Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:25][C@H:26]4[CH2:31][CH2:30][C@H:29]([CH3:32])[CH2:28][CH2:27]4)[C:15]([N:17]4[CH2:21][CH2:20][CH2:19][C@H:18]4[C:22]([OH:24])=O)=[N:16][C:12]=3[CH:11]=[C:10]([C:33]#[N:34])[N:9]=2)[CH:5]=[N:6][CH:7]=1.CCCP(=O)=O.[CH3:41][NH:42][CH2:43][CH3:44]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:25][C@H:26]4[CH2:27][CH2:28][C@H:29]([CH3:32])[CH2:30][CH2:31]4)[C:15]([N:17]4[CH2:21][CH2:20][CH2:19][C@H:18]4[C:22]([N:42]([CH2:43][CH3:44])[CH3:41])=[O:24])=[N:16][C:12]=3[CH:11]=[C:10]([C:33]#[N:34])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CCNC
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3C(=O)O)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Agent: CCCP(=O)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C)C(=O)[C@@H]1CCCN1c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a reaction vessel was added the crude residue of (S)-1-(4-(5-chloropyridin-3-yl)-6-cyano-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-2-yl)pyrrolidine-2-carboxylic acid (0.030 g, 0.063 mmol), propylphosphonic anhydride (0.10 mL, 50% w/w in DMF), and N-methylethanamine (0.0037 g, 0.063 mmol) suspended in DMF (0.5 mL). The reaction was stirred at ambient temperature for 6 hours. The reaction was diluted with H2O (2.0 mL) and was extracted with EtOAc (2×5 mL). The combined organics were concentrated in vacuo to afford (S)-1-(4-(5-chloropyridin-3-yl)-6-cyano-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-2-yl)-N-ethyl-N-methylpyrrolidine-2-carboxamide as a crude residue. MS ESI calc'd. for C28H34ClN7O [M+H]+ 520. found 520.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C.C(O)(=O)C>C1COCC1.[OH-].[Pd+2].[OH-]>[F:1][C:2]1[C:7]([CH:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:16])[CH3:15])[CH2:12][CH2:13]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)N1CC=C(c2cccnc2F)CC1
Agent: [Pd+2]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)N1CCC(c2cccnc2F)CC1
Reaction time: 5 h

Procedure:
1-(4-(2-fluoropyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone (0.14 g, 0.65 mmol), palladium hydroxide, 20 wt % pd (dry basis) on carbon, wet, degussa type e101 new (91 mg, 0.13 mmol) and acetic acid, glacial (19 uL, 0.32 mmol) were suspended in THF (13 mL) in a pressure tube. The reaction mixture was hydrogenated at 50 psi for 5 h then filtered through a pad of celite and washed with THF. The filtrate was concentrated to give 1-(4-(2-fluoropyridin-3-yl)piperidin-1-yl)ethanone as clear oil.
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11](=[O:13])[NH:10][C:9]=2[CH:14]=1)=O.[NH2:16][C:17]1[C:22]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=[CH:19][N:18]=1>>[CH2:24]([O:23][C:22]1[C:17]2[N:18]([C:2]([CH3:15])=[C:3]([C:5]3[CH:6]=[CH:7][C:8]4[O:12][C:11](=[O:13])[NH:10][C:9]=4[CH:14]=3)[N:16]=2)[CH:19]=[CH:20][CH:21]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(Br)C(=O)c1ccc2oc(=O)[nH]c2c1
Reactant: Nc1ncccc1OCc1ccccc1
Product: Cc1c(-c2ccc3oc(=O)[nH]c3c2)nc2c(OCc3ccccc3)cccn12
Yield: 27.7 %

Procedure:
5-(8-Benzyloxy-3-methylimidazo[1,2-a]pyridin-2-yl)-2-benzoxazolinone (0.8 g) was prepared in substantially the same manner as that of Example 30 from 5-(2-bromopropionyl)-2-benzoxazolinone (2.1 g) and 2-amino-3-benzyloxypyridine (4.8 g). mp. 264°-265° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]([N+:10]#[C-:11])=[CH:6]N(C)C)[CH3:2].C(N(CC)CC)C.[SH2:20]>O1CCCC1>[C:4]([C:5]1[N:10]=[CH:11][S:20][CH:6]=1)([O:3][CH2:1][CH3:2])=[O:12]
Reactant: [C-]#[N+]C(=CN(C)C)C(=O)OCC
Reactant: S
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cscn1

