Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.[I:15]CCI.[NH4+].[Cl-]>C1COCC1.O>[I:15][C:7]1[NH:6][C:14]2[C:9]([CH:8]=1)=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: c1ccc2[nH]ccc2c1
Reactant: ICCI
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Ic1cc2ccccc2[nH]1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
2-iodoindole is prepared according to the following procedure: n-butyllithium (4.2 mL, 2.5 M in solution in hexane) is added, dropwise, to a solution of indole (1.17 g, 10 mmol) in 20 mL of anhydrous THF at −70° C. The resulting suspension is left under stiffing at this temperature for 30 minutes then gaseous CO2 is bubbled through for 10 minutes. The solution which has become clear is then left under stirring for 10 minutes. The solvent and the excess CO2 are evaporated off under vacuum then the resulting solid residue is put into solution in 20 mL of anhydrous THF and cooled down to −70° C. t-butyllithium (6.2 mL; 1.7 M in solution in pentane) is then added dropwise then the resulting solution is left under stirring for 1 hour. 1,2-diiodoethane (2.82 g; 10 mmol) is then added. The reaction mixture is left at −78° C. for 1 hour then treated with 1 mL of water. The resulting solution is left to return to ambient temperature then it is treated with a saturated aqueous solution of NH4Cl. It is extracted with ether. The organic phase obtained is washed with a saturated aqueous solution of NaCl, dried over anhydrous MgSO4 and evaporated under vacuum. The solid residue obtained is purified by flash chromatography on silica gel (hexane/ether, 4/1) producing 2-iodoindole (2.19 g; 9 mmol) with a yield of 90%. The physical and spectral data are described in the article.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:26][CH3:27])[C@H:3]([N:11]1[CH2:15][C:14](=[O:16])[N:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)[C:12]1=[O:25])[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C@@H:2]([CH2:26][CH3:27])[C@H:3]([N:11]1[CH2:15][C:14](=[O:16])[N:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)[C:12]1=[O:25])[C:4]([OH:6])=[O:5]
Reactant: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CC(=O)N(Cc2cccc(C)n2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](C)[C@@H](C(=O)O)N1CC(=O)N(Cc2cccc(C)n2)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 116.9 %

Procedure:
A solution containing the product from Example 36D (0.154 g, 0.410 mmol) in dichloromethane (3 mL) was treated with trifluoracetic acid (3 mL), stirred at 25° C. for 16 hours and concentrated. The residue was purified by reversed phase chromatography on a C18 column eluting with a gradient starting with 5-100% acetonitrile in water (0.1% TFA) to give the title compound (0.153 g) as the trifluoroacetic acid salt.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43](OC)=[O:44])[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:47][CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[CH:27]=1.CCN(C(C)C)C(C)C.[CH3:63][N:64]([CH3:70])[CH2:65][CH2:66][CH2:67][CH2:68][NH2:69]>CN(C=O)C>[CH3:63][N:64]([CH3:70])[CH2:65][CH2:66][CH2:67][CH2:68][NH:69][C:43]([C:40]1[S:39][C:35]2[N:36]=[CH:37][N:38]=[C:33]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][C:28]=3[O:47][CH:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)[C:34]=2[C:41]=1[CH3:42])=[O:44]
Reactant: CN(C)CCCCN
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)NCCCCN(C)C)sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
HATU (0.073 g, 0.193 mmol) was added into a mixture of methyl 4-(4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (0.07 g, 0.175 mmol) and Hünig's base (30 μL, 0.175 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours. N1,N1-dimethylbutane-1,4-diamine (0.177 g, 0.875 mmol) was added, the coolant removed and the reaction stirred at ambient temperature overnight. The crude reaction mixture was applied to an SCX cartridge and eluted with MeOH (30 mL) followed by ammonia in MeOH. The product was purified by flash column chromatography (10% MeOH/DCM→15% MeOH/DCM/0.5% NH4OH) to give the title compound as a waxy colourless solid (0.012 g, 37%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8](=[O:22])(=[O:21])[N:9]=[C:10]([N:14]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH:16]=[N:15]2)[NH:11][CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[NH:23]C(=O)C.Cl.[OH-].[Na+]>CO>[NH2:23][C:3]1[CH:4]=[CH:5][C:6]([S:8]([N:9]=[C:10]([N:14]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH:16]=[N:15]2)[NH:11][CH2:12][CH3:13])(=[O:22])=[O:21])=[CH:7][C:2]=1[Cl:1]
Reactant: CCNC(=NS(=O)(=O)c1ccc(NC(C)=O)c(Cl)c1)N1CC(C)(C)C=N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCNC(=NS(=O)(=O)c1ccc(N)c(Cl)c1)N1CC(C)(C)C=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.4 %

