Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:24]=[C:23]([N:25]([CH3:31])[CH2:26][C:27]([O:29]C)=O)[C:22]([N+:32]([O-])=O)=[CH:21][C:20]=3[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:20]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:21][C:22]4[NH:32][C:27](=[O:29])[CH2:26][N:25]([CH3:31])[C:23]=4[N:24]=3)=[CH:17][CH:18]=2)[CH2:10][CH2:11][CH2:12]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: COC(=O)CN(C)c1nc(-c2ccc(C3(NC(=O)OC(C)(C)C)CCC3)cc2)c(-c2ccccc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: CN1CC(=O)Nc2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc21
Yield: 38.2 %

Procedure:
In a glass autoclave were added methyl 2-((6-(4-(1-((tert-butoxycarbonyl)amino)cyclobutyl)phenyl)-3-nitro-5-phenylpyridin-2-yl)(methyl)amino)acetate (800 mg, 1.46 mmol) and 10% palladium on carbon (300 mg, 0.28 mmol) in THF (100 ml). The solution was hydrogenated at room temperature under 1.5 atm hydrogen for 20 hours. The reaction mixture was filtered through celite, then concentrated to dryness under reduced pressure. The residue was purified by Biotage chromatography (cyclohexane:ethyl acetate, gradient elution from 100:0 to 0:100) to afford the title compound (270 mg, 38%). 1H NMR (500 MHz, CDCl3): 7.35 (2H, d), 7.20-7.33 (5H, m), 7.15 (2H, d), 6.98 (1H, s), 5.05 (1H, br s), 4.11 (2H, s), 3.18 (3H, s), 2.20-2.70 (4H, br m), 2.00-2.14 (1H, m), 1.77-1.87 (1H, m), 1.10-1.50 (9H, br).
Reaction SMILES: [OH:1]O.[O:3]1[CH2:14][CH:4]1[CH2:5][S:6][C:7]1[N:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1.[Na+].[Cl-]>O.CO>[O:3]1[CH2:14][CH:4]1[CH2:5][S:6]([C:7]1[N:8]=[CH:9][C:10]([Cl:13])=[CH:11][N:12]=1)=[O:1]
Reactant: OO
Reactant: Clc1cnc(SCC2CO2)nc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=S(CC1CO1)c1ncc(Cl)cn1
Yield: 24 %

Procedure:
A mixture of 35% H2O2 (1.9 mmol) and SeO2 (1.9 mmol) in water (1.5 ml H2O) was added to a solution of 2-(2,3-epoxypropyl)thio-5-chloropyrimidine (1.9 mmol) in methanol (7 ml). The mixture was stirred at room temperature for 4 h before saturated NaCl aq. (30 ml) was added and the mixture extracted with chloroform (3×15 ml). The dried (MgSO4) chloroform solution was evaporated and the residue purified by preparative TLC on silica gel using CHCl3 : EtOH (95:5); yield 24%, m.p. 92° C. 1H NMR (CDCl3): δ2.4-3.6 (5H, m), 8.84 (H-4, H-6). IR (KBr): 1050 cm-1 (SO).
Reaction SMILES: [C:1](Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:10]1C=C[CH:13]=[CH:12][CH:11]=1>>[NH:10]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH:1]=[CH:13][CH:12]=[CH:11]1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccncc1
Product: C1=CNc2ccccc2C=C1

