Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:29])[CH2:9][NH:10][C@H:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C@@H:18]([C:21]([O:23]CC)=[O:22])[CH2:19][O:20][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.O.Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:29])[CH2:9][NH:10][C@H:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C@@H:18]([C:21]([OH:23])=[O:22])[CH2:19][O:20][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H]1COc2cc(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)ccc2O1
Agent: Cl
Solvent: CCO
Solvent: O
Product: C[C@H](Cc1ccc2c(c1)OC[C@H](C(=O)O)O2)NC[C@H](O)c1cccc(Cl)c1
Yield: 67.9 %

Procedure:
To a solution of ethyl 6-(2-(R)-((2-(R)-(3-chlorophenyl )-2-hydroxyethyl)amino)propyl)-2,3-dihydro-1,4-benzodioxin-2-(R)-carboxylate (650 mg) in ethanol (2 ml) were added water (20 ml) and concentrated hydrochloric acid (0.32 ml). This solution was stirred under reflux-heating for 5 hours while removing ethanol with Dean-Stark apparatus. After the solution was concentrated under reduced pressure, acetonitrile/water (1/1) (11 ml) was added to the residue, which was then dissolved under heating. The solution was neutralized with a 5% aqueous solution of sodium hydrogencarbonate. Acetonitrile (20 ml) was added, and the crystals precipitated were dissolved under heating. The resulting solution was filtered under heating and then cooled, and the resulting crystals were filtered to give 6-(2-(R)-((2-(R)-(3-chlorophenyl)-2-hydroxyethyl)amino )-propyl)-2,3-dihydro-1,4-benzodioxin-2-(R)-carboxylic acid (412 mg). The HPLC-2 analysis of the optical isomer showed 96.5% purity (R/S=96.5/3.5, the purity of the material optical isomer used=90.5%).
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].N1C=CC=CC=1.[N+:11]([C:14]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:15]=1[CH2:16]Cl)([O-:13])=[O:12]>C1COCC1.ClCCl>[C:1]([S:3][CH2:16][C:15]1[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:14]=1[N+:11]([O-:13])=[O:12])(=[O:4])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(CCl)c([N+](=O)[O-])c1
Reactant: CC(O)=S
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)SCc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 80.1 %

Procedure:
Redistilled thioacetic acid (25.73 cm3, 0.36 mol) and then dry pyridine (19.9 cm3, 0.246 mol) were added to a stirred solution of 2,4-dinitrobenzyl chloride (13.0 g, 60.0 mmol) in dry THF (180 cm3) at room temperature. After 2 h, the products were filtered and the filtrate was concentrated under reduced pressure. The residual solid obtained was dissolved in dichloromethane (300 cm3) and the resulting solution was washed in turn with saturated aqueous sodium hydrogen carbonate (300 cm3), 1.0 mol dm-3 sulfuric acid (200 cm3) and saturated aqueous sodium hydrogen carbonate (200 cm3). The dried (MgSO4) organic layer was evaporated under reduced pressure and the residue was crystallized from ethyl acetate--petroleum ether (b.p. 60°-80° C.) to give S-(2,4-dinitrobenzyl) thioacetate 16b as a pale yellow solid (12.32 g, 80%) (Found: C, 42.3; H, 3.1; N, 10.9. C9H8N2O5S requires: C, 42.2; H, 3.15; N, 10.9%), m.p. 78°-79° C.; δH [CDCl3 ] 2.35 (3 H, s), 4.49 (2 H, s), 7.91. (1 H, d, J 8.5), 8.41 (1 H, dd, J 2.4 and 8.5), 8.88 (1 H, d; J 2.3); δC [CDCl3 ] 30.2, 30.7, 120.7, 127.6, 134.2, 140.6, 147.1, 148.0, 194.7.
Reaction SMILES: [K].[C:2]1(=[O:12])[NH:6][C:5](=[O:7])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]12.CN(C)C=O.[Cl:18][C:19]1[C:20]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=[C:21]2[C:29]3[CH2:30][CH2:31][S:32][CH2:33][C:28]=3[S:27][C:22]2=[N:23][C:24]=1[CH2:25]Cl>O>[Cl:18][C:19]1[C:20]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=[C:21]2[C:29]3[CH2:30][CH2:31][S:32][CH2:33][C:28]=3[S:27][C:22]2=[N:23][C:24]=1[CH2:25][N:6]1[C:2](=[O:12])[C:3]2[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5]1=[O:7]
Reactant: COc1ccc(-c2c(Cl)c(CCl)nc3sc4c(c23)CCSC4)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2c(Cl)c(CN3C(=O)c4ccccc4C3=O)nc3sc4c(c23)CCSC4)cc1
Temperature: 62.5 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a mixture of phthalimide potassium (6.2 kg) and dimethylformamide (110.74 L) was added 3-chloro-2-chloromethyl-5,8-dihydro-4-(4-methoxyphenyl)-6H-thiopyrano-[4′,3′:4,5]thieno[2,3-b]pyridine (11.055 kg) obtained in Reference Example 27 and the mixture was stirred at 60 to 65° C. for 1 hour. After cooling to 25° C., water (36.91 L) was added dropwise thereto and the mixture was stirred at the same temperature for 1 hour. The crystals deposited was filtered off and washed with water (29.14 L) to obtain the titled compound (14.057 kg, 99.4%). 1H-NMR (CDCl3) δ: 2.14 (2H, t, J=5.7 Hz), 2.64 (2H, t, J=5.7 Hz), 3.80 (2H, s), 3.89 (3H, s), 5.20 (2H, s), 6.98–7.13 (2H, s), 6.98–7.13 (3H, m), 7.75–7.78 (2H, m), 7.79–7.794 (2H, m).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([NH2:13])[CH:10]=[C:9]([NH2:14])[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O.C([O-])(O)=O.[Na+].CO>O>[N:1]1([C:7]2[N:8]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:14]=[C:9]3[CH:10]=[C:11]([NH2:13])[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Nc1cc(N)nc(N2CCOCC2)n1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1cc2nc(-c3ccccc3)cn2c(N2CCOCC2)n1
Yield: 59.8 %

