Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH2:14][C:13]3([CH2:19][CH2:18][CH2:17][CH:16]([C:20]([O:22][CH3:23])=[O:21])[CH2:15]3)[O:12][C:11]2=[O:24])=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[CH2:36][O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH2:14][C:13]3([CH2:19][CH2:18][CH2:17][C:16]([CH2:36][O:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:20]([O:22][CH3:23])=[O:21])[CH2:15]3)[O:12][C:11]2=[O:24])=[CH:5][CH:4]=1
Reactant: ClCOCc1ccccc1
Reactant: COC(=O)C1CCCC2(C1)CN(Cc1ccc(OC)cc1)C(=O)O2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1(COCc2ccccc2)CCCC2(CN(Cc3ccc(OC)cc3)C(=O)O2)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-{[4-(methyloxy)phenyl]methyl}-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-carboxylate (5.05 g, 15.15 mmol) in THF (38.7 mL) under nitrogen at −78° C. was added sodium bis(trimethylsilyl)amide, (1M in THF, 45.4 mL, 45.4 mmol) over 30 minutes. The reaction mixture was stirred at −78° C. for 1 h. Benzyl chloromethyl ether (7.12 g, 45.4 mmol) was then added. After 1 h, the reaction was quenched slowly with water (5 mL). Saturated aq NaCl (100 mL) was then added and the mixture was extracted with EtOAc (2×125 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The compound was then loaded onto florisil and purified using silica gel chromatography CISCO): 10-25% ethyl acetate/hexanes (30 min), 25% (5 min.), 25-45% (15 min), 45% (5 min), 120 g silica. The product eluted at 45 minutes. Methyl 3-{[4-(methyloxy)phenyl]methyl}-2-oxo-7-{[(phenylmethyl)oxy]methyl}-1-oxa-3-azaspiro[4.5]decane-7-carboxylate was obtained as a light yellow oil (4.62 g, 64% yield) and NMR and LCMS were 95% clean for trans product. MS (m/z) 454.0 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[O:6][CH:5]([C:7]([O:9]CC2C=CC=CC=2)=[O:8])[CH:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1>C(OCC)(=O)C.[C].[Pd]>[C:20]([O:19][C:17]([CH:4]1[CH2:3][C:2](=[O:1])[O:6][CH:5]1[C:7]([OH:9])=[O:8])=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)C1CC(=O)OC1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1CC(=O)OC1C(=O)O
Reaction time: 3 h
Yield: 95.9 %

Procedure:
2.70 g of 2-benzyl 3-tert-butyl (2RS,3SR)-5-oxotetrahydrofuran-2,3-dicarboxylate was dissolved in 30 ml of ethyl acetate, and 300 mg of a 10% palladium-carbon catalyst was added thereto, followed by catalytic reduction for 3 hours at room temperature under hydrogen atmospheric pressure. The catalyst was filtered off, and the filtrate was evaporated to dryness under reduced pressure to obtain 1.86 g of the above-identified compound as white solid.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH2:3][C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[NH2:20][N:21]1[N:30]=[C:29]([S:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:42].N1C=CC=CC=1>ClCCl.CN(C=O)C>[C:40]([C:37]1[CH:38]=[CH:39][C:34]([S:31]([C:29]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:42])[N:21]([NH:20][C:4](=[O:6])[CH2:3][C:2]([CH3:1])([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH3:7])[N:30]=2)(=[O:33])=[O:32])=[CH:35][CH:36]=1)#[N:41]
Reactant: CC(C)(CC(=O)O)c1ccccc1
Reactant: N#Cc1ccc(S(=O)(=O)c2nn(N)c(=O)c3ccccc23)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(CC(=O)Nn1nc(S(=O)(=O)c2ccc(C#N)cc2)c2ccccc2c1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
