for 24 hours, 2 volumes of ether were added, and the resulting mixture was vigorously stirred, filtered through Davisil® silica (W.R. Grace & Co.-Conn.), and eluted with ether. 5 mL of methyl sulfide was added to the eluted reaction mixture. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3 and extracted with EtOAc (2×). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound which was used directly at Step 9. 1H NMR (DMSO-d6): δ7.66-7.52 (m, 5H), 7.51-7.25 (m, 10H), 5.08 (s, 2H), 4.90-4.83 (m, 1H), 3.70-3.55 (m, 1H), 3.53-3.36 (m, 2H), 3.17-2.99 (m, 2H), 1.63-1.32 (m, 7H), 0.96 (s, 9H), 0.88-0.72 (m 6H), aldehyde signal missing due to hydrate form.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[N:20]([C:21]5[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=5[CH3:28])[NH2:24])[CH:19]=[C:18]([CH3:29])[N:16]4[N:17]=3)[CH:10]=[N:9]2)=CC=1.C(OC([N:39]1[CH2:44][CH2:43][N:42]([C:45]2[CH:46]=[C:47]([CH:51]=[C:52]([S:54]([F:59])([F:58])([F:57])([F:56])[F:55])[CH:53]=2)[C:48](O)=[O:49])[CH2:41][CH2:40]1)=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[OH-].[Na+]>CN(C=O)C.FC(F)(F)C(O)=O>[CH3:28][C:27]1[CH:26]=[CH:25][C:23]([NH:24][C:48](=[O:49])[C:47]2[CH:46]=[C:45]([N:42]3[CH2:43][CH2:44][NH:39][CH2:40][CH2:41]3)[CH:53]=[C:52]([S:54]([F:59])([F:58])([F:57])([F:55])[F:56])[CH:51]=2)=[CH:22][C:21]=1[N:20]1[C:15]2[N:16]([N:17]=[C:13]([C:11]3[CH:12]=[N:8][NH:9][CH:10]=3)[CH:14]=2)[C:18]([CH3:29])=[CH:19]1
Reactant: COc1ccc(Cn2cc(-c3cc4n(-c5cc(N)ccc5C)cc(C)n4n3)cn2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(C(=O)O)cc(S(F)(F)(F)(F)F)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cc(N3CCNCC3)cc(S(F)(F)(F)(F)F)c2)cc1-n1cc(C)n2nc(-c3cn[nH]c3)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
65 mg (0.16 mmol) of the compound of Example 9A, 68 mg (0.158 mmol) of the compound of Example 16A and 72 mg (0.19 mmol) of HATU were initially charged in 0.9 ml of DMF, 0.033 ml (0.19 mmol) of N,N-diisopropylethylamine were added and the mixture was stirred at RT for 1 h. The reaction was then stirred into 10 ml of 0.1 M aqueous sodium hydroxide solution. After 10 min of further stirring at RT, the precipitate formed was filtered off, washed with water and dried. The intermediate obtained in this manner was dissolved in 0.5 ml of trifluoroacetic acid and stirred at 80° C. for 6 h. The mixture was then concentrated under reduced pressure and the residue was purified by double preparative HPLC (Method 18). This gave 18 mg (19% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].[N+:12]([O-])([OH:14])=[O:13]>O>[CH3:1][C:2]1[CH:7]=[C:6]([N+:12]([O-:14])=[O:13])[C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]#[N:11]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C)c(CC#N)c1
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(C)cc1CC#N
Reaction time: 0.5 h

Procedure:
To (2,5-dimethylphenyl)acetonitrile (30 g), under ice cooling, fuming nitric acid (103 mL) was added dropwise, and the resultant was stirred for 30 minutes under ice cooling. Water was added thereto, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate, and the desiccant was filtered off. Then, the solvent was distilled off under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to the obtained residue, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate, and the desiccant was filtered off. Then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH-type silica gel; chloroform/ethyl acetate-gradient elution=100/0→90/10) and then further purified twice by silica gel column chromatography (OH-type silica gel; hexane/ethyl acetate-gradient elution=90/10→60/40) to obtain the title compound (12 g) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1)([O-:15])=[O:14].C(N(CC)CC)C>CN(C)C=O>[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][O:11][C:10](=[O:12])[CH2:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CCc1ccc(O)cc1)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 12 h