Procedure:
As described for Example 1, 5 mmol of 4- (2-chlorobenzoyl)amino!benzoyl chloride is reacted with 5 mmol of 5,6-dihydro-7H-pyrimido 5,4-d! 1!benzazepine in pyridine to give the product as a solid.
Reaction SMILES: C1([NH:7][C:8](=[O:30])[C:9]2[CH:14]=[C:13]([OH:15])[C:12]([OH:16])=[CH:11][C:10]=2NC(C2SC3C=CC=CC=3C=2Cl)=O)C=CC=CC=1.[CH3:31][C:32]([CH3:37])([CH3:36])[C:33](Cl)=[O:34]>C(Cl)Cl.N1C=CC=CC=1>[OH:15][C:13]1[C:12]([O:16][C:33]([C:32]([CH3:37])([CH3:36])[CH3:31])=[O:34])=[CH:11][CH:10]=[C:9]([CH:14]=1)[C:8]([NH2:7])=[O:30]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(Nc1ccccc1)c1cc(O)c(O)cc1NC(=O)c1sc2ccccc2c1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1ccc(C(N)=O)cc1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N-phenyl-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]4,5-dihydroxybenzamide (0.09 g, 0.21 mmol) in CH2Cl2 (1 mL) and pyridine (1 mL) at 0° C. was added trimethylacetyl chloride (0.027 mL, 0.22 mmol). The solution was allowed to warm to ambient temperature with stirring. After 16 hours, the reaction mixture was partitioned between ethyl acetate and dilute HCl. The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting oil was purified by flash chromatography on silica gel to afford 0.038 g (40% yield) of N-phenyl-2-[((3-chlorobenzo b]thien-2-yl)carbonyl)amino]-5-hydroxy4-((1,1-dimethylethyl)carbonyl)oxybenzamide as a white solid; NMR(DMSO-d6) 12.2 (s, 1), 10.8 (s, 1), 10.4 (s, 1), 8.3 (s, 1), 8.2 (d, 1), 8.0 (d, 1), 7.6-7.7 (m, 4), 7.4 (t, 2), 7.1 (t, 1), 1.3 (s, 9) ppm.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[C:34]([CH3:36])[N:35]=[C:9]23)[CH2:4][CH2:3]1.[CH3:37][S:38]([CH3:40])=O.C(OC(=O)C)(=O)C>O>[CH3:36][C:34]1[N:35]=[C:9]2[N:8]([C@H:5]3[CH2:6][CH2:7][C@H:2]([O:1][CH2:37][S:38][CH3:40])[CH2:3][CH2:4]3)[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]2[N:33]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2nc(C)nn12
Reactant: CS(C)=O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCSC)CC2)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 4′-{[4-(trans-4-hydroxycyclohexyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1.5 g), dimethyl sulfoxide (45 mL) and acetic anhydride (15 mL) was stirred at room temperature for 17 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.83 g, 49%).
Reaction SMILES: [C:1]1([CH3:28])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[CH:9][N:10]([C:12]3[C:13]4[N:14]([CH:25]=[CH:26][N:27]=4)[CH:15]=[C:16]([C:18]4[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=4)[N:17]=3)[CH:11]=2)=[CH:3][CH:2]=1.[N:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH3:38])=[C:30]=[O:31].CN(C=O)C>ClCCl>[C:33]1([CH3:38])[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[NH:29][C:30]([NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[N:17]=[C:12]([N:10]3[CH:11]=[C:7]([C:4]4[CH:3]=[CH:2][C:1]([CH3:28])=[CH:6][CH:5]=4)[N:8]=[CH:9]3)[C:13]3[N:14]([CH:25]=[CH:26][N:27]=3)[CH:15]=2)[CH:19]=1)=[O:31]
Reactant: Cc1ccc(-c2cn(-c3nc(-c4cccc(N)c4)cn4ccnc34)cn2)cc1
Reactant: Cc1ccccc1N=C=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cn(-c3nc(-c4cccc(NC(=O)Nc5ccccc5C)c4)cn4ccnc34)cn2)cc1
Yield: 59.2 %