Procedure:
A solution of 3-dimethylamino-2-isocyano-acrylic acid ethyl ester (1.0 g) and triethylamine (3.0 g) in tetrahydrofuran (30 mL) is treated with gaseous hydrogen sulfide until all starting material is consumed. The mixture is concentrated to an oil and purified by column chromatography using silica and 25% ethyl acetate-hexanes as the eluant. The purified material (0.61 g) is isolated as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][C:8]([OH:10])=O)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:54]=[C:55]([NH2:68])[C:56]4[CH:57]=[N:58][N:59](C5CCCCO5)[C:60]=4[CH:61]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1.Cl>CN(C=O)C.CO>[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:61]=[C:60]4[C:56]([CH:57]=[N:58][NH:59]4)=[C:55]([NH:68][C:8](=[O:10])[CH2:7][N:4]4[CH:5]=[CH:6][C:2]([CH3:1])=[N:3]4)[CH:54]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1
Reactant: Cc1ccn(CC(=O)O)n1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2c1cnn2C1CCCCO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccn(CC(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)n1
Reaction time: 0.5 h
Yield: 31 %

Procedure:
(3-Methyl-1H-pyrazol-1-yl)acetic acid (38 mg, 0.27 mmol) (from Art-Chem GmbH), HATU (126 mg, 0.33 mmol) and DIPEA (0.158 ml, 0.91 mmol) were dissolved in DMF (2 ml) and stirred under nitrogen for 30 mins. 6-(1H-Indol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (100 mg, 0.30 mmol) was added and the reaction was stirred for 5 h. Further (3-methyl-1H-pyrazol-1-yl)acetic acid (38 mg, 0.27 mmol), HATU (126 mg, 0.33 mmol) and DIPEA (0.158 ml, 0.91 mmol) in DMF (1 ml) was added, after stirring together for 10 mins, and the reaction was stirred for 2 days under a nitrogen atmosphere at RT. The reaction was loaded on to a PS-aminopropyl cartridge (10 g) and eluted with DCM. Appropriate fractions were combined and evaporated in vacuo. MeOH (2 ml) and 2 M HCl (aq) (45 μl, 0.09 mmol) were added and stirred for ˜30 mins at RT. The solvent was evaporated in vacuo and the residue was dissolved in MeOH:DMSO (2 ml; 1:1, v/v) and purified by Mass Directed Automated Preparative HPLC using method B. The solvent was dried under a stream of nitrogen to give title compound (31 mg).
Reaction SMILES: Cl.C(OC1C=CC(N)=CC=1)C1C=CC=CC=1.[CH3:17][C:18]1[CH:19]=[CH:20][N:21](C(O)=O)[N:22]=1.[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41](C2C=CC=CN=2)=[O:42])=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41]([C:20]2[CH:19]=[C:18]([CH3:17])[NH:22][N:21]=2)=[O:42])=[CH:36][CH:35]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1ccn(C(=O)O)n1
Reactant: O=C(Nc1ccc(OCc2ccccc2)cc1)c1ccccn1
Agent: Cl
Agent: Nc1ccc(OCc2ccccc2)cc1
Product: Cc1cc(C(=O)Nc2ccc(OCc3ccccc3)cc2)n[nH]1

Procedure:
This compound was prepared from 4-benzyloxyaniline hydrochloride (4.0 g, 17.0 mmol) and 5-methylpyrazole-2-carboxylic acid (2.25 g, 17.8 mmol), using the same method used to prepare pyridine-2-carboxylic acid (4-benzyloxyphenyl)amide, to give the product as a solid. The product was used without further purification in the subsequent reaction. MS m/z 308 (MH+). 1H NMR(CDCl3+MeOD-d4) δ 2.34 (s, 3H), 5.06 (s, 2H), 6.62 (s, 1H), 6.96 (d, 2H), 7.31 (m, 7H) and 7.58 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][C:6]=2[CH:13]=1.[Cl:14][CH2:15][NH:16][CH2:17][CH:18]=[O:19]>C1C=CC=CC=1>[Cl:14][CH2:15][N:16]([CH2:17][CH:18]=[O:19])[C:11]([NH:10][C:8]1[S:9][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:13][C:6]=2[N:7]=1)=[O:12]
Reactant: O=CCNCCl
Reactant: O=C=Nc1nc2cc(F)ccc2s1
Solvent: c1ccccc1
Product: O=CCN(CCl)C(=O)Nc1nc2cc(F)ccc2s1
Reaction time: 1 h

