Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([CH3:23])[CH:3]=1.[Cl:24][C:25]1[CH:30]=[C:29]([C:31](O)=[O:32])[CH:28]=[CH:27][N:26]=1.C(N(CC)CC)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:31]([C:29]4[CH:28]=[CH:27][N:26]=[C:25]([Cl:24])[CH:30]=4)=[O:32])=[CH:17][CH:16]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([CH3:23])[CH:3]=1
Reactant: Cc1cc(N)c2cc(C(=O)Nc3ccc(CN)cc3)ccc2n1
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(N)c2cc(C(=O)Nc3ccc(CNC(=O)c4ccnc(Cl)c4)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.3 %

Procedure:
To a solution of 27 mg (0.05 mmol) 4-Amino-N-[4-(aminomethyl)phenyl]-2-methyl-6-quinolinecarboxamide, 9 mg (0.1 mmol) 2-chloropyridine-4-carboxylic acid, and 0.07 ml (0.5 mmol) triethylamine in 2 ml dichloromethane was added 90 mg (2.0 mmol) PyBrop and stirred at room temperature for 1 d. After evaporation of the solvent the residue was purified by HPLC and lyophilized to yield 17 mg (74%) of the title compound. MS 446.3 (M+1)+, 1H-NMR (DMSO-d6) δ: 2.60 (s, 3H), 4.47 (d, 2H), 6.64 (s, 1H), 7.34 (d, 2H), 7.73 (d, 2H), 7.81 (dd, 1H), 7.87 (d, 1H), 7.91 (s, 1H), 8.35 (dd, 1H), 8.57 (d, 1H), 8.95 (s, 1H), 9.00 (br. 2H), 9.41 (t, 1H), 10.47 (s, 1H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:25](=[O:26])[C:14]3[CH:15]=[N:16][C:17]4[C:18]([O:23][CH3:24])=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[N:12]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:11]2=[O:33])[CH:7]=[CH:8][CH:9]=1.[O:34]=[S:35]1(=[O:44])[CH2:39][CH2:38][CH:37]([S:40](Cl)(=[O:42])=[O:41])[CH2:36]1>>[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:25](=[O:26])[C:14]3[CH:15]=[N:16][C:17]4[C:18]([O:23][CH3:24])=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[N:12]([CH:27]3[CH2:32][CH2:31][N:30]([S:40]([CH:37]4[CH2:38][CH2:39][S:35](=[O:44])(=[O:34])[CH2:36]4)(=[O:42])=[O:41])[CH2:29][CH2:28]3)[C:11]2=[O:33])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCNCC3)c12
Reactant: O=S1(=O)CCC(S(=O)(=O)Cl)C1
Agent: Cl
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCN(S(=O)(=O)C4CCS(=O)(=O)C4)CC3)c12

Procedure:
3-(3-Chloro-phenyl)-1-[1-(1,1-dioxo-tetrahydro-thiophene-3-sulfonyl)-piperidin-4-yl]-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (51 mg) was prepared according to general procedure H from 3-(3-chloro-phenyl)-7-methoxy-1-piperidin-4-yl-1H-pyrimido[5,4-c]quinoline-2,4-dione.dihydrochloride (50 mg, 0.1 mmol) and 1,1-dioxo-tetrahydro-thiophene-3-sulfonyl chloride. LCMS: m/z 619 [M+1]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:59][CH3:60])[C:4]1[CH:5]=[CH:6][C:7]([NH:30][C:31](=[O:58])[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][OH:57])[CH:33]=2)=[C:8]([C:10]2[CH:11]=[C:12]([CH:27]=[CH:28][N:29]=2)[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[O:14])[CH:9]=1)[CH3:2].C(N(CC)CC)C.[C:68]1([CH3:78])[CH:73]=[CH:72][C:71]([S:74](Cl)(=[O:76])=[O:75])=[CH:70][CH:69]=1>C(Cl)Cl>[CH3:78][C:68]1[CH:73]=[CH:72][C:71]([S:74]([O:57][CH2:56][CH2:55][O:54][CH2:53][CH2:52][O:51][CH2:50][CH2:49][O:48][CH2:47][CH2:46][O:45][CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38][C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([C:31](=[O:58])[NH:30][C:7]3[CH:6]=[CH:5][C:4]([N:3]([CH2:1][CH3:2])[CH2:59][CH3:60])=[CH:9][C:8]=3[C:10]3[CH:11]=[C:12]([C:13](=[O:14])[NH:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:27]=[CH:28][N:29]=3)[CH:33]=2)(=[O:76])=[O:75])=[CH:70][CH:69]=1
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(COCCOCCOCCOCCOCCOCCO)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)c1ccc(NC(=O)c2cccc(COCCOCCOCCOCCOCCOCCOS(=O)(=O)c3ccc(C)cc3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 16 h