Procedure:
A solution of 3-[8-(4-p-tolyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenylamine (5) (50 mg), 1-isocyanato-2-methyl-benzene (18 mg), in dichloromethane (DCM) (3 ml) and DMF (0.5 ml) is stirred at room temperature for 16 hr. The mixture is concentrated in vacuo, the residue slurried with diethyl ether/methanol (20:1), and filtered to give 1-o-tolyl-3-{3-[8-(4-p-tolyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea (6) (40 mg) as a cream solid.
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[NH:11][C:10](=[O:12])[C:5]3=[CH:6][CH:7]=[CH:8][C:9]=1[N:4]23.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31].O>CN(C=O)C>[C:22]1(=[O:31])[N:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:11]2[C:3]3=[CH:2][N:1]=[C:9]4[CH:8]=[CH:7][CH:6]=[C:5]([N:4]34)[C:10]2=[O:12])[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]12
Reactant: O=c1[nH]c2cnc3cccc1n32
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCCCn1c(=O)c2cccc3ncc1n32
Yield: 20.9 %

Procedure:
To a suspension of 81 mg (0.51 mmol) of 3,4-dihydro-1,3,7b-triazacyclopent[cd]inden-4-one in 1 ml of DMF was added, while stirring under ice-cooling, 25 mg (0.63 mmol) of 60% sodium hydride (dispersion in oil). The mixture was stirred for 15 minutes at the same temperature. To the reaction mixture was added a solution of 151 mg (0.51 mmol) of N-(5-bromopentyl)phthalimide in 1 ml of DMF. The mixture was stirred for two hours at 110° C. After cooling, the reaction mixture was poured into water, extracted with ethyl acetate. The extract was washed with an aqueous saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent:ethyl acetate/ethanol=10:1) to afford 40 mg of the desired compound (20.9%, a colorless solid).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH3:8])=[C:6]([CH:9]=[O:10])[N:5]=[CH:4]1)[CH3:2].[BH4-].[Na+].O>CO>[CH2:1]([N:3]1[C:7]([CH3:8])=[C:6]([CH2:9][OH:10])[N:5]=[CH:4]1)[CH3:2]
Reactant: CCn1cnc(C=O)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCn1cnc(CO)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
To a 0° C. solution of 1-ethyl-5-methyl-1H-imidazole-4-carbaldehyde (700 mg, 5.1 mmol) in anhydrous methanol (75 mL) was added sodium borohydride (380 mg, 10.0 mmol). The reaction mixture was stirred at room temperature for 2 hours. Water (20 mL) was added. The mixture was evaporated. The resultant residue was treated with EtOAc (30 mL) and water (5 mL). The mixture was dried over MgSO4, filtered, evaporated, and dried in vacuo, affording (1-ethyl-5-methyl-1H-imidazol-4-yl)methanol (350 mg, 49% yield). The product was used without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][C:3]=1[F:10].C(=O)([O-])[O-].[K+].[K+].[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:18][SH:19]>CN(C=O)C>[CH2:22]([O:21][C:17]([C:18]1[S:19][C:2]2[C:3]([F:10])=[CH:4][N:5]=[CH:6][C:7]=2[C:8]=1[NH2:9])=[O:20])[CH3:23]
Reactant: CCOC(=O)CS
Reactant: N#Cc1cncc(F)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2c(F)cncc2c1N
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 97.6 %

Procedure:
To a mixture of 4-chloro-5-fluoro-nicotinonitrile (1.0 g, 6.4 mmol) and potassium carbonate (4.4 g, 32 mmol) in DMF (15 mL) at 0° C. was added ethyl thioglycolate (0.73 mL, 6.7 mmol) dropwise. The reaction mixture was stirred at 0° C. for 10 min, at room temperature for 20 min and then at 40° C. for 30 min. The reaction mixture was cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was separated and washed with water followed by brine, dried over sodium sulphate and concentrated in vacuo to give the title compound as a yellow solid (1.5 g, quant.). LCMS (method B): RT=3.41 min, M+H+=241.
Reaction SMILES: [F:1][C:2]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[N:11][C:12]([C:14]([OH:16])=O)=[CH:13][C:8]=2[N:7]=[CH:6]1.[CH2:22]([O:25][NH2:26])[CH:23]=[CH2:24]>>[CH2:22]([O:25][NH:26][C:14]([C:12]1[N:11]=[CH:10][C:9]2[N:5]([CH2:4][C:3]3[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:2]=3[F:1])[CH:6]=[N:7][C:8]=2[CH:13]=1)=[O:16])[CH:23]=[CH2:24]
Reactant: O=C(O)c1cc2ncn(Cc3cccc(F)c3F)c2cn1
Reactant: C=CCON
Product: C=CCONC(=O)c1cc2ncn(Cc3cccc(F)c3F)c2cn1