Procedure:
5-Fluorobenzothiazol-2-yl isocyanate dimer (0.1 mole), the dimethyl acetal of 2-chloromethylaminoacetaldehyde (0.2 mole) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at ambient temperatures for a period of about one hour. After this time the reaction mixture is filtered, and the filtrate is stripped of solvent to yield the desired product the dimethyl acetal of 2-[1-chloromethyl-3-(5-fluorobenzothiazol-2-yl)ureido]-acetaldehyde as the residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[N+:11]([O-])=O.C([O-])([O-])=O.[Na+].[Na+]>CC(O)=O.CCO.O.[Fe]>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[NH2:11]
Reactant: COc1cccc(OC)c1[N+](=O)[O-]
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc(OC)c1N
Temperature: 90 °C
Yield: 97.6 %

Procedure:
To a solution of 78 (170 mg, 0.93 mmol) in AcOH (5 mL), EtOH (5 mL) and H2O (2.5 mL) was added iron powder (311 mg, ˜325 mesh, 5.57 mmol) portion wise. The mixture was then heated at 90° C. under N2 overnight. After cooling to room temperature, the mixture was poured onto ice, basified using solid Na2CO3 and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to yield 79 as a pale yellow solid (139 mg, 98%). MS (APCI): m/z 154 (100%, [M+H]+) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])CN[C:6](=[O:9])[C:5]2[S:10][C:11]([N:13]3[C:18]4[CH:19]=[C:20](O)[CH:21]=[CH:22][C:17]=4[O:16][CH2:15][CH2:14]3)=[N:12][C:4]=2[CH2:3]1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH3:32]C(C)([O-])C.[Na+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:32][C:2]1([CH3:1])[CH2:3][C:4]2[N:12]=[C:11]([N:13]3[C:18]4[CH:19]=[C:20]([NH:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH:21]=[CH:22][C:17]=4[O:16][CH2:15][CH2:14]3)[S:10][C:5]=2[C:6](=[O:9])[CH2:24]1
Reactant: CC(C)(C)[O-]
Reactant: CC1(C)CNC(=O)c2sc(N3CCOc4ccc(O)cc43)nc2C1
Reactant: Nc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CC(=O)c2sc(N3CCOc4ccc(Nc5ccccc5)cc43)nc2C1
Temperature: 140 °C
Yield: 15.7 %

Procedure:
Using Example 7 (40 mg, 0.11 mmol), aniline (0.040 mL, 0.460 mmol), sodium tert-butoxide (28 mg, 028 mmol), palladium(II) acetate (4 mg, 0.010 mmol) and (But)3PBF4 (8 mg, 0.022 mmol) in DMF (3 mL) heated to 140° C. under microwave irradiation, for 40 min. The crude material was purified by prep HPLC to give the title compound as an off-white solid (7 mg, 15%). δH (CDCl3) 1.14 (6H, s), 2.42 (2H, s), 2.75 (2H, s) 4.13-4.20 (2H, m), 4.29-4.35 (2H, m), 5.61 (1H, br s), 6.80-6.93 (3H, m), 7.00-7.05 (2H, m), 7.23-7.31 (2H, m), 7.77 (1H, d, J 2.3 Hz). LCMS (ES+) 406 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[N:9]([CH3:18])[C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:5].[CH2:23]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1)[CH3:24]>C(O)CC>[ClH:1].[CH2:23]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[N:9]([CH3:18])[C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:5])[CH3:24]
Reactant: CN1C(=O)c2ccccc2N(C(=O)CCCl)c2ccccc21
Reactant: CCC1CCCCN1
Solvent: CCCO
Product: CCC1CCCCN1CCC(=O)N1c2ccccc2C(=O)N(C)c2ccccc21
Product: Cl
Yield: 58.8 %