Procedure:
A mixture of 2-morpholin-4-yl-pyrimidine-4,6-diamine (1.0 g, 5.1 mmol), w-bromoacetophenone (1.02 g, 5.1 mmol), NaHCO3 (473 mg, 6 mmol) and methanol (15 ml) was heated under an atmosphere of argon to reflux (3 h). After cooling, water (10 ml) was added (the gummy precipitate could not be isolated). Methanol was evaporated, the residue was taken up in ethyl acetate, washed (water), and dried (Na2SO4). The solvent was evaporated and the title compound (900 mg, 50%) was isolated from the mixture by column chromatography (silica gel, heptane:ethyl acetate=80:20-60:40). MS (m/e)=296.3 [M+H+].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([NH:24][C:25](=[O:32])[CH2:26][C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)[CH:21]=[CH:22][CH:23]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH3:33][N:34]1[CH2:43][CH2:42][C:41]2[C:36](=[CH:37][C:38]([NH2:44])=[CH:39][CH:40]=2)[CH2:35]1>CC(O)C.Cl>[F:17][C:13]1[C:12]2[N:11]([N:10]=[C:9]([C:18]3[CH:19]=[C:20]([NH:24][C:25](=[O:32])[CH2:26][C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)[CH:21]=[CH:22][CH:23]=3)[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:44][C:38]3[CH:37]=[C:36]4[C:41]([CH2:42][CH2:43][N:34]([CH3:33])[CH2:35]4)=[CH:40][CH:39]=3)[N:7]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cc1cccs1)Nc1cccc(-c2nn3cccc(F)c3c2-c2ccnc(Cl)n2)c1
Reactant: CN1CCc2ccc(N)cc2C1
Agent: Cl
Solvent: CC(C)O
Product: CN1CCc2ccc(Nc3nccc(-c4c(-c5cccc(NC(=O)Cc6cccs6)c5)nn5cccc(F)c45)n3)cc2C1
Yield: 59 %

