Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([Cl:10])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[OH:11][C@H:12]1[C@@H:19]2[N:15]([C:16](=[O:33])N(C3C4CCCCC=4C(C#N)=CC=3)[C:18]2=[O:20])[CH2:14][CH2:13]1>>[Cl:10][C:4]1[C:5]([C:8]#[N:9])=[N:6][CH:7]=[C:2]([N:1]2[C:18](=[O:20])[C@@H:19]3[C@H:12]([OH:11])[CH2:13][CH2:14][N:15]3[C:16]2=[O:33])[CH:3]=1
Reactant: N#Cc1ncc(N)cc1Cl
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2c1CCCC2
Product: N#Cc1ncc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)cc1Cl

Procedure:
The title compound was synthesized from compound 44D by procedures analogous to those described for Examples 2E to 2F. HPLC: 100% at 1.67 min. (retention time) (Conditions: Shim-Pak VP-ODS (4.6×50 mm); Eluted with 0% to 100% B, 4 min gradient, 1 min hold. (A=90% H2O-10% MeOH-0.1% H3PO4 and B=10% H2O-90% MeOH-0.1% H3PO4); Flow rate at 4 mL/min UV detection at 220 nm); MS (ES) m/z 293 [M+H]+.
Reaction SMILES: C([N:5]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6])(C)(C)C.[C:15]([C:23]([OH:25])=O)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:8]([N:6]([C:23]([C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:25])[NH:5][C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:13])([CH3:9])[CH3:7]
Reactant: CC(C)(C)N(N)C(=O)c1ccccc1
Reactant: O=C(O)C(=O)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
N'-t-butyl-N'-benzoylhydrazine (1 g), benzoyl formic acid (0.7 g) and methanesulfonyl chloride (0.7 g) were stirred in toluene (30 ml) and saturated sodium bicarbonate (10 ml) at approximately 5° C. Triethylamine was added slowly, dropwise to the reaction mixture and stirred 1 hour at room temperature. After stirring for 1 hour, the reaction mixture was diluted with toluene (25 ml) and washed with water several times. The organic layers were dried over magnesium sulfate, filtered and the toluene rotavapped off to afford a white solid. After column chromatography, the product was obtained as a white solid in approximately 70% yield.
Reaction SMILES: [Na].O[CH:3]=[CH:4][C:5]#[N:6].[CH2:7]([NH:9][CH2:10][CH3:11])[CH3:8].C(O)(=O)C>C(#N)C>[CH2:7]([N:9]([CH2:10][CH3:11])[CH:3]=[CH:4][C:5]#[N:6])[CH3:8]
Reactant: N#CC=CO
Reactant: CCNCC
Agent: [Na]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCN(C=CC#N)CC
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.5 %

Procedure:
32.5 g (0.25 mol) of sodium-3-hydroxyacrylonitrile (content 70%) is added to a solution of 25.6 g (0.35 mol) of diethylamine, 21.0 g (0.35 mol) of acetic acid and 150 ml of acetonitrile, and the mixture is stirred for 16 h at 25° C. After working up as in Example 50, 19.7 g of 3-diethylaminoacrylonitrile was obtained (63.6%).
Reaction SMILES: CCN=C=NCCCN(C)C.[I:12][C:13]1[CH:14]=[C:15]([NH:20][C:21](=[O:34])[C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:24][CH:23]=2)[CH:16]=[CH:17][C:18]=1[CH3:19].[OH:35][C:36]1[CH:40]=[C:39]([CH2:41][CH2:42][C:43](O)=[O:44])[O:38][N:37]=1.COC(C1CCC(C(N2CCN(C3C=CC(C(=O)NC4C=CC=C(C(C)(C)C)C=4)=CN=3)CC2)=O)CC1)=O>>[OH:35][C:36]1[CH:40]=[C:39]([CH2:41][CH2:42][C:43]([N:31]2[CH2:30][CH2:29][N:28]([C:25]3[CH:26]=[CH:27][C:22]([C:21]([NH:20][C:15]4[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([I:12])[CH:14]=4)=[O:34])=[CH:23][N:24]=3)[CH2:33][CH2:32]2)=[O:44])[O:38][N:37]=1
Reactant: Cc1ccc(NC(=O)c2ccc(N3CCNCC3)nc2)cc1I
Reactant: O=C(O)CCc1cc(O)no1
Agent: CCN=C=NCCCN(C)C
Agent: COC(=O)C1CCC(C(=O)N2CCN(c3ccc(C(=O)Nc4cccc(C(C)(C)C)c4)cn3)CC2)CC1
Product: Cc1ccc(NC(=O)c2ccc(N3CCN(C(=O)CCc4cc(O)no4)CC3)nc2)cc1I