Procedure:
The title compound can be prepared by coupling of 3-(2,3-difluorobenzyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid and N-allyloxyamine under the same conditions as those in step (c) of example 1.
Reaction SMILES: [N+]([O-])([O-])=O.[Na+].[F:6][C:7]([F:18])([F:17])[C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[N:13][NH:14]2)=[CH:10][CH:9]=1.S(=O)(=O)(O)O.O.[NH3:25]>>[NH2:25][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:8]=1[C:7]([F:6])([F:17])[F:18])[NH:14][N:13]=[CH:12]2
Reactant: FC(F)(F)c1ccc2cn[nH]c2c1
Reactant: N
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Nc1cc2cn[nH]c2cc1C(F)(F)F
Reaction time: 1 h
Yield: 94 %

Procedure:
Under ice-cooling, 1.01 g (12.0 mmol) of sodium nitrate was added to a mixture of 1.54 g (8.29 mmol) of 6-trifluoromethylindazole and 5 ml of concentrated sulfuric acid, and the mixture was stirred for 1 hour. The reaction mixture was poured onto ice and after ammonia water was added dropwise to the mixture under ice-cooling until pH reached 10 or higher, the precipitated solid was collected by filtration and then washed with water, followed by drying. The resulting crude product was dissolved in 50 ml of methanol, activated carbon was added to the mixture, and the mixture was filtered. 0.20 g of 5% Palladium-on-carbon was added to the filtrate, and the mixture was stirred under a hydrogen atmosphere at room temperature for 14 hours. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to give 1.57 g (yield: 94%, two steps) of 5-amino-6-trifluoromethylindazole.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]([CH3:12])[CH3:11])[N:4]=1.C([O:15][C:16](=[O:28])[CH:17]([CH3:27])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([Cl:26])[CH:20]=1)C>>[Cl:26][C:21]1[CH:20]=[C:19]([CH2:18][CH:17]([CH3:27])[C:16]([OH:28])=[O:15])[CH:24]=[CH:23][C:22]=1[O:25][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]([CH3:12])[CH3:11])[N:4]=1
Reactant: CCOC(=O)C(C)Cc1ccc(O)c(Cl)c1
Reactant: CC(C)Sc1cccc(CCl)n1
Product: CC(C)Sc1cccc(COc2ccc(CC(C)C(=O)O)cc2Cl)n1
Yield: 77.4 %

Procedure:
2-Chloromethyl-6-isopropylsulfanyl-pyridine (35 mg, 0.17 mmol) obtained in Step C of Preparation Example 16 and 3-(3-chloro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (47 mg, 0.19 mmol) obtained in Step B of Preparation Example 46 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (50 mg, 89%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[N:41]=5)=[O:56])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cccc(C)n4)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cccc(C)n4)cc2)CCN3CC(C)C)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 46.8 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(6-methyl-2-pyridinyl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.46 g) was dissolved in methylene chloride (13.8 ml), m-chloroperbenzoic acid (87 mg) was added to the mixture at 0° C., and the mixture was stirred for 20 minutes at 0° C. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(6-methyl-2-pyridinyl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 214) (157 mg).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])C>[OH-].[Na+]>[CH3:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:33])=[O:3]
Reactant: CCOC(=O)CCCCCOCCOCCOCCOCCOCCOCCOCCOC
Agent: [Na+]
Agent: [OH-]
Product: COCCOCCOCCOCCOCCOCCOCCOCCCCCC(=O)O
Reaction time: 18 h
Yield: 70.3 %

