Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([N+:27]([O-:29])=[O:28])=[CH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:12]([C:22](=[O:25])[NH:23][CH3:24])[C:11]=2[CH:26]=1)(=O)=O.[CH3:32][O:33][C:34]1[CH:43]=[CH:42][C:41](B2OC(C)(C)C(C)(C)O2)=[CH:40][C:35]=1[C:36]([O:38][CH3:39])=[O:37].C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[O:14][C:10]3[CH:9]=[C:8]([N+:27]([O-:29])=[O:28])[C:7]([C:41]4[CH:42]=[CH:43][C:34]([O:33][CH3:32])=[C:35]([CH:40]=4)[C:36]([O:38][CH3:39])=[O:37])=[CH:26][C:11]=3[C:12]=2[C:22](=[O:25])[NH:23][CH3:24])=[CH:16][CH:17]=1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1OC
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(OS(=O)(=O)C(F)(F)F)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(-c3ccc(OC)c(C(=O)OC)c3)cc12
Temperature: 100 °C

Procedure:
To a mixture of 2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-nitrobenzofuran-5-yl trifluoromethanesulfonate (750 mg, 1.622 mmol), methyl 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (569 mg, 1.947 mmol) and cesium carbonate (1057 mg, 3.24 mmol) in dioxane (20 mL)/water (1.0 mL) at rt under nitrogen was added Pd(PPh3)4(0) (187 mg, 0.162 mmol). The reaction mixture was heated to 100° C. and maintained at the same temperature for overnight. The reaction mixture was filtered through celite, and the celite bed washed with ethyl acetate. The filtrate was concentrated and the residue purified by Combiflash using MeOH/CHCl3 as eluant. The desired fraction was collected at 2.5% MeOH in CHCl3. Yield: 0.650 g (83%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH3:21]>CN(C=O)C.C(OCC)C.[I-].[K+]>[CH2:19]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6])[CH2:20][CH3:21]
Reactant: COc1ccc(C=O)cc1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCOc1cc(C=O)ccc1OC
Temperature: 65 °C
Reaction time: 5 h
Yield: 101.4 %

Procedure:
To a suspension of 3-hydroxy-4-methoxybenzaldehyde (2.00 g, 13.2 mmol), potassium carbonate (2.74 g, 19.8 mmol) and potassium iodide (60.0 mg, 0.361 mmol) in DMF (15 mL) was slowly added 1-bromopropane (1.56 mL, 17.2 mmol) via syringe. The reaction mixture was stirred at 65° C. for 5 hours. After cooling to room temperature, the mixture was diluted with diethyl ether (100 mL), and the organic phase was washed with water (2×50 mL). After drying over anhydrous MgSO4, filtration and evaporation of the filtrate in vacuo gave crude 3-(propyloxy)-4-methoxybenzaldehyde (2.60 g) which was used in the next step without further purification.
Reaction SMILES: C(O)C.[C:4]([CH:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([O:18]CC)=[O:17])[C:10]=2[CH2:9][CH2:8][CH2:7]1)#[N:5].[OH-].[Na+]>O>[C:4]([CH:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([OH:18])=[O:17])[C:10]=2[CH2:9][CH2:8][CH2:7]1)#[N:5]
Reactant: CCOC(=O)c1cccc2c1CCCC2C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#CC1CCCc2c(C(=O)O)cccc21
Temperature: 50 °C

Procedure:
In 90 ml. of ethanol is dissolved 9.6 g. of ethyl 1-cyano-1,2,3,4-tetrahydro-5-naphthoate and a solution of 2.5 g. of sodium hydroxide in 90 ml. of water is added. The mixture is stirred under heating at 50° C for 3 hours, after which the ethanol is distilled off. Then, following the addition of 2N hydrochloric acid, the residue is extracted with chloroform. The organic layer is washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the crystalline residue is recrystallized from benzene. The described procedure gives 1-cyano-1,2,3,4-tetrahydro-5-naphthoic acid, melting point: 177°-179° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[CH2:12]([Mg]Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: Cl[Mg]Cc1ccccc1
Reactant: COc1cc(C=O)ccc1F
Solvent: C1CCOC1
Product: COc1cc(C(O)Cc2ccccc2)ccc1F
Temperature: 50 °C
Yield: 60.2 %

