Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrCCBr.[Mg].[CH3:6][N:7]1[CH2:12][CH2:11][CH:10](Cl)[CH2:9][CH2:8]1.[Br:14][C:15]1[CH:16]=[C:17]2[CH2:26][CH2:25][N:24]3[C:18]2=[C:19]([CH:32]=1)[CH:20]=[N:21][C:22]1[CH:30]=[C:29]([Br:31])[CH:28]=[CH:27][C:23]=13.[OH-].[NH4+]>O1CCCC1.ClCCl>[Br:14][C:15]1[CH:16]=[C:17]2[CH2:26][CH2:25][N:24]3[C:18]2=[C:19]([CH:32]=1)[CH:20]([CH:10]1[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]1)[NH:21][C:22]1[CH:30]=[C:29]([Br:31])[CH:28]=[CH:27][C:23]=13
Reactant: CN1CCC(Cl)CC1
Reactant: Brc1cc2c3c(c1)CCN3c1ccc(Br)cc1N=C2
Agent: [Mg]
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CN1CCC(C2Nc3cc(Br)ccc3N3CCc4cc(Br)cc2c43)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,2-Dibromoethane (0.5 ml) was added to a refluxing slurry of magnesium chips (6 gm) in tetrahydrofuran (70 ml) to initiate a Grignard reaction. A solution of N-methyl-4-chloropiperidine (35 ml) in tetrahydrofuran (100 ml) was added rapidly. The reaction mixture was refluxed for 2 hours, during which a white precipitate formed. The mixture was cooled to room temperature and transferred to a flask containing 4,9-dibromo-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine (20 gm) in tetrahydrofuran (200 ml) in one portion at ice-temperature. After 1 hour of stirring, the mixture was poured into ice-water/concentrated hydrochloric acid (600 ml:35 ml), and stirred for 15 minutes. The acid solution was slowly added to a stirred mixture prepared from dichloromethane (1 L) and an ammonium hydroxide solution (40 ml). The organic solution was separated, washed with water (500 ml) and brine (2×500 ml) and dried over anhydrous magnesium sulfate. The solution was filtered and concentrated to an oil (26 gm).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13].Cl[CH2:15][O:16][CH3:17]>O1CCCC1>[Br:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:13][CH2:15][O:16][CH3:17]
Reactant: O=[N+]([O-])c1ccc(O)c(Br)c1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1ccc([N+](=O)[O-])cc1Br
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 310.8 %

Procedure:
4.2 g (140 mmol) of a sodium hydride dispersion (55% in oil) are added portion-wise at 0° C. to a solution of 15.3 g 2-bromo-4-nitrophenol (70 mmol) in 250 ml tetrahydrofuran. Subsequently the reaction mixture is stirred for 50 minutes at 0° C. and then mixed with 1.83 g of chloromethyl-methyl ether (19.4 mmol). The mixture is stirred for an additional hour at 0° C. and then poured into ice, extracted with ethyl acetate and the organic phase is washed with a saturated aqueous salt solution, dried over Na2SO4, filtered and concentrated. The residue so obtained is concentrated over silica gel with petroleum ether/ethyl acetate (9:1). 15.8 g (80% theoretical yield) of 2-bromo-1-methoxymethoxy-4-nitrobenzene are obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7](=[O:15])[C:6]=2[CH:16]=1.FC1C=CC(B(O)O)=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2[C:40]2[C:45]([O:46][CH3:47])=[CH:44][CH:43]=[CH:42][C:41]=2OC)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:47][O:46][C:45]1[CH:40]=[CH:41][C:42]([C:2]2[CH:3]=[CH:4][C:5]3[C:14]4[C:9](=[N:10][CH:11]=[CH:12][CH:13]=4)[NH:8][C:7](=[O:15])[C:6]=3[CH:16]=2)=[CH:43][CH:44]=1
Reactant: O=c1[nH]c2ncccc2c2ccc(Cl)cc12
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: COc1ccc(-c2ccc3c(c2)c(=O)[nH]c2ncccc23)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 165.4 %

Procedure:
8-Chloro-5H-benzo[c][1,8]naphthyridin-6-one (50 mg, 0.22 mmol), 4-fluorophenylboronic acid (61 mg, 0.43 mmol), palladium(II) acetate (2 mg, 0.01 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (7 mg, 0.02 mmol), and potassium carbonate (90 mg, 0.65 mmol) were dissolved in dioxane/H2O (2.2 mL, 10/1, v/v), and stirred overnight at 100° C. The reaction mixture was diluted with MeOH, filtered through a membrane plug, and purified via prep-LC-MS to provide 15 (10 mg, 16% yield) as a white solid. LC-MS (M+H=291, obsd.=291). 1H NMR (400 MHz, d6-DMSO): δ 12.15 (s, 1H), 8.88 (dd, 1H), 8.64 (d, 1H), 8.54 (dd, 1H), 8.52 (dd, 1H), 8.22 (dd, 1H), 7.90 (m, 2H), 7.37 (m, 3H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C@H:29]([OH:32])[CH2:30][OH:31])=[CH:23][C:8]=1[C:9]([NH:11][CH2:12][C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2)=[O:10].C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C@H:29]([OH:32])[CH2:30][O:31][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:23][C:8]=1[C:9]([NH:11][CH2:12][C:13]12[CH2:20][CH:19]3[CH2:18][CH:17]([CH2:16][CH:15]([CH2:21]3)[CH2:14]1)[CH2:22]2)=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CC[C@H](O)CO)ccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@@H](O)CCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
Methanesulfonylchloride (0.08 mL) was added to a solution of 2-chloro-5-[(3S)-3,4-dihydroxybutyl]-N-(tricyclo(3.3.1.13,7]dec-1-ylmethyl)benzamide (Example 1b) (0.33 g) and triethylamine (0.33 ml) in dichloromethane (10 mL). After 1 hour the reaction mixture was concentrated, redissolved in ethyl acetate and the organic layer washed with water, brine, dried over anhydrous magnesium sulfate, filtered and evaporated. Purification by normal phase HPLC (gradient 0–5% ethanol (EtOH) in dichloromethane on silica Novapak™ column), gave the sub-titled compound (0.14 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][C@@H:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]3=[O:22])=[CH:12][CH:11]=2)[CH2:5]1.C(N(CC)CC)C.[Cl:30][C:31]1[S:35][C:34]([C:36](Cl)=[O:37])=[CH:33][CH:32]=1>C(#N)C>[Cl:30][C:31]1[S:35][C:34]([C:36]([NH:2][CH2:3][C@@H:4]2[O:8][C:7](=[O:9])[N:6]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][C:17]4=[O:22])=[CH:12][CH:11]=3)[CH2:5]2)=[O:37])=[CH:33][CH:32]=1
Reactant: NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Reactant: O=C(Cl)c1ccc(Cl)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.5 %

Procedure:
Under an atmosphere of nitrogen to a suspension of 0.164 g of 4-((S)-5-aminomethyl-2-oxo-oxazolidin-3-yl)-phenyl-morpholin-3-one hydrochloride (MW=327.77; 1 eq.) in 7 mL of acetonitrile were added 0.101 g of triethylamine (MW=101.12; 2.0 eq.). After stirring for 10 min at room temperature, the suspension was cooled to 0° C. and then 0.091 g of 5-chloro-thiophene-2-carbonyl chloride (MW=181.04; 1.0 eq.) were added. After stirring for 80 min at 0° C., the resulting slurry was filtered and the cake washed with 5 mL of acetonitrile and 5 mL of water. After drying in vacuo at 30° C., 0.180 g of the title compound in the form of a white crystalline powder was isolated. Yield=82.7%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[NH:32][C:31]4[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].Br[CH2:45][C:46]1[S:47][CH:48]=[CH:49][CH:50]=1>>[CH3:43][O:42][C:38]1[CH:37]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:39]=1[O:40][CH3:41])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[N:29]([CH2:45][C:46]4[S:47][CH:48]=[CH:49][CH:50]=4)[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[N:32]=3)[CH2:23][CH2:22]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: BrCc1cccs1
Reactant: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Product: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5n4Cc4cccs4)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 35.1 using 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (RrR)-di-p-anisoyltartaric acid salt) and 2-(bromomethyl)thiophene (J. Am. Chem. Soc., 71 1201-1204 (1949)) to give the title compound.
