Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.[CH3:16][NH2:17]>O1CCCC1.C(Cl)Cl>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([NH:17][CH3:16])=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CC(Oc2ccc(F)cc2)C1
Reactant: CN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)N1CC(Oc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 129.3 %

Procedure:
A solution of 4.6 g (0.02 mole) of 3-(4-fluorophenoxy)-1-azetidinecarbonyl chloride in 15 ml of tetrahydrofuran was stirred while 6.2 g (0.08 mole) of 40% aqueous methylamine was added. The reaction mixture was exothermic and was allowed to cool to ambient temperature while stirring for 18 hr. The reaction mixture was diluted with 200 ml of ice water and the oil droplets which separated quickly crystallized. Filtration yielded 6.6 g of crude product. The solid was dissolved in 100 ml of methylene chloride, treated with 15 g of silica gel and stirred for 2 hr. The silica gel was removed by filtration and washed with 200 ml of 50/50 ethyl acetatemethylene chloride. The combined filtrates were concentrated on a rotary evaporator, yielding 5.8 g of solid residue. The solid was recrystallized by dissolving in 22 ml of acetone and adding 88 ml of isopropyl ether. The volume was reduced to 40 ml by boiling under nitrogen atmosphere and upon cooling the product crystallized. Filtration yielded 2.95 (66.7%) of white crystals, m.p. 140°-142° C.
Reaction SMILES: Br[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH3:10])([CH3:9])[CH2:4][C:3]1=O.[NH2:12][C:13]([NH2:15])=[S:14]>C(O)C.O.C(=O)(O)[O-].[Na+]>[NH2:15][C:13]1[S:14][C:2]2[C:7](=[O:8])[CH2:6][C:5]([CH3:10])([CH3:9])[CH2:4][C:3]=2[N:12]=1
Reactant: NC(N)=S
Reactant: CC1(C)CC(=O)C(Br)C(=O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(C)CC(=O)c2sc(N)nc2C1
Yield: 83.7 %

Procedure:
28 g of 2-bromo-5,5-dimethylcyclohexane-1,3-dione and 11.7 g of thiourea are dissolved in 200 ml of ethanol. After the weakly exothermic reaction has subsided, the mixture is refluxed for a further 6 hours. The solution is diluted with 400 ml of water and neutralised with saturated sodium bicarbonate solution. The precipitated crystals are collected by filtration and dried in vacuo at 80° C., affording 21 g of 2-amino-5,5-dimethyl-7-oxo-4,5-dihydro-6H-benzthiazole with a melting point of 203°-205° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[C:18]([CH3:19])[C:11]=12)[NH2:5].[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[C:23]([NH2:28])[N:22]=1.Cl.[OH-].[Na+]>O>[Cl:20][C:21]1[N:22]=[C:23]([NH2:28])[N:24]=[C:25]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]4[NH:16][CH:17]=[C:18]([CH3:19])[C:11]=34)=[C:2]([F:1])[CH:3]=2)[CH:26]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Cc1c[nH]c2nccc(Oc3ccc(N)cc3F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c[nH]c2nccc(Oc3ccc(Nc4cc(Cl)nc(N)n4)cc3F)c12

Procedure:
35 mg (0.14 mmol) of 3-fluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]aniline and 24.5 mg (0.15 mmol) of 4,6-dichloropyrimidine-2-amine are suspended in 2.5 ml of water. 17 μl (0.18 mmol) of 37% strength hydrochloric acid are added, and the mixture is heated at reflux overnight. Using 1N aqueous sodium hydroxide solution, the pH is adjusted to 10, resulting in the precipitation of crystals. The crystals are filtered off with suction and purified by column chromatography on silica gel (mobile phase: dichloromethane:methanol (7N ammonia) 100:5).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([C@H:16]4[C@H:20]([CH3:21])[CH2:19][NH:18][CH2:17]4)[NH:13][C:14](=[O:15])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:22]1[N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][C:25]2=[C:24]([CH:31]=O)[CH:23]=1>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([C@H:16]4[C@H:20]([CH3:21])[CH2:19][N:18]([CH2:31][C:24]5[CH:23]=[N:22][N:26]6[CH2:27][CH2:28][CH2:29][CH2:30][C:25]=56)[CH2:17]4)[NH:13][C:14](=[O:15])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1cnn2c1CCCC2
Reactant: C[C@@H]1CNC[C@H]1c1nc2c(cnn2C2CCCC2)c(=O)[nH]1
Product: C[C@@H]1CN(Cc2cnn3c2CCCC3)C[C@H]1c1nc2c(cnn2C2CCCC2)c(=O)[nH]1