Procedure:
To a solution of 4-fluoro-3-methoxybenzaldehyde (25 g, 162 mmol) in THF (150 mL) was added a solution of benzyl magnesium chloride (2 M solution in THF, 122 mL, 243 mmol) in THF (50 mL). The reaction mixture was heated at 50° C. for 2 h. The reaction mixture was allowed to cool to rt and quenched by addition of sat. NH4Cl. The reaction mixture was extracted with EtOAc (3×) and the combined organic layers were washed with sat. NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, eluting with 0-40% EtOAc/hexane) to yield 1-(4-fluoro-3-methoxyphenyl)-2-phenylethanol as a yellow oil (24 g, 60% yield). 1H NMR (500 MHz, CDCl3) δ ppm 7.27-7.32 (m, 2H), 7.21-7.27 (m, 1H), 7.16 (d, J=7 Hz, 2H), 7.01 (dd, J=11, 8 Hz, 1H), 6.92 (dd, J=8, 2 Hz, 1H), 6.82 (ddd, J=8, 4, 1 Hz, 1 H), 4.80-4.88 (m, 1H), 4.66 (d, J=6 Hz, 1H), 3.84 (s, 3H), 2.91-3.04 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C1COCC1>[CH3:22][S:23]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCCOCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCCOCc1ccccc1

Procedure:
The 5-benzyloxypentanol (Aldrich, 0.32 g, 1.7 mmol), triethylamine (0.67 mL, 5.0 mmol), and methanesulfonyl chloride (0.19 mL, 2.5 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].O[N:21]1[C:25](=[O:26])[CH2:24][CH2:23][C:22]1=[O:27].C1CCC(N=C=NC2CCCCC2)CC1>O1CCOCC1>[NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])[C@H:2]([C:7]([O:9][N:21]1[C:25](=[O:26])[CH2:24][CH2:23][C:22]1=[O:27])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Z-Leu-OH (15.92 g) and N-hydroxysuccinimide (6.9 g) were dissolved in dioxane and cooled to 0° C. To the cooled solution, DCC was added and stirred at 0° C. for 0.5 h, then room temp overnight. After filtering off the byproduct urea, the filtrate was concentrated to give crude Z-Leu-OSu as an oil.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([B:14]3[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:23][N:24]([CH2:26][C:27]1C=CC(N)=[CH:29][CH:28]=1)[CH3:25]>>[CH3:23][N:24]([CH2:26][C:27]1[CH:28]=[CH:29][C:1]([NH:4][C:5]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([B:14]3[O:15][C:16]([CH3:22])([CH3:21])[C:17]([CH3:19])([CH3:20])[O:18]3)=[CH:12][CH:13]=2)=[O:6])=[CH:3][CH:2]=1)[CH3:25]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Product: CN(C)Cc1ccc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1

Procedure:
A procedure analogous to that used for the preparation of 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea was used, using 4-((dimethylamino)methyl)aniline as the amine component.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][C:7]#[C:8][CH2:9][N:10]1[CH2:33][CH2:32][CH2:31][C@:12]2([O:16][CH2:15][C@H:14]([C:17]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=3[O:27][CH:28]([CH3:30])[CH3:29])[CH2:13]2)[C@@H:11]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CS(C)=O.O>[N:1]([CH2:6][C:7]#[C:8][CH2:9][N:10]1[CH2:33][CH2:32][CH2:31][C@:12]2([O:16][CH2:15][C@H:14]([C:17]3[CH:22]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:20]=[CH:19][C:18]=3[O:27][CH:28]([CH3:30])[CH3:29])[CH2:13]2)[C@@H:11]1[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[N+:2]=[N-:3]
Reactant: CC(C)Oc1ccc(C(F)(F)F)cc1[C@H]1CO[C@]2(CCCN(CC#CCCl)[C@H]2c2ccccc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)Oc1ccc(C(F)(F)F)cc1[C@H]1CO[C@]2(CCCN(CC#CCN=[N+]=[N-])[C@H]2c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
Sodium azide (15 mg) was added to a solution of (3S,5R,6S)-7-(4-chlorobut-2-yn-1-yl)-3-[2-isopropoxy-5-(trifluoromethyl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4,5]decane (Description 75, 100 mg) in dimethylsulfoxide (1 ml). The mixture was stirred at room temperature overnight, diluted with water (20 ml) and extracted with ether (3×5 ml). The combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under pressure to give the title compound as a colorless oil (98 mg). m/z (ES+) m/z 513 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:29][CH3:30])=[C:10]([CH2:19][NH:20][C:21]([C:23]3([C:26](O)=[O:27])[CH2:25][CH2:24]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:31][N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][C:39]2[CH:40]=[C:41]([C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([CH2:51]N)[CH:46]=3)[CH:42]=[CH:43][CH:44]=2)[CH2:34][CH2:33]1.C[N:54]1CCC(CC2C=C(C3C=CC=C(CN)C=3)C=CC=2)CC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:29][CH3:30])=[C:10]([CH2:19][N:20]([CH2:51][C:47]3[CH:46]=[C:45]([C:41]4[CH:42]=[CH:43][CH:44]=[C:39]([CH2:38][CH:35]5[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]5)[CH:40]=4)[CH:50]=[CH:49][CH:48]=3)[C:21]([C:23]3([C:26]([NH2:54])=[O:27])[CH2:24][CH2:25]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)C1(C(=O)O)CC1
Reactant: CN1CCC(Cc2cccc(-c3cccc(CN)c3)c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1cccc(-c2cccc(CC3CCN(C)CC3)c2)c1)C(=O)C1(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.8 %