A solution of 3-methyl-3-phenyl butanoic acid (37.7 mg, 0.212 mmol) and oxalyl chloride (0.024 mL, 0.275 mmol) in dichloromethane (0.80 mL) with a drop of DMF was stirred at room temperature for 90 minutes, concentrated to dryness, and re-dissolved in DCM (0.80 mL). To this solution was added the product from Example 224A (60.6 mg, 0.186 mmol) and pyridine (0.020 mL, 0.248 mmol), and the mixture was stirred at room temperature for 2 hours, concentrated, and chromatographed (2% acetone/DCM) to afford 46.4 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.55 (s, 1H), 8.55 (d, J=8.1 Hz, 1H), 8.41 (d, J=7.4 Hz, 1H), 8.16-8.23 (m, 4H), 8.11-8.17 (m, 1H), 8.04 (t, J=7.6 Hz, 1H), 7.40 (d, J=1.7 Hz, 1H), 7.37-7.38 (m, 1H), 7.28-7.34 (m, 2H), 7.19 (t, J=7.2 Hz, 1H), 2.50-2.56 (m, 2H), 1.29 (s, 6H); MS (ESI+) M/Z 487 (M+H)+,504 (M+NH4)+.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:37])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[C:20]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:19][N:18]([C:29]3[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:36])[N:17]=2)=[O:15])[CH:8]=1>C1COCC1.O>[Cl:36][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([Cl:35])[C:29]=1[N:18]1[N:17]=[C:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=2)[C:6]([OH:37])=[O:5])=[O:15])[C:20]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:19]1
Reactant: COC(=O)c1cccc(NC(=O)c2nn(-c3c(Cl)cccc3Cl)nc2COc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(NC(=O)c2nn(-c3c(Cl)cccc3Cl)nc2COc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.6 %

Procedure:
Lithium hydroxide monohydrate (386 mg, 9.20 mmol) was added to a solution of the product from step d (915 mg, 1.84 mmol) in THF/water (18 mL each). The reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was partitioned between ethyl acetate (40 mL) and 2M aqueous hydrochloric acid (40 mL). The aqueous phase was discarded and the organic phase was washed with brine (40 mL) and dried (MgSO4). The filtrate was evaporated to yield the title compound (841 mg, 95%). 1H NMR (DMSO-d6) 12.9 (1H, br s), 10.9 (1H, br s), 8.51 (1H, m), 7.97 (1H, m), 7.84-7.68 (4H, m), 7.49-7.46 (1H, m), 7.32-7.26 (2H, m), 7.05-6.95 (3H, m), 5.56 (2H, s). The material was further analysed as its N-methyl D-glucamine salt. Microanalysis found: C, 52.76; H, 4.98; N, 9.99%; C23H16Cl2N4O4—C7H17NO5-0.5H2O requires: C, 52.41; H, 4.98; N, 10.17%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[O:17]1[CH2:19][C@H:18]1[CH2:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>CS(C)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH2:12][CH2:13][N:14]([CH2:19][C@H:18]([OH:17])[CH2:20][O:21][C:22]4[CH:30]=[CH:29][CH:28]=[C:27]5[C:23]=4[CH:24]=[CH:25][NH:26]5)[CH2:15][CH:16]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Solvent: CS(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CC=C(c2c[nH]c3cc(F)ccc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 6-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (1.00 g, 4.63 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.88 g, 4.6 mmol). The resulting free base was obtained as a yellow foam. Yield 1.2 g (64%). mp 95°-100° C. FDMS m/e=405 (M+ of free base). α[D]589 =5.15 (c=1.01, dimethylsulfoxide).
Reaction SMILES: [CH:1]1([N:4]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[S:5]([C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[C:11]([O:13]CC[Si](C)(C)C)=[O:12])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl>C1COCC1>[CH:1]1([N:4]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[S:5]([C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[C:11]([OH:13])=[O:12])(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CCCN(C1CC1)S(=O)(=O)c1cccc(C(=O)OCC[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)CCCN(C1CC1)S(=O)(=O)c1cccc(C(=O)O)c1
Yield: 96.7 %

Procedure:
A mixture of 2.48 g of 2-(trimethylsilyl)ethyl 3-[cyclopropyl(4-ethoxy-4-oxobutyl)sulfamoyl]benzoate, a solution of TBAF in THF (1.0 M, 10 mL), and 25 mL of THF was stirred at room temperature for 2 hours. To the reaction mixture was added 0.2 M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with 0.2 M hydrochloric acid, water, saturated brine in this order, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.87 g of 3-[cyclopropyl(4-ethoxy-4-oxobutyl)sulfamoyl]benzoic acid as a colorless solid.
