Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:7]=[N:6][N:5]([CH2:8][C@@H:9]2[C@H:12]([NH:13][C:14](=[O:30])/[C:15](=[N:22]\[O:23][C:24]3([C:27]([OH:29])=[O:28])[CH2:26][CH2:25]3)/[C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)[C:11](=[O:31])[N:10]2[S:32]([OH:35])(=[O:34])=[O:33])[N:4]=1.Cl.[N:37]1([C:42](N)=[NH:43])C=CC=N1.CCN(C(C)C)C(C)C>CN(C=O)C.C1(C)C=CC=CC=1>[NH2:21][C:18]1[S:19][CH:20]=[C:16](/[C:15](=[N:22]/[O:23][C:24]2([C:27]([OH:29])=[O:28])[CH2:25][CH2:26]2)/[C:14]([NH:13][C@@H:12]2[C:11](=[O:31])[N:10]([S:32]([OH:35])(=[O:34])=[O:33])[C@@H:9]2[CH2:8][N:5]2[N:4]=[C:3]([CH2:2][NH:1][C:42]([NH2:43])=[NH:37])[CH:7]=[N:6]2)=[O:30])[N:17]=1
Reactant: NCc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)n1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: N=C(N)NCc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.2 %

Procedure:
To a solution of 1-(((Z)-(2-(((2R,3S)-2-((4-(aminomethyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)-cyclopropanecarboxylic acid (582 mg, 1.10 mmol) in DMF (12 mL) at 0° C. was added pyrazole-1-carboxamidine hydrochloride (322 mg, 2.20 mmol) and DIPEA (1.54 mL, 8.80 mmol). After 16 h of stirring at rt, the solution was diluted with toluene (60 mL), causing a dense oil to separate out. The top layer was decanted and the remaining oil was purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (240 mg, 37%) as an off-white powder. LCMS: Rt=0.31 min, m/z=572.2 (M+H) Method 2m_acidic; 1H NMR (400 MHz, D2O) δ 7.59 (s, 1H), 6.99 (br s, 1H), 5.43 (d, J=5.5 Hz, 1H), 4.91-4.75 (m, 2H assumed; obscured by solvent residual peak), 4.70 (dd, J=8.2, 6.3 Hz, 1H), 4.41-4.34 (m, 2H), 1.20 (br s, 2H), 1.05 (br s, 2H). E-isomer was also obtained. LCMS: Rt=0.33 min, m/z=572.2 (M+H) Method 2m_acidic; 1H NMR (400 MHz, D2O) δ 7.58 (s, 1H), 7.46 (br. s., 1H), 5.45 (br. s., 1H), 4.84 (s, 3H), 4.37 (s, 2H), 1.33-1.08 (m, 4H).
Reaction SMILES: O[C:2]([CH3:13])([CH3:12])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(N(S(F)(F)[F:20])CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:20][C:2]([CH3:13])([CH3:12])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(O)CNC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(F)CNC(=O)OC(C)(C)C
Temperature: -78 °C
Yield: 79.4 %

Procedure:
A stirred solution of tert-butyl 2-hydroxy-2-methylpropylcarbamate (7.81 g, 41.3 mmol) dissolved in 300 mL of anhydrous CH2Cl2 was cooled to −78° C. under an atmosphere of N2. The reaction mixture was treated with diethylaminosulfur trifloride (DAST) (6.2 mL, 47 mmol) and allowed to warm to ambient temperature overnight. The reaction mixture was treated with saturated NaHCO3 solution and the layers were separated. The organic portion was washed successively with saturated NaHCO3 solution, H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 10% EtOAc/hexanes) gave 6.27 g of tert-butyl 2-fluoro-2-methylpropylcarbamate as an amber oil which solidified on standing.
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])=[CH2:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:33][N:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][C:41]=2[CH2:43]O)[CH:36]=[C:35]1[CH3:45].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:33][N:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][C:41]=2[CH2:43][N:6]2[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]([C:1]([CH3:3])=[CH2:2])[C:5]2=[O:13])[CH:36]=[C:35]1[CH3:45]
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Reactant: Cc1cc2cccc(CO)c2n1C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C(C)n1c(=O)n(Cc2cccc3cc(C)n(C)c23)c2ccccc21
Reaction time: 16 h
Yield: 46.4 %