Procedure:
Following the procedure for the preparation of 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 1-cyclopentyl-6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carbaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 7.99 (s, 1H), 7.35 (s, 1H), 5.16-5.09 (m, 1H), 4.11-4.06 (m, 2H), 3.68 (d, J=13.3 Hz, 1H), 3.57 (d, J=13.3 Hz, 1H), 3.32 (t, J=8.7 Hz, 1H), 3.00 (d, J=9.9 Hz, 1H), 2.94-2.80 (m, 2H), 2.78-2.77 (m, 1H), 2.49-2.45 (m, 1H), 2.38-2.33 (m, 1H), 2.11-1.83 (m, 11H), 1.73-1.61 (m, 2H), 1.17 (d, J=7.1 Hz, 3H). MS: (M+H m/z=422.1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Si:10]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH:25]=1)[CH:21]=[O:22])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>>[Si:10]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:28])[CH3:29])[CH:25]=1)[CH:21]([OH:22])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: COc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(C=O)cc(O[Si](C)(C)C(C)(C)C)c1
Product: COc1ccc(C(O)c2cc(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)c2)cc1
Yield: 81.3 %

Procedure:
Combining 4-bromoanisole (0.43 g) and aldehyde 9a (0.76 g) provided 3,5-di-(tert-butyldimethylsilyloxy)-4′-methoxybenzhydrol 15d as a faint yellow oil (0.80 g, 82%): EIMS m/z 474 (M+), 459, 417, 361, 343, 73; IR (KBr, cm−1) νmax 3420, 2932, 2859, 2361, 1591, 1451, 1252, 1163, 1026, 833; 1H-NMR δ 7.29 (2H, d, J=9.04 Hz), 6.89 (2H, d, J=9.0 Hz), 6.52 (2H, d, J=2.0 Hz), 6.28 (1H, t, J=2.0 Hz), 5.70 (1H, s), 3.83 (3H, s, OCH3), 1.00 (18H, s, C(CH3)3×2), 0.20 (12H s, Si(CH3)2×2); 13C-NMR (75.5 MHz) δ 159.0, 156.5, 146.1, 136.0, 127.9, 113.7, 111.5, 111.0, 75.5, 55.3, 25.7, 18.2, −4.4. Anal. (C26H42O4Si2) C, H.
Reaction SMILES: Cl[S:2]([C:5]1[N:9]=[CH:8][N:7]([C:10](=[O:14])[N:11]([CH3:13])[CH3:12])[N:6]=1)(=[O:4])=[O:3].C(OCC)(=O)C.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[N:21]1([S:2]([C:5]2[N:9]=[CH:8][N:7]([C:10](=[O:14])[N:11]([CH3:13])[CH3:12])[N:6]=2)(=[O:4])=[O:3])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CN(C)C(=O)n1cnc(S(=O)(=O)Cl)n1
Reactant: c1ccncc1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)n1cnc(S(=O)(=O)N2CCCCC2)n1
Reaction time: 1 h

Procedure:
To a mixture of 3-chlorosulfonyl-1-dimethylcarbamoyl-1H-1,2,4-triazole (240 mg) and ethyl acetate (2 ml) was added pyridine (0.2 ml) on a water bath at room temperature. At this temperature the mixture was stirred for 1 hour. The reaction solution was washed with water, followed by saturated aqueous sodium chloride solution, and concentrated. The residue was subjected to a silica-gel column chromatography with 20 to 30% (20% 2-propanol/ethyl acetate)/hexane to yield the title compound (29 mg).
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=1.[Br:16][C:17]1[CH:22]=[C:21]([C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[C:38]#[N:39])=[N:24]S(C(C)(C)C)=O)[CH:20]=[CH:19][N:18]=1.Cl>C1COCC1.CO>[Br:16][C:17]1[CH:22]=[C:21]([C:23]2([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([CH:13]4[CH2:15][CH2:14]4)[CH:8]=3)[C:31]3[C:32](=[C:33]([F:37])[CH:34]=[CH:35][CH:36]=3)[C:38]([NH2:39])=[N:24]2)[CH:20]=[CH:19][N:18]=1
Reactant: CC(C)(C)S(=O)N=C(c1ccnc(Br)c1)c1cccc(F)c1C#N
Reactant: Brc1ccnc(C2CC2)c1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Product: NC1=NC(c2ccnc(Br)c2)(c2ccnc(C3CC3)c2)c2cccc(F)c21
Temperature: -100 °C
Reaction time: 0.33 h
Yield: 45.3 %