Procedure:
1.66 g (10 mmol) of 3-(4-hydroxyphenyl)-propionic acid in 80 ml of dimethylformamide are treated at room temperature and while stirring with 2.16 g (10 mmol) of 4-nitrobenzyl bromide and 1.4 ml (10 mmol) of triethylamine. After 12 hours, the mixture is evaporated in vacuo and the residue obtained partitioned between ethyl acetate and water. The organic phase is separated, washed with 10% potassium hydrogen carbonate solution and water, dried over sodium sulphate and then evaporated to dryness. The residue crystallizes from diisopropyl ether/petroleum ether. There is obtained 3-(4-hydroxyphenyl)-propionic acid 4-nitrobenzyl ester in the form of colourless needles of melting point 80°-82° C. The product is chromatographically pure in cyclohexane/chloroform/acetic acid (45:45:10). The yield amounts to 1.6 g (53% of theory).
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]#N)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[NH:14]1[CH2:17][CH:16]([CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH3:28])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15]1
Reactant: N#Cc1ccc2[nH]cc(CC3CN(C(c4ccccc4)c4ccccc4)C3)c2c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1ccc2[nH]cc(CC3CNC3)c2c1

Procedure:
A mixture of 3-(1-benzhydryl-azetidin-3-ylmethyl)-1H-indole-5-carbonitrile (8) (0.56 g, 1.5 mmol), palladium on carbon (10%, 0.1 g) and ammonium formate (0.37 g, 5.9 mmol) in ethanol (20 ml) was refluxed for 2 hours. The mixture was filtered through celite and the solvent removed under vacuum. Diphenylmethane was removed by triturating the residue with ether, methylene chloride and decanting. The remaining product was dried under vacuum. The crude material was directly used in next step. MS ES m/e 200 (M+H)+.
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[CH:8]=O.[F:19][C:20]1[CH:21]=[C:22]([C@H:26]2[N:34]3[C@@H:29]([CH2:30][CH2:31][CH:32](P(=O)(OCC)OCC)[C:33]3=[O:35])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1.C(O)C>O1CCCC1>[F:19][C:20]1[CH:21]=[C:22]([C@H:26]2[N:34]3[C@@H:29]([CH2:30][CH2:31]/[C:32](=[CH:8]\[C:7]4[CH:10]=[CH:11][C:12]([N:13]5[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]5)=[C:5]([O:4][CH3:3])[CH:6]=4)/[C:33]3=[O:35])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Reactant: CCOP(=O)(OCC)C1CC[C@H]2CC[C@@H](c3cccc(F)c3)N2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(/C=C2\CC[C@H]3CC[C@@H](c4cccc(F)c4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 77.7 %

Procedure:
Lithium hydroxide (0.217 g) was added to a mixed solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (0.49 g) and diethyl [(3S,8aR)-3-(3-fluorophenyl)-5-oxooctahydroindolizin-6-yl]phosphonate (1.9 g) in tetrahydrofuran (4 mL)-ethanol (16 mL), and the reaction solution was stirred under shading at room temperature for 12 hours. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 0.76 g of the title compound as a colorless solid. The property values of the compound are as follows.
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[CH3:22][C:23]1[S:24][C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)=[C:26]([C:28](O)=[O:29])[N:27]=1>>[CH3:22][C:23]1[S:24][C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:38])[F:39])[CH:32]=2)=[C:26]([C:28]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[CH3:21])=[O:12])=[O:29])[N:27]=1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(C(F)(F)F)c2)s1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Product: Cc1nc(C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2cccc(C(F)(F)F)c2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-methyl-5-(3-trifluoromethyl-phenyl)-thiazole-4-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH:15]2[C:10]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([N:11]=[C:12]([NH:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:13][CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.C(Cl)(Cl)Cl>[C:18]([NH:17][C:12]1[S:13][CH2:14][C@@H:15]2[CH2:16][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C@:10]2([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:11]=1)(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CC2CSC(NC(=O)c3ccccc3)=NC2(c2ccccc2)C1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccccc2)C1