Procedure:
To the solution of N-{3-[3-(2-chloro-4-pyrimidinyl)-4-fluoropyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(2-thienyl)acetamide (0.080 g) in i-PrOH (5 mL) was added 2-methyl-1,2,3,4-tetrahydro-7-isoquinolinamine (0.041 g) and 2 drops of concentrate hydrochloric acid. The reaction was microwaved in a sealed tube at 180° C. for 10 min. The i-PrOH was removed by rotary evaporation and the residue was treated with sat. NaHCO3 (5 mL), extracted with EtOAc (2×5 mL), and dried (Na2SO4). Concentration and purification with column chromatography afforded the title compound as a white solid (0.060 g, 60% yield). 1H NMR (400 MHz, DMSO-d6) δ 2.25 (s, 3H), 2.63 (s, 2H), 3.17 (s, 2H), 3.84 (s, 2H), 6.80 (s, 1H), 6.89 (dd, 1H, J=4.94, 3.11 Hz), 6.95 (d, 2H, J=3.66 Hz), 6.99-7.05 (m, 1H), 7.08 (d, 1H, J=7.68 Hz), 7.18 (s, 1H), 7.24-7.30 (m, 2H), 7.35-7.37 (m, 1H), 7.58 (d, 1H, J=1.10 Hz), 8.05 (t, 1H, J=1.83 Hz), 8.44 (d, 1H, J=5.12 Hz), 8.72 (d, 1H, J=6.95 Hz), 9.39 (s, 1H), 10.32 (s, 1H). ES-LC/MS m/z=590 [M+H]+.
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[N:13]=[C:14]([C:17]([O:19]CC)=[O:18])[S:15][CH:16]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.O[Li].O>O.C1COCC1>[Br:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[N:13]=[C:14]([C:17]([OH:19])=[O:18])[S:15][CH:16]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1
Reactant: CCOC(=O)c1nc(-c2c[nH]c3ncc(Br)cc23)cs1
Agent: Br
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc(-c2c[nH]c3ncc(Br)cc23)cs1
Reaction time: 3 h
Yield: 82.6 %

Procedure:
To a stirred solution of ethyl 4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)thiazole-2-carboxylate hydrobromide (XXIII-a) (4.03 g, 9.30 mmol) in water:THF 1:1 (50 mL) was added LiOH·H2O (900 mg, 21.45 mmol) portionwise over 30 min. After stirring for 3 h, the reaction mixture was filtered to afford a yellow solid (2.49 g). The filtrate was then concentration to ˜20 mL by evaporation, and filtered again to afford a further 820 mg of yellow solid. The solids were combined to afford (XXIII-b) (3.31g, crude yield >100%). 1H NMR (400 MHz, D-6 DMSO) δ 7.76 (s, 1H), 8.03 (s, 1H), 7.73-7.78 (m, 3H), 8.32 (d, J=2.3 Hz, 1H), 8.74 (d, J=2.3 Hz, 1H), 12.09 (br s, 1H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([CH3:47])([CH3:46])[O:39]C3CCCCO3)=[CH:29][CH:28]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][O:17][Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C>S(=O)(=O)(O)O.C1COCC1.O>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([CH3:47])([OH:39])[CH3:46])=[CH:31][CH:32]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][OH:17]
Reactant: CC(C)(CCCCCc1ccc(C=Cc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)cc1)OC1CCCCO1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)CCCCCc1ccc(C=Cc2ccc(CO)c(CO)c2)cc1

Procedure:
In a manner similar to Example 25(d), by reacting 5 drops of concentrated sulphuric acid with 335 mg (0.49 mmol) of 2-[6-(4-{2-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenyl]vinyl}phenyl)-1,1-dimethylhexyloxy]tetrahydropyran in 5 ml of THF and 5 ml of water, white crystals (m=94 mg; Y=52%) are obtained. m.p. 112-4° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12.[CH:11]1([C:14]([NH2:16])=[O:15])[CH2:13][CH2:12]1>>[NH:8]1[C:7]2=[C:2]([NH:16][C:14]([CH:11]3[CH2:13][CH2:12]3)=[O:15])[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9]1
Reactant: NC(=O)C1CC1
Reactant: Clc1nccc2cc[nH]c12
Product: O=C(Nc1nccc2cc[nH]c12)C1CC1
Yield: 7.59 %

Procedure:
N-(1H-pyrrolo[2,3-c]pyridin-7-yl)cyclopropanecarboxamide (Intermediate 7, yield: 7.59%) was synthesized from 7-chloro-1H-pyrrolo[2,3-c]pyridine using cyclopropanamide.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:4]=1)#[N:2].[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>C1C=CC=CC=1>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([N:21]([CH2:22][CH3:23])[CH2:19][CH3:20])=[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:4]=1)#[N:2]
Reactant: CCNCC
Reactant: N#Cc1nc(Cl)c(Cc2ccccc2)nc1C#N
Solvent: c1ccccc1
Product: CCN(CC)c1nc(C#N)c(C#N)nc1Cc1ccccc1
Yield: 75.5 %