Procedure:
A mixture of 1-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]cyclopropanecarboxylic acid (100 mg, 0.241 mmol), ({3′-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)amine 1-{3′-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methanamine (92 mg, 0.241 mmol), HBTU (110 mg, 0.289 mmol) and Et3N (0.101 mL, 0.722 mmol) in DCM was stirred at room temperature overnight. The crude mixture was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with brine and then concentrated under vacuum to give crude residue. The crude product was purified by reverse phase hplc with a Gilson HPLC (acidic conditions: 0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined, washed with saturated NaHCO3 and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and then concentrated under vacuum to give N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-({3′-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)-1,1-cyclopropanedicarboxamide as a solid (18 mg, 10.8%). LC-MS m/z 692 (M+H)+, 0.75 min (ret time).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].C(N(CC)CC)C.[F:15][C:16]([F:50])([F:49])[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[N:20]=[C:19]([C:33]2[CH:34]=[C:35]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([S:45](Cl)(=[O:47])=[O:46])[CH:40]=3)[CH:36]=[CH:37][CH:38]=2)[N:18]=1>C1COCC1>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[S:45]([C:41]1[CH:40]=[C:39]([C:35]2[CH:36]=[CH:37][CH:38]=[C:33]([C:19]3[N:18]=[C:17]([C:16]([F:15])([F:49])[F:50])[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=4)[N:20]=3)[CH:34]=2)[CH:44]=[CH:43][CH:42]=1)(=[O:46])=[O:47]
Reactant: OCCNCCO
Reactant: O=S(=O)(Cl)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1)N(CCO)CCO
Temperature: 0 °C
Yield: 52.4 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of diethanolamine (0.12 g, 1.14 mmol), triethylamine (0.06 ml, 0.42 mmol) and THF (2 ml) was added drop wise a solution of 3′-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-biphenyl-3-sulfonyl chloride (example I.3) (0.21 g, 0.39 mmol) in THF (3 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (diethyl ether/hexane) yielded the title compound as a white solid (0.125 g, 53%). MS (ISP) 611.6 [(M+H)+]; mp 111.5° C.
Reaction SMILES: C[NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].NC1C=CC(O)=CC=1.CNC(C1C=C([Cl:37])C=CN=1)=O>>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:9]2[CH:8]=[CH:7][N:6]=[C:5]([C:3]([NH2:2])=[O:4])[CH:10]=2)=[CH:13][C:14]=1[Cl:37]
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Agent: Nc1ccc(O)cc1
Product: NC(=O)c1cc(Oc2ccc(N)c(Cl)c2)ccn1

Procedure:
The title compound was prepared in the same manner described for 4-(4-aminophenoxy)pyridine-2-carboxylic acid methylamide, substituting 4-amino-3-chlorophenol for 4-aminophenol, and substituting 4-chloro-2-pyridinecarboxamide for 4-chloropyridine-2-carboxylic acid methylamide. 1H-NMR (DMSO-d6) δ 8.45 (d, J=5.4 Hz, 1H), 8.08 (s, 1H), 7.67 (s, 1H), 7.32 (d, J=2.7 Hz, 1H), 7.15 (d, J=2.7 Hz, 1H), 7.09 (dd, J=2.7, 5.4 Hz, 1H), 6.93 to 6.84 (m, 2H), 5.44 (s, 2H); MS LC-MS (M+H)+=264.1, RT=2.40 min.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[NH:4][N:3]=1.[C:14]([OH:25])(=O)[C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1>>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[NH:4][N:3]=[C:2]([NH:1][C:19](=[O:21])[C:18]3[CH:17]=[CH:16][C:15]([C:14]([NH:1][C:2]4[CH:6]=[C:5]([C:7]5[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=5)[NH:4][N:3]=4)=[O:25])=[CH:23][CH:22]=3)[CH:6]=2)=[CH:8][CH:9]=1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: Cc1ccc(-c2cc(N)n[nH]2)cc1
Product: Cc1ccc(-c2cc(NC(=O)c3ccc(C(=O)Nc4cc(-c5ccc(C)cc5)[nH]n4)cc3)n[nH]2)cc1