Procedure:
Under an atmosphere of argon, tert-butyllithium (1.7 M in pentane) (0.576 mL, 0.98 mmol) was added dropwise to anhydrous tetrahydrofuran (4.00 mL) at −100° C. 4-Bromo-2-cyclopropylpyridine (0.097 g, 0.49 mmol) in anhydrous THF (2.00 mL) was added dropwise to the mixture. The solution was stirred for 2 minutes before dropwise addition of a solution of N-((2-bromopyridin-4-yl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (0.200 g, 0.49 mmol) in anhydrous THF (2.00 mL). The reaction was stirred at −100° C. for 20 minutes, then the temperature was raised to −78° C. over a period of 10 minutes. The reaction was stirred at −78° C. for another 60 minutes. MeOH (2.0 mL) was added dropwise at −78° C. followed by hydrogen chloride (1.25 M in methanol) (1.176 mL, 1.47 mmol). The cooling bath was removed and the reaction was left to stir at ambient temperature for 60 minutes. The solvents were evaporated and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc (×2), the organics were combined, dried (Na2SO4), filtered and evaporated. Purification by silica chromatography using 0 to 5% (3.5 M ammonia in methanol) in dichloromethane gave the title compound (0.094 g, 45%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([S:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:8]#[N:9].C[O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[CH2:36][NH:35][CH2:34][CH2:33]2>>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([C:7]([S:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH:34]2[CH2:33][CH2:32][C:37]3[CH:38]=[C:39]4[O:40][CH2:41][O:29][C:30]4=[CH:31][C:36]=3[NH:35]2)[C:8]#[N:9])[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: COc1ccc(C(C#N)(CCCCCCl)Sc2ccc(C)cc2)cc1OC
Product: COc1ccc(C(C#N)(CCCCCC2CCc3cc4c(cc3N2)OCO4)Sc2ccc(C)cc2)cc1OC
Yield: 60.9 %

Procedure:
The procedure of Example 3 is repeated using 0.854 g of α-(5-chloropentyl)-3,4-dimethoxy-α-[(4-methylphenyl)thio]-benzeneacetonitrile and 0.677 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline. This affords 0.701 g of the desired product.
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([N:6]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14][CH:13]=2)=[CH:9][C:8]([C:20]2[CH:21]=[C:22]([C:26]([NH:29][S:30]([CH2:33][C:34]([F:37])([F:36])[F:35])(=[O:32])=[O:31])([CH3:28])[CH3:27])[CH:23]=[CH:24][CH:25]=2)=[N:7]1)[CH3:5].[Cl-].[NH4+]>O1CCCC1>[CH2:4]([N:6]1[C:10]([O:11][C:12]2[CH:13]=[CH:14][C:15]([CH:18]([OH:19])[CH3:1])=[CH:16][CH:17]=2)=[CH:9][C:8]([C:20]2[CH:21]=[C:22]([C:26]([NH:29][S:30]([CH2:33][C:34]([F:37])([F:35])[F:36])(=[O:31])=[O:32])([CH3:28])[CH3:27])[CH:23]=[CH:24][CH:25]=2)=[N:7]1)[CH3:5]
Reactant: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C=O)cc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C(C)O)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 76.5 %