Procedure:
2,3-Dicyano-5-chloro-6-benzylpyrazine (1.27 g; 0.005 mole) was dissolved in 30 ml of benzene, and the solution was cooled to 5° to 10° C. With stirring, the mixture was worked up in the same way as in Example 13 using 0.80 g (0.01 mole) of diethylamine. Recrystallization from ethanol afforded 1.10 g (yield 75%) of 2,3-dicyano-5-diethylamino-6-benzylpyrazine.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]=[C:35]=[O:36]>O1CCCC1>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][C:35](=[O:36])[O:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH2:9][N:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:14]=1
Reactant: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Reactant: COc1ccccc1N=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1NC(=O)Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Temperature: 35 °C

Procedure:
A mixture of 1-benzyl-1,2,3,4-tetrahydroquinolin-7-ol (500 mg, 2.09 mM) and triethylamine in dry tetrahydrofuran (THF, 5 ml) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, 2-methoxyphenyl isocyanate (417 mg/ml, 3.14 mM) was added at once and then the reaction mixture was further stirred for 72 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chloroform-hexane (1:9) to give 8i as solid. Yield: 0.623 g, 76.85%.
Reaction SMILES: [C:1]([C-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1)#[CH:2].[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:13].[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCCC1.N1C=CC=CC=1.C(NC(C)C)(C)C.[Pd].CC([O-])=O.CC([O-])=O.[Pd+2].[Cu]I>[C-:3]1([C:1]#[C:2][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([Br:14])[CH:16]=2)[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:13]
Reactant: C#C[c-]1cccc1
Reactant: Brc1cccc(I)c1
Agent: [Cu]I
Agent: [Fe+2]
Agent: [Pd+2]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: c1ccncc1
Product: Brc1cccc(C#C[c-]2cccc2)c1

Procedure:
1-(Ferrocenylethynyl)-3-bromobenzene 204 was prepared following the general procedure found in General Procedure for the Palladium-Catalyzed Cross-Coupling Reactions using 500 mg (2.38 mmol) of ethynylferrocene 200, 642 mg (2.27 mmol) of 1-bromo-3-iodobenzene 202, 25.5 mg (0.114 mmol) Pd(OAc)2, 89.2 mg (0.341 mmol) of PPh3, and 10.8 mg (0.0568 mmol) of CuI in 25 mL tetrahydrofuran, 5 mL pyridine and 5 mL diisopropylamine at 25° C. The residue was purified using a 5:1 hexane/CH2Cl2 solvent mixture to afford 761 mg (92%) of an orange-red solid, m.p. 130° C. Spectral data for 1-(ferrocenylethynyl)-3-bromobenzene 204: IR (cm−1, KBr): 3094 (C—H), 3057 (C—H), 2218 (CoC), 2204 (C≡C), 1591 (C═C, benzene), 1583 (C═C, benzene), 1552 (C═C, benzene), 1411 (C═C, ferrocene). H NMR (d in CDCl3): 7.63 (t, J=1.7 Hz, 1H), 7.41 (m, 2H), 7.17 (t, J=7.8 Hz, 1H), 4.50 (t, J=1.9 Hz, 2H), 4.25 (t, J=1.9 Hz, 2H), 4.24 (s, 5H). Analysis for 1-(ferrocenylethynyl)-3-bromobenzene 204 (C18H13FeBr) Calcd: C, 59.22%; H, 3.59%. Found: C, 59.15%; H, 3.84%.
Reaction SMILES: [C:1](=[O:61])([O:3][C@@H:4]([C@@H:55]([CH3:60])/[CH:56]=[CH:57]\[CH:58]=[CH2:59])[C@@H:5]([CH3:54])[C@H:6]([O:44]CC1C=CC(OC)=CC=1)[CH2:7][CH2:8]/[CH:9]=[CH:10]\[C@H:11]([CH3:43])[C@H:12]([O:33]CC1C=CC(OC)=CC=1)[C@@H:13]([CH3:32])/[CH:14]=[CH:15]\[CH2:16][CH2:17][C@H:18]1[C@H:23]([CH3:24])[C@H:22]([O:25][CH2:26][O:27][CH3:28])[C@@H:21]([CH3:29])[C@H:20]([O:30][CH3:31])[O:19]1)[NH2:2].C(=O)(O[C@@H]([C@@H](C)/C=C\C=C)[C@@H](C)[C@H](O)CC/C=C\[C@H](C)[C@H](O)[C@@H](C)/C=C\CC[C@H]1[C@@H](C)[C@H](O)[C@@H](C)C(=O)O1)N>CCOC(C)=O.CCCCCC>[C:1](=[O:61])([O:3][C@@H:4]([C@@H:55]([CH3:60])/[CH:56]=[CH:57]\[CH:58]=[CH2:59])[C@@H:5]([CH3:54])[C@H:6]([OH:44])[CH2:7][CH2:8]/[CH:9]=[CH:10]\[C@H:11]([CH3:43])[C@H:12]([OH:33])[C@@H:13]([CH3:32])/[CH:14]=[CH:15]\[CH2:16][CH2:17][C@H:18]1[C@H:23]([CH3:24])[C@H:22]([O:25][CH2:26][O:27][CH3:28])[C@@H:21]([CH3:29])[C@H:20]([O:30][CH3:31])[O:19]1)[NH2:2]
Reactant: C=C/C=C\[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@@H](CC/C=C\[C@H](C)[C@H](OCc1ccc(OC)cc1)[C@@H](C)/C=C\CC[C@@H]1O[C@@H](OC)[C@H](C)[C@@H](OCOC)[C@H]1C)OCc1ccc(OC)cc1
Agent: C=C/C=C\[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O)CC/C=C\[C@H](C)[C@H](O)[C@@H](C)/C=C\CC[C@@H]1OC(=O)[C@H](C)[C@@H](O)[C@@H]1C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=C/C=C\[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O)CC/C=C\[C@H](C)[C@H](O)[C@@H](C)/C=C\CC[C@@H]1O[C@@H](OC)[C@H](C)[C@@H](OCOC)[C@H]1C
Yield: 91.8 %

