Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[N:4]=[C:5]([S:31][CH3:32])[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23](OC)=[CH:22][C:21]=1[F:30])=NC1C=CC(C2N=C(C)ON=2)=CC=1.[F:34][C:35]([F:49])([F:48])[C:36]1[O:40][N:39]=[C:38]([C:41]2[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=2)[N:37]=1.FC1[C:58]([O:59][CH2:60][CH2:61][O:62]C)=CC(OC)=CC=1C=O.CC1ON=C(C2C=CC(N)=CC=2)N=1.FC1C=C(OC)C(OC)=CC=1C=O>>[CH3:1][O:2][C:3](=[O:33])[N:4]=[C:5]([S:31][CH3:32])[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:62][CH2:61][CH2:60][O:59][CH3:58])[C:21]=1[F:30])=[N:47][C:44]1[CH:43]=[CH:42][C:41]([C:38]2[N:37]=[C:36]([C:35]([F:48])([F:34])[F:49])[O:40][N:39]=2)=[CH:46][CH:45]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c(OC)cc1F
Reactant: COCCOc1cc(OC)cc(C=O)c1F
Reactant: Nc1ccc(-c2noc(C(F)(F)F)n2)cc1
Agent: COc1cc(F)c(C=O)cc1OC
Agent: Cc1nc(-c2ccc(N)cc2)no1
Product: COCCOc1cc(OC)cc(C(=Nc2ccc(-c3noc(C(F)(F)F)n3)cc2)C(=NC(=O)OC)SC)c1F

Procedure:
The same procedure was carried out as in Examples (1a) to (1d), except that 4-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)phenylamine (Example (188a)) and 2-fluoro-5-methoxy-3-(2-methoxyethoxy)benzaldehyde were used instead of respectively the 4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamine and 2-fluoro-4,5-dimethoxybenzaldehyde in Example (1a), to give the title compound as a light yellow solid.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH2:9]([C@H:16]1[CH2:20][O:19][C:18](=[O:21])[N:17]1[C:22](=[O:27])[CH2:23][CH2:24][CH2:25]Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N:28]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[N:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>C1COCC1.C(Cl)Cl.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-]>[C:40]([O:39][C:37]([N:28]1[CH2:2][CH2:25][CH2:24][C@@H:23]([C:22]([N:17]2[C@@H:16]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:20][O:19][C:18]2=[O:21])=[O:27])[N:29]1[C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)[N-]C(C)C
Reactant: O=C(CCCBr)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)N1C(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 2 h
Yield: 49.3 %

Procedure:
To a solution of diisopropylamine (0.77 mL, 5.53 mmol) in THF (4 mL) at 0° C. is added BuLi (2.17 mL, 5.42 mmol, 2.5 M in hexane) dropwise. The solution is stirred at 0° C. for 30 minutes to form an LDA solution. The LDA solution is cold to −70° C. and added to a solution of (S)-4-benzyl-3-(4-bromo-butyryl)-oxazolidin-2-one (1.72 g, 5.07 mmol) in THF (4 mL) at −70° C. dropwise. After stirring at −70° C. for 2 hours, a solution of di-t-butyl azodicarboxylate (1.40 g, 6.08 mmol) in CH2Cl2 (4 mL) is added slowly. After stirring at −70° C. for 15 minutes, Bu4NI (0.28 g, 0.76 mmol) is added in one portion. After stirring at −70° C. for 10 minutes, the flask with reaction mixture is moved to a −20° C. bath and stirred overnight (16 hours). The reaction mixture is quenched to ether (50 mL) with buffer solution (50 mL, Ph=7), and the mixture is extracted with ether (3×50 mL). The organic layer is dried over Na2SO4 and concentrated. The crude product is purified by chromatography (hexane/EtOAc:70/30) to give (S)-3-((S)-4-benzyl-2-oxo-oxazolidine-3-carbonyl)-tetrahydro-pyridazine-1,2-dicarboxylic acid di-tert-butyl ester as white solid (1.22 g, 49.3%). (NMR and MS data confirmed, U-3133-55-30).
Reaction SMILES: [CH2:1]([N:5]1[CH2:12][CH:11]2[C:13]([CH3:15])([CH3:14])[CH:7]([CH2:8][N:9]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25]C(=O)C)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:10]2)[CH2:6]1)[CH2:2][CH2:3][CH3:4].[OH-].[K+].O>C(O)C>[CH2:1]([N:5]1[CH2:6][CH:7]2[C:13]([CH3:14])([CH3:15])[CH:11]([CH2:10][N:9]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:8]2)[CH2:12]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CC2CN(S(=O)(=O)c3ccc(NC(C)=O)cc3)CC(C1)C2(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCN1CC2CN(S(=O)(=O)c3ccc(N)cc3)CC(C1)C2(C)C
Yield: 87.5 %