Procedure:
To a solution of 1-isopropenylbenzimidazolone (220 mg, 1.3 mmol) in dry THF (10 mL) are added triphenylphosphine (397 mg, 1.5 mmol) and (1,2-Dimethyl-1H-indol-7-yl)-methanol (220 mg, 1.3 mmol). Then diisopropyl azodicarboxylate (0.31 mL, 1.5 mmol) is added drop wise into the above solution at room temperature. The mixture is stirred for 16 hrs and then the solvent is removed under vacuum. The residue is purified by flash column chromatography using 10-30% EtOAc in hexanes to give 200 mg (48%) of 1-(1,2-dimethyl-1H-indol-7-ylmethyl)-3-isopropenyl-1,3-dihydro-benzimidazol-2-one.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[C@@H:16]([O:22][C:23]([C:25]1([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24])[CH2:15]2>CC#N>[Br-:1].[C:10]([C:9]1[CH:12]=[CH:13][C:6]([CH2:5][O:4][CH2:3][CH2:2][N+:14]23[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]2)[C@@H:16]([O:22][C:23]([C:25]2([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])[CH2:15]3)=[CH:7][CH:8]=1)#[N:11]
Reactant: N#Cc1ccc(COCCBr)cc1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Solvent: CC#N
Product: N#Cc1ccc(COCC[N+]23CCC(CC2)[C@@H](OC(=O)C2(c4ccccc4)CCCCCC2)C3)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.2 %

Procedure:
A mixture of 4-(2-bromo-ethoxymethyl)-benzonitrile (41 mg, 0.17 mmol) and 1-phenyl -cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 14e) (51 mg) in MeCN (1 mL) was stirred at room temperature for 16 h then heated to 80° C. under nitrogen overnight. The resulting solid was filtered off, washed with ether and dried under vacuum to give the title compound (70 mg) as a white solid.
Reaction SMILES: [H-].[Na+].CS([CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:9](O)[CH2:8]1)(=O)=O.C1(O)C=CC=CC=1>CN(C)C=O>[C:13]([N:10]1[CH2:9][CH2:8][CH2:7][CH2:12][CH2:11]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCC(S(C)(=O)=O)CC1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Oc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCCC1
Temperature: 80 °C

Procedure:
Sodium hydride (Aldrich, 2 g, 50 mmol) was added to a solution of 4-(methylsulfonyl)hydroxy-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester of Example 14, B (10 g, 25 mmol) and the phenol from part 2 (5.5 g, 50 mmol) dissolved in dimethylformamide (60 mL) at 25° C. and under N2. The mixture was stirred and heated to 80° C. for 16 hours. After this time, the solvent was removed by roto-evaporation, followed by taking the residue up in ethyl acetate (150 mL) and H2O (100 mL). The layers were separated and the aqueous was extracted via ethyl acetate (2×-150 mL). The organics were washed with saturated K2CO3 (2×-100 mL), H2O (1×-150 mL), and brine (1×-150 mL), then dried over Na2SO4, filtered, and concentrated to afford a crude oil. The oil was purified on silica gel to give 10 g of the N-boc piperidine as a clear oil. 1H NMR and mass spectroscopy was consistent with the desired compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([CH3:17])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)=[O:4].C(N(CC)CC)C.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:28]=[C:29]([CH2:33][SH:34])[CH:30]=[CH:31][CH:32]=1>C(Cl)Cl>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]2[O:8][N:7]=[C:6]([CH3:17])[C:5]=2[C:3](=[O:4])[CH2:2][S:34][CH2:33][C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:25])([F:35])[F:36])[CH:28]=2)=[CH:11][CH:12]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CBr
Reactant: FC(F)(F)c1cccc(CS)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CSCc1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
2-Bromo-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanone and triethylamine were combined in CH2Cl2. (3-trifluoromethyl-phenyl)-methanethiol was added, and the reaction was stirred at room temperature for at least 1 hour. After workup, the crude material was purified by silica gel chromatography.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]([O:17]CC)=[O:16])=[CH:12][C:11]=3[CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[OH-].[K+]>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][C:11]=3[CH:20]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cc2cc(-c3ccccc3)ccc2o1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1cc2cc(-c3ccccc3)ccc2o1