Procedure:
Carbamate 39 (4.25 mg, 0.005 mmol) was subjected to the deprotection procedure of PMB described in the preparation of 40. Flash chromatography (EtOAc/hexane 3:2) of the crude product provided 42 (2.8 mg, 92%) as a colorless oil: IR (CHCl3) 3115, 2749, 2328, 1676, 1508, 1215 cm−1; 1H NMR (300 MHz, CDCl3) 6.76 (ddd, 1H, J=16.8, 11.0, 10.1 Hz), 6.18 (t, 1H, J=10.8 Hz), 5.70–5.46 (m, 5H), 5.35 (d, 1H, J=16.8 Hz), 4.49 (dd, J=4.5, 6.6 Hz), 4.82 (d, 2H, J=2.4 Hz), 4.73 (br s, 2H), 4.43 (d, 1H, J=5.1 Hz), 4.15, (m, 1H), 3.78 (m, 1H), 3.56 (s, 3H), 3.54 (s, 3H), 3.36 (t, 2H, J=6.9 Hz), 3.14 (m, 1H), 2.76 (m, 2H), 2.35–2.18 (m, 6H), 2.00–1.60 (m, 7H), 1.22 (d, 3H, J=7.2 Hz), 1.16–1.12 (m, 12H), 1.07 (d, 3H, J=7.2 Hz); 13C NMR (125 MHz, CDCl3) 157.3, 133.7, 133.5, 132.2, 132.0, 130.0, 128.7, 118.0, 109.6, 103.0, 96.5, 82.1, 79.7, 79.1, 72.7, 55.8, 39.9, 39.5, 38.3, 35.5, 35.0, 34.8, 34.6, 30.2, 29.8, 24.3, 18.1, 17.7, 15.7, 15.4, 14.2, 13.2, 8.1; LRMS (ESI) 632.4 (M+Na); HRMS (ESI) calcd for C33H55NO8Na 632.4138, found 632.4139; [α]20D +21.6 (c 0.25, CHCl3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Br.C(=O)([O-])[O-].[K+].[K+].O>CC(CC)=O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH2:16][C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)c(F)c1

Procedure:
A mixture of 10.0 g (64 mmol) 2-fluoro-4-nitrophenol, 13.24 g (70 mmol) 3-fluorobenzyl bromide and 17.6 g (127 mmol) potassium carbonate in 200 ml methyl-ethylketone is heated overnight at 80°. Water is added and the product is extracted with ethyl acetate, dried and evaporated. Recrystallisation from diethyl ether/hexane yields 12.68 g (75%) of a slightly yellow solid. MS: m/e=265.1 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:28]([O:30]CC)=[O:29])[O:13][CH2:12][C:11]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.O.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:28]([OH:30])=[O:29])[O:9][CH2:10][C:11]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)([C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[CH2:12][O:13]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(c2ccc(Cl)cc2)OCC(c2ccc(F)cc2)(c2ccc(F)cc2)CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1(c2ccc(Cl)cc2)OCC(c2ccc(F)cc2)(c2ccc(F)cc2)CO1