Procedure:
5.1 g of 7-(n-Butyl)-3-[(4-acetylaminophenyl)-sulfonyl]-9,9-dimethyl-3,7-diazabicyclo[3.3.1]nonane (for preparation see Example 2) and 1.5 g of potassium hydroxide were refluxed for 6 hours in 100 ml of ethanol. The reaction mixture was then cooled, water was added, and the mixture was extracted twice with diethyl ether. The combined ether extracts were dried with magnesium sulfate and concentrated. 4.0 g of 7-(n-butyl)-3-[(4-aminophenyl)-sulfonyl]-9,9-dimethyl-3,7-diazabicyclo[3.3.1]nonane were obtained, which were employed in the following reaction step without further purification.
Reaction SMILES: [CH2:1]([N:8]([CH3:23])[C@H:9]([CH2:21][OH:22])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[Si:29](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.O>[Si:29]([O:22][CH2:21][C@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:23])([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN(Cc1ccccc1)[C@H](CO)CCCNC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)[C@@H](CCCNC(=O)OC(C)(C)C)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 10 h
Yield: 91 %

Procedure:
A solution of Nα-benzyl-Nδ-Boc-Nα-methylornithinol (560 mg), dimethylformamide (1.5 ml), and t-butyldimethylsilyl chloride (330 mg), triethylamine (290 μl) and 4-(N,N-dimethylamino)pyridine (21 mg) was stirred at 0° C., under nitrogen atmosphere, for 1 hr. Then the mixture was stirred, at 25° C., for 10 hrs and then poured into water (20 ml) and extracted with dichloromethane (2×20 ml). The combined organic phase was washed with water and brine, and dried over sodium sulfate. Evaporation of the solvent afforded titled compound (690 mg) as a clear solid: 1H NMR (400 MHz, CDCl3) δ0.06 (s, 6H), 0.91 (s, 9H), 1.43 (s, 9H), 1.45-1.73 (m, 4H), 2.22 (s, 3H), 2.68 (m, 1H), 3.12 (m, 2H), 3.62 (dd, J=10.4; 5.2 Hz, 1H), 3.68 (d, J=13.6 Hz, 1H), 3.78 (m, 2H), and 7.30 (m, 5H).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:10])[CH2:4]/[CH:5]=[CH:6]/[C:7](O)=[O:8].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH2:34][CH3:35])[N:29]=[CH:28][C:27]([C:36]#[N:37])=[C:26]2[NH:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([C:45]#[CH:46])[CH:40]=1>C1COCC1.CN1CCCC1=O>[C:36]([C:27]1[CH:28]=[N:29][C:30]2[C:25]([C:26]=1[NH:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([C:45]#[CH:46])[CH:40]=1)=[CH:24][C:23]([NH:22][C:7](=[O:8])/[CH:6]=[CH:5]/[CH2:4][N:3]([CH3:10])[CH3:2])=[C:32]([O:33][CH2:34][CH3:35])[CH:31]=2)#[N:37]
Reactant: CN(C)C/C=C/C(=O)O
Reactant: C#Cc1cccc(Nc2c(C#N)cnc3cc(OCC)c(N)cc23)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: C#Cc1cccc(Nc2c(C#N)cnc3cc(OCC)c(NC(=O)/C=C/CN(C)C)cc23)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
A solution of (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (1.28 g, 7.73 mmol, 2.1 equiv) in THF (18 ml) and a catalytic amount of DMF was cooled to 5° C. while oxalyl chloride (0.67 ml, 0.007 mol, 1.9 equiv) was added slowly. The reaction mixture was then warmed to room temperature and stirred for 3 hours. A solution of 6-amino-7-ethoxy-4-(3-ethynylphenylamino)quinoline-3-carbonitrile (1.2 g, 3.66 mmol, 1.00 equiv) in N-methyl-2-pyrrolidinone (15 ml) was added dropwise over 10 minutes. The mixture was stirred for overnight, quenched with water (200 ml). Aqueous sodium hydroxide was added to bring the pH to 11. The mixture was stirred for 1 hour which formed precipitate. The resulting precipitate was filtered and washed with water and the wet solid was dried to give 1.43 g product. MS (ESI) m/z: 563 (M+1).
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:15]1[CH2:39][CH2:40][NH:41][S:42]([CH2:45][C:46]1[C:51]([F:52])=[CH:50][CH:49]=[CH:48][C:47]=1[F:53])(=[O:44])=[O:43])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+]>CO>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=2)(=[O:27])=[O:28])=[C:15]1[CH2:39][CH2:40][NH:41][S:42]([CH2:45][C:46]1[C:51]([F:52])=[CH:50][CH:49]=[CH:48][C:47]=1[F:53])(=[O:43])=[O:44])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)Cc3c(F)cccc3F)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)Cc3c(F)cccc3F)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 96 %