Procedure:
A mixture of 1.3 g of 10B and 50 ml of 10% alcoholic potassium hydroxide was refluxed for 4 hours. The solvent was evaporated under reduced pressure and the residue was washed with ether and dissolved in water. The basic solution was acidified with dilute hydrochloric acid and extracted with ether. The ether layer was extracted with dilute sodium bicarbonate solution. The aqueous extract was acidified with dilute hydrochloric acid and extracted with ether. The ether extract was dried (Na2SO4), concentrated under reduced pressure, and the resulting residue was crystallized from ethanol to give 5-phenyl-2-benzofurancarboxylic acid (10C), as white solid, mp: 220°-221° C.
Reaction SMILES: [CH3:1][N:2]1[C:7](=S)[CH2:6][O:5][C:4]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][CH2:26]4)=[CH:21][CH:20]=3)[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:12][C:3]1=2.[CH3:37][O:38][NH3+:39].[Cl-]>N1C=CC=CC=1>[CH3:37][O:38][N:39]=[C:7]1[CH2:6][O:5][C:4]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][CH2:26]4)=[CH:21][CH:20]=3)[C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:12][C:3]=2[N:2]1[CH3:1]
Reactant: CN1C(=S)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Reactant: CO[NH3+]
Agent: [Cl-]
Solvent: c1ccncc1
Product: CON=C1COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2N1C
Yield: 20.5 %

Procedure:
In a round-bottomed flask was added tert-butyl 1-(4-(1-methyl-7-phenyl-2-thioxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (0.1 g, 0.199 mmol) and o-methylhydroxylamine hydrochloride (0.067 g, 0.797 mmol) in Pyridine (Volume: 2 ml). The resulting solution was stirring and heating at 70 degree for 18 h. The reaction mixture was concentrated to dryness and partitioned between ethyl acetate (20 ml) and water (20 ml). The organic phase was separated and washed with water (2×15 ml), brine (15 ml) concentrated to give the crude product which was purified by column (biotage, 25 g) eluted with ethyl acetate/cyclohexane (0-50%) to give product (21 mg) 1H NMR (500 MHz, CDCl3) 7.20-7.29 (m, 9H), 7.10 (s, 1H), 5.19 (s, 2H), 4.95 (s, 1H), 3.81 (s, 3H), 3.31 (s, 3H), 2.2-2.6 (m, 4H), 1.95-2.15 (m, 1H), 1.75-1.85 (m, 1H), 1.2-1.4 (br, 9H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:37])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:17][CH:16]2[C:34]([OH:36])=O)[CH:12]=[CH:13][CH:14]=1.[NH2:38][CH2:39][C:40]([CH3:44])([CH3:43])[CH2:41][OH:42].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>C(Cl)Cl>[OH:42][CH2:41][C:40]([CH3:44])([CH3:43])[CH2:39][NH:38][C:34]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:37])[C:19]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:31])([CH3:33])[CH3:32])[NH:17]1)=[O:36]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1
Reactant: CC(C)(CN)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)NCC(C)(C)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1
Yield: 83.2 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.2 g, 0.36 mmol) was reacted with 3-amino-2,2-dimethyl-1-propanol (TCI-US) (0.2 g, 2 mmol), HATU (0.2 g, 0.5 mmol) and iPr2NEt (0.2 g, 1.6 mmol) in CH2Cl2 (20 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-hydroxy-2,2-dimethyl-propyl)-amide as a white solid (0.16 g, 83%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][C@H:14]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:15]1=[O:25])[C:6]([O:8][CH3:9])=[O:7].C(N(C(C)C)C(C)C)C.[Cl:35][C:36]1[CH:37]=[C:38]([F:43])[C:39](F)=[N:40][CH:41]=1>CN(C=O)C.CCOC(C)=O>[Cl:35][C:36]1[CH:37]=[C:38]([F:43])[C:39]([N:22]2[CH2:23][CH2:24][CH:19]([N:16]3[CH2:17][CH2:18][C@H:14]([O:13][C:12]4[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=4[F:2])[C:15]3=[O:25])[CH2:20][CH2:21]2)=[N:40][CH:41]=1
Reactant: COC(=O)c1ccc(O[C@H]2CCN(C3CCNCC3)C2=O)c(F)c1
Reactant: Fc1cc(Cl)cnc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(O[C@H]2CCN(C3CCN(c4ncc(Cl)cc4F)CC3)C2=O)c(F)c1
Temperature: 60 °C
Yield: 54.6 %