Procedure:
Methylmagnesium bromide (3.00 M in diethyl ether, 0.135 mL, 0.404 mmol, 2.00 equiv) was added to a solution of N-(1-{3-[1-ethyl-5-(4-formylphenoxy)-1H-pyrazol-3-yl]phenyl}-1-methylethyl)-2,2,2-trifluoroethanesulfonamide (100 mg, 0.202 mmol, 1 equiv) in tetrahydrofuran (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 5 minutes, then was treated with saturated aqueous ammonium chloride solution. The biphasic mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, and the washed solution was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The residue was purified by flash-column chromatography (hexanes, grading to 90% ethyl acetate-hexanes) to afford N-[1-(3-{1-ethyl-5-[4-(1-hydroxyethyl)phenoxy]-1H-pyrazol-3-yl}phenyl)-1-methylethyl]-2,2,2-trifluoroethanesulfonamide (79 mg, 77%). Calcd (M+1)+: 512.2. Found: 512.1.
Reaction SMILES: C([NH:8][C:9]1[C:10]2[CH:25]=[N:24][N:23]([CH2:26][CH3:27])[C:11]=2[N:12]=[CH:13][C:14]=1[C:15]1[CH2:22][C:18]2([CH2:21][CH2:20][CH2:19]2)[O:17][N:16]=1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH2:26]([N:23]1[C:11]2[N:12]=[CH:13][C:14]([C:15]3[CH2:22][C:18]4([CH2:19][CH2:20][CH2:21]4)[O:17][N:16]=3)=[C:9]([NH2:8])[C:10]=2[CH:25]=[N:24]1)[CH3:27]
Reactant: CCn1ncc2c(NCc3ccccc3)c(C3=NOC4(CCC4)C3)cnc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCn1ncc2c(N)c(C3=NOC4(CCC4)C3)cnc21
Reaction time: 12 h

Procedure:
Palladium hydroxide/carbon (1 gm) is added to a solution of N-benzyl-1-ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (1 gm, 0.0022 mole) (example 9) in methanol and the reaction mixture is stirred under hydrogen balloon for about 12 hours. It is filtered through a bed of celite and residue is washed with methanol. The combined filtrate is concentrated under reduced pressure to get the title compound.
Reaction SMILES: [OH:1][C:2]([C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)([C:5]1[N:9]([CH3:10])[CH:8]=[N:7][CH:6]=1)[CH2:3][OH:4].F[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=1[Br:28].C(=O)([O-])[O-].[K+].[K+]>CN(C1C=CN=CC=1)C.CS(C)=O>[Br:28][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:20]=1[O:4][CH2:3][C:2]([C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)([OH:1])[C:5]1[N:9]([CH3:10])[CH:8]=[N:7][CH:6]=1)[C:24]#[N:25]
Reactant: N#Cc1ccc(F)c(Br)c1
Reactant: Cn1cncc1C(O)(CO)c1ccc(C#N)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1cncc1C(O)(COc1ccc(C#N)cc1Br)c1ccc(C#N)cc1
Yield: 72 %

Procedure:
A suspension of Example 93C (1.19 g, 4.9 mmol), 4-fluoro-3-bromobenzonitrile (1.50 g, 7.5 mmol), DMAP (0.12 g, 1 mmol), and potassium carbonate (5.00 g, 36 mmol) in DMSO (13 mL) at room temperature was stirred for 16 hours, quenched with water (20 mL), treated with ethyl acetate (70 mL), and filtered. The filter cake was washed with water and dried at 40° C. under vacuum to provide 1.50 g (72% yield, HPLC purity 95.6%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, 1H), 7.84-7.80 (m, 3H), 7.61-7.58 (m, 3H), 7.37 (d, 1H), 7.16 (d, 1H), 6.56 (br s, 1H), 4.67 (d, 1H), 4.52 (d, 1H), 3.19 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH:20]([N:23]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[N:24]1)([CH3:22])[CH3:21].CCCC>>[CH:20]([N:23]1[CH:27]=[C:26]([C:2]2[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=2)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:25]=[N:24]1)([CH3:22])[CH3:21]
Reactant: CC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)OC(=O)CCOCCc1cccc(Br)c1
Solvent: CCCC
Product: CC(C)n1cc(-c2cccc(CCOCCC(=O)OC(C)(C)C)c2)cn1