Procedure:
Non-polydispersed ester 21 (0.25 g, 0.46 mmol) was stirred for 18 hours in 0.71 ml of 1 N NaOH. After 18 hours, the mixture was concentrated in vacuo to remove the alcohol and the residue dissolved in a further 10 ml of water. The aqueous solution was acidified to pH 2 with 2 N HCl and the product was extracted into dichloromethane (30 ml×2). The combined organics were then washed with brine (25 ml×2), dried over Na2SO4, filtered and concentrated in vacuo to yield the non-polydispersed title compound as a yellow oil (0.147 g, 62%). FAB MS: m/e 499 (M+H), 521 (M+Na).
Reaction SMILES: [CH2:1]([NH:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([N:18]=[C:19]=[O:20])[CH:14]=[CH:15][C:16]=1[Cl:17]>C1C=CC=CC=1>[OH:9][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:19]([NH:18][C:13]1[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([Cl:10])[CH:12]=1)=[O:20]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: ONCc1ccccc1
Solvent: c1ccccc1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N(O)Cc1ccccc1
Yield: 83.9 %

Procedure:
A mixture of 13.3 g of N-benzyl-hydroxylamine in 260 ml of anhydrous benzene was added to a solution of 20.3 g of 3,4-dichlorophenyl isocyanate in 400 ml of anhydrous benzene and the mixture was refluxed for half an hour and then was cooled with stirring. The mixture was vacuum filtered and the recovered crystals were empasted with benzene to obtain 28.2 g of N-hydroxy-N-benzyl-N'-(3',4'-dichlorophenyl)-urea melting at 157° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].OS(O)(=O)=O.[CH3:22][CH2:23]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:16])([CH3:15])[C:12]([O:14][CH2:22][CH3:23])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCO
Reactant: COc1ccc(C(C)(C)C(=O)O)cc1OC
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)(C)c1ccc(OC)c(OC)c1
Temperature: 25 °C