Procedure:
Compound 472 was prepared from 3-amino-5-(4-methylphenyl)pyrazole and terephthalic acid. [M+H]+ calcd for C28H25N6O2: 477.20; found: 476.92.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[F:13][C:14]([F:37])([F:36])[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23][C:24]2[CH:35]=[CH:34][CH:33]=[CH:32][C:25]=2[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([NH:6][C:7]([N:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][C:14]([F:13])([F:36])[F:37])=[CH:21][CH:20]=1)[S:23][C:24]1[CH:35]=[CH:34][CH:33]=[CH:32][C:25]=1[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])=[O:8])=[O:5]
Reactant: CC(C)OC(=O)c1ccccc1SNc1ccc(OC(F)(F)F)cc1
Reactant: O=C=NC(=O)c1ccccc1Cl
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)c1ccccc1SN(C(=O)NC(=O)c1ccccc1Cl)c1ccc(OC(F)(F)F)cc1
Temperature: -5 °C
Reaction time: 18 h
Yield: 87.1 %

Procedure:
A solution of 2-chlorobenzoyl isocyanate (2.7 g) in dry toluene (5.0 ml) was added to a stirred suspension of isopropyl 2-[[[4-(trifluoromethoxy)phenyl]amino]thio]benzoate (3.7 g) in the same solvent (20.0 ml) at room temperature. After 18 hours, a cake of crystals had formed. The reaction mixture was cooled to -5° C. and filtered, washing the crystals with cold toluene followed by light petroleum. After drying at 40° C. under vacuum, the pure product was obtained as colourless crystals (4.8 g). Melting point 143°-144° C.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:37][C:38]1[CH:46]=[CH:45][C:41]([CH2:42][CH2:43][NH2:44])=[CH:40][CH:39]=1>>[CH3:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:44][CH2:43][CH2:42][C:41]4[CH:45]=[CH:46][C:38]([CH3:37])=[CH:39][CH:40]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: Cc1ccc(CCN)cc1
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Product: Cc1ccc(CCNC(=O)c2ccc3n2Cc2ccccc2N(C(=O)c2ccc(-c4ccccc4C)c(C)c2)C3)cc1

Procedure:
The title compound was synthesized in the manner of Example 13 from 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 and 4-methylphenethylamine, m.p. 161-163° C. MS [(+)ESI, m/z]: 554 [M+H]+
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH3:18].[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([OH:32])=[C:26]([CH:31]=1)[C:27]([O:29]C)=[O:28].Cl.C(N=C=NCCCN(C)C)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[OH:32][C:25]1[CH:24]=[CH:23][C:22]([NH:21][C:1](=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH3:18])=[CH:31][C:26]=1[C:27]([OH:29])=[O:28]
Reactant: CC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)O
Reactant: COC(=O)c1cc(N)ccc1O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: CC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)Nc1ccc(O)c(C(=O)O)c1
Reaction time: 14 h
Yield: 80.9 %

Procedure:
To a solution of (9Z,12Z,15Z)-octadeca-9,12,15-trienoic acid (1.66 g, 5.98 mmol) and methyl 5-amino-2-hydroxybenzoate (1.0 g, 5.98 mmol) in methylene chloride (100 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.16 g, 6.0 mmol) and dimethylaminopyridine (100 mg). The mixture was stirred under N2 (14 h) and then diluted with methylene chloride (100 mL) and washed successively with 3N HCl, saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give the corresponding amide (2.0 g).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH2:42](Cl)[O:43][CH3:44]>C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:42][O:43][CH3:44])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 39 mg, 0.090 mmol) in CH2Cl2 (2.0 ml) was added i-Pr2NEt (47 μl, 0.27 mmol) and MOMCl (35 μl, 0.45 mmol). The reaction was stirred at room temperature for 4 h, and was purified directly by PTLC on silica gel (30% EtOAc-hexanes) to yield the title compound as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])(=[O:17])=[O:16])=[CH:11][CH:10]=1.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][NH2:41])[CH:35]=1>>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([NH:41][CH2:40][C:36]4[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=4)=[O:30])=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])(=[O:16])=[O:17])=[CH:11][CH:10]=1
Reactant: COc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Reactant: NCc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Product: COc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)NCc4cccnc4)cc3)oc2C)cc1
Yield: 51.3 %