Procedure:
6-{4-[3-(3-Hydroxy-isoxazol-5-yl)-propionyl]-piperazin-1-yl}-N-(3-iodo-4-methyl-phenyl)-nicotinamide was synthesized from the EDCI coupling of N-(3-iodo-4-methyl-phenyl)-6-piperazin-1-yl-nicotinamide and 3-(3-hydroxy-isoxazol-5-yl)-propionic acid in a manner similar to the one described in the synthesis of 4-{4-[5-(3-tert-butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carbonyl}-cyclohexanecarboxylic acid methyl ester, above. LCMS calcd for C23H24IN5O4 (m/e) 561, obsd 562 (M+H),
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[F:23])=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.[F:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[CH:28]=[C:29]([F:32])[C:30]=1O>>[F:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH:28]=[C:29]([F:32])[C:30]=1[O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[F:23])=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13]
Reactant: Cc1ccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)c(F)c1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Product: Cc1ccc(-c2nsc(C(F)(F)F)c2COc2c(F)cc(CCC(=O)O)cc2F)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (3-(2-fluoro-4-methylphenyl)-5-(trifluoromethyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CD3OD) δ 7.22-7.26 (m, 1H), 7.05-7.09 (m, 2H), 6.73-6.78 (m, 2H), 5.17 (s, 2H), 2.84 (t, J=7.2 Hz, 2H), 2.59 (t, J=7.8 Hz, 2H), 2.44 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C21H15F6NO3S, 476.1 (M+H). found 476.1.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][C@H:3]2[CH2:7][CH2:8][CH2:9][C@@H:2]12.F[C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][N:12]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[I:17][C:14]1[CH:15]=[CH:16][C:11]([N:1]2[C:5](=[O:6])[CH2:4][C@H:3]3[CH2:7][CH2:8][CH2:9][C@@H:2]23)=[N:12][CH:13]=1
Reactant: Fc1ccc(I)cn1
Reactant: O=C1C[C@H]2CCC[C@H]2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1C[C@H]2CCC[C@H]2N1c1ccc(I)cn1
Temperature: 105 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
To a solution of (3aR,6aR)-hexahydrocyclopenta[b]pyrrol-2(1H)-one (210 mg, 1.68 mmol) and 2-fluoro-5-iodopyridine (412 mg, 1.85 mmol, 1.1 equiv.) in toluene (1.1 ml) were added Cs2CO3 (656 mg, 2.01 mmol, 1.2 equiv.) The reaction was stirred for 16 h at 105° C. The residue was taken up in ethyl acetate, the solids were filtered off and washed with ethyl acetate. The filtrate was concentrated in vaccuo and the residue was purified by flash chromatography (SiO2, 20 g) using a 0% to 60% ethyl acetate in heptane gradient. One obtains the title compound, (300 mg 55%), as a colorless oil, MS: m/e=329.4 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][NH2:9].C([O-])([O-])=O.[Na+].[Na+].[CH2:16]([S:18](Cl)(=[O:20])=[O:19])[CH3:17]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][NH:9][S:18]([CH2:16][CH3:17])(=[O:20])=[O:19]
Reactant: CCS(=O)(=O)Cl
Reactant: NCc1ccncc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCS(=O)(=O)NCc1ccncc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.1 %