Procedure:
Racemic tert-butyl-2-benzamido-7a-phenyl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate (1.6 g, 3.66 mmol) is dissolved in ethanol/chloroform (30 ml/14 ml) and is separated into its constituent enantiomers by chiral SFC (Supercritical Fluid Chromatography) (Chiralpak AD 8×40.5 cm (20 μm); eluent: 100% ethanol in CO2; flow: 350 mL/min at UV 280 nm; 0.4 g/injection). The first eluting isomer is the title compound (593 mg, 37%). Chiral analysis of this isomer: (Chiralpak AD-H 4.6×150 mm; eluent: 100% ethanol with 0.2% isopropyl amine) in CO2; flow 1 mL/min at UV 225 nm) Rt=3.03 to (>98% ee). ES/MS (m/e): 438 (M+H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:29][C:28]=1[NH:42][C:43]([C:45]1[N:46]([CH3:54])[C:47]2[C:52]([CH:53]=1)=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:44].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:31]3[CH:30]=[CH:29][C:28]([NH:42][C:43]([C:45]4[N:46]([CH3:54])[C:47]5[C:52]([CH:53]=4)=[CH:51][CH:50]=[CH:49][CH:48]=5)=[O:44])=[C:27]([O:26][CH3:25])[CH:32]=3)[C:10]=12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 80 °C
Reaction time: 21.5 h

Procedure:
A suspension of trans-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.100 g, 0.227 mmol) in ethylene glycol dimethyl ether (8 mL) was treated with N2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-1H-2-indolecarboxamide (0.097 g, 0.238 mmol), tetrakis(triphenylphosphine)palladium (0.016 g, 0.014 mmol), and a solution of sodium carbonate (0.057 g, 0.538 mmol) in water (4 mL). The reaction mixture was stirred for 21.5 h at 80° C. The precipitate was filtered, and the organic layer was evaporated under reduced pressure. Dichloromethane (15 mL) was added and the layers were partitioned. The aqueous layer was extracted with dichloromethane (200 mL). The combined organic layers were dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a 10% methanol in dichloromethane to 50% methanol in dichloromethane step gradient on Sq 16× ISCO CombiFlash. The column afforded 0.083 g (68%) of trans-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide. 1H NMR (d6-DMSO) δ 9.4316 (s, 1H), 8.2427 (s, 1H), 8.1207-8.1003 (d, 1H, J=8.16 Hz), 7.7173-7.6974 (d, 1H, J=7.96 Hz), 7.5979-7.5769 (d, 1H, J=8.4 Hz), 7.3507-7.2758 (m, 4H), 7.1695-7.1321 (t, 1H), 4.6893-4.6324 (m, 1H), 4.0400 (s, 3H), 3.9571 (s, 3H), 2.5 (m, 3H), 2.4055-2.3279 (m, 5H), 2.1606 (s, 3H), 2.1094-1.9367 (m, 6H), 1.5214-1.4624 (m, 2H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium Acetate in Water to 95% Acetonitrile over 6 min, 0.8 to 0.5 mL/min) Rt 2.12 min (100%), M+ 594.3.
Reaction SMILES: [CH:1]([N:4]1[CH2:11][CH:10]2[CH2:12][CH:6]([CH2:7][NH:8][CH2:9]2)[CH2:5]1)([CH3:3])[CH3:2].[OH-].[Na+].[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.O>C(Cl)Cl.CCOCC>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:8]2[CH2:9][CH:10]3[CH2:12][CH:6]([CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:11]3)[CH2:7]2)=[O:21])=[CH:18][CH:17]=1
Reactant: CC(C)N1CC2CNCC(C2)C1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: CC(C)N1CC2CC(CN(C(=O)c3ccc(Cl)cc3)C2)C1
Reaction time: 3 h
Yield: 78.5 %

