Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:15])[CH2:9][CH:10]([OH:14])[CH2:11][CH:12]=[CH2:13])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22]>CN(C=O)C.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:15])[CH2:9][CH:10]([O:14][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:28])[CH3:27])[CH2:11][CH:12]=[CH2:13])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCC(O)CC(=O)c1cccc(Br)c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCC(CC(=O)c1cccc(Br)c1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(3-bromophenyl)-3-hydroxyhex-5-en-1-one (9.08 g, 33.7 mmol), 1H-imidazole (5.34 g, 77.6 mmol) and tert-butyldimethylchlorosilane (6.29 g, 40.5 mmol) in DMF (40 mL) is stirred at room temperature for 2 h. The mixture is diluted with dichloromethane and is washed sequentially with water and saturated ammonium chloride aqueous solution. The organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product is purified by silica gel chromatography eluting with a linear gradient of 0% to 5% ethyl acetate in hexanes over 20 minutes to give the title compound as a racemic mixture (11.3 g, 88%). ES/MS m/e (79Br/81Br) 383, 385 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:2]1.Br[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.[Cu]=O>[CH2:15]([O:14][C:12]([CH2:11][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:2]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)CCc1c[nH]c2ccccc12
Reactant: Brc1cccnc1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CCOC(=O)CCc1cn(-c2cccnc2)c2ccccc12

Procedure:
A solution of 8.0 g of ethyl 3-(3-indolyl)propionate and 6.3 g of 3-bromopyridine in 100 ml of pyridine is refluxed with 5.0 g of copper oxide and 10 g of anhydrous potassium carbonate for 48 hours. Evaporation and chromatography on 300 g of silica with 1:1 ethyl ether:hexane as eluant yields 3-[2-(ethoxycarbonyl)ethyl]-N-(3-pyridyl)indole as an oil; Rf =0.2, IR (CH2Cl2) 1725 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([S:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:20]=[C:14]2[C:15](=[O:19])[NH:16][CH2:17][CH:18]=[C:13]2[N:12]=1.C([O-])(=[O:23])C.[Na+].BrBr>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:10])=[O:23])[CH:6]=[CH:5][C:4]=1[C:11]1[N:20]=[C:14]2[C:15](=[O:19])[NH:16][CH2:17][CH:18]=[C:13]2[N:12]=1
Reactant: CC(=O)[O-]
Reactant: COc1cc(SC)ccc1C1=NC2=CCNC(=O)C2=N1
Agent: BrBr
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(S(C)=O)ccc1C1=NC2=CCNC(=O)C2=N1

Procedure:
0.3 g of 2-(2-methoxy-4-methylmercapto-phenyl)-5H-imidazo[4,5-c]pyridin-4-one were suspended in 10 ml of 50% acetic acid, and 0.2 g of anhydrous sodium acetate were added thereto. 0.15 g of bromine, dissolved in 2 ml of glacial acetic acid, was added dropwise to the mixture, while stirring. After the reaction had ended the mixture was poured over ice, and the precipitate thus obtained was recrystallized from ethanol. Melting point: 267°-272° C. (decomposition).
Reaction SMILES: [CH2:1]([C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([OH:14])[C:4]=1[CH2:15]/[CH:16]=[C:17](\[CH3:24])/[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH3:2].N1C=CN=C1.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>CN(C)C=O>[Si:30]([O:14][C:5]1[C:4]([CH2:15]/[CH:16]=[C:17](\[CH3:24])/[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[C:3]([CH2:1][CH3:2])[C:11]([CH3:12])=[C:10]2[C:6]=1[C:7](=[O:13])[O:8][CH2:9]2)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCc1c(C)c2c(c(O[Si](C)(C)C(C)(C)C)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of methyl (E)-6-(1,3-dihydro-6-ethyl-4-hydroxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate (8.61 g) and imidazole (3.5 g) in dimethyl formamide (40 ml) was treated with t-butyldimethylsilyl chloride (4.50 g) and stirred at 25° C. for 14 hours. The reaction mixture was then poured into ice water and extracted with ether. Drying over magnesium sulfate and evaporation gave methyl (E)-6-(4-t-butyldimethylsilyloxy-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH:46]1([C:49]2[CH:68]=[CH:67][C:52]([CH2:53][NH:54][CH2:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[C:59]([C:63]([F:66])([F:65])[F:64])[CH:58]=3)=[CH:51][CH:50]=2)[CH2:48][CH2:47]1>CN(C=O)C.O>[CH:46]1([C:49]2[CH:68]=[CH:67][C:52]([CH2:53][N:54]([CH2:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[C:59]([C:63]([F:66])([F:65])[F:64])[CH:58]=3)[C:12]([C:9]3[C:10]([F:11])=[C:2]([Cl:1])[CH:3]=[C:4]4[C:8]=3[NH:7][CH:6]=[CH:5]4)=[O:14])=[CH:51][CH:50]=2)[CH2:48][CH2:47]1
Reactant: FC(F)(F)c1cccc(CCNCc2ccc(C3CC3)cc2)c1
Reactant: O=C(O)c1c(F)c(Cl)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1c(F)c(Cl)cc2cc[nH]c12)N(CCc1cccc(C(F)(F)F)c1)Cc1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 49.1 %