Procedure:
To a mixture of Example 168 (500 mg, 0.595 mmol) and triethylamine (167 μL, 1.19 mmol) in DCM (3 mL) was added p-toluenesulfonyl chloride (136 mg, 0.714 mmol) in several portions and the solution stirred for 16 h. The solution was then diluted with DCM and washed with aqueous HCl and H2O, then dried over Na2SO4 and the solvent removed. The residue was purified by silica gel chromatography, using a gradient of 20% to 100% EtOAc in hexanes as eluent and the solvent removed. This gave 560 mg (95%) of the product as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[N:16]=[C:15]([C:17](Cl)=[O:18])[CH:14]=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:1][C:17]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:10]([F:21])([F:9])[F:20])[N:16]=2)=[O:18])[CH:7]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)n1
Reactant: Nc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cc(Cl)ncn1)c1cccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-6-chloropyrimidine (230 mg, 1.78 mmol) in DCM (15 mL) is added 6-(trifluoromethyl)picolinoyl chloride (276 mg, 1.78 mmol) and DIPEA (0.912 ml, 5.33 mmol). The mixture is stirred overnight at RT. The mixture is diluted with DCM (10 mL), washed with saturated NaHCO3 solution (25 mL). The organic layer is dried over MgSO4 and evaporated under reduced pressure. The residue is purified by prep HPLC E, delivering the title compound as a yellowish solid (102 mg, 19%); LC-MS A: tR=0.89 min; [M+H]+=302.92.
Reaction SMILES: C([NH:8][C@@H:9]([C@@H:13]([O:15][CH3:16])[CH3:14])[C:10](O)=O)(OC(C)(C)C)=O.[CH3:17][CH:18]([C:20]1[CH:21]=[C:22]([NH2:27])[C:23]([NH2:26])=[CH:24][CH:25]=1)[CH3:19]>>[CH3:16][O:15][C@@H:13]([CH3:14])[C@@H:9]([C:10]1[NH:26][C:23]2[CH:24]=[CH:25][C:20]([CH:18]([CH3:19])[CH3:17])=[CH:21][C:22]=2[N:27]=1)[NH2:8]
Reactant: CC(C)c1ccc(N)c(N)c1
Reactant: CO[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CO[C@@H](C)[C@H](N)c1nc2cc(C(C)C)ccc2[nH]1

Procedure:
The title compound was prepared according to Method 4 using N-boc-(2S,3S)-2-amino-3-methoxybutanoic acid and 4-(1-methylethyl)-1,2-benzenediamine.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[CH:18]=2)[N:9]=1.Br[CH2:33][CH3:34].C([O-])([O-])=O.[K+].[K+]>CC#N.C(Cl)Cl>[CH2:33]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@H:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH3:25])[CH:18]=2)[N:9]=1)[CH3:34]
Reactant: CC(Nc1cc(-c2cc3nccn3c(N3CC4CC3CN4)n2)ccn1)c1ccccc1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CCN1C[C@@H]2C[C@H]1CN2c1nc(-c2ccnc(N[C@@H](C)c3ccccc3)c2)cc2nccn12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The mixture of 50 mg (0.12 mmol) {4-[5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-imidazo [1,2-c]pyrimidin-7-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine in 20 mL CH3CN was treated with 26 mg (0.24 mmol) bromoethane and 33 mg (0.24 mmol) K2CO3. The mixture was stirred at rt for 15 h. MS showed all starting materials were converted. The mixture was diluted with 50 mL DCM, washed with 20 mL sat. NaHCO3, dried over anhydrous Na2SO4. After purification by chromatography, obtained the title compound in 20 mg as a yellow solid. MS (ES+): 440 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:10]([OH:14])[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH2:21])=[N-]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:10]([OH:14])[C:11]([O:13][CH3:21])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)[C@H](O)C(=O)O
Reactant: C=[N+]=[N-]
Solvent: CO
Product: COC(=O)[C@@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C

