Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]3[N:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:11][C:10]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:5][CH:4]=1.[NH:27]1[CH2:32][CH2:31][CH:30]([N:33]2[C:37]3=[N:38][CH:39]=[N:40][C:41]([NH2:42])=[C:36]3[CH:35]=[N:34]2)[CH2:29][CH2:28]1.CCN(C(C)C)C(C)C.CO>C1COCC1>[C:21]1([C:10]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:2][N:27]4[CH2:32][CH2:31][CH:30]([N:33]5[C:37]6=[N:38][CH:39]=[N:40][C:41]([NH2:42])=[C:36]6[CH:35]=[N:34]5)[CH2:29][CH2:28]4)=[CH:8][CH:7]=3)=[N:14][CH:13]=[C:12]([C:15]3[N:16]=[CH:17][CH:18]=[CH:19][N:20]=3)[CH:11]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccc(-c2ncc(-c3ncccn3)cc2-c2ccccc2)cc1
Reactant: Nc1ncnc2c1cnn2C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ncnc2c1cnn2C1CCN(Cc2ccc(-c3ncc(-c4ncccn4)cc3-c3ccccc3)cc2)CC1

Procedure:
A mixture of crude 2-{6-[4-(bromomethyl)phenyl]-5-phenylpyridin-3-yl}pyrimidine (0.050 g, 0.124 mmol), 1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.030 g, 0.137 mmol), and DIEA (0.065 mL, 0.373 mmol) in 1:1 MeOH:THF (1 mL) was stirred for 1 hr. Reaction concentrated and the residue was purified by reverse phase HPLC (5% CH3CN: 95% H2O: 0.01% TFA to 95% CH3CN: 5% H2O: 0.01% TFA) to give the title compound. 1H-NMR (500 MHz, d6 DMSO) δ 9.77 (bs, 1H), 9.60 (d, 1H, J=2.0 Hz), 9.00 (d, 2H, J=4.9 Hz), 8.70 (bs, 1H), 8.68 (d, 2H, J=2.0 Hz), 8.45 (bs, 1H), 8.37 (s, 1H), 8.30 (s, 1H), 7.58 (t, 1H, J=4.9 Hz), 7.54-7.37 (m, 9H), 5.05-4.93 (m, 1H), 4.35 (s, 2H), 3.49 (d, 2H, J=11.23 Hz), 3.37-3.21 (m, 2H), 2.47-2.33 (m, 2H), 2.15 (d, 2H, J=11.7 Hz) HRMS m/z (M+H) Calcd: 540.2619, found: 540.2616.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:6][B:5]([OH:7])[C:4]2[CH:8]=[C:9](/[CH:12]=[CH:13]/[N+:14]([O-])=O)[CH:10]=[CH:11][C:3]1=2.[ClH:18]>CO.[OH-].[OH-].[Pd+2]>[ClH:18].[NH2:14][CH2:13][CH2:12][C:9]1[CH:10]=[CH:11][C:3]2[C:2]([CH3:1])([CH3:17])[O:6][B:5]([OH:7])[C:4]=2[CH:8]=1
Reactant: CC1(C)OB(O)c2cc(/C=C/[N+](=O)[O-])ccc21
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CC1(C)OB(O)c2cc(CCN)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (E)-3,3-dimethyl-6-(2-nitrovinyl)benzo[c][1,2]oxaborol-1(3H)-ol (117 mg, 0.5 mmol) in MeOH (15 mL) at rt was added Pd(OH)2 (20%) dust (48 mg, 0.078 mmol) and HCl (3N, 0.3 mL). The reaction mixture was stirred at rt for 8 h under H2 atmosphere. Methanol was added and the mixture was filtered through Celite. The organic layer was concentrated under reduced pressure to give the crude compound 6-(2-aminoethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride as a light yellow oil. It was used in next step without further purification. MS: m/z=206.1 (M+1, ESI+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[OH:18].[Br:19][CH2:20][CH2:21]Br>C(#N)C>[Br:19][CH2:20][CH2:21][O:18][C:10]1[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:9]=1[O:8][CH3:7]
Reactant: BrCCBr
Reactant: COc1cc([N+](=O)[O-])ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc([N+](=O)[O-])ccc1OCCBr
Yield: 57.2 %