Procedure:
The subtitled compound (1.03 g) was prepared from tert-butyl 3-(3-bromophenethoxy)propanoate [Preparation 3, Step i)] and 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [Example 20, Step i)] using a similar method to that described in Example 18, Step i). MS [M+H-C4H9]+=303 (MultiMode+) 1H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.67 (s, 1H), 7.36-7.23 (m, 3H), 7.07 (d, J=7.4 Hz, 1H), 4.53 (septet, J=6.7 Hz, 1H), 3.70 (t, J=6.5 Hz, 2H), 3.68 (t, J=7.3 Hz, 2H), 2.89 (t, J=7.1 Hz, 2H), 2.49 (t, J=6.5 Hz, 2H), 1.55 (d, J=6.7 Hz, 6H), 1.43 (s, 9H)
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]([F:38])([O:17][C:18]1[CH:37]=[CH:36][C:21]2[NH:22][C:23]([S:25][CH:26]([C:28]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][N:29]=3)[CH3:27])=[N:24][C:20]=2[CH:19]=1)[CH:14]([F:16])[F:15].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[F:38][C:13]([F:12])([O:17][C:18]1[CH:37]=[CH:36][C:21]2[NH:22][C:23]([S:25]([CH:26]([C:28]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][N:29]=3)[CH3:27])=[O:6])=[N:24][C:20]=2[CH:19]=1)[CH:14]([F:15])[F:16]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccnc(C(C)Sc2nc3cc(OC(F)(F)C(F)F)ccc3[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccnc(C(C)S(=O)c2nc3cc(OC(F)(F)C(F)F)ccc3[nH]2)c1
Temperature: -40 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
9.8 g of 80% m-chloroperoxybenzoic acid in 200 ml of dichloromethane are added dropwise at -65° C. to a solution of 19.5 g of ±-5-(1,1,2,2-tetrafluoroethoxy)-2-{[1-(4-methoxy-2-pyridyl)ethyl]thio}-1H-benzimidazole in 1.5 l of dichloromethane. The reaction mixture is stirred for a further 2 h at -40° C. and then stirred into a sodium carbonate solution. The organic phase is separated off, and the aqueous phase is extracted once more with dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated. A sparingly soluble diastereomer thus crystallises. The other diastereomer remains in the mother liquor and can either be purified by chromatography or can, by leaving it to stand, preferably in the presence of bases, be rearranged into the less soluble diastereomer. Recrystallisation of sparingly soluble product from ethyl acetate/diisopropyl ether gives 10 g (51%) of the title compound of m.p. 156°-157° C.
Reaction SMILES: Br[C:2](Br)=[CH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:6][CH2:5]1.C([Li])CCC.O>O1CCCC1.CCCCCC>[C:3]([C@H:4]1[CH2:5][CH2:6][C@H:7]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:22][CH:23]=3)=[CH:16][CH:17]=2)[CH2:8][CH2:9]1)#[CH:2]
Reactant: CCCCCc1ccc(-c2ccc(CC[C@H]3CC[C@H](C=C(Br)Br)CC3)cc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: C#C[C@H]1CC[C@H](CCc2ccc(-c3ccc(CCCCC)cc3)cc2)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 97.7 %