Procedure:
To a solution of 1.00 g (3.8 mmole) of (2S,3S)-3-(t-butoxycarbonyl)amino-2-hydroxy-5-methylhexaneoic acid prepared according to the method of R. L. Johnson [J. Med. Chem., 25, 605 (1982)] in 30 ml. of methanol was added, with stirring and ice-cooling, an ethereal solution of diazomethane. The mixture was stirred at room temperature for 1 hour. The solvent was removed by distillation, and the solid thus obtained was recrystallized from hexane, to afford 952 mg. of colourless needles, melting at 84°-85° C.; [α]22 -10.2° (C=1.26, methanol).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].Cl>C(Cl)Cl>[CH:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6](=[CH:16][C:17]3[N:22]=[C:21]([NH:23][S:32]([CH3:31])(=[O:34])=[O:33])[CH:20]=[CH:19][CH:18]=3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(C=C2c3ccccc3CCc3ccccc32)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc(C=C2c3ccccc3CCc3ccccc32)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
Mix 6-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-pyridin-2-ylamine (70 mg, 0.235 mmol), triethylamine (68 μL, 0.470 mmol), N,N-dimethylaminopyridine (3 mg, 0.024 mmol), and methanesulfonyl chloride (19 μL, 0.247 mmol) in CH2Cl2 (2 mL). Stir at room temperature overnight and add 150 □L triethylamine and 40 μL methanesulfonyl chloride. Stir at room temperature for 6 h and add 1.00N aqueous HCl (1 mL). Load mixture onto a Varian ChemElut CE1005 solid-phase extraction cartridge, then elute, collect, and concentrate 45 mL CH2Cl2. Dissolve crude product in THF (5 mL), add 1.0M tetrabutylammonium fluoride (0.25 mL), and heat to reflux for 1 h. Cool to room temperature and dilute with H2O and brine. Extract into ethyl acetate, dry (MgSO4) and concentrate organics. Chromatograph on silica gel (10 g), eluting with 20% to 35% ethyl acetate/hexanes to afford 61 mg (69%) of the title compound as a yellow oil. MS (ES) 377 (M+H), 375 (M−H); BPLC shows 96% purity.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([N+:14]([O-:16])=[O:15])[C:8]=2[N:7]=[C:6]1[C:17]1[C:22](F)=[CH:21][CH:20]=[CH:19][C:18]=1[F:24].FC1C=CC=C(F)C=1CBr.[H-].[Na+].[CH2:42]([O:44]C(=O)C)C.CCCCCC>C1COCC1>[F:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([N+:14]([O-:16])=[O:15])[C:8]=2[N:7]=[C:6]1[C:17]1[C:22]([O:44][CH3:42])=[CH:21][CH:20]=[CH:19][C:18]=1[F:24]
Reactant: O=[N+]([O-])c1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Reactant: CCOC(C)=O
Agent: Fc1cccc(F)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc(F)c1-c1nc2c([N+](=O)[O-])cccc2n1Cc1c(F)cccc1F
Reaction time: 8 h

Procedure:
To 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-nitrobenzimidazole (2.00 g, 8 mmol)was added 2,6-difluorobenzylbromide (2.0.2 g, 9.76 mmol, 130 M %) dissolved in THF (20 mL) was added NaH (0.84 g, 21 mmol, 290 M %). After 8 h, the reaction was quenched with m ethanol and concentrated. The residue was dissolved in CH2Cl2, and washed with water and NaCl (sat. aq.). The combined washings were dried (Na2SO4), filtered, concentrated. The crude product was purified by flash chromatography eluting with ethylacetate:hexane (1:1) (2.33 g, 5.64 mmol, 78%). M.p. 189-192° C. 1H-NMR (200 MHz, CD2Cl2) δ 8.11 (dd, J=8.1, 1.0 Hz, 1H, H5), 7.84 (dd, J=8.1, 1.0 Hz, 1H, H7), 7.52 (m, 1H, H4′), 7.40 (dd, J=8.1 Hz, 1H, H6), 7.26 (m, 1H, H4″), 6.89-6.74 (m, 4H, H3′,5′,3″,5″), 5.36 (d, J=3.4 Hz, 2H, CH2PhF2 (rotamers)), 3.73 (s, 3H, OCH3).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.OS(O)(=O)=O.[CH3:19][CH2:20]O>CCOC(C)=O>[OH:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:19][CH3:20])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: CCO
Reactant: O=C(O)c1cc(O)c2[nH]ncc2c1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(O)c2[nH]ncc2c1
Yield: 73 %