Procedure:
Method E. Reaction of oxalyl chloride (76 λL, 0.88 mmol) and benzoic acid 35 (226 mg, 0.58 mmol) with subsequent coupling to 3-pyridinylmethylamine (65 λL, 0.64 mmol) gave benzamide 36 (142 mg, 51%) as a white powder: mp (MeOH/EtOAc) 189-191° C.; 1H NMR δ 9.22 (t, J=5.8 Hz, 1H, CONH), 8.57 (d, J=1.7Hz, 1 H, H-2′), 8.47 (dd, J=4.7, 1.6Hz, 1 H, H-6′), 8.00 (dd, J=8.6, 1.8Hz, 2 H, H-2, H-6), 7.91 (dd, J=8.6, 1.8Hz, 2 H, H-3, H-5), 7.74 (ddd, J=8.0, 2.1, 1.4Hz, 1 H, H-4′), 7.70 (ddd, J=8.9, 3.0, 2.0Hz, 2 H, H-2″, H-6″), 7.36 (ddd, J=7.9, 4.7, 0.7Hz, 1 H, H-5′), 7.13 (ddd, J=8.9, 3.0, 2.0Hz, 2 H, H-3″, H-5″), 4.60 (s, 2 H, CH2SO2), 4.51 (d, J=5.8Hz, 2 H, CH2N), 3.84 (s, 3 H, OCH3), 2.13 (s, 3 H, CH3); 13C NMR δ 165.5, 163.3, 157.9, 149.8, 148.9, 148.0, 135.3, 135.1, 134.8, 130.4 (2), 129.8, 128.8, 128.0 (2), 126.1, 125.3 (2), 123.4, 114.3 (2), 55.7, 53.0, 40.4, 9.6; MS m/z 477.6 (MH+, 100%). Anal. calcd for C25H23N3O5S.½CH3OH: C, 62.06; H, 5.11; N, 8.51. Found: C, 61.85; H, 4.88; N, 8.62%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NC[CH2:22][CH2:23][N:24]([CH3:26])C.Cl.ON1C(=O)CCC1=O.CCN(C(C)C)C(C)C.N1CCC1>C(Cl)Cl>[N:24]1([C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:13]([CH3:15])[CH3:14])[CH2:23][CH2:22][CH2:26]1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: C1CNC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
(S)-2-(Tert-butoxycarbonylamino)-3-methylbutanoic acid (50.0 g, 230.1 mmol), EDC hydrochloride (52.9 g, 276.2 mmol) and 1-hydroxypyrrolidine-2,5-dione (39.7 g, 345.2 mmol) was mixed in DCM (180 mL). The mixture was cooled to 0° C. and DIPEA (160 mL, 920.6 mmol) was added. After 1 h at 0° C. was azetidine (18.62 mL, 276.2 mmol) added. The resultant mixture was stirred at rt over night. The mixture was concentrated and the residue dissolved in DCM (200 mL). The organic phase was washed with NaHCO3 (saturated, 2×150 mL), HCl (1M aq. solution, 2×200 mL) and brine (150 mL), filtered through a phase separator and concentrated under reduced pressure to give the title compound (42 g, 71%). The obtained crude product was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1OS(C(F)(F)F)(=O)=O)=[O:5])[CH3:2].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(-c2ccccc2)nc1OS(=O)(=O)C(F)(F)F
Reactant: C1CCNCC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1sc(-c2ccccc2)nc1N1CCCCC1
Temperature: 80 °C
Yield: 96 %

Procedure:
To a solution of the above-prepared 2-phenyl-4-trifluoromethanesulfonyloxy-thiazole-5-carboxylic acid ethyl ester (0.75 mmol) in toluene (5 mL) was added piperidine (4.5 mmol). The reaction mixture was heated to 80° C. for 2 hours. The mixture was then diluted in ethyl acetate, washed successively with water and brine, and dried over MgSO4. Silica gel chromatography of the crude mixture provided title compound (96%) as a yellowish oil.