Procedure:
To a solution of (3-bromopyridin-4-yl) methanamine (720 mg, 3.9 mmol) in DCM (20 mL) is added Na2CO3 (1.2 g, 11 mmol). Then ethanesulfonyl chloride (740 mg, 5.8 mmol) is added dropwise under N2 atmosphere at 0° C. The mixture is stirred at room temperature for 16 hrs and it is diluted with DCM. The mixture is washed with water and brine, dried over Na2SO4, filtered and concentrated. The crude product is purified by flash column chromatography to give 600 mg of ethanesulfonic acid (3-bromo-pyridin-4-ylmethyl)-amide.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:28][CH2:29][CH3:30])[C:4](=[O:27])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([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:15]=3)=[N:8][C:9]=2[N:10]=1.[NH3:31]>>[NH2:31][C:2]1[N:3]([CH2:28][CH2:29][CH3:30])[C:4](=[O:27])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([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:15]=3)=[N:8][C:9]=2[N:10]=1
Reactant: N
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Product: CCCn1c(N)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Temperature: 127.5 °C
Yield: 41 %

Procedure:
A mixture of 2-Chloro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one (0.2 g, 0.45 mmol) (prepared as given in Example 1), ammonia solution (20 ml) was heated at 125-130° C. in a sealed tube for 5 days. Reaction mixture was cooled to 0° C. and solid was filtered, washed with methanol, dried and purified by column chromatography using silica gel (100-200 mesh) and 6 to 8% methanol in DCM as an eluent to obtain 2-Amino-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one (0.079 g, 41%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:16][S:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1.CCN=C=NCCCN(C)C.N1(O)C2C=CC=CC=2N=N1.[N:46]1[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][NH2:53])[CH:47]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:53][CH2:52][C:48]3[CH:47]=[N:46][CH:51]=[CH:50][CH:49]=3)=[O:12])=[CH:14][CH:15]=2)=[N:4][C:3]=1[CH2:16][S:17][C:18]1[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=1
Reactant: NCc1cccnc1
Reactant: Cc1ccc(SCc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(SCc2nc(-c3ccc(C(=O)NCc4cccnc4)cc3)oc2C)cc1
Temperature: 0 °C
Yield: 52.3 %

Procedure:
A solution of 4-(5-methyl-4-(p-tolylthiomethyl)oxazol-2-yl)benzoic acid (500 mg, 1.47 mmol, 1.00 equiv), EDCI (340 mg, 1.78 mmol, 1.21 equiv), 1H-1,2,3-benzotriazol-1-ol (240 mg, 1.78 mmol, 1.21 equiv), pyridin-3-ylmethanamine (190 mg, 1.76 mmol, 1.19 equiv) and triethylamine (450 mg, 4.46 mmol, 3.02 equiv) in N,N-dimethylformamide (10 mL) was stirred overnight at room temperature. The resulting solution was diluted with 20 mL of an ice/water mixture. The precipitate was collected by filtration, washed with 3×10 mL of hexane and 4×10 mL of 66% aqueous methanol to give 0.33 g (52%) of 4-(5-methyl-4-(p-tolylthiomethyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide as a white solid. LC-MS: (ES, m/z): 471