Reaction SMILES: Cl.[NH2:2][OH:3].O.[OH-].[Na+].[CH2:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16](=O)[CH3:17])[CH:13]=[CH:12][N:11]=1)[CH3:8]>CO>[CH2:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16](=[N:2][OH:3])[CH3:17])[CH:13]=[CH:12][N:11]=1)[CH3:8]
Reactant: CCNc1cc(C(C)=O)ccn1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCNc1cc(C(C)=NO)ccn1
Yield: 87 %

Procedure:
To a mixture of 7 g. (0.1 mole) of hydroxylamine hydrochloride in 40 ml. of water and 50 ml. of 2 N sodium hydroxide was added 11.5 g. (70 mmoles) of 1-(2-ethylamino-4-pyridyl)-1-ethanone, and the resulting mixture heated to boiling. Methanol was carefully added until the mixture became homogeneous. Heating was continued until the mixture became cloudy. The mixture was cooled and the resulting precipitate filtered, washed with water and dried. Recrystallization from toluene gave 10.9 g. (87%) of the desired product, m.p. 155°-156° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[H-].[Na+].[CH3:15]I>CN(C)C=O>[CH3:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
To a solution of 5-hydroxy-2-nitrobenzaldehyde (300 mg, 1.80 mmol) in 3.6 mL of dry N,N-dimethylformamide was added sodium hydride (94 mg, 55%, 2.1 mmol) under nitrogen at 0° C. After the solution was stirred at room temperature for 30 min, methyl iodide (0.17 mL, 2.7 mmol) was added with additional stirring for 30 min. The reaction mixture was quenched with saturated NH4Cl aqueous solution at 0° C., and the mixture was extracted with diethyl ether. The extract was washed with saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20 to 70/30) to obtain the title compound as a pale yellow powder (298 mg, 91%).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])[C:20]([O:22][CH3:23])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.N1C(C)=CC=CC=1C.[Br:59][C:60]1[N:61]([C:70]2[C:79]3[C:74](=[CH:75][CH:76]=[CH:77][CH:78]=3)[C:73]([CH:80]3[CH2:82][CH2:81]3)=[CH:72][CH:71]=2)[C:62]([S:65][CH2:66][C:67](O)=[O:68])=[N:63][N:64]=1>ClCCl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:67](=[O:68])[CH2:66][S:65][C:62]3[N:61]([C:70]4[C:79]5[C:74](=[CH:75][CH:76]=[CH:77][CH:78]=5)[C:73]([CH:80]5[CH2:82][CH2:81]5)=[CH:72][CH:71]=4)[C:60]([Br:59])=[N:64][N:63]=3)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C(CCCCN)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)C(CCCCNC(=O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-6-aminohexanoate (N-α-Fmoc-Lysine (NH2)—OMe, 1.48 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.86 mmol), 1-hydroxy-7-azabenzotriazole (1.86 mmol) and 2,6-lutidine (0.43 mL. 3.71 mmol) are added to a solution of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid (0.5 g, 1.24 mmol) in dichloromethane (6.18 mL). The mixture is stirred at room temperature for 18 hours and then is purified by SGC (0-100% EtOAc/Hexanes).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>CN(C=O)C.O>[Si:14]([O:3][C@@H:2]([CH3:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CCOC(=O)[C@H](C)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](C)O[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of (S)-ethyl lactate (11.8 g, 100 mmol) in DMF (50 mL) was added imidazole (10.2 g, 150 mmol). The mixture was cooled in an ice bath and tert-butyldimethylsilyl chloride (15.8 g, 105 mmol) was added in three portions, at intervals of 30 min between each addition. The reaction mixture was stirred overnight. The reaction mixture was diluted with water (30 mL) and extracted with Et2O (50 mL×2). The combined extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was distilled under vacuum (bp 70-78° C., 0.5 mmHg) to afford 22.07 g (95%) of (S)-ethyl 2-(tert-butyldimethylsilyloxy)propanoate: 1H NMR (400 MHz, CHLOROFORM-d) δ 4.32 (q, J=6.6 Hz, 1H), 4.11-4.25 (m, 2H), 1.40 (d, J=6.6 Hz, 3H), 1.29 (t, J=7.1 Hz, 3H), 0.93 (s, 9H), 0.12 (s, 3H), 0.09 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:68])[C@H:10]([CH2:62][CH:63]1[CH2:67][CH2:66][CH2:65][CH2:64]1)[NH:11]C(=O)[C@H](C(C)(C)C)NC(=O)[C@H](CC1C=CC=CC=1C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>N1CCCCC1.ClCCl>[CH2:1]([O:8][C:9](=[O:68])[C@H:10]([CH2:62][CH:63]1[CH2:64][CH2:65][CH2:66][CH2:67]1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@H](C(=O)N[C@@H](CC1CCCC1)C(=O)OCc1ccccc1)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCNCC1
Solvent: ClCCl
Product: N[C@@H](CC1CCCC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 520 mg (0.56 mmol) of N-[N-[N-[O-tert-butyl-N-[(9-fluorenyl)methoxycarbonyl]-L-a-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-3-cyclopentyl-L-alanine benzyl ester in 3 ml of piperidine and 12 ml of dichloromethane was stirred at room temperature for 30 minutes. The solvent was removed by evaporation and the residue was chromatographed on silica gel using firstly ethyl acetate/petrol (1:1) and then methanol/dichloromethane (1:9) for the elution. The resulting amine was added to a solution of 207 mg (0.504 mmol) of N-(9-fluorenyl-methoxycarbonyl)-O-tert-butyl-L-α-aspartic acid, 78 mg (0.51 mmol) of 1-hydroxybenzotriazole and 134 mg (0.7 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 10 ml of dichloromethane and stirred at room temperature for 18 hours. The solution was then extracted with 2M hydrochloric acid and saturated sodium bicarbonate solution and dried over anhydrous magnesium sulphate. Evaporation, trituration with diethyl ether and filtration gave 440 mg of N-[N-[N-[N-O-tert-butyl-N-[(9-fluorenyl)methoxycarbonyl]-L-a-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-3-cyclopentyl-L-alanine benzyl ester as a white solid; MS: m/e 1101 [M+H].