Procedure:
To a solution of (S)-methyl 3-fluoro-4-(2-oxo-1-(piperidin-4-yl)pyrrolidin-3-yloxy)benzoate hydrochloride (Example 151, Step B; 2.0 g, 5.9 mmol) in DMF (3 mL) was added N-ethyl-N-isopropylpropan-2-amine (3.8 g, 30 mmol) and 5-chloro-2,3-difluoropyridine (2.7 g, 18 mmol) and the reaction was heated to 60° C. overnight. The reaction was next diluted with EtOAc (30 mL) and washed with water (30 mL), and brine (30 mL), and the combined organic phases were dried over MgSO4, filtered and concentrated under vacuum. The crude material was purified on silica using a gradient of DCM to 1:19 EtOAc:DCM as eluent to yield (S)-methyl 4-(1-(1-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)-3-fluorobenzoate (1.5 g, 54%)
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][C:8](=[O:18])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C)C=O>[CH3:30][C:29]([Si:26]([CH3:28])([CH3:27])[O:25][CH2:24][CH2:23][CH:7]([C:8](=[O:18])[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:19])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)CC(=O)CCc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(CCO[Si](C)(C)C(C)(C)C)C(=O)CCc1ccc(Br)cc1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 66 %

Procedure:
A solution of the compound (9.7 g) obtained from step 1 above in dimethylformamide (25 ml) was added dropwise over 20 minutes to a stirred suspension of sodium hydride (1.42 g) in dimethylformamide (25 ml) at 0° C. under nitrogen atmosphere and stirred the reaction mixture for 20 minutes. To it was added (2-bromoethoxy)-t-butyldimethylsilane (8.50 g) dropwise over 20 minutes at 0° C. then the reaction mixture was heated to 70° C. for about 3-4 hour. On cooling to room temperature the reaction was quenched with water. The residue was partitioned between saturated aqueous ammonium chloride solution and dichloromethane. The organic phases were combined, washed with water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography using 8% ethyl acetate in hexane as eluant to furnish the title compound (9.5 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:14](OC(=O)C)(=[O:16])[CH3:15].CC([O-])=O.[K+]>>[C:14]([NH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8])(=[O:16])[CH3:15]
Reactant: Nc1cc(C(=O)O)cc(C(=O)O)c1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [K+]
Product: CC(=O)Nc1cc(C(=O)O)cc(C(=O)O)c1
Temperature: 20 °C
Reaction time: 0.75 h