Reaction SMILES: Cl.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:9]2[CH2:14][CH:13]([C:15]3[C:16]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[N:17][S:18][N:19]=3)[CH2:12][N:11]=[CH:10]2)C=CC=CC=1.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>>[F:43][C:42]([F:45])([F:44])[C:40]([OH:46])=[O:41].[CH2:21]([O:20][C:16]1[C:15]([CH:13]2[CH2:14][NH:9][CH:10]=[N:11][CH2:12]2)=[N:19][S:18][N:17]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCOc1nsnc1C1CN=CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCOc1nsnc1C1CN=CNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
1-Triphenylmethyl-5(3(1-n-heptanoxy)-1,2,5-thiadiazol-4-yl)-1,4,5,6-tetrahydropyrimidine HCl (580 mg, 1 mmol) is dissolved in TFA (1 ml) and stirred overnight at room temperature. The TFA is evaporated and the resulting dark oil triturated with ether. After decanting the ether, the remaining solids are recrystallized from methanol/ether to give 344 mg (87%) white crystals identified by 300 MHz nmr, ms m/z=360.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[C:12]2[C:7](=[CH:8][C:9]([O:28][CH3:29])=[C:10]([O:26][CH3:27])[C:11]=2C)[N:6]=1.[BH4-].[Na+].O1CCCC1.CO>O>[CH3:27][O:26][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:28][CH3:29])[N:6]=[C:5]([CH2:4][CH2:3][OH:2])[N:14]=[C:13]2[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1
Reactant: COC(=O)Cc1nc(-c2ccc(OC)c(OC)c2)c2c(C)c(OC)c(OC)cc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2nc(CCO)nc3cc(OC)c(OC)cc23)cc1OC
Yield: 83.5 %

Procedure:
To a mixture of methyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinazoline-2-acetic acid methyl ester (4.0 g), sodium borohydride (1.9 g) and tetrahydrofuran (80 ml), methanol (15 ml) was added dropwise under continuous reflux, followed by refluxing for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated under reduced pressure to yield 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(2-hydroxyethyl) quinazoline (3.0 g, 81%). Recrystallization from ethyl acetate gave a colorless needle crystal having a melting point of 165° to 166° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13](Br)[C:12]([NH:17][C:18](=[O:48])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:47])[CH:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]([CH2:40][CH3:41])([CH3:39])[CH3:38])=[CH:33][C:32]=3[C:42]([CH2:45][CH3:46])([CH3:44])[CH3:43])[CH2:28][CH3:29])[CH:20]=2)=[N:11]1.[CH3:49][C:50]1[CH:51]=[N:52][NH:53][CH:54]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]([C:51]2[C:50]([CH3:49])=[CH:54][NH:53][N:52]=2)[C:12]([NH:17][C:18](=[O:48])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:47])[CH:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]([CH2:40][CH3:41])([CH3:39])[CH3:38])=[CH:33][C:32]=3[C:42]([CH2:45][CH3:46])([CH3:44])[CH3:43])[CH2:28][CH3:29])[CH:20]=2)=[N:11]1
Reactant: Cc1cn[nH]c1
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cccc(C(=O)NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2Br)c1
Solvent: CCOC(C)=O
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cccc(C(=O)NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2c2n[nH]cc2C)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
45 g of 1-(2,4,6-trichlorophenyl)-3-{3-[2-(2,4-di-tert-amylphenoxy)butyramido]benzamido}-4-bromo-5-oxo-2-pyrazoline and 19 g of 4-methylpyrazole were mixed with each other, then stirred for 2 hours under heating at 90° C. To the reaction mixture was added 500 ml of ethyl acetate, followed by washing several times with water. The ethyl acetate layer was dried with anhydrous sodium sulfate and concentrated. Upon crystallization of the residue from a solvent mixture of 100 ml of acetonitrile and 20 ml of benzene, 19 g of Coupler (2) was obtained. The melting point of the coupler was 142° to 145° C.