Reaction SMILES: [CH2:1](OC(=O)C(OC1C=C(C(F)(F)F)C=C(N)C=1)(C)C)C.[CH2:21]([O:23][C:24](=[O:47])[C:25]([O:28][C:29]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:30]=1)([CH3:27])[CH3:26])[CH3:22].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(=O)([O-])O.[Na+]>O1CCOCC1.O>[CH2:21]([O:23][C:24](=[O:47])[C:25]([O:28][C:29]1[CH:34]=[C:33]([C:35]([F:37])([F:38])[F:36])[CH:32]=[C:31]([N:39]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH3:1])[CH:30]=1)([CH3:27])[CH3:26])[CH3:22]
Reactant: CCOC(=O)C(C)(C)Oc1cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c1
Reactant: CCOC(=O)C(C)(C)Oc1cc(N)cc(C(F)(F)F)c1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1cc(N(C)C(=O)OC(C)(C)C)cc(C(F)(F)F)c1

Procedure:
In analogy to the procedures described in example 5D], 5E] and 5F], 2-(3-amino-5-trifluoromethyl-phenoxy)-2-methyl-propionic acid ethyl ester was converted into 2-(3-tert-butoxycarbonylamino-5-trifluoromethyl-phenoxy)-2-methyl-propionic acid ethyl ester by treatment with di-tert-butyl dicarbonate and sodium hydrogen carbonate in dioxane/water at r.t., methylated at nitrogen to yield 2-[3-(tert-butoxycarbonyl-methyl-amino)-5-trifluoromethyl-phenoxy]-2-methyl-propionic acid ethyl ester and deprotected again to yield the title compound as light yellow oil.
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[OH-].[Na+].[NH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C@@H:26]2[CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([CH3:38])[C:33]=3[O:36][CH3:37])[C@H:28]([CH2:39][NH:40][CH:41]=[O:42])[O:27]2)[CH2:22][CH2:21]1.[F:43][C:44]1[CH:52]=[CH:51][C:47]([C:48](Cl)=[O:49])=[CH:46][CH:45]=1.C(O)C(N)(CO)CO>C(Cl)(Cl)Cl.ClCCl>[F:43][C:44]1[CH:52]=[CH:51][C:47]([C:48]([NH:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([C@@H:26]3[CH2:35][C:34]4[C:29](=[CH:30][CH:31]=[C:32]([CH3:38])[C:33]=4[O:36][CH3:37])[C@H:28]([CH2:39][NH:40][CH:41]=[O:42])[O:27]3)[CH2:22][CH2:21]2)=[O:49])=[CH:46][CH:45]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1c(C)ccc2c1C[C@@H](C1CCN(CCN)CC1)O[C@H]2CNC=O
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1c(C)ccc2c1C[C@@H](C1CCN(CCNC(=O)c3ccc(F)cc3)CC1)O[C@H]2CNC=O
Reaction time: 6 h

Procedure:
(1R,3S)-N-{3-[1-(2-Amino-ethyl)-piperidin-4-yl]-5-methoxy-6-methyl-isochroman-1-ylmethyl}formamide was obtained by distributing the dihydrochloride between aqueous sodium hydroxide and dichloromethane and then evaporating the organic phase. To a mixture of IRA-67 (1.2 g) and (1R,3S)-N-{3-[1-(2-amino-ethyl)-piperidin-4-yl]-5-methoxy-6-methyl-isochroman-1-ylmethyl}formamide (0.3 g, 0.69 mmole) add chloroform (12 mL) and 4-fluorobenzoyl chloride (0.310 g, 1.95 mmole) in chloroform (2 mL). After 24 hours add additional 4-fluorobenzoyl chloride (0.3 g, 1.89 mmole) and IRA-67 (2 g). After an additional 18 hours add PS-trisamine (1.0 g of 3.75 mmole/g) and stir for 6 hours. Filter and concentrate, then flush the product over a 35 g silica gel cartridge (eluting with ammonium hydroxide:methanol:ethyl acetate 1:4:95). Collect the appropriate fraction and concentrate to obtain the title compound. CIMS 484, tR (min)=0.46.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=2)=[O:4].[C:23](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[C:12]([C:13]=1[O:14][CH3:23])=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2cc(OC)ccc2n1-c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)c1c(OC)c2cc(OC)ccc2n1-c1ccccc1

Procedure:
A mixture of 10.8 g (0.036 mole) of 3-hydroxy-5-methoxy-1-phenyl-1H-indole-2-carboxylic acid methyl ester [P. C. Unangst and M. E. Carethers, J. Heterocyclic Chem., 21, 709 (1984)] and 5.5 g (0.040 mole) of anhydrous potassium carbonate in 100 ml of acetone was treated with 3.7 ml (4.9 g; 0.039 mole) of dimethyl sulfate. The mixture was stirred and heated at reflux for 16 hours, cooled, and filtered. The filter cake was washed several times with fresh acetone, and the combined filtrates were evaporated (vacuum) to yield a crude residue of 3,5-dimethoxy-1-phenyl-1H-indole-2-carboxylic acid methyl ester.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[N:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.Br[C:32]1[S:36][C:35]([CH:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[N:34][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>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(Cl)Cl.COCCOC>[CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[N:10][C:11]([C:32]4[S:36][C:35]([CH:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)=[N:34][CH:33]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C[C@@H](Oc1nc(B2OC(C)(C)C(C)(C)O2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: Brc1cnc(C2CCOCC2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: C[C@@H](Oc1nc(-c2cnc(C3CCOCC3)s2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 100 °C
Yield: 10.1 %

Procedure:
To a microwave tube equipped with a stirring bar, (R)-4-((R)-1-((3-cyclopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one: (182.8 mg, 0.443 mmol), 5-bromo-2-(tetrahydro-2H-pyran-4-yl)thiazole (50 mg, 0.201 mmol), 1,2-dimethoxyethane (2 mL), 1 N Na2CO3 aqueous solution (0.60 mL, 0.60 mmol) were added, the mixture was bubbled N2 for 5 minutes before Pd(PPh3)4 (11.6 mg, 0.01 mmol) was added. The tube was sealed and heated in an oil bath at 100° C. for 2 hrs. DCM (200 mL) was added and the resulting mixture was washed with saturated NaHCO3 aqueous solution (20 mL×4), brine (20 mL×1), dried over anhydrous Na2SO4, filtered, removed solvents in vacuo. The resulting residue was passed a ISCO silica gel column (MeOH:DCM=5:95) to give light yellow solids, 9.2 mg (yield 10.1%). 1H NMR (300 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.28 (s, 1H), 7.79 (s, 1H), 7.57 (broad s, 1H), 5.49-5.35 (m, 1H), 3.94 (dm, J=11.5 Hz, 2H), 3.73-3.63 (m, 1H), 3.52-3.43 (m, 2H), 3.43-3.36 (m, 1H), 3.27-3.15 (m, 2H), 2.92-2.76 (m, 1H), 2.37-2.28 (m, 2H), 2.05-1.92 (m, 2H), 1.85-1.65 (m, 2H), 1.40 (d, J=6.2 Hz, 3H), 1.17-1.09 (m, 2H), 1.10-0.98 (m, 2H) ppm; MS (ESI+) m/z 454.65 (M+H).
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:15][C@H:14]([O:16][Si](C(C)(C)C)(C)C)[CH2:13][CH2:12][C@@H:11]1[C:24]1[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([O:9][C@H:10]1[CH2:15][C@H:14]([OH:16])[CH2:13][CH2:12][C@@H:11]1[C:24]1[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1nccc1[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1OC(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cn1nccc1[C@H]1CC[C@@H](O)C[C@@H]1OC(=O)c1ccccc1
Yield: 96.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 120c by using the (1S*,2R*,5R*)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl benzoate (739 mg, 1.78 mmol) prepared in Example 163a, tetrabutyl ammonium fluoride (1.0 M solution in THF; 5.34 mL, 5.34 mmol) and THF (5.0 mL), to yield the title compound (517 mg, 97%) as a colorless solid.