Procedure:
5-Aminoisophthalic acid (30.33 g, 0.167 mol) was charged into a 250 mL round bottom flask with acetic anhydride (56.24 g, 0.551 mol) and KOAc (0.88 g). The reaction temperature was 60°-110° C. for 45 minutes. The resulting white solid was filtered after the reaction was allowed to cool to room temperature (about 20° C.). Yield 31.98 g (86%). 1H NMR (d-6 DMSO)--10.30, 8.41, 8.14, 2.06. 13C NMR (d-6 DMSO)--69.17, 166.82, 140.16, 131.92, 124,61, 123.59, 24.05.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:42][CH3:43])=[C:10]([CH2:19][NH:20][C:21](=[O:41])[CH2:22][C:23]([NH:25][CH2:26][C:27]3[CH:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35](C=O)[CH:34]=4)[CH:30]=[CH:31][CH:32]=3)=[O:24])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.[BH-](OC(C)=O)(OC(C)=O)O[C:53](C)=O.[Na+].CC(O)=O>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:42][CH3:43])=[C:10]([CH2:19][NH:20][C:21](=[O:41])[CH2:22][C:23]([NH:25][CH2:26][C:27]3[CH:28]=[C:29]([C:33]4[CH:34]=[CH:35][CH:36]=[C:37]([CH2:44][N:45]5[CH2:50][CH2:49][N:48]([CH3:53])[CH2:47][CH2:46]5)[CH:38]=4)[CH:30]=[CH:31][CH:32]=3)=[O:24])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CN1CCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1cccc(-c2cccc(C=O)c2)c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1cccc(-c2cccc(CN3CCN(C)CC3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.2 %

Procedure:
To N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-3-biphenylyl)methyl]propanediamide (30 mg, 0.051 mmol) was added 1-methylpiperazine (4.43 mg, 0.051 mmol) followed by NaB(OAc)3H (36.4 mg, 0.172 mmol) and AcOH (4.91 μL, 0.086 mmol) in dimethyl sulfoxide (DMSO) (0.5 mL). The mixture was stirred overnight at room temperature. The reaction was quenched with saturated NaHCO3 and extracted with EtOAc (3×1 mL). Combined organic layers were washed with saturated NaCl, dried (Na2SO4) and concentrated. The crude products were redissolved in MeOH/DMSO (1/1) and purified using a Gilson HPLC (acidic conditions) and basified with an amine cartridge to afford 14.0 mg (39%) of the title compound. LC-MS m/z 667 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:9]1([CH3:14])[O:13][CH2:12][CH2:11][O:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:15][C:16]1[CH:17]=[C:18]2[C:23](=O)[O:22][C:20](=[O:21])[C:19]2=[CH:25][CH:26]=1>>[Br:15][C:16]1[CH:17]=[C:18]2[C:19](=[CH:25][CH:26]=1)[C:20](=[O:21])[N:1]([CH2:2][CH:3]([C:9]1([CH3:14])[O:10][CH2:11][CH2:12][O:13]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:23]2=[O:22]
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Reactant: CCOC(=O)C(CN)C1(C)OCCO1
Product: CCOC(=O)C(CN1C(=O)c2ccc(Br)cc2C1=O)C1(C)OCCO1

Procedure:
Ethyl 3-(5-bromo-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.42 g, 52%) in the same manner as described in the above example 5 (20) from ethyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.40 g, 1.97 mmol) and 4-bromophthalic anhydride (0.58 g, 2.56 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.O.C(=O)(O)[O-:14].[Na+]>S(=O)(=O)(O)O>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH2:11])=[O:14])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: N#Cc1ccc2scnc2c1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NC(=O)c1ccc2scnc2c1

Procedure:
A solution of 1,3-benzothiazole-5-carbonitrile (100 mg, 0.62 mmol, 1.00 equiv) in sulfuric acid (3.0 mL) was heated for 2 h at 45° C. After cooling down, the reaction mixture was poured into 15 mL of water. The pH value of the solution was adjusted to 7 with saturated aqueous sodium bicarbonate. The resulting solution was extracted with of ethyl acetate (5×10.0 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and then concentrated under vacuum. This resulted in 60.0 mg of the title compound as a crude product, which was used directly for next step without further purification. MS m/z [M+H]+ (ESI): 179.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[CH:5][N:6]=1.[NH2:17][C:18]1[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=1>CC(O)C>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([C:4]2[O:3][C:2]([NH:17][C:18]3[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=3)=[N:6][CH:5]=2)=[CH:8][CH:9]=1
Reactant: FC(F)(F)c1ccc(-c2cnc(Cl)o2)cc1
Reactant: CS(=O)(=O)Nc1cccc(N)c1
Solvent: CC(C)O
Product: CS(=O)(=O)Nc1cccc(Nc2ncc(-c3ccc(C(F)(F)F)cc3)o2)c1
Temperature: 80 °C
Yield: 40.9 %