Procedure:
2.8 g of ethyl 2-(4-chlorophenyl)-5,5-bis(4-fluorophenyl)-[1,3]dioxane-2-carboxylate are refluxed for 7 hours in 60 ml of methanol and 15 ml of water containing 0.7 g of NaOH. After concentrating, the residue is diluted with water and stirred until a solution is obtained. This solution is washed with ether and the aqueous phase is acidified with HCl. The solid formed is filtered off and washed with water and pentane. The product is recrystallized from 100 ml of toluene. (m.p.=228-30° C.; weight obtained 1.9 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH3:29][O:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:29][O:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH:33][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:26])([F:27])[F:28])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: COC(C)(C)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(C)(C)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 56.3 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-methoxy-2-methyl-propyl)-amide (68 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzo-thiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), 2-methoxy-2-methyl-propylamine (58 mg), HBTU (111 mg), and DIEA (64 uL). LC/MS: m/z 494.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.40 (bs, 1H), 8.17 (t, 1H), 8.08 (s, 1H), 7.92 (s, 1H), 7.78 (d, 1H), 7.73 (d, 1H), 7.48 (d, 1H), 7.36 (d, 1H), 3.64 (bs, 3H), 3.36 (d, 2H), 3.18 (s, 3H), 1.14 (d, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[C:13](I)[C:14]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:15]=4[N:16]=3)=[N:9][N:8]([CH2:24][C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=3)[C:5]2=[N:6][CH:7]=1.[F:32][C:33]([F:37])([F:36])[CH2:34][NH2:35]>CN1CCCC1=O>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[C:13]([NH:35][CH2:34][C:33]([F:37])([F:36])[F:32])[C:14]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:15]=4[N:16]=3)=[N:9][N:8]([CH2:24][C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ncccc4F)c4ncc(F)cc34)nc(I)c21
Reactant: NCC(F)(F)F
Solvent: CN1CCCC1=O
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ncccc4F)c4ncc(F)cc34)nc(NCC(F)(F)F)c21
Temperature: 150 °C

Procedure:
150 mg (0.155 mmol, approx. 55% purity) of the compound obtained in example 21A was dissolved in 1-methyl-2-pyrrolidone (2.7 ml) in a reaction vessel suitable for a microwave and 0.675 ml 2,2,2-trifluoroethylamine was added. Then it was sealed with a corresponding septum and heated in the microwave at 150° C. for 21 h. After cooling, the reaction mixture was purified by preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 31 mg of the title compound was obtained (39% of theor.).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O>>[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1
Reactant: OB(O)c1ccccc1Br
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccccc2Br)cn1
Yield: 11 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (68.2 mg, 0.3 mmol) was converted, using 2-bromophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (12 mg, 11%) which was obtained as an off-white solid. MS: m/e=381.5[M+H]+.
Reaction SMILES: C([N:11]1[CH2:34][CH2:33][CH2:32][C@H:12]1[C:13]([NH:15][CH2:16][CH:17]1[O:31][C:20]2=[C:21]3[C:26](=[C:27]([CH3:29])[CH:28]=[C:19]2[CH2:18]1)[NH:25][C:24](=[O:30])[CH:23]=[CH:22]3)=[O:14])(OCC1C=CC=CC=1)=O.[H][H].CCOCC>CN(C)C=O.CO.[Pd]>[CH3:29][C:27]1[CH:28]=[C:19]2[CH2:18][CH:17]([CH2:16][NH:15][C:13](=[O:14])[C@@H:12]3[CH2:32][CH2:33][CH2:34][NH:11]3)[O:31][C:20]2=[C:21]2[C:26]=1[NH:25][C:24](=[O:30])[CH:23]=[CH:22]2
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)[C@@H]1CCCN1)C2
Yield: 109.6 %

Procedure:
2-(Carbobenzyloxy-L-prolyl)aminomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (1.04 g, 2.25 mmol) was dissolved in dimethylformamide (130 ml). To the obtained solution, 10% palladium-on-carbon (1.04 g) was added, followed by stirring at room temperature for 4 hours in the atmosphere of hydrogen. The reaction mixture was filtered, and the filtrate was condensed under reduced pressure. The resultant residue was dissolved in methanol (65 ml), to which 1.37 N-HCl--methanol (1.81 ml) was added. The mixture was condensed under reduced pressure. The resultant residue was submitted to a recrystallizing procedure using methanol--ether to obtain 807 mg of the title compound as pale yellow powdery crystals (98.6%).