Procedure:
A solution of 7-hydroxy-1H-indazole-5-carboxylic acid (1.08 g, 6.06 mmol) in EtOH (50 mL) containing conc. H2SO4 (0.34 mL) was heated at reflux overnight. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3. The aqueous phase was back extracted with EtOAc (3×). The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated to afford ethyl 7-hydroxy-1H-indazole-5-carboxylate (918 mg, 73%).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][S:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[Cl:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[Cl:41])[CH2:36][NH2:37].CS(C)=O>C(#N)C>[Br:28][C:25]1[CH:26]=[CH:27][C:22]([S:21][CH2:20][C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:37][CH2:36][C:35]4[CH:38]=[CH:39][C:40]([Cl:41])=[C:33]([Cl:32])[CH:34]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:29])=[CH:23][CH:24]=1
Reactant: O=C(CSc1ccc(Br)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Reactant: NCc1ccc(Cl)c(Cl)c1
Solvent: CS(C)=O
Solvent: CC#N
Product: O=C(NCc1ccc(Cl)c(Cl)c1)c1ccc2n1Cc1ccccc1N(C(=O)CSc1ccc(Br)cc1)C2
Temperature: 85 °C

Procedure:
To an 18×150 mm reaction vessel was added 2,2,2-trichloro-1-[10-{[(4-bromophenyl)thio]acetyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl]-ethanone of Example 80 (0.23 mmol), acetonitrile (2.5 mL), 3,4-dichlorobenzylamine (0.49 mmol), and dimethylsulfoxide (0.81 mmol). The stirred solution was heated to 85° C. for 20 hours. The solvent was evaporated and the residue was dissolved in 5 mL dichloromethane. The solution was washed twice with water, dried over anhydrous sodium sulfate, and evaporated. The crude product was purified using normal phase HPLC with a two phase solvent system (A=hexane, B=dichloromethane/methanol, 4:1) to give the title product, m.p. 150° C. MS [(+)ESI, m/z]: 614 [M+H]+ Anal. Calcd for C28H22BrCl2N3O2S: C, 54.65; H, 3.60; N, 6.83. Found: C, 54.68; H, 3.50; N, 6.73.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[CH3:13][O:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][O:25][CH3:26])[CH:20]=[CH:19][C:18]=1[CH:27]1[CH2:32][CH2:31][CH2:30][CH:29]([NH2:33])[CH2:28]1>ClCCl>[CH3:13][O:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][O:25][CH3:26])[CH:20]=[CH:19][C:18]=1[CH:27]1[CH2:32][CH2:31][CH2:30][CH:29]([NH:33][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:28]1
Reactant: CS(=O)(=O)Cl
Reactant: COCOc1ccc(C2CCCC(N)C2)c(OCOC)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOc1ccc(C2CCCC(NS(C)(=O)=O)C2)c(OCOC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (0.014 ml) and methanesulfonyl chloride (8 μl) were added to a solution of (±)-3-[2,4-bis(methoxymethoxy)phenyl]cyclohexylamine (27 mg) in dichloromethane (1 ml), and the mixture was stirred under argon at ambient temperature. After 1 hr, the mixture was partitioned between ethyl acetate (20 ml) and sodium hydrogen carbonate (20 ml of a saturated aqueous solution). The aqueous layer was extracted with ethyl acetate (2×20 ml), and the combined organic extracts were dried over magnesium sulfate and evaporated in vacuo to furnish the title compound as an oil and a mixture of diastereoisomers; m/z (ES+) 374 (M+H)+.
Reaction SMILES: CC1N=C([C:7]2[CH:31]=[CH:30][CH:29]=[CH:28][C:8]=2[C:9]([NH:11][C@H:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=2)=[O:10])ON=1.[N:32]1[N:33](C2C=CC=CC=2C(O)=O)[N:34]=[CH:35][CH:36]=1.Cl.FC(F)(F)C1C=CC(N[C@H]2CCC[C@@H]2N)=NC=1>>[N:32]1[N:33]([C:7]2[CH:31]=[CH:30][CH:29]=[CH:28][C:8]=2[C:9]([NH:11][C@H:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][N:19]=2)=[O:10])[N:34]=[CH:35][CH:36]=1
Reactant: Cc1noc(-c2ccccc2C(=O)N[C@H]2CCC[C@@H]2Nc2ccc(C(F)(F)F)cn2)n1
Reactant: O=C(O)c1ccccc1-n1nccn1
Agent: Cl
Agent: N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1ccccc1-n1nccn1