Procedure:
Methyl 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-difluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate (1 eq), THF (0.1M), MeOH (1 mL/1 mL THF), and NaOH (1N) (11 eq) were stirred together overnight. Solvents were removed and the resulting residue was taken up in water. The solution was acidified with 1N HCl and collected resulting precipitate by filtration. Obtained 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-difluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoic acid (white-yellow solid) in 96% yield. HRMS calc for [C39H33ClF2N2O6S2−H] 761.13638 found 761.13565.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[CH:8](=O)/[CH:9]=[CH:10]/[CH3:11]>C(O)C>[CH2:8]([NH:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])[CH:9]=[CH:10][CH3:11]
Reactant: COC(CN)OC
Reactant: C/C=C/C=O
Solvent: CCO
Product: CC=CCNCC(OC)OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
200 g of molecular sieve are initially introduced into 1000 ml of ethanol, and 105 g (1 mol) of aminoacetaldehyde dimethyl acetal and 70 g (1 mol) of crotonaldehyde are added. The mixture is allowed to stand overnight at room temperature, the liquid phase is decanted off from the molecular sieve and cooled to 0° C., and 40 g of sodium borohydride are added in 1 g portions. The mixture is subsequently stirred overnight at room temperature and concentrated, the concentrate is taken up in 500 ml of water, and the potassium carbonate is added until an organic phase separates off. The mixture is extracted using chloroform, and the extract is dried over potassium carbonate, concentrated and distilled.
Reaction SMILES: [C:1]([C:3]1[CH:14]=[C:13]([NH:15][C:16]([CH:18]2[CH2:21][CH2:20][CH2:19]2)=[O:17])[CH:12]=[CH:11][C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8]Cl)#[N:2].[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>C(O)C>[C:1]([C:3]1[CH:14]=[C:13]([NH:15][C:16]([CH:18]2[CH2:21][CH2:20][CH2:19]2)=[O:17])[CH:12]=[CH:11][C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8][NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])#[N:2]
Reactant: CC(C)(C)N
Reactant: N#Cc1cc(NC(=O)C2CCC2)ccc1OCC(O)CCl
Solvent: CCO
Product: CC(C)(C)NCC(O)COc1ccc(NC(=O)C2CCC2)cc1C#N