Procedure:
680 mg N-(2-Chloro-4-{[(4,4-dimethyl-4,5-dihyd ro-pyrazol-1-yl)-ethylamino-methylene]-sulfamoyl}-phenyl)-acetamide was dissolved in 5 mL MeOH, and 5 mL of concentrated HCl was added. The mixture was stirred overnight at room temperature. The mixture was basified with 2M NaOH, and extracted twice with DCM. The combined organic layers were dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (DCM/MeOH 99:1) to give 240 mg (40%) of 4-Amino-3-chloro-N-[(4,4-dimethyl-4,5-dihydro-pyrazol-1-yl)-ethylamino-methylene]-benzenesulfonamide as an orange oil. 1H NMR (400 MHz, CDCl3) δ 1.17 (t, J=7 Hz, 3H), 1.21 (s, 6H), 3.43-3.52 (m, 2H), 3.75 (br.s., 2H), 4.37 (br.s., 2H), 6.73 (s, 1H), 6.76 (d, J=8 Hz, 1H), 6.86 (br.s., 1H), 7.62 (dd, J=2 and 8 Hz, 1H), 7.83 (d, J=2 Hz, 1H).
Reaction SMILES: [CH:1]1[C:6](/[CH:7]=[CH:8]/[CH:9]=[CH:10]/[C:11](N2CCCCC2)=[O:12])=[CH:5][C:4]2[O:19][CH2:20][O:21][C:3]=2[CH:2]=1.[OH-:22].[K+].Cl>C(O)C>[O:21]1[C:3]2[CH:2]=[CH:1][C:6](/[CH:7]=[CH:8]/[CH:9]=[CH:10]/[C:11]([OH:12])=[O:22])=[CH:5][C:4]=2[O:19][CH2:20]1
Reactant: [OH-]
Reactant: O=C(/C=C/C=C/c1ccc2c(c1)OCO2)N1CCCCC1
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: O=C(O)/C=C/C=C/c1ccc2c(c1)OCO2
Yield: 79.2 %

Procedure:
Piperine (200 mg, 0.70 mmol) dissolved in anhydrous ethanol and KOH (1.18 g, 21.0 mmol) were mixed and heated to reflux for 12 hours. Upon completion of the experiment, the pH value of the reaction mixture solution was adjusted to 2-3 using hydrochloric acid. After the ethanol was distilled under reduced pressure, the residue was diluted with EtOAC (30 mL) and washed with a saturated solution of NaCl, followed by drying over anhydrous Na2SO4. The solvent was distilled under reduced pressure to give a target compound (121 mg, yield: 79.1%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][C:13]3[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=3)=[N:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]([NH:33][S:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:30]=[N:31][CH:32]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:18][N:15]1[CH:16]=[CH:17][C:13]([NH:12][C:8]2[CH:7]=[N:6][C:5]3[C:10]([N:9]=2)=[CH:11][C:2]([C:27]2[CH:28]=[C:29]([NH:33][S:34]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)(=[O:35])=[O:36])[CH:30]=[N:31][CH:32]=2)=[CH:3][CH:4]=3)=[N:14]1
Reactant: CC1(C)OB(c2cncc(NS(=O)(=O)c3ccccc3)c2)OC1(C)C
Reactant: Cn1ccc(Nc2cnc3ccc(Br)cc3n2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cn1ccc(Nc2cnc3ccc(-c4cncc(NS(=O)(=O)c5ccccc5)c4)cc3n2)n1
Temperature: 25 °C
Yield: 47.9 %