Procedure:
Prepared according to the procedure for 2-(3-methyl-1,2,4-oxadiazol-5-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide (Example 8) from 2-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS number 1001401-62-2; 57 mg, 0.28 mmol) and (1S,2S)-1-N-[5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 1; 72 mg, 0.26 mmol) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.Cl.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[N:17][CH:18]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:12][C:13]2[CH:18]=[N:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[O:7])=[CH:4][N:3]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Nc1ccc(O)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(O)nc1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 6-chloro-nicotinoyl chloride (0.40 g, 2.27 mmol) and 5-amino-2-hydroxypyridine hydrochloride (0.33 g, 2.25 mmol) in dry tetrahydrofuran (15 mL) was stirred at room temperature for 1 hour. Saturated sodium bicarbonate (aq) was added and the solution was extracted three times with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo. The residue was dissolved in a mixture of methanol (10 mL) and aqueous sodium hydroxide (1N, 2 mL). After stirring for 2 hours at room temperature water was added and the solution was extracted with dichloromethane. The organic layer was dried over sodium sulphate, filtered and evaporated in vacuo, yielding the title compound which was used without further purification.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[C@@H:15]1([NH2:25])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1>>[C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:25][C@@H:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)[CH:2]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Reactant: N[C@H]1CCCc2ccccc21
Product: c1ccc(-c2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1

Procedure:
[1,1′-Biphenyl]-3-carbaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7].Cl[C:17]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:18]=1[C:19]#[N:20].O>CN(C=O)C>[C:19]([C:18]1[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:17]=1[N:5]([O:4][CH3:3])[S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7])#[N:20]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CONS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CON(c1ccc([N+](=O)[O-])cc1C#N)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 68.1 %

Procedure:
To a suspension of sodium hydride (60%, 0.09 g (2.25 mmol)) in 3.0 ml of DMF, N-methoxy-p-toluenesulfonamide (0.45 g (2.20 mmol)) was added under cooling with ice and with stirring. To the resulting mixture, after 15 minutes' stirring under cooling with ice, 2-chloro-5-nitrobenzonitrile (0.37 g (2.03 mmol)) was added and the mixture was stirred under cooling with ice for one hour and at room temperature for 18 hours. The reaction mixture was then poured into water and extracted with diethyl ether. The extract was washed twice with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:5) as eluent to give 0.48 g (68%) of the title compound as pale yellow crystals.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[N:11][C:10]([NH:13][NH2:14])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](O)(=O)[CH2:16][OH:17].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:15]([CH2:16][OH:17])=[N:14][N:13]=3)[N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NNc1ccc(-c2ccccc2)nn1
Reactant: O=C(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: OCc1nnc2ccc(-c3ccccc3)nn12

Procedure:
A mixture of 1-(6-phenylpyridazin-3-yl)hydrazine (2.00 g, 10.7 mmol), glycolic acid (0.825 g, 10.8 mmol), p-TsOH.H2O (2.55 g, 13.4 mmol) in PhMe (50 mL) was refluxed for 14 h. PhMe was removed in vacuo. The resulting solids were diluted with water (30 mL). The mixture was brought to pH˜10 with 2N NaOH. The solids were isolated solid by filtration, washed with water and dried under vacuum to give an off white solid which was used without further purification. (ESI, pos. ion) m/z: 227.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:22](=[CH:23][CH:24]=1)[C:8]1([CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])[CH2:10][CH2:9]1)[C:7](=[O:25])[C:6]([C:26]([NH:28][CH2:29][C:30]([O:32]C)=[O:31])=[O:27])=[C:5]2[OH:34].O.[OH-].[Li+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:22](=[CH:23][CH:24]=1)[C:8]1([CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])[CH2:10][CH2:9]1)[C:7](=[O:25])[C:6]([C:26]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:27])=[C:5]2[OH:34]
Reactant: COC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCN(C(=O)c3ccccc3)CC2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCN(C(=O)c3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The ester was treated with lithium hydroxide hydrate (0.025 g, 0.60 mmol) in THF (1.4 mL) and water (0.6 mL) and stirred at 25° C. for 30 minutes. The reaction was quenched with Dowex 50 (W×8) acidic resin (prewashed with MeOH) to pH<4.0 and filtered. The filtrate was concentrated and azeotroped with toluene (2×5 mL), to give the title compound (0.017 g). MS m/e=469.5 (M+H)+. Calculated for C24H21ClN2O6 468.11.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([NH2:7])=[N:5][N:6]=1.[CH3:8][O:9][CH2:10][C:11](=O)[CH3:12].C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH3:8][O:9][CH2:10][CH:11]([NH:7][C:4]1[NH:3][C:2]([CH3:1])=[N:6][N:5]=1)[CH3:12]
Reactant: Cc1nnc(N)[nH]1
Reactant: COCC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COCC(C)Nc1nnc(C)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.3 %

Procedure:
To a solution (40 mL) of 5-methyl-4H-1,2,4-triazol-3-amine (2.5 g) and 1-methoxypropan-2-one (2.7 g) in acetic acid was added sodium cyanoborohydride (8.1 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (1.4 g, 32%).