Procedure:
8.5 gm (0.027 mol) of 5-(3-chloro-propionyl)-5,10-dihydro-10-methyl-11H-dibenzo[b,e][1,4]diazepin-11-one and 8.5 gm (0.075 mol) of 2-ethyl-piperidine were refluxed in 85 ml of n-propanol for 3 hours, and the reaction mixture was worked up as described in Example 10. After recrystallization from a mixture consisting of equal parts of dioxane and acetone, 6.8 gm of the hydrochloride were obtained.
Reaction SMILES: C1(O[C:8](=[O:19])[NH:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[CH3:18])C=CC=CC=1.[CH3:20][C:21]([CH3:37])([CH3:36])[CH2:22][CH2:23][NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][CH3:35])=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[CH2:32]([C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:24]([CH2:23][CH2:22][C:21]([CH3:20])([CH3:37])[CH3:36])[C:8]([NH:9][C:10]2[C:11]([CH3:18])=[CH:12][C:13]([Cl:17])=[CH:14][C:15]=2[CH3:16])=[O:19])=[CH:31][CH:30]=1)[CH2:33][CH2:34][CH3:35]
Reactant: Cc1cc(Cl)cc(C)c1NC(=O)Oc1ccccc1
Reactant: CCCCc1ccc(CNCCC(C)(C)C)cc1
Solvent: Cc1ccccc1
Product: CCCCc1ccc(CN(CCC(C)(C)C)C(=O)Nc2c(C)cc(Cl)cc2C)cc1

Procedure:
A solution of 825 mg of phenyl-N-(4-chloro2,6-dimethylphenyl)carbamate and 740 mg of N-[3,3-dimethylbutyl]-4-n-butylbenzenemethanamine in 40 ml of toluene was refluxed for 1 hour, cooled, and the solution was washed with 1N sodium hydroxide, brine, dried, and evaporated to dryness to yield a solid. The solid was recrystallized from hexane to yield 1-[(4-butylphenyl)methyl]-1-[3,3-dimethylbutyl]-3-[4-chloro-2,6-dimethylphenyl]urea as a white solid, mp 138°-139° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]([F:40])([F:39])[C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH:34]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:34][C:33]3[CH:36]=[CH:37][CH:38]=[C:31]([C:30]([F:29])([F:39])[F:40])[CH:32]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 3-trifluoromethyl-benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 537.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9][CH2:10][N:11]([CH3:15])[CH2:12][CH2:13][NH2:14])=[CH:4][CH:3]=1.[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23].[N:34]1([CH2:40][C:41]2[CH:42]=[C:43]([CH:49]=[CH:50][CH:51]=2)[O:44][CH2:45][CH2:46][CH2:47][NH2:48])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][NH:14][C:22]([NH:48][CH2:47][CH2:46][CH2:45][O:44][C:43]2[CH:49]=[CH:50][CH:51]=[C:41]([CH2:40][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:42]=2)=[O:23])[CH3:15])=[CH:4][CH:3]=1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CN(CCN)CCC(c1ccc(Cl)cc1)c1ccccn1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Product: CN(CCNC(=O)NCCCOc1cccc(CN2CCCCC2)c1)CCC(c1ccc(Cl)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 63, using 0.92 g (3 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,2-ethanediamine, an equimolar amount of 1,1'-carbonyldiimidazole and 0.88 g (3.5 mmol) of 3-[3-(piperidinomethyl)phenoxy]propaneamine as starting materials. Working up by chromatography (eluant: ethyl acetate) analogously to Example 63 yields the purified title compound in the form of an oil; MS (+FAB method): m/z (rel. int.[%])=578 ([M+H]+, 2), 230 (38), 78 (100); IR (KBr): 1637 cm-1 (C=O). For analytical purposes a sample is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from ether/isopropanol; m.p.: 99°-105° C.
Reaction SMILES: N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:39]([C:40]3[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:41]=3[Cl:47])[N:38]=[C:37]([C:48]([OH:50])=O)[C:36]=2[CH3:51])=[CH:31][CH:30]=1.[NH2:52][CH:53]1[CH2:58][CH2:57][N:56]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:55][CH2:54]1.C(N(CC)CC)C>O1CCCC1>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[N:39]([C:40]3[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:41]=3[Cl:47])[N:38]=[C:37]([C:48]([NH:52][CH:53]3[CH2:54][CH2:55][N:56]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:57][CH2:58]3)=[O:50])[C:36]=2[CH3:51])=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reaction time: 16 h
Yield: 87.5 %