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[F:13][C:14]1[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17].S(Cl)(Cl)=O>CC(N(C)C)=O.C(Cl)Cl.C(COC)OC>[F:13][C:14]1[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:20]=[CH:19][C:15]=1[C:16]([NH:10][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])=[O:17]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: COCCOC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)NS(=O)(=O)c2ccccc2)c(F)c1
Reaction time: 0.5 h

Procedure:
A solution of 31.4 g of benzenesulfonamide in 250 ml. of dry dimethylacetamide is added dropwise, with stirring and cooling, to a suspension of 5.5 g. of sodium hydride in 100 ml of dry dimethylacetamide during 30 minutes at room temperature. Stirring is continued for 30 minutes. In the meantime, a mixture of 36.2 g. of 2-fluoro-4-(hexadecylamino)benzoic acid in 100 ml of methylene chloride, 300 ml. of dimethoxyethane, and 40 ml. of thionyl chloride is refluxed for 1 hour and 15 minutes. The solution is evaporated and to the resulting oil residue is added, in one portion, the previously prepared mixture of sodium benzenesulfonamide in dimethylacetamide. The mixture is stirred for 30 minutes, without cooling, and then filtered. The filtrate is poured into 2 l. of water and 250 ml. of saturated sodium chloride solution. The product is collected by filtration and then dissolved in methylene chloride, the mixture is filtered through diatomaceous earth, and brine is added to break the emulsion. The layers are separated, the organic phase is dried and evaporated. The residue is crystallined from toluene to yield 2-fluoro-4-(hexadecylamino)-N-(phenylsulfonyl)benzamide.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]([NH:22][C:23]2[C:28]([CH:29]([CH3:31])[CH3:30])=[CH:27][CH:26]=[C:25](N)[C:24]=2[CH:33]([CH3:35])[CH3:34])=[O:21])[CH2:15][CH2:14]1.N([O-])=[O:37].[Na+].O.C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][N:16]([CH2:19][C:20]([NH:22][C:23]2[C:28]([CH:29]([CH3:31])[CH3:30])=[CH:27][CH:26]=[C:25]([OH:37])[C:24]=2[CH:33]([CH3:35])[CH3:34])=[O:21])[CH2:17][CH2:18]1
Reactant: CC(C)c1ccc(N)c(C(C)C)c1NC(=O)CN1CCN(CCSc2nc3ccccc3o2)CC1
Reactant: O=N[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)c1ccc(O)c(C(C)C)c1NC(=O)CN1CCN(CCSc2nc3ccccc3o2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
2-[4-[2-(Benzoxazol-2-ylthio)ethyl]piperazin-1-yl]-N-(3-amino-2,6-diisopropylphenyl)acetamide (198 mg, 0.4 mmol) was dissolved in 6% aqueous solution of sulfuric acid (3.4 ml), an aqueous solution (0.8 ml) of sodium nitrite (35 mg, 0.5 mmol) was added thereto at 0° C. and the mixture was stirred at that temperature for 30 minutes. The reaction solution was slowly dropped into a boiling water (40 ml) which was heating and stirring at an external temperature of 140° C. After 10 minutes from the dropping, the reaction solution was allowed to cool, neutralized with sodium bicarbonate and extracted with chloroform. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by a preparative thin layer chromatography (developing solvent, chloroform:ammonia-saturated methanol=20:1) to provide 178 mg (yield 89%) of the desired compound, which was recrystallized from ethanol-hexane to provide colorless needles.