Procedure:
A slurry of 7-bromo-N-(1-methyl-1H-pyrazol-3-yl)-2-quinoxalinamine (0.37 mmol), N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (0.55 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (0.03 mmol) in 1,4-dioxane (4 ml) and 2M solution potassium carbonate (2 ml) was stirred at 100° C. for 2 hours. The reaction was cooled to ambient temperature, separated the organic layer and purified directly on silica by column chromatography (10% methanol/ethyl acetate). The desired fractions were combined and concentrated to give the title compound (81 mg, 32%) as a pale green solid. MS(ES)+ m/e 458.1 [M+H]+.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH2:7]([O:9][C:10]([C@H:12]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:13][C@@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15](O)=[O:16])=[O:11])[CH3:8]>C(Cl)Cl>[CH2:7]([O:9][C:10]([C@H:12]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:13][C@@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15]([Cl:4])=[O:16])=[O:11])[CH3:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)[C@H](Cc1ccccc1)C[C@@H](Cc1ccccc1)C(=O)O
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccccc1)C[C@@H](Cc1ccccc1)C(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: 4.0 g of (S,S)-2,4-dibenzylglutaric anhydride is refluxed in 40 ml of ethanol:toluene (3:2) overnight. The reaction mixture is concentrated to yield 4-ethoxycarbonyl-(S,S)-2,4-dibenzylbutyric acid as an oil. Oxalyl chloride (3.5 ml) is added to the solution of 4.5 g of 4-ethoxycarbonyl-(S,S)-2,4-dibenzylbutyric acid in 10 ml of methylene chloride. The mixture is stirred at room temperature overnight and evaporated to yield 4-ethoxycarbonyl-(S,S)-2,4-dibenzylbutyryl chloride, which is used as such without further purification.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[O:8])(=O)C.[OH-].[Na+].C(Cl)(Cl)Cl>CO>[SH:4][CH2:5][CH:6]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:8]
Reactant: COC(=O)CCCCCCCNC(=O)C(CSC(C)=O)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(O)CCCCCCCNC(=O)C(CS)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.8 %