Procedure:
A 25-mL, three-necked, round-bottomed flask was equipped with a magnetic stirrer, a standard condenser with a N2 inlet, a 10-mL addition funnel and two glass stoppers. To a mixture of the amine (31, 0.60 g, 3.57 mmol) in CH2Cl2 (5 mL) and 10% NaOH (3.58 g, 8.93 mmol) was added dropwise a solution of 4-chlorobenzoyl chloride (0.69 g, 3.92 mmol) in CH2Cl2 (5 mL) over 15 min. Stirring of the mixture was continued for an additional 3 h under N2. An aqueous mixture, formed upon addition of H2O (30 mL), was extracted (CH2Cl2, 4×25 mL). Combined extracts were dried (Na2SO4, 2 h), filtered, and concentrated to give a viscous yellow oil. Chromatography of the oil was performed by adding an ether solution of the oil to a neutral alumina column (69 g, 1.7 cm×30 cm) and then using 60:40 hexanes/ethyl acetate as eluant. Fractions (Rf =0.41) were saved and concentrated (rotary evaporator then vacuum pump, overnight, RT/0.2 mm Hg) to give 0.86 g (80.4%) of off-white solid (33); mp 97°-98° C. IR (KBr) cm-1 3085, 3070 (Ar C--H), 2965, 2935, 2865, 2800, 2770 (C--H), 1630 (C=O); 1H NMR (DCCl3) δ0.95 (d;, 3H, CH3, J=6.5 Hz), 1.05 (d, 3H, CH3, J=6.4 Hz), 1.63-1.75 [m, 3H, H(5) and H(9)], 1.97 [bs, 1H, H(1)], 2.41 [bd, 1H, H(4)ax, J=10.6 Hz], 2.50 [bd, 1H, H(6)ax, J=11.2H], 2.59 [heptet, 1H, CH(CH3)2, J=6.5 Hz] , 2.71 [bd, 1H, H(6)eq, J=11.0 Hz], 3.03-3.06 [m, 2H, H(2)ax and H(4)eq ], 3.31 [bd, 1H, H(8)ax, J=12.8 Hz], 3.71 [bd, 1H, H(8)eq, 13.1 Hz], 4.77 [bd, 1H, H(2)eq, J=13.2 Hz], 7.27-7.37 (m, 4H, Ar--H); 13C NMR (DCCl3) ppm 16.37, 19.35 (CH3), 29.07 [C(1)], 29.07 [C(1)], 29.80 [C(5)], 32.29 [C(9)], 46.68 [C(2)], 52.22 [C(4)], 52.56 [C(8)], 54.38 [CH(CH3)2 ], 54.79 [C(6)], 128.35, 128.51, 134.67, 136.11 (Ar-- C), 169.03 (C=O). Anal. Calcd. for C17H23ClN2O: C, 66.55; H, 7.56. Found: C, 66.45; H, 7.71.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([S:20](Cl)(=[O:22])=[O:21])[CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.Cl.[NH2:33][C:34]([NH2:36])=[NH:35]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([S:20](=[O:22])(=[O:21])[N:33]=[C:34]([NH2:36])[NH2:35])[CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N=C(N)N
Reactant: COC(=O)CC(c1ccccc1)c1ccc(OC)c(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC(c1ccccc1)c1ccc(OC)c(S(=O)(=O)N=C(N)N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(3-chlorosulfonyl-4-methoxy-phenyl)-3-phenyl-propionic acid methyl ester (500 mg, 1.36 mmol) in DCM (50 mL) is added triethylamine (0.57 ml, 4.08 mmol) and guanidine hydrochloride (0.14 g, 1.50 mmol). The reaction mixture is stirred at RT overnight, then diluted with DCM (100 mL). The reaction mixture is washed with an aqueous saturated solution of NaHCO3 (30 mL), water (30 mL) then brine (30 mL). The organic phase is then dried over MgSO4, filtered and concentrated in vacuo. Purification of the residue by reverse phase chromatography (Isolute™ C18, 0-100% acetonitrile in water with 0.1% TFA) affords the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:14][C:15]1[N:16]=[CH:17][N:18]=[C:19]([NH:1][C:2]2[CH:13]=[CH:12][C:5]([CH2:6][NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH:20]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CS(=O)(=O)NCc1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CS(=O)(=O)NCc1ccc(Nc2cc(Cl)ncn2)cc1
Temperature: 25 °C
Yield: 46 %