Procedure:
Benzotriazole-1-yl-oxytris(dimethylamino)phosphonium-hexafluorophosphate (BOP) (1 eq, 490 mg, 1.11 mmol) was added to a solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1 eq, 422 mg, 1.11 mmol), tert-butyl 4-amino-1-piperidinecarboxylate (1 eq, 222 mg, 1.11 mmol), and triethylamine (3 eq., 0.46 mL, 3.32 mmol) in tetrahydrofuran (5 mL). The reaction mixture was stirred for 16 h. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-100% ethyl acetate/hexane to yield pure tert-butyl 4-[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-amido]piperidine-1-carboxylate (548 mg, 88%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.33-1.51 (m, 9H) 1.93-2.10 (m, 2H) 2.37 (s, 3H) 2.91 (t, J=11.82 Hz, 2H) 3.89-4.23 (m, 2H) 6.84 (d, J=8.19 Hz, 1H) 7.00-7.12 (m, 2H) 7.19-7.36 (m, 4H) 7.43 (d, J=1.32 Hz, 1H).
Reaction SMILES: C(OC(=O)[N:7]([CH2:31][CH:32]1[CH2:34][CH2:33]1)[C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=2[F:29])=[CH:13][CH:12]=1)(C)(C)C.[ClH:36].COC1CCCC1>C1COCC1>[ClH:36].[CH:32]1([CH2:31][NH:7][C@@H:8]2[CH2:10][C@H:9]2[C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:30])[C:19]3[CH:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:22]=[CH:21][C:20]=3[F:29])=[CH:15][CH:16]=2)[CH2:33][CH2:34]1
Reactant: CC(C)(C)OC(=O)N(CC1CC1)[C@@H]1C[C@H]1c1ccc(NC(=O)c2cc(C(F)(F)F)ccc2F)cc1
Agent: Cl
Solvent: COC1CCCC1
Solvent: C1CCOC1
Product: O=C(Nc1ccc([C@@H]2C[C@H]2NCC2CC2)cc1)c1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl(cyclopropylmethyl)[trans-2-(4-{[2-fluoro-5-(trifluoromethyl)benzoyl]amino}phenyl)-cyclopropyl]carbamate (110 mg) in THF (1 mL) was ice-cooled, and 4N hydrochloric acid/cyclopentyl methyl ether solution (15 mL) was added. The mixture was stirred at room temperature overnight and the solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropyl ether to give the title compound (72.0 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[C:7]1([CH3:35])[CH:12]=[CH:11][C:10]([S:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])(=[O:15])=[O:14])=[CH:9][CH:8]=1>>[C:7]1([CH3:35])[CH:8]=[CH:9][C:10]([S:13]([O-:16])(=[O:14])=[O:15])=[CH:11][CH:12]=1.[CH3:1][N+:2]1[CH:6]=[CH:5][N:4]([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])[CH:3]=1
Reactant: CCCCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Cn1ccnc1
Product: CCCCCCCCCCCCCCCCCCn1cc[n+](C)c1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 91.3 %

Procedure:
In a 100 ml flask equipped with a stirrer, a condenser and a calcium chloride dryer tube were charged 3.7 g of 1-methylimidazole and 10.0 g of octadecyl p-toluenesulfonate, and the mixture was stirred at 120° C. for 5 hours. After cooling the reaction mixture to room temperature, precipitated crystals were collected by filtration under reduced pressure. The resulting crystals were recrystallized from acetone to obtain 10.9 g of the title compound. Melting point: 71° C.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][NH:18][CH2:19][CH2:20][CH:21]=2)=[C:12]([OH:22])[CH:11]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(O)C.[H][H]>[Pd].C(OCC)(=O)C>[CH3:9][C:2]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[C:12]([OH:22])[CH:11]=1)([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: [H][H]
Reactant: CCCCCCC(C)(C)c1ccc(C2=CCCNC2)c(O)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCCCC(C)(C)c1ccc(C2CCCNC2)c(O)c1
Yield: 62 %

Procedure:
A mixture of 7.4 g. (24.5 mmoles) of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-1,2,5,6-tetrahydropyridine and 2.0 g. of 10% palladium-on-carbon in 150 ml. of ethanol and 75 ml. of ethyl acetate is stirred under one atmosphere of hydrogen for 2.5 hours. The reaction is filtered through diatomaceous earth and evaporated. Crystallization of the residue from ether-pentane gave 4.6 g. (62%) of the title compound.
Reaction SMILES: [ClH:1].[CH:2]([N:5]1[CH2:8][CH:7]([CH2:9]O)[CH2:6]1)([CH3:4])[CH3:3].S(Cl)([Cl:13])=O>ClCCl>[ClH:13].[Cl:1][CH2:9][CH:7]1[CH2:8][N:5]([CH:2]([CH3:4])[CH3:3])[CH2:6]1
Reactant: CC(C)N1CC(CO)C1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: CC(C)N1CC(CCl)C1
Temperature: 0 °C