Procedure:
The methyl ester product from part (b) (1.69 g., 4.3 mmole) is dissolved in methanol (13 ml.) and chilled in an ice bath under nitrogen. 1N Sodium hydroxide (13 ml., about 3 eq.) is added dropwise over 10 minutes to this solution. The mixture is stirred at 0° for 10 minutes and then allowed to warm to room temperature and stirred for 4 hours. This solution is then flushed with argon and stored under refrigeration overnight. (A white precipitate forms after stirring for about 3.5 hours.) Methanol is added and the solution is concentrated in vacuo to remove all the methanol. The residue is diluted with water (40 ml.), washed with chloroform (2×20 ml.), and the aqueous portion is acidified to pH of about 1.5 with concentrated hydrochloric acid. The resulting white suspension is extracted with ethyl acetate (3×15 ml.). These extracts are combined, washed with water and brine (20 ml. each), dried (Na2SO4), and concentrated to yield 720 mg. of a white solid. The original chloroform layer is reextracted with 1N sodium hydroxide (2×15 ml.). The aqueous portion is acidified, combined with the previous acidified layer, and extracted with ethyl acetate (2×20 ml.). These extracts are washed with water and brine, dried and concentrated to yield an additional 380 mg. of white solid. The two portions of solid are combined to give 1.10 g of (±)-8-[[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]amino]octanoic acid; m.p. 81°-83° (sinters above 68°). TLC (silica gel, benzene/acetic acid 4:1) Rf =0.42.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:18])=[CH:4][C:5]2[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:8][S:7][C:6]=2[C:16]=1[Cl:17].Br[CH2:20][C:21]([O:23]CC)=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([O:18][CH2:20][C:21]([OH:23])=[O:22])=[CH:4][C:5]2[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:8][S:7][C:6]=2[C:16]=1[Cl:17]
Reactant: Oc1cc2c(-c3ccccc3)csc2c(Cl)c1Cl
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)COc1cc2c(-c3ccccc3)csc2c(Cl)c1Cl
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
A mixture of 2.7 g of 6,7-dichloro-5-hydroxy-3-phenylbenzo[b]thiophene, 1.6 g of ethyl bromoacetate, 1.3 g of potassium carbonate and 30 ml of dimethylformamide is stirred at 60°-70° for 30 min. The mixture is filtered to remove inorganic salts and the filtrate is concentrated in vacuo to an oily residue. To the residue is added 10 mil of 40% sodium hydroxide and 30 ml of water and the mixture was heated on a steam bath for 30 min. After acidification of the mixture to pH 2, the solid product was extracted into ether, washed and dried. Concentration in vacuo gives 2.6 g of [(6,7-dichloro-3-phenylbenzo[b]thien-5-yl)oxy]acetic acid as crystals which have mp 152°-154° after recrystallization from acetone-hexane.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][C:23]([C:26]([OH:28])=O)=[CH:22][C:20]=3[N:21]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].C(Cl)CCl.[NH4+:37]>CN(C1C=CN=CC=1)C>[CH3:32][C:2]([CH3:1])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][C:23]([C:26]([NH2:37])=[O:28])=[CH:22][C:20]=3[N:21]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29]
Reactant: [NH4+]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1nc2cc(C(=O)O)ccc2o1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1nc2cc(C(N)=O)ccc2o1
Yield: 7 %

Procedure:
2-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzooxazole-5-carboxylic acid (150 mg, 0.343 mmol), DMAP (125 mg, 1.03 mmol) and EDC (99 mg, 0.514 mmol) and aqueous ammonium hydrroxide (1.0 mL, 30%) is reacted analogous to Example 2 to give the title product (10 mg, 7%). MS (ES) m/e: 437.3 (M+1).
Reaction SMILES: C([Li])CCC.[CH2:6]([O:10][CH:11]1[NH:15][C:14](=[O:16])[CH2:13][CH2:12]1)[CH2:7][CH2:8]C.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCCCCC.O1CCCC1>[C:17]([N:15]1[CH:11]([O:10][CH2:6][CH2:7][CH3:8])[CH2:12][CH2:13][C:14]1=[O:16])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCOC1CCC(=O)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCOC1CCC(=O)N1C(=O)c1ccccc1
Temperature: -60 °C
Reaction time: 0.25 h
Yield: 63.6 %

Procedure:
17 cm3 of a 1.5M solution of n-butyllithium in n-hexane is added at -60° C. to a solution of 4 g of 5-(1-butyloxy) pyrrolidin-2-one in 90 cm3 of tetrahydrofuran. The whole is agitated for 15 minutes at -60° C. then, at this temperature, a solution of 3.58 g of benzoyl chloride in 25 cm3 of tetrahydrofuran is added. After allowing the temperature to return to the ambient, the solvent is evaporated under reduced pressure and the residue is chromatographed on silica (eluent: ethyl acetate-n-hexane 1-3) and 4 g of expected product is obtained. b.p. =200°-210° C. under 0.07 mbar.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C:10]1([CH:16]([NH2:26])[C:17]2[NH:25][C:20]3=[CH:21][N:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([CH:16]([C:17]2[NH:25][C:20]3=[CH:21][N:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)[NH:26][C:1](=[O:9])[C:2]2[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NC(c1ccccc1)c1cc2ccncc2[nH]1
Reactant: O=C(O)c1ccncc1
Product: O=C(NC(c1ccccc1)c1cc2ccncc2[nH]1)c1ccncc1
Yield: 44 %