Procedure:
7.5 gm (0.024 mol) of 1-(2-cyano-4-cyclobutylcarbonylamino-phenoxy)-3-chloro-propan-2-ol were dissolved in 80 ml of ethanol, and the solution was mixed with 8.7 gm (0.12 mol) of tert. butylamine, and the mixture was refluxed for four hours. The solvent was distilled off in vacuo, the residue was extracted by shaking with dilute hydrochloric acid with the addition of ether, and the organic phase was separated. The aqueous phase was washed with ether and made alkaline with NH4OH. The base which precipitated was extracted with ethyl acetate, and the organic phase was dried over MgSO4. The ethyl acetate was distilled off, and the crystalline residue was recrystallized twice from acetonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([C:25]2[O:29][N:28]=[CH:27][C:26]=2[CH2:30][CH2:31][C:32](O)=[O:33])[CH:21]=[CH:22][C:23]=1[F:24].ON1C2N=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O>[Cl:17][C:18]1[CH:19]=[C:20]([C:25]2[O:29][N:28]=[CH:27][C:26]=2[CH2:30][CH2:31][C:32]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][P:7]([O:8][CH2:9][CH3:10])([O:11][CH2:12][CH3:13])=[O:14])=[CH:15][CH:16]=2)=[O:33])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Reactant: O=C(O)CCc1cnoc1-c1ccc(F)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1ccc(NC(=O)CCc2cnoc2-c2ccc(F)c(Cl)c2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A mixture of diethyl 4-aminobenzylphosphonate (36 mg), 3-[5-(3-chloro-4-fluorophenyl)-4-isoxazolyl]propionic acid (27 g), 1-hydroxy-7-aza-1H-1,2,3-benzotriazole (20 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (30 mg) and N,N-dimethylformamide (0.5 ml) was stirred at room temperature overnight. The reaction mixture was poured into 1N aqueous hydrochloric acid solution and the mixture was extracted with ethyl acetate. The ethyl acetate layer was concentrated, and the obtained solid was purified by preparative HPLC to give 3-[5-(3-chloro-4-fluorophenyl)-4-isoxazolyl]-N-[4-(diethylphosphonomethyl)phenyl]propionamide.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH:24]=[CH:23][CH:22]=[N:21]2)=[CH:16][CH:15]=1.[CH2:25]([Cl:27])Cl>>[Cl:27][C:25]1[CH:11]=[CH:10][C:9]([C:24]2[N:20]([C:17]3[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=3)[N:21]=[C:22]([CH2:16][CH2:15][C:14](=[O:13])[CH3:19])[CH:23]=2)=[CH:8][CH:7]=1
Reactant: c1cc[nH+]cc1
Reactant: COc1ccc(-n2cccn2)cc1
Reactant: ClCCl
Agent: O=[Cr](=O)([O-])Cl
Product: COc1ccc(-n2nc(CCC(C)=O)cc2-c2ccc(Cl)cc2)cc1
Reaction time: 4 h
Yield: 70 %