Reaction SMILES: [CH2:1]([CH:5]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[NH:7][C:6]1=[O:15])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:19][C:20]([O:22]CC)=[O:21]>CN(C=O)C.O>[CH2:1]([CH:5]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([CH2:19][C:20]([OH:22])=[O:21])[C:6]1=[O:15])[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)CBr
Reactant: CCCCC1Sc2ccccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC1Sc2ccccc2N(CC(=O)O)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-butyl-2H-benzo[b][1,4]thiazin-3(4H)-one (6.3 mmol, 1400 mg) in DMF (5 ml) was added NaH (6.9 mmol, 167 mg) and the reaction mixture was stirred at room temperature for 1 h before the dropwise addition of ethyl bromoacetate (6.3 mmol, 1052 mg). The reaction mixture was stirred at room temperature overnight, diluted with water and extracted with ethyl acetate. The organic layer was washed with 1N HCl, Sat. NaHCO3, dried over Na2SO4 and evaporated to dryness. The crude compound was dissolved in MeOH (10 ml) and 1 N NaOH (10 ml) and stirred at room temperature for 2 h. The MeOH was removed under reduced pressure and the resulting aqueous solution extracted with EtOAc. The aqueous layer was acidified to pH 2 with 1N HCl and extracted with EtOAc. The organic phase was dried over Na2SO4 and the solvent was evaporated to give the title compound. LC/MS (10% to 99%): M/Z (M+H)+ (obs)=280.2; tR=3.01.
Reaction SMILES: [CH3:1][C@:2]1([NH:21][C:22]2[CH:27]=[N:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8]([C:10]1[C:15]([N:16]2[N:20]=[CH:19][CH:18]=[N:17]2)=[CH:14][CH:13]=[CH:12]N=1)=[O:9].C[C@]1(NC2C=NC(C(F)(F)F)=CN=2)CCC[C@@H]1N.[Cl:50][C:51]1C=CC=C(N2N=CC=N2)C=1C(O)=O>>[Cl:50][C:51]1[CH:12]=[CH:13][CH:14]=[C:15]([N:16]2[N:20]=[CH:19][CH:18]=[N:17]2)[C:10]=1[C:8]([NH:7][C@H:3]1[CH2:4][CH2:5][CH2:6][C@:2]1([CH3:1])[NH:21][C:22]1[CH:27]=[N:26][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:24][N:23]=1)=[O:9]
Reactant: O=C(O)c1c(Cl)cccc1-n1nccn1
Reactant: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1ncccc1-n1nccn1
Agent: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1N
Product: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1c(Cl)cccc1-n1nccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide (Example 77) from (1S,2S)-1-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine (Intermediate 25; 63 mg, 0.24 mmol) and 2-chloro-6-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 15; 65 mg, 0.29 mmol) except this was purified by column chromatography (silica, 0-30% ethyl acetate/petrol) followed by trituration with diethyl ether/pentane to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:12][S:13]([C:16]([CH3:21])([CH3:20])[C:17](Cl)=[O:18])(=[O:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:29]>O1CCCC1.C(OCC)(=O)C>[C:17]([C:16]([S:13]([CH2:12][CH:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])(=[O:15])=[O:14])([CH3:21])[CH3:20])(=[O:18])[NH2:29]
Reactant: CC(C)(C(=O)Cl)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C(N)=O)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Yield: 91.2 %