Procedure:
Using the procedure described for Example 43 with isonicotinic acid at room temperature, the reaction was stopped once 1-phenyl-1-(1H-pyrrolo[2,3-c]pyridin-2-yl)methylamine was consumed as judged by TLC analysis. Upon addition of water a solid precipitated. The solid was collected by filtration and dried to provide N-[phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methyl]isonicotinamide (58 mg, 44%) as an off-white solid: mp 182-192° C.; 1H NMR (300 MHz, CD3OD) δ6.34 (1H, s), 6.67 (1H, s), 7.30-7.55 (7H, m), 7.84-7.87 (2H, m), 8.04 (1H, d, J=5.7 Hz), 8.63 (1H, s), 8.69-8.71 (1H, m); ESI MS m/z 329 [C20H16N4O+H]+; HPLC (Method A) >99% (AUC) tR=14.1 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C@@H:6]([C:8]1[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)[NH2:7])[CH3:2].C([O-])(O)=O.[Na+].[N+]([C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[S:34](Cl)(=[O:36])=[O:35])([O-])=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][C@@H:6]([C:8]1[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)[NH:7][S:34]([C:26]1[CH:25]=[CH:30][C:29]([N+:31]([O-:33])=[O:32])=[CH:28][CH:27]=1)(=[O:35])=[O:36])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=O)C[C@H](N)c1ccc(OC)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C[C@H](NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1ccc(OC)nc1
Reaction time: 12 h

Procedure:
A solution of aminoester 16-5 (3.0 g, 13.0 mmol) in CH2Cl2 (20 mL) was treated with aq NaHCO3 (4.4 g in 20 mL H2O). 2,4-Dinitrobenzenesulfonyl chloride (4.3 g, 16 mmol) was added and the reaction mixture stirred for 12 h. The solution was extracted with CH2Cl2 (3×40 mL) and the combined organic solutions washed with satd aq NaHCO3 (40 mL) and brine (40 mL). The solution was dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (97:3 CH2Cl2/MeOH) to give the desired product 16-6.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][OH:8].C([Li])CCC.CCCCCC.[CH2:20]([O:24][C:25]1[C:29](S(C)(=O)=O)=[N:28][S:27][N:26]=1)[CH2:21][CH2:22][CH3:23]>C1COCC1>[CH2:20]([O:24][C:25]1[C:29]([O:8][CH2:7][C@@H:3]2[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])=[N:28][S:27][N:26]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCOc1nsnc1S(C)(=O)=O
Reactant: CN1CCC[C@H]1CO
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCOc1nsnc1OC[C@@H]1CCCN1C

Procedure:
A solution of (S)-1-methyl-2-pyrrolidinemethanol (0.86, 0.0075 mol) in THF (20 mL) was treated with 1.6M n-butyllithium in hexane (4.7 mL, 0.0075 mol). To the solution was added 3-butyloxy-4-methanesulfonyl-1,2,5-thiadiazole (1.2 g, 0.005 mol) and the reaction heated to reflux for 6.5 h. The solvent was evaporated, the residue acidified with cold 1N HCl, and the mixture extracted with ether. The aqueous was made basic and extracted with EtOAc. The extracts were washed with water, dried, and the solvent evaporated to give a liquid. The HCl salt (0.72 g) crystallized from EtOAc, m.p. 115°-116° C. (Compound 31).
Reaction SMILES: Br[C:2]1[C:3]([NH:22][CH2:23][CH2:24][OH:25])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[OH:25][CH2:24][CH2:23][NH:22][C:3]1[C:2]([C:30]2[CH:31]=[N:32][C:27]([CH3:26])=[CH:28][CH:29]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(NCCO)c(Br)c1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2NCCO)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 152 using 5-bromo-6-((2-hydroxyethyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 159.1) and (6-methylpyridin-3-yl)boronic acid. LC-MS (Condition 6) tR=0.87 min, m/z=433.0 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12]C)[CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].Cl.N1C=CC=CC=1>O>[CH2:1]([CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1CCc2ccc(OC)cc21
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCC1CCc2ccc(O)cc21
Temperature: 210 °C
Yield: 84.8 %