Procedure:
A mixture of 2-chloro-5-(4-(trifluoromethyl)phenyl)oxazole 31 (0.599 g, 2.42 mmol) and commercially available N-(3-aminophenyl)methanesulfonamide 6 (0.451 g, 2.42 mmol) in 2-propanol (20 mL) was heated to 80° C. for 14 h with stirring. Upon cooling, solvent was evaporated and silica column purified (Biotage) (Acetone/hexane as an eluent) to provide N-(3-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)phenyl)methane sulfonamide 33 (0.393 g, 41% yield) as a solid. MS (ES) m/z 398 (M+H+).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][S:5][CH2:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[CH3:12].[S-:13][C:14]#[N:15].[K+]>C(O)C>[CH3:12][C:11]1[NH:10][CH:9]=[N:8][C:7]=1[CH2:6][S:5][CH2:4][CH2:3][S:13][C:14]#[N:15]
Reactant: Cc1[nH]cnc1CSCCCl
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: Cc1[nH]cnc1CSCCSC#N

Procedure:
1-Chloro-2(5-methyl-4-imidazolylmethylthio)ethane hydrochloride (2.1 g) and potassium thiocyanate (0.97 g) were heated together under reflux in ethanol (50 ml) for 3 days. The mixture was evaporated to dryness and the residue was taken up in water, basified with sodium carbonate and extracted with chloroform. The chloroform extracts were dried (MgSO4) and evaporated to a residue which was recrystallised from acetonitrile to give 2-(5-methyl-4-imidazolylmethylthio)ethylthiocyanate m.p. 101°-103°. (Found: C, 45.3; H, 5.3; N, 19.5; S, 29.3. C8H11N3S2 requires: C, 45.0; H, 5.2; N, 19.7; S, 30.1%).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8]([NH:9][C:10](=[O:18])OC2C=CC=CC=2)=[C:7]([S:19][CH3:20])[CH:6]=[C:5]([CH3:21])[N:4]=1.C(N(CC)CC)C.[CH2:29]([NH:36][CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][CH2:47][OH:48])[CH2:41][CH2:40]1)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C1(C)C=CC=CC=1.O>[CH3:1][S:2][C:3]1[C:8]([NH:9][C:10](=[O:18])[N:36]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][CH2:47][OH:48])[CH2:41][CH2:40]2)=[C:7]([S:19][CH3:20])[CH:6]=[C:5]([CH3:21])[N:4]=1
Reactant: CCCCCCCNCCN1CCN(CCCO)CC1
Reactant: CSc1cc(C)nc(SC)c1NC(=O)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCN(CCN1CCN(CCCO)CC1)C(=O)Nc1c(SC)cc(C)nc1SC
Temperature: 80 °C
Reaction time: 3 h
Yield: 82.5 %

Procedure:
To a solution of this phenyl carbamate (188 mg, 0.59 mmol) in toluene (3 ml) were added triethylamine (72 mg, 0.71 mmol) and 3-[4-(2-heptylaminoethyl)piperazin-1-yl]propanol (168 mg, 0.59 mmol) and the mixture was stirred at 80° C. for 3 hours. The reaction solution was diluted with water and extracted with chloroform. The organic layer was washed with water and a saturated sodium chloride solution successively, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (silica gel 15 g, developing solvent; chloroform:methanol=40:1 10:1) to provide 249 mg (yield 83%) of N′-[2,4-bis(methylthio)-6-methyl-3-pyridyl]-N-heptyl-N-[2-[4-(3-hydroxypropyl)piperazin-1-yl]ethyl]urea as colorless oil.