Procedure:
A solution of 1.05 g (2.5 mmol) of crude (RS)-2-[[2-[(benzyloxy)carbonyl]-3-phenylpropyl]sulfonyl]-2-methylpropionyl chloride in 29 ml (9.3 mmol) of 0.32M ammonia in tetrahydrofuran was stirred at room temperature for 5 hours. Subsequently, the reaction solution was diluted with 40 ml of ethyl acetate and extracted with 20 ml of 1N hydrochloric acid. The ethyl acetate extract was then washed with 20 ml of saturated sodium hydrogen carbonate solution and 20 ml of saturated sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. There was obtained 0.92 g of benzyl rac-α-[[(1-carbamoyl-1-methylethyl)sulfonyl]methyl]hydrocinnamate as a colourless solid, MS: 312 (M-benzyl)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.[OH:13][C@@H:14]([CH3:28])[CH2:15][CH2:16]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCCCCC>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:16][CH2:15][C@@H:14]([OH:13])[CH3:28])[CH:6]=1
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCC[C@H](C)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(OCC[C@H](C)O)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 44.2 %

Procedure:
To a stirring solution of (3-hydroxy-phenyl)-acetic acid methyl ester (0.93 g, 0.0056 mole) and toluene-4-sulfonic acid-(S)-3-hydroxy-butyl ester (1.5 g, 0.0061 mole) in anhydrous DMF (10 mL) was added Cs2CO3 (2.0 g, 0.006 mole). The reaction was heated to 100° C. and stirred for 4 hours. The mixture was cooled to RT and filtered. The filtrate was poured into H2O (50 mL) and extracted three times with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography over silica gel (silica gel 60, EM Science) using 30% EtOAc:hexane as eluent to afford 0.59 g (44% yield) of the title compound as an oil: MS (ESI) 239.0 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH:11]=O)[NH:8][C:7]=1[CH3:13])=[O:5])[CH3:2].[NH2:14][NH2:15]>CCO>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH:11]=[N:14][NH2:15])[NH:8][C:7]=1[CH3:13])=[O:5])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)c1cc(C=O)[nH]c1C
Solvent: CCO
Product: CCOC(=O)c1cc(C=NN)[nH]c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-formyl-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (6.30 g, 0.034 mol) in EtOH (6.3 mL) was added a solution of hydrazine (1.69 mL, 0.034 mol). The reaction mixture was stirred at RT overnight. The resulting precipitate was filtered and dried in vacuo to give the titled compound, 6.79 g as a light yellow solid. This material was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O)([O-:3])=[O:2].Br[C:14]1[S:22][C:21]2[C:20]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=4)=[CH:26][CH:25]=3)=[N:19][CH:18]=[N:17][C:16]=2[CH:15]=1>>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([NH:30][C:27]2[CH:26]=[CH:25][C:24]([NH:23][C:20]3[C:21]4[S:22][C:14]([C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N+:1]([O-:3])=[O:2])=[CH:15][C:16]=4[N:17]=[CH:18][N:19]=3)=[CH:29][CH:28]=2)=[CH:32][CH:33]=1
Reactant: O=[N+]([O-])c1ccccc1B(O)O
Reactant: COc1ccc(Nc2ccc(Nc3ncnc4cc(Br)sc34)cc2)cc1
Product: COc1ccc(Nc2ccc(Nc3ncnc4cc(-c5ccccc5[N+](=O)[O-])sc34)cc2)cc1

Procedure:
The title compound was prepared from 2-nitrobenzeneboronic acid and N-(6-Bromo-thieno[3,2-d]pyrimidin-4-yl)-N′-(4-methoxy-phenyl)-benzene-1,4-diamine by a procedure analogous to example 2. M.P. 228-237° C. ; LC-MS: 383.56 (MH+); HPLC RT: 6.885 minutes.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:27][N:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34](B(O)O)[CH:35]=2)[CH:30]=[N:29]1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:34]5[CH:35]=[C:36]6[C:31]([CH:30]=[N:29][N:28]6[CH3:27])=[CH:32][CH:33]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cn1ncc2ccc(B(O)O)cc21
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc6cnn(C)c6c5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 1-methyl-indazole-6-boronic acid following a procedure analogous to that described for Intermediate 6. LC (method 3): tR=0.65 min; Mass spectrum (ESI+): m/z=489 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.[N:10]1([S:16]([C:19]2[CH:20]=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C(O)(=O)C>[CH3:9][C:5]1[C:6]([NH2:8])=[N:7][C:2]([NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([S:16]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)(=[O:18])=[O:17])[CH:20]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(S(=O)(=O)N2CCCCC2)c1
Reactant: Cc1cnc(Cl)nc1N
Solvent: CC(=O)O
Product: Cc1cnc(Nc2cccc(S(=O)(=O)N3CCCCC3)c2)nc1N
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.25 g, 1.74 mmol) and 3-(piperidine-1-sulfonyl)-phenylamine (0.50 g, 2.1 mmol) in acetic acid (4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 130° C. for 15 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken in water (20 mL) and pH adjusted to 9 with 10% NaOH solution. The resulting solution was extracted with EtOAc (2×30 mL) and the organic layer separated. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the crude product (˜0.6 g) used in the next step without purification. MS (HS t): m/z 348 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: NCCN1CCOCC1
Product: O=S(=O)(NCCN1CCOCC1)c1cccc(Br)c1
Yield: 90.8 %

Procedure:
Prepared by general procedure III from 3-Bromobenzenesulfonyl chloride (5.0 g, 20 mmol) and 4-(2-Aminoethyl)-morpholine (2.80 mL, 22 mmol) to give the title compound (6.34 g, 93%) as a white solid. MS (ISN) 347.1[(M−H)−], 349.3[(M+2−H)−].
Reaction SMILES: [N:1]1([S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)(=[O:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:22][C:23]1[CH:32]=[CH:31][C:26]2[N:27]=[C:28]([NH2:30])[S:29][C:25]=2[CH:24]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:1]1([S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([NH:30][C:28]2[S:29][C:25]3[CH:24]=[C:23]([CH3:22])[CH:32]=[CH:31][C:26]=3[N:27]=2)=[O:18])(=[O:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc2nc(N)sc2c1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCc3ccccc32)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2nc(NC(=O)c3cccc(S(=O)(=O)N4CCc5ccccc54)c3)sc2c1