Procedure:
A solution of 2-(3,4-dimethoxyphenyl)-2-methylpropanoic acid (2.5 g, 11.15 mmol) in EtOH (50 mL) with H2SO4 (cat.) was heated at reflux 12 h. The mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc and washed with satd NaHCO3 and brine. The organic layer was dried over MgSO4, filtered and concentrated to give ethyl 2-(3,4-dimethoxyphenyl)-2-methylpropanoate (2.81 g, quant), which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 6.95-6.78 (m, 3H), 4.14 (q, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 1.56 (s, 6H), 1.19 (t. 3H).
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]1[NH:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:6]=1[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)=O.B.Cl>O1CCCC1>[CH3:1][NH:3][CH2:4][C:5]1[NH:9][N:8]=[C:7]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[C:6]=1[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1
Reactant: O=CNCc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CNCc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 5-(N-formylaminomethyl)-4-(4-pyridyl)-3-(4-fluorophenyl)pyrazole (8.74 g, 29.5 mmol) in 90 mL anhydrous tetrahydrofuran was added a 1.0 M solution of borane in tetrahydrofuran (90 mL, 90 mmol) and the mixture was stirred at room temperature for 24 h. 1 N aqueous hydrochloric acid (100 mL) was then added to this mixture and the solution was refluxed for 5 hours and cooled to room temperature. The solution was extracted with ether (2×250 mL) and the pH of the aqueous layer adjusted to 9 by addition of concentrated ammonium hydroxide. The aqueous layers (pH˜9) were then extracted with ethyl acetate (4×150 mL). The organic extracts were dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was triturated with acetonitrile and filtered to obtain the title compound as a white solid: MS (M+H): 283 (base peak).
Reaction SMILES: I[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:7]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.O>[F:18][C:19]1[CH:20]=[C:21]([CH2:2][C:3]2[S:4][CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)[N:7]=2)[CH:22]=[CH:23][C:24]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: FC(F)(F)c1cccc(-c2csc(CI)n2)c1
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(Cc2nc(-c3cccc(C(F)(F)F)c3)cs2)cc1F
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, to a mixed solvent of the compound (270 mg, 0.72 mmol) obtained in Example 190c, 3-fluoro-4-methoxycarbonylphenylboronic acid (170 mg, 0.86 mmol) and cesium carbonate (1.2 g, 3.6 mmol) in tetrahydrofuran-water (v/v=5/1, 6 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (120 mg, 0.14 mmol), and the mixture was stirred at 90° C. overnight. The resulting salt was filtered and removed, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by column chromatography (hexane-hexane/ethyl acetate=75/25) to give the title compound as colorless crystals.
Reaction SMILES: [NH2:1][C@@H:2]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:3]([N:5]([CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:6])=[O:4].[F:24][C:25]([F:40])([F:39])[C:26]1[CH:27]=[C:28]([N:36]=[C:37]=[S:38])[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1>C(Cl)Cl>[CH:7]([N:5]([CH3:6])[C:3](=[O:4])[C@@H:2]([NH:1][C:37]([NH:36][C:28]1[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=[C:26]([C:25]([F:24])([F:39])[F:40])[CH:27]=1)=[S:38])[C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: FC(F)(F)c1cc(N=C=S)cc(C(F)(F)F)c1
Reactant: CN(C(=O)[C@@H](N)C(C)(C)C)C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CN(C(=O)[C@@H](NC(=S)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C)(C)C)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A 100-mL round-bottomed flask containing (S)-2-amino-N-benzhydryl-N,3,3-trimethylbutanamide (6b) (2.98 g, 9.60 mmol, 1.0 equiv) was charged with anhydrous CH2Cl2 (30 mL). 3,5-Bis(trifluoromethyl)phenylisothiocyanate (1.75 mL, 9.60 mmol, 1.0 equiv) was added in one portion via syringe. The flask was capped with a plastic stopper, and the reaction mixture was stirred for 2 h at room temperature. The clear, yellow solution was concentrated using a rotary evaporator. The residue was subjected to purification by flash column chromatography on silica gel (gradient elution, hexanes→1:1 hexanes/Et2O, 100 g silica gel, 1.5 L solvent). The product (4e) was isolated as a white solid in ˜98% 1H-NMR purity (5.14 g, 8.83 mmol, 92% yield; 74% yield over three steps). The compound exists as a 15:1 mixture of amide rotamers in CDCl3. [α]=−83.4° (c 1.0, CHCl3). 1H NMR (500 MHz, CDCl3), major rotamer: δ 8.26 (1H, br s), 8.92 (1H, br s), 7.69 (2H, s), 7.59 (1H, s), 7.31-7.37 (3H, m), 7.13-7.16 (2H, m), 6.95-7.06 (5H, m), 5.65 (1H, d, J=9 Hz), 3.13 (3H, s), 1.13 (9H, s); selected minor rotamer resonances: δ 2.76 (3H, s), 0.92 (9H, s). 13C {1H} NMR, major rotamer: δ 182.5, 174.2, 139.7, 139.0, 137.3, 131.9 (q, JC-F=34 Hz), 129.8, 128.8, 128.7, 128.4, 128.2, 127.5, 127.2, 126.3 (m), 123.1 (q, JC-F=274 Hz), 119.3 (m), 62.4, 62.3, 36.5, 34.0, 27.6. IR (cm−1): 3313 (br m), 2967 (m), 1609 (m), 1529 (m), 1473 (m), 1380 (m), 1276 (s), 1172 (m), 1127 (s), 961 (m), 889 (w), 847 (w), 758 (w), 698 (m), 681 (m). LRMS (ESI): 582.2 (80%) [M+H].