Procedure:
A mixture of potassium carbonate (27.6 g, 0.2 mol), 2-methoxy-4-nitrophenol (16.9 g, 0.1 mol), 1,2-dibromoethane (94 g, 0.50 mol) and acetonitrile was refluxed for 2 days, concentrated, extracted in ethyl acetate with water three times, dried, filtered, concentrated to a white powder, triturated with ether, filtered, then concentrated to give a pale yellow powder (15.8 g, 58%). 1H NMR (300 MHz, DMSO-d6) δ 7.90 (d, 1H), 7.80 (s, 1H), 7.20 (d, 1H), 4.55 (t, 2H), 3.80 (s, 3H), 3.75 (t, 2H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:15][O:16][CH:17]([O:22]C)[C:18](OC)=O>N>[CH3:15][O:16][C:17]([CH:18]1[NH:1][C:2]2[N:3]=[CH:4][CH:5]=[CH:6][C:7]=2[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2)=[O:22]
Reactant: COC(=O)C(OC)OC
Reactant: Nc1ncccc1Cc1ccccc1
Agent: N
Product: COC(=O)C1Nc2ncccc2Cc2ccccc21
Yield: 337 %

Procedure:
A mixture of 2-amino-3-benzylpyridine (18.3 g, 99.4 mmol; crude) and methyl 2,2-dimethoxyacetate (22 g, 21.6 mmol, 1.9 eq.) in a 250 ml round-bottomed flask was treated at room temperature with concentrated, sulphuric acid (50 ml) by quick addition while stirring. A vigorous exothermic reaction took place. After stirring for 30 minutes the dark mixture was poured on ice water (1000 ml). Concentrated ammonia (25% aq.; 250 ml) was added to basify the mixture. Extraction with dichloromethane (2×150 ml). The combined organic layers were dried with Na2SO4. Evaporation under vacuum gave 10,11-dihydro-5H-benzo[e]pyrido[2,3-b]azepine-10-carboxylic acid methyl ester as a yellow foam (18.5 g, 72.8 mmol) in 73% yield. An analytically pure sample can be obtained by chromatography on silica gel. Rf=0.3 (EtOAc/n-heptane=1:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][CH2:11]Cl)[CH:3]=1.[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:9][CH2:10][CH2:11][N:27]1[CH2:28][CH2:29][CH:24]([C:20]2[CH:19]=[C:18]([NH:17][C:15](=[O:16])[CH:14]([CH3:13])[CH3:30])[CH:23]=[CH:22][CH:21]=2)[CH2:25][CH2:26]1
Reactant: ClCCCOc1cccc(Cl)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCOc3cccc(Cl)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-chloro-3-(3-chloropropoxy)benzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 415.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].Cl[C:9]1[N:14]=[C:13]([F:15])[C:12]2[O:16][C:17]3[C:22]([C:23]4([C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:25]([NH2:32])=[N:24]4)[C:11]=2[CH:10]=1)=[CH:21][C:20]([C:33]1[C:34]([F:39])=[N:35][CH:36]=[CH:37][CH:38]=1)=[CH:19][CH:18]=3.[F:40][C:41]1[CH:46]=[C:45](B(O)O)[CH:44]=[CH:43][N:42]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:15][C:13]1[C:12]2[O:16][C:17]3[C:22]([C:23]4([C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:25]([NH2:32])=[N:24]4)[C:11]=2[CH:10]=[C:9]([C:45]2[CH:44]=[CH:43][N:42]=[C:41]([F:40])[CH:46]=2)[N:14]=1)=[CH:21][C:20]([C:33]1[C:34]([F:39])=[N:35][CH:36]=[CH:37][CH:38]=1)=[CH:19][CH:18]=3
Reactant: NC1=NC2(c3cc(-c4cccnc4F)ccc3Oc3c2cc(Cl)nc3F)c2ccccc21
Reactant: OB(O)c1ccnc(F)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: NC1=NC2(c3cc(-c4cccnc4F)ccc3Oc3c2cc(-c2ccnc(F)c2)nc3F)c2ccccc21
Temperature: 100 °C
Yield: 48.1 %