Procedure:
3-(indolin-1-ylsulfonyl)benzoic acid (3) (200 mg, 0.66 mmol) and 6-methylbenzo[d]thiazol-2-amine (90 mg, 0.55 mmol) in DMF (4 mL) was added DIPEA (213 mg, 1.65 mmol) and pybop (429 mg, 0.82 mmol). using method C. The residue was purified using flash chromatography eluting with 0-30% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give 3-(indolin-1-ylsulfonyl)-N-(6-methylbenzo[d]thiazol-2-yl)benzamide as a white solid. Yield: 78 mg (32%). 1H-NMR: 8.58 (s, 1H), 8.38 (d, J=8 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.82 (s, 1H), 7.77-7.65 (m, 3H), 7.53 (d, J=8.5 Hz, 1H), 7.30 (dd, J=8.5, 1.0 Hz, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.16 (d, J=7.0 Hz, 1H), 6.99 (dt, J=7.5, 7.5, 1.0 Hz, 1H), 4.02 (t, J=8.5 Hz, 2H), 2.92 (t, J=8.5 Hz, 2H), 2.43 (s, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[N:7]=[C:6]([C:19]([OH:21])=O)[CH:5]=1)([CH3:3])[CH3:2].S(Cl)(Cl)=O.[NH2:26][C:27]1[NH:31][N:30]=[N:29][N:28]=1>>[NH:28]1[C:27]([NH:26][C:19]([C:6]2[CH:5]=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=3)[N:7]=2)=[O:21])=[N:31][N:30]=[N:29]1
Reactant: CC(C)c1cc(C(=O)O)nc(-c2ccc([N+](=O)[O-])cc2)c1
Reactant: Nc1nnn[nH]1
Solvent: O=S(Cl)Cl
Product: CC(C)c1cc(C(=O)Nc2nnn[nH]2)nc(-c2ccc([N+](=O)[O-])cc2)c1
Yield: 42.5 %

Procedure:
In the same manner as described in Example 13-(1), 4-isopropyl-6-(4-nitrophenyl)-2-pyridinecarboxylic acid (1.62 g), thionyl chloride (15 ml) and 5-aminotetrazole (0.63 g) are reacted to give N-(5-tetrazolyl)-4-isopropyl-6-(4-nitrophenyl)-2-pyridinecarboxamide (0.85 g). M.P. 270°-272° C. (decomp.) (recrystallized from dimethylformamide-ethanol)
Reaction SMILES: N([O-])=O.[Na+].S(=O)(=O)(O)O.N[C:11]1[C:18]([CH3:19])=[C:17]([F:20])[C:16]([F:21])=[CH:15][C:12]=1[C:13]#[N:14].C(OCC)(=O)C.[ClH:28]>C(O)(=O)C>[Cl:28][C:11]1[C:18]([CH3:19])=[C:17]([F:20])[C:16]([F:21])=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: Cc1c(N)c(C#N)cc(F)c1F
Reactant: Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1c(F)c(F)cc(C#N)c1Cl
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
Sodium nitrite (5.6 g) is added to conc. sulfuric acid (59 ml) at below 70° C. The mixture is heated at 70° C. for 10 minutes and then cooled, and thereto is added dropwise a solution of 2-amino-4,5-difluoro-3-methylbenzonitrile (12.3 g) in acetic acid (123 ml) at below 40° C. The mixture is stirred at the same temperature for 30 minutes and then added in portions to a solution of cuprous chloride (20 g) in conc. hydrochloric acid (200 ml), and thereafter is heated at 80° C. for 30 minutes. After cooling, to the reaction mixture is added ice water, and ethyl acetate is distilled off. The resulting residue is purified by silica gel column chromatography (solvent, dichloromethane:n-hexane=1:1) to give 2-chloro-4,5-difluoro-3-methylbenzonitrile (8.0 g), as a white crystal, m.p. 59°-61° C.