Procedure:
To a solution of 37 mg (0.17 mmol) 5-chloro-6-fluoro-1H-indole-7-carboxylic acid and 54 mg of TBTU (0.17 mmol) in 2 ml DMF, were added 0.148 ml (0.87 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 51 mg (0.17 mmol) (4-cyclopropyl-benzyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine in 1 ml DMF was added. After stirring for 17 h at rt, the reaction mixture was diluted with 30 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; diethylether/heptane 1:1; then 8 g silicagel DCM/heptane 70:30 to 90:10) to give 43 mg white foam (48%). MS (EI) 514.1 (M)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.[CH2:12]1[O:14][CH2:13]1>>[OH:14][CH2:13][CH2:12][NH:1][CH:2]1[CH2:3][C:4]([CH3:11])([CH3:10])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7]1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: C1CO1
Product: CC1(C)CC(NCCO)CC(C)(C)N1

Procedure:
156 parts of 4-amino-2,2,6,6-tetramethylpiperidine were heated to 150° C. and ethylene oxide was introduced until 44 parts thereof had been taken up. After fractional distillation, there were obtained 111 parts of 4-(β-hydroxy-ethyl)amino-2,2,6,6-tetramethylpiperidine boiling at 125° C./0.1 torr (melting point 89° to 91° C.) as well as compound 4) as higher boiling fraction.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC([N:89]1[CH2:94][CH2:93][NH:92][CH2:91][CH2:90]1)=O)(C)(C)C>O1CCOCC1.[Pd]>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([N:89]3[CH2:94][CH2:93][NH:92][CH2:91][CH2:90]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[C:13]([C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:20])[CH:14]=1
Reactant: O=C(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(N2CCNCC2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of heterocyclyl and heteroaryl substituted phenylsulfonyl derivatives previously described, using 4-Bromo-N-[4-chloro-2-(pyridine4-carbonyl)-phenyl]-benzenesulfonamide 0.1 g (0.22 mmol), potassium phosphate tribasic monohydrate 0.30 g (1.2 mmol), rac-2,2′-bis (diphenylphosphino)-1,1′-binaphthyl 0.02 g (0.032 mmol), piperazine-1-carboxylic acid tert-butyl ester 0.18 g (1 mmol) and Pd (II) trifluoroacetate 10 mg (0.01 mmol) in 6 ml dioxane. The compound was then deprotected to yield free amine using dichloromethane (2 mL) with trifluoroacetic acid (3 mL) for 1 hour at room temperature. The crude material was concentrated under vacuo, purified by HPLC, to give yellow solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:22]4[CH:24]=[C:25]([NH:28][C:29](=[O:37])[C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[Cl:36])[CH:26]=[CH:27][C:21]=4[CH2:20][CH2:19][C:18]=3[C:17]([C:38]([NH2:40])=[O:39])=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[Cl:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:29]([NH:28][C:25]1[CH:26]=[CH:27][C:21]2[CH2:20][CH2:19][C:18]3[C:17]([C:38]([NH2:40])=[O:39])=[N:16][N:15]([C:12]4[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=4)[C:23]=3[C:22]=2[CH:24]=1)=[O:37]
Reactant: NC(=O)c1nn(-c2ccc(OCc3ccccc3)cc2)c2c1CCc1ccc(NC(=O)c3ccccc3Cl)cc1-2
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1nn(-c2ccc(O)cc2)c2c1CCc1ccc(NC(=O)c3ccccc3Cl)cc1-2
Temperature: 25 °C
Reaction time: 84 h
Yield: 101.2 %