Procedure:
A microwave vial was charged with 3-chloro-1-fluoro-7-(2-fluoropyridin-3-yl)spiro[chromeno[2,3-c]pyridine-5,1′-isoindol]-3′-amine 2,2,2-trifluoroacetate (43 mg, 0.077 mmol, step 3), 2-fluoropyridine-4-boronic acid (27.0 mg, 0.192 mmol, Aldrich), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (5.43 mg, 7.67 μmol, Aldrich) and potassium phosphate (48.8 mg, 0.230 mmol, Aldrich). The vial was evacuated and backfilled with N2 gas (2×). Dioxane (0.6 mL) and water (0.2 mL) were added, and the vial was heated in the microwave for 30 min at 100° C. The reaction mixture was partitioned between EtOAc and water. The organic phase was separated and the solvent was removed under reduced pressure. The residue was purified by reversed-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 100% over 20 min to obtain the title product (23 mg, 0.037 mmol, 48.3% yield) as a light-yellow solid. MS m/z=508.1 [M+H]+. Calculated for C29H16F3N5OC2HF3O2: 621.49 (TFA salt). 1H-NMR (300 MHz, MeOH) δ ppm 7.14 (t, J=1.61 Hz, 1H) 7.30-7.39 (m, 1H) 7.39-7.48 (m, 1H) 7.53-7.70 (m, 3H) 7.72-7.86 (m, 4H) 7.92 (ddd, J=9.94, 7.75, 1.90 Hz, 1H) 8.16 (d, J=4.97 Hz, 1H) 8.22 (d, J=5.41 Hz, 1H) 8.26-8.37 (m, 1H).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]1[CH2:13][CH:12]([CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[O:11][N:10]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[N:15]1([CH2:14][CH:12]2[O:11][N:10]=[C:9]([CH2:8][OH:7])[CH2:13]2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: C1CCC(OCC2=NOC(CN3CCOCC3)C2)OC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: OCC1=NOC(CN2CCOCC2)C1
Temperature: 25 °C
Yield: 95 %

Procedure:
A mixture of [5-((morpholin-4-yl)methyl)-4,5-dihydro-isoxazol-3-yl]methyl 2-tetrahydropyranyl ether (0.63 g) with pyridinium p-toluenesulfonate (10 mol %) in methanol was heated under reflux for 24 h. After cooling to room temperature the solvent was removed in vacuo and the residue purified by flash chromatography (SiO2, CH2Cl2/MeOH/NH4OH 92/7.5/0.5) to afford [5-((morpholin-4-yl)methyl)-4,5-dihydro-isoxazol-3-yl]methanol (95%). Rf 0.17 (CH2Cl2/MeOH/NH4OH 92/7.5/0.5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1Cl.[CH3:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:16]1[CH:17]=[C:13]([CH3:12])[N:14]=[CH:15]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: Cc1c[nH]cn1
Solvent: CCOC(C)=O
Product: Cc1cn(-c2ccc([N+](=O)[O-])cc2Cl)cn1

Procedure:
The title compound was prepared from 3,4-dichloronitrobenzene and 4-methylimidazole using in analogous manner the procedure described in example 4a). Chromatography on silica gel using ethyl acetate as eluent gave the title compound as a slightly greenish solid in 64% yield. MS ISP (m/e): 238.0/240.2 (100/40) [(M+H)+].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:27]([NH:13][CH2:14][CH2:15][N:11]([CH3:12])[CH3:8])=[O:26])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Solvent: C1COCCO1
Product: CN(C)CCNC(=O)Nc1cc(CN2C(=O)N(c3ccc(C(C)(C)C)cc3)C(=O)C2(C)C)ccn1
Yield: 127.2 %