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[CH:16]=[C:15]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH3:28])[CH:23]=3)[CH:18]=2)[N:14]([C@H:29]([C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][CH:32]=2)[CH3:30])[N:13]=1.Cl.[C:41]([O:45][C:46](=[O:50])[CH2:47][CH2:48][NH2:49])([CH3:44])([CH3:43])[CH3:42].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:9])[F:11])=[CH:4][C:3]=1[C:12]1[CH:16]=[C:15]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH3:28])[CH:23]=3)[CH:18]=2)[N:14]([C@H:29]([C:31]2[CH:32]=[CH:33][C:34]([C:35]([NH:49][CH2:48][CH2:47][C:46]([O:45][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:50])=[O:37])=[CH:38][CH:39]=2)[CH3:30])[N:13]=1
Reactant: COc1ccc2cc(-c3cc(-c4cc(C(F)(F)F)ccc4F)nn3[C@@H](C)c3ccc(C(=O)O)cc3)ccc2c1
Reactant: CC(C)(C)OC(=O)CCN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2cc(-c3cc(-c4cc(C(F)(F)F)ccc4F)nn3[C@@H](C)c3ccc(C(=O)NCCC(=O)OC(C)(C)C)cc3)ccc2c1
Reaction time: 0.17 h

Procedure:
4-{(1S)-1-[3-[2-Fluoro-5-(trifluoromethyl)phenyl]-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl]ethyl}benzoic acid (2.93 g, 5.48 mmol), beta-alanine t-butyl ester hydrochloride (2.73 g, 15 mmol), and DIEA (3.5 ml, 20 mmol) were dissolved in DMF (35 ml), followed by slow addition of PyBOP (2.93 g, 5.62 mmol) in DMF (10 ml). The reaction was stirred for 10 min, and diluted with ethyl acetate (200 ml), washed with 1N HCl 2×, 5% K2CO3 2×, and brine 2×. The solvent was evaporated and resulting residue was purified by flash chromatography (SiO2, 0-6% ethyl acetate in DCM gradient) to give tert-butyl N-(4-{(1S)-1-[3-[2-fluoro-5-(trifluoromethyl)phenyl]-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl]ethyl}benzoyl)-β-alaninate as a dry foam. NMR (500 MHz, DMSO-d6) δ: 1.35 (s, 9H); 1.92 (d, J=6.9 Hz, 3H); 2.44 (t, J=7.0 Hz, 2H); 3.41 (q, J=7.0 Hz, 2H); 3.89 (s, 3H); 5.80 (q, J=6.9 Hz, 1H); 6.94 (d, JF-H=3.8 Hz, 1H); 7.21 (d, J=8.3 Hz, 2H); 7.22 (dd, J=2.6 Hz, 9.0 Hz, 1H); 7.39 (d, J=2.6 Hz, 1H); 7.44 (dd, J=2.6 Hz, 8.5 Hz, 1H); 7.58 (t, J=9.7 Hz, 1H); 7.72 (d, J=8.3 Hz, 2H); 7.79 (m, 1H); 7.83 (d, J=9.0 Hz, 1H); 7.89 (d, J=2.6 Hz, 1H); 7.90 (d, J=8.5 Hz, 1H); 8.33 (dd, J=2.8 Hz, 6.6 Hz, 1H); 8.44 (t, J=5.5 Hz, NH). MS C37H35F4N3O4 Cald: 661.26; Obsd (M+1): 662.29.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[NH:12][C:13]([C:15]1[S:16][CH:17]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:19]=1)=O)(=[O:3])[CH3:2].CC(C)([O-])C.[K+]>CC(O)(C)C>[CH:20]([C:18]1[N:19]=[C:15]([C:13]2[CH:2]=[C:1]([OH:3])[C:4]3[C:5](=[CH:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=3)[N:12]=2)[S:16][CH:17]=1)([CH3:22])[CH3:21]
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
To a solution of compound 217a (4.312 g, 1 eq.) in tBuOH (60 mL) was added potassium t-butoxide (3.8 g, 2.5 eq.) under nitrogen. The mixture was stirred at 70° C. for 16 hrs, and then cooled down to 0° C. and quenched with MeOH (10 mL) and acetic acid (2.5 mL). The solvent was removed under reduced pressure and the residue was triturated in a mixture of MeOH/water, isolated by filtration, washed with ACN, and then petroleum ether to yield compound 218a as a yellow solid in 71% yield. 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 1.32 (d, J=6.98 Hz, 6H), 3.14 (m, 1H), 3.89 (s, 3H), 7.06 (br s, 1H), 7.50-7.66 (m, 3H), 8 (d, J=9.05 Hz, 1H), 11.62 (br s, 1H); MS (ESI, EI+): m/z=301 (MH+).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12](Br)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.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>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[C:27]([O:28][CH3:29])[CH:26]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2cccnc21