Procedure:
(1-isopropylazetidin-3-yl)methanol hydrochloride (2.6 g, 15.7 mmol) was dissolved in dichloromethane (50 ml) and cooled to 0° C. Thionyl chloride (1.4 ml, 19.2 mmol) was added dropwise over 5 min. The reaction mixture was then stirred whilst warming to ambient temperature. Stirred at ambient temperature for 48 hours. The reaction mixture was concentrated in vacuo and azeotroped with toluene (40 ml) to give the title compound as a beige hygroscopic powder (2.8 g, 99%). LRMS ESI+ m/z 148/150 [M+H]+ (CI isotopes).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:8]1[CH:23]=[CH:22][C:11]([O:12][C:13]2[N:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15](Cl)=[O:16])=[CH:10][CH:9]=1)(=[O:7])[CH3:6].O>[N+](C1C=CC=CC=1)([O-])=O>[C:5]([C:8]1[CH:23]=[CH:22][C:11]2[O:12][C:13]3=[N:21][CH:20]=[CH:19][CH:18]=[C:14]3[C:15](=[O:16])[C:10]=2[CH:9]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)c1ccc(Oc2ncccc2C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)c1ccc2oc3ncccc3c(=O)c2c1
Temperature: 80 °C

Procedure:
1.68 g of powdered anhydrous aluminum chloride is added to a solution of 1.15 g of 2-(p-acetylphenoxy)nicotinoyl chloride in 5 ml of nitrobenzene at 20°-30°C, and the mixture is heated at 80°C for 3.5 hours. After cooling, water is added to the reaction mixture to decompose the aluminum chloride. After removing the nitrobenzene by distillation, the mixture is extracted with chloroform, and the extract is concentrated. The residue is recrystallized from toluene to give 7-acetyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine melting at 195-196°C.
Reaction SMILES: [C:1]1([N:7]2[C:11]([S:12][CH2:13][N:14]3[C:24](=[O:25])[C:23]4[C:18](=[C:19]([O:29][CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])[CH:20]=[CH:21][C:22]=4[O:26][CH2:27][CH3:28])[S:15]3(=[O:17])=[O:16])=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>FC(F)(F)C(O)=O.ClCCl.CC(C)=O>[C:1]1([N:7]2[C:11]([S:12][CH2:13][N:14]3[C:24](=[O:25])[C:23]4[C:18](=[C:19]([O:29][CH2:30][C:31]([OH:33])=[O:32])[CH:20]=[CH:21][C:22]=4[O:26][CH2:27][CH3:28])[S:15]3(=[O:17])=[O:16])=[N:10][N:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOc1ccc(OCC(=O)OC(C)(C)C)c2c1C(=O)N(CSc1nnnn1-c1ccccc1)S2(=O)=O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCOc1ccc(OCC(=O)O)c2c1C(=O)N(CSc1nnnn1-c1ccccc1)S2(=O)=O
Temperature: 0 °C
Yield: 17 %

Procedure:
A solution of 2-(1-phenyltetrazol-5-yl)thiomethyl-4-ethoxy-7-(t-butoxycarbonylmethoxy)saccharin (Example 52, 0.47 g) in trifluoroacetic acid (5-10 mL) and dichloromethane (5-10 mL) was stirred at room temperature for two hours, then stripped of volatiles, then stripped three times more from dichloromethane, then stripped once more from acetone. A solution of the residual oil in acetone (1 mL) was added to ice-water (100 mL) containing concentrated hydrochloric acid (1 mL). The resulting solid was collected, washed with water and dried (0.34 g). A solution thereof in dichloromethane was eluted through silica gel in a 15-mL sintered glass funnel with chloroform-methanol (95:5) affording 2-(1-phenyltetrazol-5-yl)thiomethyl-4-ethoxy-7-carboxymethoxysaccharin, 70 mg, 17% yield, mp 187°-189° C.