Procedure:
A solution of 100 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9 in 2 mL of dioxane and 35 μl of N,N-dimethyl-1,3-ethylenediamine is heated by microwave at 130° C. for 15 minutes. The reaction mixture is concentrated under reduced pressure and the residue is purified by chromatography on a column of silica, eluting with a gradient (100/0 to 75/25 by volume) of dichloromethane and methanol/aqueous ammonia (6/1 by volume) to give 72 mg of 1-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)-3-[2-(dimethylamino)ethyl]urea, the characteristics of which are as follows:
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:8]=[C:7]([O:17][CH3:18])[C:6]=12.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21].C(N(CC)CC)C.[Al]>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.[Cu]I.CN(C=O)C>[CH3:18][O:17][C:7]1[C:6]2[N:5]([N:4]=[CH:3][C:2]=2[C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[CH:8]=1
Reactant: COc1cc(-c2cnn(C)c2)cn2ncc(I)c12
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Al]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(-c2cnn(C)c2)cn2ncc(C#C[Si](C)(C)C)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-iodo-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (860. mg, 2.43 mmol), tetrakis(triphenylphosphine)palladium(0) (281 mg, 0.243 mmol), trimethylsilylacetylene (1.01 ml, 7.29 mmol) and copper (I) iodide (277 mg, 1.46 mmol) were combined in a round bottom flask. DMF (25 mL) and triethylamine (0.677 mL, 4.86 mmol) were added, then the flask was wrapped with aluminum foil and sparged with nitrogen for 5 minutes. The reaction was stirred at ambient temperature for 30 mins, then diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was separated and the aqueous layer was back extracted two times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The liquid was purified by column chromatography on silica gel (methanol/ethyl acetate gradient) to give 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)-3-[(trimethylsilyl)ethynyl]pyrazolo[1,5-a]pyridine LRMS (ESI) calculated for C17H21N4OSi [M+H]+, 325.1; found 325.1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][OH:20])=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=2)=[CH:7][C:6]=1[C:25]([F:28])([F:27])[F:26].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH3:29][S:30]([O:20][CH2:19][CH2:18][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][O:1][S:30]([CH3:29])(=[O:32])=[O:31])=[C:6]([C:25]([F:26])([F:27])[F:28])[CH:7]=2)=[CH:12][C:13]=1[C:21]([F:22])([F:23])[F:24])(=[O:32])=[O:31]
Reactant: OCCCc1ccc(-c2ccc(CCCO)c(C(F)(F)F)c2)cc1C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCCCc1ccc(-c2ccc(CCCOS(C)(=O)=O)c(C(F)(F)F)c2)cc1C(F)(F)F
Reaction time: 8 h

Procedure:
To a solution of 3-[4′-(3-hydroxy-propyl)-3,3′-bis-trifluoromethyl-biphenyl-4-yl]-propan-1-ol (intermediate 6) (5.4 g, 13.3 mmol) in dichloromethane (40 mL) triethylamine (2.5 g, 24.7 mmol) and methanesulfonyl chloride (2.7g, 23.6 mmol) were added dropwise. The mixture was stirred overnight, diluted with dichloromethane (50 mL) and washed with water (2×15 mL). Evaporation of the organic solution gave 3,3′-bistrifluoromethyl-4,4′-biphenyl-dipropanol bismethanesulfonate.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20](=[O:49])[C:21]3[CH:47]=[C:46]([OH:48])[CH:45]=[C:23]([C:24]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]4[CH:43]=[C:42]5[C:37]([CH:38]=[CH:39][C:40](=[O:44])[O:41]5)=[CH:36][CH:35]=4)=[O:25])[CH:22]=3)=[CH:7][CH:8]=2)[O:3]1.[Cl:50][CH2:51][CH2:52][CH2:53][CH2:54]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>C1(C)C=CC=CC=1>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20](=[O:49])[C:21]3[CH:47]=[C:46]([O:48][CH2:54][CH2:53][CH2:52][CH2:51][Cl:50])[CH:45]=[C:23]([C:24]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]4[CH:43]=[C:42]5[C:37]([CH:38]=[CH:39][C:40](=[O:44])[O:41]5)=[CH:36][CH:35]=4)=[O:25])[CH:22]=3)=[CH:7][CH:8]=2)[O:3]1
Reactant: OCCCCCl
Reactant: O=C(OCCCCCCOc1ccc2ccc(=O)oc2c1)c1cc(O)cc(C(=O)OCCCCCCOc2ccc3ccc(=O)oc3c2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(OCCCCCCOc1ccc2ccc(=O)oc2c1)c1cc(OCCCCCl)cc(C(=O)OCCCCCCOc2ccc3ccc(=O)oc3c2)c1