Procedure:
A solution of 2.87 g of 4-[2-[trans-4-(2,2-dibromovinyl)cyclohexyl]ethyl]-4'-pentylbiphenyl in 100 ml of absolute tetrahydrofuran was placed at -20° C. in a sulphonation flask under argon gasification and treated within 15 minutes with 20.6 ml of a 0.8N solution of butyl lithium in hexane (slight exothermic reaction). The mixture was subsequently stirred for a further 1.5 hours with gradual warming to 0° C., then poured into 100 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed a further twice with 100 ml of water each time, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the residue (1.98 g) on silica gel with 1% ethyl acetate/petroleum ether as the eluant gave 1.94 g (98%) of 4-[2-(trans-4-ethynylcyclohexyl)ethyl]-4'-pentylbiphenyl. Two-fold recrystallization from ethanol and repeated low-pressure chromatography (0.5 bar) of the crystallizate on silica gel with hexane as the eluant finally yielded 732 mg of mixed fractions and 684 mg of pure 4-(2-(trans-4-ethynylcyclohexyl)ethyl]-4'-pentylbiphenyl with m.p. (C-S) 66.0° C., t.p. (S-S) 107° C., t.p. (S-N) 115.5° C. and cl.p. (N-I) 126.4° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([C:19](OC)=[O:20])=[CH:14][N:13]=2)([O-:3])=[O:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].CC(C)=O.[O-]S([O-])=O.[Na+].[Na+]>C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([CH2:19][OH:20])=[CH:14][N:13]=2)([O-:3])=[O:2]
Reactant: COC(=O)c1cnc2sc(-c3ccccc3[N+](=O)[O-])nc2c1
Agent: O=S([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1-c1nc2cc(CO)cnc2s1
Temperature: -60 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
A solution of methyl 2-(2-nitrophenyl)thiazolo[5,4-b]pyridine-6-carboxylate (1 eq) in THF was added over 8 h to a mixture of lithium aluminum hydride (LAH) (4.4 eq) in THF maintaining the internal temperature at −55° C. The reaction mixture was stirred an additional 4 h at −60° C. Acetone (18 eq) was added followed by sat. aq Na2SO3. The resultant solids were removed by filtration and rinsed with THF. The combined organics were concentrated in vacuo and the crude residue crystallized from CH2Cl2 to give (2-(2-nitrophenyl)thiazolo[5,4-b]pyridin-6-yl)methanol (50% yield).
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([O:17][CH:18]([C:22]3[S:26][C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)=[N:24][C:23]=3[CH3:37])[CH:19]([CH3:21])[CH3:20])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[OH-].[Na+]>>[CH3:20][CH:19]([CH3:21])[CH:18]([C:22]1[S:26][C:25]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:31][CH:32]=2)=[N:24][C:23]=1[CH3:37])[O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[CH:9][N:8]2[CH2:7][C:6]([OH:38])=[O:5]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(Oc1cccc2c1ccn2CC(=O)OC(C)(C)C)C(C)C
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(Oc1cccc2c1ccn2CC(=O)O)C(C)C

Procedure:
In analogy to the procedure described in example 2 c], [rac]-(4-{2-methyl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-indol-1-yl)-acetic acid tert-butyl ester was treated with NaOH to obtain [rac]-(4-{2-methyl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-indol-1-yl)-acetic acid as yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][O:18][C:19]([NH:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:23]=1[CH2:24]Cl)=[O:20].O>CN(C)C=O>[CH3:17][O:18][C:19]([NH:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:23]=1[CH2:24][O:1][C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:20]
Reactant: O=[N+]([O-])c1ncccc1O
Reactant: COC(=O)Nc1cccc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Nc1cccc(C)c1COc1cccnc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
A mixture of 3-hydroxy-2-nitropyridine (3.08 g) and potassium carbonate (3.04 g) in N,N-dimethylformamide (31 ml) was stirred at room temperature for 15 minutes and then 2-methoxycarbonylamino-6-methylbenzyl chloride (4.7 g) was added. After being stirred for 6 hours, the mixture was poured into water and the resulting precipitates were collected by filtration, washed with water, and air-dried to give 3-(2-methoxycarbonylamino-6-methylbenzyloxy)-2nitropyridine (6.35 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:36][C:37]1[N:38]=[CH:39][NH:40][CH:41]=1)[C:13]([N:15]([CH2:22][C:23]([NH:25][CH2:26][C:27]([CH3:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:28])=[O:24])[CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.O.[OH-].[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:36][C:37]1[N:38]=[CH:39][NH:40][CH:41]=1)[C:13]([N:15]([CH2:22][C:23]([NH:25][CH2:26][C:27]([CH3:28])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:35])=[O:24])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCN(CC(=O)NCC(C)(C)c1ccccc1)C(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(CNC(=O)CN(CCC(=O)O)C(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
The product from Example 4 (0.30 g, 0.53 mmol) was dissolved in tetrahydrofuran (10 mL), methanol (10 mL) and water (1 mL). Sodium hydroxide (42 mg, 1.05 mmol) was added and the reaction was stirred overnight at room temperature. The solution was concentrated in vacuo and the residue taken up in 0.1 M NaPO4 buffer (100 mL). The pH was brought to 6 by the addition of 1N HCl. The product was extracted three times with ethyl acetate. The ethyl acetate was washed twice with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification was carried out via reversed-phase HPLC (0.1 % trifluoroacetic acid in acetonitrile and 0.1% aqueous trifluoroacetic acid as eluent; C-18 column) to give a white powder; 0.078 g (27% yield). MS-APCI: M+1=550.3.