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: [K+]
Solvent: C1CCOC1
Product: COc1ccc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)cc1OC
Temperature: 120 °C

Procedure:
1-Benzenesulfonyl-3-bromo-1H-pyrrolo[2,3-b]pyridine (4, 1.00 g, 2.96 mmol) was dissolved in tetrahydrofuran (16 mL) and 3,4-dimethoxyphenyl boronic acid (1.35 g, 7.41 mmol), tetrakis(triphenylphosphine)palladium(0) (200 mg, 0.1 mmol), and 1 M potassium carbonate (8 mL) were added. The reaction mixture was heated in a CEM Discover microwave at 120° C. for 10 minutes. The reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate and water. The organic portions were dried with anhydrous magnesium sulfate, filtered, and the filtrate was adsorbed onto silica. The mixture was purified by flash chromatography (30% ethyl acetate:hexanes) to provide the desired product, 5, (909 mg, 78%). MS(ESI) [M+H+]+=394.9.
Reaction SMILES: [CH2:1]([C:3]([OH:21])([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12]Br)=[CH:6][CH:5]=1)[CH3:2].[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH2:1]([C:3]([OH:21])([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCC(O)(c1ccc(F)cc1)c1ccc(OCCBr)cc1
Reactant: C1CCNCC1
Product: CCC(O)(c1ccc(F)cc1)c1ccc(OCCN2CCCCC2)cc1
Reaction time: 2 h

Procedure:
17.6 g. of α-ethyl-α-(4-fluorophenyl)-4-(2-bromoethoxy)-benzylalcohol and 30 ml. of dry piperidine are refluxed with stirring for two hours. Piperidine is distilled off from the reaction mixture under reduced pressure, to the residue water is added, and it is extracted with ether. The ethereal phase is washed to neutral with water, dried over anhydrous potassium carbonate, and then ether is distilled off. Crystallization of the residue from n-hexane yields 14.9 g. of the named compound, melting at 72° to 73° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[OH:15])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[F:24][CH:25]([F:27])Cl>CN(C)C=O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH:25]([F:27])[F:24])[CH:10]=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=Cc1ccc(O)c(OC2CCCC2)c1
Reactant: FC(F)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC(F)F)c(OC2CCCC2)c1

Procedure:
A solution of 3-cyclopentyloxy-4-hydroxybenzaldehyde (5.1 g) in dimethylformamide (50 mL) is treated with potassium carbonate (4.83 g) and potassium iodide (1.2 g) and the solution is heated at 70°-75° C. whilst difluorochloromethane is bubbled though it at a slow rate, during 5 hours. Water (100 mL) is added and the mixture is extracted with ethyl acetate (2×100 mL). The combined organic extracts are dried over magnesium sulfate and concentrated to give a brown oil. The oil is subjected to flash chromatography, eluting with a mixture of diethyl ether and pentane (1:4 v/v), to give 3-cyclopentyloxy-4-difluoromethoxybenzaldehyde, in the form of a pale yellow oil (4.7 g). [NMR (CDCl3): 9.92(s,1H);7.5-7.24(m,3H); 6.34°-5.96(t, 1H); 4.9(m, 1H);2.0-1.6(m,8H)].