Procedure:
Preparation can be carried out analogously to Synthetic Example 1 using 6.71 g (10.0 mmol) bis{6-[(2-oxo-2H-chromen-7-yl)oxy]hexyl}5-hydroxyisophthalate, 1.14 g (10.5 mmol) 4-chloro-1-butanol, 2.88 g (11.0 mmol) triphenylphosphine and 4.79 g (11.0 mmol) of a 40% solution of azodicarboxylic acid diethyl ester in toluene to yield bis{6-[(2-oxo-2H-chromen-7-yl)oxy]hexyl}5-(4-chlorobutoxy)isophthalate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1C1(C=CC=CC1)CO.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl>>[Cl:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[NH:1][C:27](=[O:33])[O:26][CH:24]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:3]=3[CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(-c2cccc(Cl)c2)cc1C1(CO)C=CC=CC1
Product: O=C1Nc2ccc(-c3cccc(Cl)c3)cc2C(c2ccccc2)O1

Procedure:
Prepared from 1-(4-amino-3′-chloro-biphenyl-3-yl)-benzyl alcohol and triphosgene according to the procedure of Example 9. Off-white solid: mp 177-178° C.; 1H-NMR (DMSO-d6) δ10.5 (s, 1H), 7.68 (dd, 1H, J=8.7, 1.7 Hz), 7.62 (t, 1H, J=1.74 Hz), 7.54-7.5 (m, 1H), 7.48-7.34 (m, 8H), 7.04 (d, 1H, J=8.7 Hz), 6.6 (s, 1H); MS (ESI) m/z 336 ([M+H]+, 30%)
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][O:7][C:8](=[O:35])[CH2:9][CH:10]([NH:20][C:21]([C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=O)[C:11]([C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)=O>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[N:5]=[C:21]([C@@H:23]3[CH2:27][CH2:26][CH2:25][N:24]3[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[NH:20][C:10]=2[CH2:9][C:8]([O:7][CH3:6])=[O:35])=[CH:14][CH:15]=1
Reactant: [NH4+]
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)c1ccc(Br)cc1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: COC(=O)Cc1[nH]c([C@@H]2CCCN2C(=O)OC(C)(C)C)nc1-c1ccc(Br)cc1
Temperature: 140 °C
Reaction time: 4 h
Yield: 46.4 %

Procedure:
Ammonium acetate (9.4 g, 157 mmol) was added to a solution of Example J7, (2S)-tert-butyl 2-(4-(methoxy)-1-(4-bromophenyl)-1,4-dioxobutan-2-ylcarbamoyl)pyrrolidine-1-carboxylate (7.6 g, 15.7 mmol) in xylene (80 mL) and stirred for 4 hours at 140° C. in a screw capped 150 mL pressure vessel. After being cooled, the reaction mixture was diluted with ethyl acetate and washed with sat NaHCO3 and brine before being concentrated by rotory evaporation under high vacuum. The crude product was taken up in CH2Cl2 and charged to a 40 (M) Biotage silica gel cartridge. Gradient elution 15-100% B over 2 L (A=CH2Cl2; B=ethyl acetate) gave Example J8, (S)-tert-butyl 2-(4-(4-bromophenyl)-5-(2-methoxy-2-oxoethyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate 3.38 g (46%). 1H NMR (500 MHz, DMSO-d6) δ 7.54 (s, 4H), 4.83-4.73 (m, 1H), 3.81 (br. s, 1H), 3.62 (s, 3H), 3.53-3.51 (m, 1H), 3.38-3.31 (m, 2H), 2.25-2.15 (m, 1H), 1.99-1.83 (m, 3H), 1.41/1.16 (s, 9H). RT=1.6 minutes (Condition 1). LCMS: Anal. Calcd. for C21H26BrN3O4 464.11. found: 464.40 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH:28]4[CH2:30][CH2:29]4)[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][C@H:19]4[C@@H:18]([N:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36])[CH2:17][CH2:16][C@@:15]35[OH:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.C1COCC1.[C:51](Cl)(=[O:58])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.C(=O)([O-])O.[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH:28]4[CH2:29][CH2:30]4)[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][C@H:19]4[C@@H:18]([N:31]1[CH2:35][CH2:34][CH:33]([C:51](=[O:58])[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:32]1=[O:36])[CH2:17][CH2:16][C@@:15]35[OH:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1CCCN1[C@H]1CC[C@@]2(O)[C@H]3Cc4ccc(OCc5ccccc5)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1)C1CCN([C@H]2CC[C@@]3(O)[C@H]4Cc5ccc(OCc6ccccc6)c6c5[C@@]3(CCN4CC3CC3)[C@H]2O6)C1=O
Reaction time: 1 h