Procedure:
5.309 g N-(4-Amino-benzyl)-methanesulfonamide (obtained in Step 2, 26.5 mmol) and 4.739 g 4,6-dichloropyrimidine (31.81 mmol) was dissolved in 120 cm3 of isopropyl-alcohol, 6.93 cm3 N,N-diisopropyl-ethylamine (5.140 g, 39.76 mmol) was added and the mixture was refluxed for four days. The reaction mixture was cooled to room temperature and the precipitated compound was filtered off. The light yellow product was washed well with diethyl-ether and air-dried. 3.813 g N-[4-(6-Chloro-pyrimidin-4-ylamino)-benzyl]-methanesulfonamide was obtained above 98% purity in 46% overall yield. For analitical results and compound identification see Table 1. The compound was used as a starting material in the preparation of Example 34-58 and 76.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:23]=[C:22](F)[CH:21]=[CH:20][C:17]=1[C:18]#[N:19].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:22]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([Cl:15])[CH:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C#N)c(Cl)c2)CC1
Temperature: 120 °C
Yield: 44.8 %

Procedure:
A mixture of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (427 mg; 2.13 mmol), 2-chloro-4-fluoro-benzonitrile (302 mg; 1.94 mmol) and potassium carbonate (1.07 g; 7.76 mmol) is diluted in dimethylsulfoxide (5 mL) and is heated to 120° C. for 7 hours. After cooling to room temperature, the mixture is diluted with dichloromethane (50 mL) and is filtered. The filtrate is washed with 1N aq. hydrochlorid acid (2×15 mL), with water (20 mL) is then dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product is finally purified by column chromatography on silica gel (dichloromethane:methanol 1:0 and then 98:2) to afford the desired product (290 mg; 0.87 mmol).
Reaction SMILES: C(O)(C)C.C([NH:13][C:14]([NH:16][CH2:17][CH2:18][S:19][CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)=[S:15])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O>[NH:24]1[CH:25]=[C:21]([CH2:20][S:19][CH2:18][CH2:17][NH:16][C:14]([NH2:13])=[S:15])[N:22]=[CH:23]1
Reactant: O=C(NC(=S)NCCSCc1c[nH]cn1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: NC(=S)NCCSCc1c[nH]cn1
Yield: 61.7 %

Procedure:
A solution of 4(5)-[(2-aminoethyl)thiomethyl]imidazole (6.0 g.) and benzoyl isothiocyanate (6.0 g.) in chloroform (150 ml.) was heated under reflux for one hour. Concentration followed by recrystallisation from ethyl acetate-isopropyl acetate afforded N-benzoyl-N'-[2-(4-imidazolylmethylthio)-ethyl]thiourea (7.5 g.). An analytically pure sample (from aqueous isopropyl alcohol) had m.p. 126°-128°. (ii) The benzoyl thiourea (6.0 g.) was added to a solution of potassium carbonate (1.4 g.) in water (80 ml.), at 60°. The solution was maintained at this temperature for one hour, concentrated to low bulk and acidified with hydrochloric acid. Benzoic acid was removed by filtration and the filtrate was basified with potassium carbonate and concentrated under reduced pressure. Following extraction with isopropyl alcohl and concentration, the product was crystallised from isopropyl acetate. Recrystallisation from water gave N-[2-(4-imidazolylmethylthio)ethyl]thiourea (2.5 g.) m.p. 135°-137°. (Found: C, 38.9; H, 5.5; N, 26.1; S, 29.6. C7H12N4S2 requires: C, 38.9; H, 5.6; N, 25.9; S, 29.6).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][NH2:19])=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]([N:30]=[C:31]=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][C:31]([NH:19][NH:18][C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]1[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)=[O:17])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C=NCc1ccccc1
Reactant: NNC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Product: O=C(NCCCOc1cccc(CN2CCCCC2)c1)NNC(=O)NCc1ccccc1

Procedure:
The compound is prepared by a method analogous to that of Example 20 from N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-hydrazine carboxamide and benzyl isocyanate. The analytical values are summarized in Table I.