Procedure:
The final product from Example 259 (7.5 g, 0.014 mol) was dissolved of TFA (120 mL) and the dark brown solution was stirred at room temperature for 84 h. Solvent was removed and the residue was taken up with 200 mL of water. The solid was collected and air-dried to give 6.5 g of product as a pale white solid (83% yield); 1HNMR (DMSO, 400 MHz) δ: 10.29 (s, 1H), 9.84 (s, 1H), 7.24–7.51 (m, 11H), 6.87 (d, 2H), 2.90 (m, 4H); Anal. Calcd. for C25H19ClN4O3+1.0 H2O: C, 62.96; H, 4.44; N, 11.75. Found: C, 62.92; H, 4.28; N, 11.76.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>[Pd].CCO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11]2)=[CH:8][CH:9]=1
Reactant: COC(=O)C1CCC(c2ccc([N+](=O)[O-])cc2)C1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C1CCC(c2ccc(N)cc2)C1
Reaction time: 16 h
Yield: 88.3 %

Procedure:
10% palladium on carbon (78 mg) was added to a stirred solution of methyl 3-(4-nitrophenyl)cyclopentanecarboxylate (782 mg, 3.14 mmol) in EtOH (40 mL). The mixture was stirred under an atmosphere of hydrogen for 16 h then filtered through diatomaceous earth and the filter washed with EtOAc. Volatile material was removed by evaporation to give the title compound (Intermediate 84) (608 mg, 88%) as an oil; 1H NMR δ 2.24-1.45 (m, 6H), 3.03-2.83 (m, 2H), 3.62 (s, 3H), 4.80 (s, 2H), 6.53-6.46 (m, 2H), 6.92-6.86 (m, 2H); MS m/e MH+ 220.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>CO>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:3]([OH:21])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid methyl ester (50.96 g, 0.16 mol) in methanol (410 mL) was treated with a 1 N aqueous sodium hydroxide solution (345 mL, 0.35 mol). The reaction mixture was stirred at 25° C. for 24 h. The reaction mixture was concentrated in vacuo to remove methanol. The resulting aqueous residue was acidified to pH=2 with concentrated hydrochloric acid and then extracted with ethyl acetate (5×200 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford pure 3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid (43.61 g, 90%) as a white solid which was used without further purification: mp 152-154° C.; EI-HRMS m/e calcd for C15H20O4S (M+) 296.1082, found 296.1080.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:15])([CH3:14])[C:12]#[N:13])=[C:7]([F:16])[CH:6]=1)[CH3:4].[C:17]([C:19]1[C:24]2[N:25]([CH2:28][C:29](O)=[O:30])[CH:26]=[N:27][C:23]=2[CH:22]=[CH:21][CH:20]=1)#[N:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:17]([C:19]1[C:24]2[N:25]([CH2:28][C:29]([NH:2][CH:3]([C:5]3[CH:10]=[CH:9][C:8]([C:11]([C:12]#[N:13])([CH3:15])[CH3:14])=[C:7]([F:16])[CH:6]=3)[CH3:4])=[O:30])[CH:26]=[N:27][C:23]=2[CH:22]=[CH:21][CH:20]=1)#[N:18]
Reactant: CC(N)c1ccc(C(C)(C)C#N)c(F)c1
Reactant: N#Cc1cccc2ncn(CC(=O)O)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(NC(=O)Cn1cnc2cccc(C#N)c21)c1ccc(C(C)(C)C#N)c(F)c1
Reaction time: 0.17 h

Procedure:
2-(7-Cyano-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-fluorophenyl]ethyl}acetamide is synthesized according to example 1 by mixing 2-[4-(1-Aminoethyl)-2-fluorophenyl]-2-methylpropanenitrile hydrochloride (260 mg, 0.94 mmol) prepared according to scheme 7, (7-cyano-1H-benzimidazol-1-yl)acetic acid (200 mg, 0.94 mmol) prepared according to scheme 3 and DMAP (228 mg, 1.89 mmol, 1.00 mL) and HATU (358 mg, 2.49 mmol) in DMF (5.0 mL). The product is purified by HPLC: Waters prep LCMS, Flow rate: 27 ml/min, Column: SynerSi (4μ) Polar RP, 21.2×50 mm, Mobile phase: A=water (0.05% TFA) B=MeCN, Gradient used 40% to 60% B in A, in 10 min. The fractions are combined, NaOH 1N is added and the desired compound is extracted with ethyl acetate. The combined organic fractions are concentrated under reduced pressure to yield the product (69 mg, 1.77 mmol, 19%). 1H NMR (400 MHz, METHANOL-D4) δ ppm 1.50 (d, J=7.03 Hz, 3H) 1.72-1.78 (m, 6H) 5.02 (q, J=6.97 Hz, 1H) 5.31 (d, J=17.58 Hz, 1H) 5.36 (d, J=17.58 Hz, 1H) 7.17-7.25 (m, 2H) 7.39 (dd, J=8.20, 7.62 Hz, 1H) 7.43 (t, J=8.40 Hz, 1H) 7.67 (dd, J=7.62, 0.78 Hz, 1H) 7.97 (dd, J=8.20, 0.98 Hz, 1H) 8.26 (s, 1H); MS [M+H], calcd: 390.2, found: 390.3.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=1)[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.[CH:19]([C:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2)=[O:20].O>CCCCCC.C1COCC1>[C:21]12([CH:19]([OH:20])[CH:10]([C:9]3[CH:16]=[CH:17][CH:18]=[C:7]([Cl:6])[CH:8]=3)[N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)[CH2:28][CH:27]3[CH2:26][CH:25]([CH2:24][CH:23]([CH2:29]3)[CH2:22]1)[CH2:30]2
Reactant: O=CC12CC3CC(CC(C3)C1)C2
Reactant: Clc1cccc(Cn2ccnc2)c1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(C(c1cccc(Cl)c1)n1ccnc1)C12CC3CC(CC(C3)C1)C2
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 30.1 %