Procedure:
In 10 mL of THF, 482 mg (0.96 mmol) of 1-(3-benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6α-yl)-pyrrolidin-2-one obtained in Example 36-1 was dissolved, and 6.9 mL (2.89 mmol) of 0.42 N LDA/THF solution was added thereto at −78° C., followed by stirring the mixture for 1 hour. Thereafter, 0.22 mL (1.92 mmol) of benzoyl chloride was added and the mixture was stirred for 2 hours. Aqueous saturated sodium hydrogen carbonate solution was then added to the reaction mixture, and the resulting mixture was extracted with chloroform. Organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated to obtain 1-(3-benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6α-yl)-3-benzoyl-pyrrolidin-2-one as a crude product.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[S:3]([O:6][C:7]1[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:9]2[C:14](=[CH:15][C:16]=1Cl)[N:13]=[C:12](C)[CH:11]=[CH:10]2)(=[O:5])=[O:4].Cl[C:29]1C=CC(C2C(O)=C(C)C=C3C=2C=CC=N3)=CC=1>>[F:27][C:2]([F:1])([F:26])[S:3]([O:6][C:7]1[C:8]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[C:9]2[C:14](=[CH:15][C:16]=1[CH3:29])[N:13]=[CH:12][CH:11]=[CH:10]2)(=[O:4])=[O:5]
Reactant: Cc1cc2ncccc2c(-c2ccc(Cl)cc2)c1O
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c(OS(=O)(=O)C(F)(F)F)c(Cl)cc2n1
Product: Cc1cc2ncccc2c(-c2ccc(Cl)cc2)c1OS(=O)(=O)C(F)(F)F

Procedure:
Compound 3F was prepared following the procedure used to prepare compound 1F of Example 1, except that 5-(4-chloro-phenyl)-7-methylquinolin-6-ol (3E) was used instead of compound 1E. LCMS-ESI+ (m/z): 402.0, 404.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[OH:17][C:18]1[CH:19]=[C:20]([CH:27]=[CH:28][CH:29]=1)[CH2:21][CH:22]([C:24]([OH:26])=[O:25])[NH2:23]>>[C:24]([CH:22]([NH:23][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:20]1[CH:27]=[CH:28][CH:29]=[C:18]([OH:17])[CH:19]=1)([OH:26])=[O:25]
Reactant: NC(Cc1cccc(O)c1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1Cl
Product: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1NC(Cc1cccc(O)c1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6,8-trichloroquinoline-3-carboxylic acid is reacted with 3-hydroxy-DL-phenylalanine to provide the title compound in moderate yield. LCMS m/z 421 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[NH:20][C:21]([C@H:23]2[CH2:28][CH2:27][C@H:26]([N:29]([CH3:41])[CH2:30][CH2:31][CH2:32][NH:33]C(=O)OC(C)(C)C)[CH2:25][CH2:24]2)=[O:22])=[O:10])=[N:6][CH:7]=1.Cl.O1CCOCC1>O1CCOCC1>[NH2:33][CH2:32][CH2:31][CH2:30][N:29]([CH3:41])[C@H:26]1[CH2:25][CH2:24][C@H:23]([C:21]([NH:20][C:12]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:18]3[O:19][C:11]=2[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:10])=[O:22])[CH2:28][CH2:27]1
Reactant: CN(CCCNC(=O)OC(C)(C)C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3cccnc23)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CN(CCCN)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3cccnc23)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
t-Butyl {3-[(trans-4-{[(2-{[(5-chloropyridin-2-yl)amino]carbonyl}-furo[3,2-b]pyridin-3-yl)amino]carbonyl}cyclohexyl)(methyl)amino]-propyl}carbamate (265 mg) obtained in Example 120 is dissolved in dioxane (3 ml), and thereto is added 4N hydrogen chloride-dioxane solution (6 ml), and the mixture is stirred at room temperature for 20 hours. The reaction solution is concentrated under reduced pressure, and the residue is suspended in diethyl ether. The precipitates are collected by filtration. The resulting solid is suspended in chloroform, and thereto is added saturated aqueous sodium hydrogen carbonate solution, and the organic layer is separated. The organic layer is washed with saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure to give the title compound (206 mg).