Procedure:
To a suspension of pyridinium chlorochromate (3.65 g, 16.93 mM) in CH2Cl2 (20 ml) was added the alcohol 20, (3.02 g, 8.46 mM) in CH2Cl2 (15 ml). After stirring for 4 hours, the reaction solution was decanted from the chromium precipitates that were washed with EtOAc (2×150 ml). The reaction solution and the washes were combined, filtered through florosil, and concentrated in vacuo. Chromatography (120 g, Baker 40 gm silica gel) with Et2O:hexane (1:1 to 100% Et2O) as eluent, followed by crystallization from Et2O:hexane afforded 23, (2.09 g, 70%) as a white crystalline solid, mp=85°-86° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Cl[S:24]([OH:27])(=O)=[O:25].[CH3:28][NH2:29]>O1CCCC1>[CH3:28][NH:29][S:24]([C:10]1[S:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1)(=[O:27])=[O:25]
Reactant: CS(=O)(=O)c1ccc(-c2ccsc2-c2ccc(F)cc2)cc1
Reactant: CN
Reactant: O=S(=O)(O)Cl
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(4-Fluorophenyl)-3-[4-(methylsulfonyl)phenyl]thiophene (1.1 g) was added portionwise to chlorosulfonic acid (1 ml), and the mixture was stirred at ambient temperature for 1 hour. The mixture was added to a mixture of 25% methylamine aqueous solution (20 ml) and tetrahydrofuran (20 ml), and stirred at 0° C. for 1 hour. The reaction mixture was extracted with ethyl acetate, and the extract was washed with water, dried and concentrated. The oily residue (2.4 g) was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (20:1), and then recrystallized from ethanol to give colorless crystals of N-methyl-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-sulfonamide (1.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7](OC)=[N:6][S:5](=[O:10])[N:4]=1.[NH2:11][C:12]1[C:13]([CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])=[N:14][CH:15]=[C:16]([Br:18])[CH:17]=1>CO>[NH2:11][C:12]1[C:13]([CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:7]2[C:3]([O:2][CH3:1])=[N:4][S:5](=[O:10])[N:6]=2)=[N:14][CH:15]=[C:16]([Br:18])[CH:17]=1
Reactant: NCCCCc1ncc(Br)cc1N
Reactant: COC1=NS(=O)N=C1OC
Solvent: CO
Product: COC1=NS(=O)N=C1NCCCCc1ncc(Br)cc1N
Yield: 74 %

Procedure:
A solution of 3,4-dimethoxy-1,2,5-thiadiazole-1-oxide (0.995 g) in methanol (25 ml) was reacted with a solution of 3-amino-5-bromo-(4-aminobutyl)pyridine (1.5 g) in methanol (25 ml) at room temperature for 3 hours. The solvent was removed in vacuo and the residue was chromatographed on silica in ethanol to give an oil which was triturated with ether and recrystallised from ethanol/ether to give 3-[4-(3-amino-5-bromopyrid-2-yl)butylamino]-4-methoxy-1,2,5-thiadiazole-1-oxide (1.7 g) m.p. 118°-120° C.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][C:16]([F:19])([F:18])[F:17])[C:5]=2[CH2:20][O:21][CH:22]2[CH2:28][CH:27]3[N:29]([C:30]4[CH:39]=[CH:38][C:33]([C:34]([O:36]C)=[O:35])=[CH:32][C:31]=4[F:40])[CH:24]([CH2:25][CH2:26]3)[CH2:23]2)[CH2:3][CH2:2]1.CO.[OH-].[K+].Cl>O1CCCC1.C(OCC)(=O)C>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][C:16]([F:18])([F:17])[F:19])[C:5]=2[CH2:20][O:21][CH:22]2[CH2:23][CH:24]3[N:29]([C:30]4[CH:39]=[CH:38][C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]=4[F:40])[CH:27]([CH2:26][CH2:25]3)[CH2:28]2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(N2C3CCC2CC(OCc2c(-c4ccccc4OC(F)(F)F)noc2C2CC2)C3)c(F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(N2C3CCC2CC(OCc2c(-c4ccccc4OC(F)(F)F)noc2C2CC2)C3)c(F)c1
Temperature: 70 °C

Procedure:
The ester above, methyl 4-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorobenzoate (24 mg, 0.043 mmoles) was dissolved in tetrahydrofuran (0.5 mL) and methanol (0.5 mL) and subjected to an aqueous solution of potassium hydroxide (6 N aqueous solution, 0.5 mL, 3.0 mmoles). The mixture was heated to 70° C. for 2 hours and then cooled to RT. The pH of the solution was adjusted to 6 using aqueous HCl (0.5 mL of 6N). The mixture was diluted with ethyl acetate (20 mL), extracted and water washed (3×1 mL). The organics were dried (MgSO4) then evaporated in vacuo. The product crystallized upon concentration of the ethyl acetate mother liquor, was washed with sparing ice cold ethyl acetate (0.5 mL), and the white solid dried to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C[OH:27]>Cl>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:27])[N:6]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CO
Reactant: Nc1nc(NC2CCCCC2)nc2c1nc(Br)n2Cc1ccccc1
Agent: Cl
Product: Nc1nc(NC2CCCCC2)nc2c1nc(O)n2Cc1ccccc1
Yield: 23 %