Procedure:
15.5 ml (23 mmol) of a 1.5 molar solution of n-butyl-lithium in hexane were added dropwise to a solution of 3.85 g (20 mmol) of N-(3-chlorobenzyl)-imidazole in 46 ml of absolute THF at -70° C. The mixture was stirred for 30 minutes at -70° C., after which a solution of 3.20 g (20 mmol) of 1-formyladamantane in 20 ml of absolute THF was added dropwise at -70° C. Stirring was continued for 1 hour at about -70° C. and for 2 hours at about -70° C. to room temperature, 120 ml of water were added at about 10° C., while cooling, and the suspension formed was stirred for 1.5 hours at 5°-8° C. Thereafter, the crystalline substance (crude product) was filtered off under suction and rinsed with water and hexane, and the crystalline product, dissolved in CH2Cl2, was filtered over a silica gel/CH2Cl2 column (diameter 2.0 cm, height 20 cm). The filtered solution was evaporated down in vacuo and the residue (2.36 g) was crystallized from acetone. 2.15 g (=30.1% yield) of pure 1-(1-adamantyl)-2-(3-chlorophenyl)-2-(1-imidazolyl)-ethanol of melting point 115° C. were obtained.
Reaction SMILES: [C:1]1([C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:8]2[CH:12]=[C:11](CCCC(OCC)=O)[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+].[CH2:46]1C[O:49][CH2:48][CH2:47]1>C(OCC)(=O)C>[C:27]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:8]2[CH:12]=[C:11]([CH2:46][CH2:47][CH2:48][OH:49])[N:10]=[CH:9]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Product: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 12 h

Procedure:
The above ester (7.5 g; 18.3 mmol), dissolved in freshly distilled THF (75 ml), is added dropwise to a solution of 0.8 g of lithium aluminium hydride (21 mmol) in freshly distilled THF (45 ml) in the cold and with stirring. Stirring is continued at room temperature for 12 hours, and the lithium aluminium hydride is then decomposed by adding saturated sodium sulphate solution dropwise. The resulting complex is filtered off, and the THF is dried over magnesium sulphate, giving an oil which is reduced in ethyl acetate to give 1-(triphenylmethyl)-4-(3-hydroxypropyl)-1H-imidazole in the form of a white powder (5.8 g; 87%); m.p.: 130° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:3]=1N.[BrH:12].[N+]([O-])([O-])=O.[Na+]>O>[Br:12][C:3]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1]
Reactant: Cc1cccc([N+](=O)[O-])c1N
Reactant: Br
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cccc([N+](=O)[O-])c1Br
Temperature: 15 °C
Reaction time: 16 h