Procedure:
A mixture of 41 g of 3-ethyl-5-methoxy-indane and 111 g of pyridine hydrochloride was heated for 5 hours at 210° C. After it had cooled, 800 ml of water were added. The aqueous phase was extracted by shaking with chloroform. The combined organic phases were washed until neutral, and dried. Molecular distillation gave 32 g of 3-ethyl-5-hydroxy-indane; boiling point : 144° C/10 mm Hg. ##STR29##
Reaction SMILES: Cl.[C:2]1([C:8]([C:35]([F:38])([F:37])[F:36])=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:22][CH:21]=2)[C:10]2[CH:15]=[CH:14][C:13]([O:16]COC)=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[C:2]1([C:8]([C:35]([F:38])([F:37])[F:36])=[C:9]([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:22][CH:21]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOc1ccc(C(=C(c2ccccc2)C(F)(F)F)c2ccc(OCCN3CCOCC3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Oc1ccc(C(=C(c2ccccc2)C(F)(F)F)c2ccc(OCCN3CCOCC3)cc2)cc1
Reaction time: 1 h
Yield: 79.2 %

Procedure:
10 ml of a 9% methanolic hydrochloric acid are added to a solution of 3.08 g (6 mmoles) of 2-phenyl-3,3,3-trifluoro-1-[4-(2-morpholinoethoxy)-phenyl]-1-(4-methoxymethoxy-phenyl)-propene in 40 ml of methanol, and the mixture is boiled for one hour. The solution is rendered alkaline with 1.5 ml of a 10 n sodium hydroxide solution and then evaporated. The residue is dissolved in 400 ml of ether, the solution is washed with water until neutral, dried and evaporated. The residue is crystallized from acetone. 2.23 g (73.6%) of the aimed compound are obtained; m.p.: 154°-157° C.
Reaction SMILES: [O-2:1].[Mg+2:2].[C:3](=[O:5])=[O:4]>O>[C:3](=[O:1])([OH:5])[O-:4].[Mg+2:2].[C:3](=[O:1])([OH:5])[O-:4]
Reactant: O=C=O
Reactant: [O-2]
Agent: [Mg+2]
Solvent: O
Product: O=C([O-])O
Reaction time: 3.5 h

Procedure:
Magnesium oxide is hydrated for 1.5 hours at 85° C. The weight ratio of water to magnesium oxide is 2:1. Then water is added into the mixture to prepare slurry at a weight ratio of water to magnesium oxide of 30:1. After that, carbon dioxide (85 vt %) is introduced into the slurry to react. for 3.5 hours at 18° C. Subsequently, a pure magnesium bicarbonate solution (MgO: 29.2 g/L, Fe: 1.5 ppm, Al: 0.3 ppm) is obtained after clarification and filtration.
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13](O)=[O:14])=[C:8]3[N:7]=[C:6]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:5]=2)[CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:28]=[C:29]([S:34]([NH:37][C:38]([CH3:42])([CH3:41])[CH2:39][OH:40])(=[O:36])=[O:35])[CH:30]=[CH:31][C:32]=1[CH3:33]>>[OH:40][CH2:39][C:38]([NH:37][S:34]([C:29]1[CH:30]=[CH:31][C:32]([CH3:33])=[C:27]([NH:26][C:13]([C:12]2[CH:11]=[N:10][N:9]3[C:4]([CH:1]4[CH2:2][CH2:3]4)=[CH:5][C:6]([C:16]4[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=4)=[N:7][C:8]=23)=[O:14])[CH:28]=1)(=[O:36])=[O:35])([CH3:42])[CH3:41]
Reactant: Cc1ccc(S(=O)(=O)NC(C)(C)CO)cc1N
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1ccc(S(=O)(=O)NC(C)(C)CO)cc1NC(=O)c1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-cyclopropyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.29) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-4-methyl-benzenesulfonamide (example B. 11) according to general procedure II. Pale-yellow solid. Mp 232-233° C.