Procedure:
6-Amino-9-benzyl-8-bromo-2-cyclohexylaminopurine (82 mg, 0.20 mmol) in concentrated hydrochloric acid (30 ml) and methanol (20 ml) were refluxed for 5 hours under heating. After removal of methanol, the reaction mixture was made basic with 28% aqueous ammonia. The resulting crystals were filtered, washed with water and dried to give the subject compound (7 mg, yield 23%).
Reaction SMILES: COS([O:6][CH3:7])(=O)=O.[Br:8][C:9]1[CH:14]=[CH:13][C:12](O)=[C:11]([Cl:16])[CH:10]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([O:6][CH3:7])=[C:11]([Cl:16])[CH:10]=1
Reactant: Oc1ccc(Br)cc1Cl
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(Br)cc1Cl
Temperature: 25 °C
Yield: 95.9 %

Procedure:
Under nitrogen, 7.3 mL (77 mmol) of dimethylsulfate was added to a stirred suspension of 10 g (48 mmol) of 4-bromo-2-chlorophenol and 5.4 g (38 mmol) of powered K2CO3 in 75 mL of fresh acetone. After 2 hours at reflux, the reaction was cooled to ambient temperature, filtered, and concentrated in vacuo. The residue was dissolved in ethyl acetate; the resulting solution was washed with water and dried over MgSO4. Concentration in vacuo gave 10.2 g (96%) of 4-bromo-2-chloroanisole as a colorless solid: mp 68.5°-70.5° C.; NHR (CDCl3) δ 3.88 (s, 3H), 6.80 (d, J=9 Hz, 1H), 7.33 (dd, J=2, 9 Hz, 1H), 7.50 (d, J=2 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]([CH2:11][CH3:12])[C:8](O)=[O:9])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].S(Cl)([Cl:21])=O>C(Cl)Cl.N1C=CC=CC=1>[F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]([CH2:11][CH3:12])[C:8]([Cl:21])=[O:9])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16]
Reactant: CCC(Oc1ccc(F)c(C(F)(F)F)c1)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(Oc1ccc(F)c(C(F)(F)F)c1)C(=O)Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.7 %

Procedure:
To 1.2 g (4.5 mmole) of (-)-2-(4-fluoro-3-trifluoromethylphenoxy)butanoic acid dissolved in 15 ml methylene chloride was added one drop of pyridine and further added dropwise 0.6 g of thionyl chloride. The reaction mixture was further stirred at room temperature for 4 hours and then thionyl chloride and methylene chloride were removed under reduced pressure to obtain 1.2 g of (-)-2-(4-fluoro3-trifluoromethylphenoxy)butanoic acid chloride. The resulting mixture was applied for the next reaction without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[CH3:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1B1OC(C)(C)C(C)(C)O1)[CH:33]=[O:34].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:11]1([N:8]2[C:9]3[CH:10]=[C:2]([C:37]4[CH:36]=[CH:35][C:32]([CH:33]=[O:34])=[CH:31][C:30]=4[CH3:29])[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]4[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=4[CH3:26])=[O:17])[C:5]=3[CH:6]=[N:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Cc1cc(C=O)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)cc3C)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of 6-bromo-1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide (0.2 g, 0.45 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (0.138 g, 0.56 mmol) and Pd(PPh3)4 (0.052 g, 0.045 mmol) in 1,4-dioxane (6 mL) was purged with argon for 10 min. 2 M Na2CO3 solution (0.14 g, 1.35 mmol) was then added to it and mixture purged with argon again for 10 min. The reaction mixture was stirred at 100° C. for 2 h. After completion of the reaction, water was added to it and the extraction was carried out using 5% MeOH in DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(4-formyl-2-methylphenyl)-1H-indazole-4-carboxamide (0.15 g, 69%).