Procedure:
A stirred solution of 75.0 grams (0.493 mole) of 2-methyl-6-nitroaniline and 40 ml of aqueous 48% hydrobromic acid in 135 ml of water was cooled to 0° C. and a solution of 36.2 grams (0.510 mole) of sodium nitrate in 60 ml of water was added dropwise during a one hour period. Upon complete addition the mixture was filtered through glass wool into a large dropping funnel. This solution was added dropwise to a second solution of 77.8 grams (0.542 mole) of cuprous bromide in 165 ml of aqueous 48% hydrobromic acid that was being stirred at 15° C. Upon complete addition the reaction mixture was stirred at 15° C. for a few minutes then was allowed to warm to ambient temperature where it stirred for one hour. The reaction mixture stood for 16 hours then was heated to 60° C. where it stirred for two hours. The reaction mixture was subjected to steam distillation. The distillate was extracted with three portions of 150 ml each of methylene chloride. The combined extracts were washed with two portions of 150 ml each of aqueous 2 N sodium hydroxide and five portions of 200 ml each of an aqueous solution saturated with sodium chloride (until the wash was pH-7). The organic layer was dried with magnesium sulfate while being slurried with decolorizing carbon. The mixture was filtered and the filtrate concentrated under reduced pressure to give 6.6 grams of 2-bromo-3-nitrotoluene; mp 36°-41° C. The nmr spectrum was consistent with the proposed structure. The pot residue from the steam distillation was extracted with 400 ml of methylene chloride. The extract was washed with aqueous 2 N sodium hydroxide then with an aqueous solution saturated with sodium chloride (until the salt wash was pH-7). The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 18.0 grams of 2-bromo-3-nitrotoluene, which was combined with the 6.6 grams of above to give a total yield of 24.6 grams.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([S:12](Cl)(=[O:14])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1.[CH3:27][NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:27][N:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:2](=[O:1])[N:3]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:4][CH2:5]2)[CH2:7][CH2:8]1)(=[O:14])=[O:13]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)Cl)CC2
Reactant: CNc1ccccc1
Product: CN(c1ccccc1)S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
This material was prepared in analogy to example 285 step B) from 1-Oxo-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-8-sulfonyl chloride and methyl-phenyl-amine. The reaction was subjected to work-up and purification after stirring for 2 h at room temperature. MS (ESI): 484.4 (MH+).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[OH:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[CH:18]=[C:17]4[CH:23]=[CH:24][CH:25]=[CH:26][C:16]4=[CH:15][C:14]=3[NH:13][C:12]=2[CH:11]=[C:10](O)[CH:9]=1.[I-].[K+]>CN(C)C=O>[OH:7][C:8]1[CH:9]=[C:1]2[O:4][C:16]([CH3:26])([CH3:17])[CH:15]=[CH:10][C:11]2=[C:12]2[C:21]=1[C:20](=[O:22])[C:19]1[CH:18]=[C:17]3[CH:23]=[CH:24][CH:25]=[CH:26][C:16]3=[CH:15][C:14]=1[NH:13]2
Reactant: O=c1c2cc3ccccc3cc2[nH]c2cc(O)cc(O)c12
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)C=Cc2c(cc(O)c3c(=O)c4cc5ccccc5cc4[nH]c23)O1
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 88.8 %

Procedure:
2 g of anhydrous potassium carbonate are added to a solution of 2 g of the product of Step A in 50 ml of anhydrous dimethylformamide, under an inert atmosphere. After stirring for 15 minutes at 65° C., 2.4 g of anhydrous potassium iodide and 4.4 g of 3-chloro-3-nmethyl-1-butyne are added and the reaction mixture is maintained at 65° C. for 24 hours and then at 130° C. for 1 hour 30 minutes. After cooling, the solution is hydrolysed and then extracted with dichloromethane. The combined organic phases are washed with water and then with a 1M solution of potassium hydroxide, dried over sodium sulphate and then evaporated. After chromatography on silica gel (cyclohexane/acetone: 90/10), 1.10 g of the expected product are isolated.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12](C(=O)C)=[C:11]([F:18])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].ClC1C=CC=[C:23]([C:27]([O:29]O)=[O:28])C=1>ClCCl>[CH2:1]([O:3][C:4](=[O:19])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:29][C:27](=[O:28])[CH3:23])=[C:11]([F:18])[CH:10]=1)([CH3:6])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C(C)=O)c(F)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Oc1ccc(OC(C)=O)c(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.5 %

Procedure:
A solution of 3.0 g (11.2 mmol) of 2-(4-acetyl-3-fluoro-phenoxy)-2-methyl-propionic acid ethyl ester in 30 ml dichloromethane was treated with 4.1 g (70%, 16.8 mmol) of 3-chloro perbenzoic acid. The reaction was stirred at RT. After 1 day additional 1.2 g (70%, 4.7 mmol), after 2 days 0.8 g (70%, 3.1 mmol) and after 3 days 0.6 g (70%, 2.3 mmol) of 3-chloro perbenzoic acid were added. The mixture was poured on ice/aqueous 10% disodium pyrosulfite solution and extracted with ether (three times). The organic phases were washed with aqueous 10% NaHCO3, aqueous saturated NH4Cl, aqueous 10% NaCl and dried over sodium sulfate to give 3.2 g of the title compound as light yellow oil.