Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[O:5][N:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:35][C@H:36]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[C:56]([Cl:58])[CH:55]=[CH:54][C:53]=2[F:59])=[CH:48][CH:47]=1)[CH2:37][C@:38]([CH2:43][OH:44])([CH3:42])[C:39]([OH:41])=[O:40].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:58][C:56]1[CH:55]=[CH:54][C:53]([F:59])=[C:52]([C:49]2[CH:48]=[CH:47][C:46]([CH2:45][C@@H:36]([NH:35][C:8]([C:6]3[O:5][N:4]=[C:3]([O:2][CH3:1])[CH:7]=3)=[O:10])[CH2:37][C@:38]([CH2:43][OH:44])([CH3:42])[C:39]([OH:41])=[O:40])=[CH:51][CH:50]=2)[CH:57]=1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2cc(Cl)ccc2F)cc1)C(=O)O
Reactant: COc1cc(C(=O)O)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N[C@H](Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@](C)(CO)C(=O)O)on1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20 %

Procedure:
3-Methoxyisoxazole-5-carboxylic acid (8 mg, 55 μmol) and HATU (20.8 mg, 55 μmol) were combined in DMF (0.2 mL) and allowed to stand at room temperature for 10 minutes. (2S,4R)-4-Amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxymethyl-2-methylpentanoic acid (20 mg, 55 μmol) in DMF and DIPEA (28.6 μL, 164 μmol) were added, and the resulting mixture was stirred for 20 minutes at room temperature. The mixture was concentrated under reduced pressure and the residue was dissolved in AcOH purified by preparative HPLC to yield the title compound (5.4 mg). MS m/z [M+H]+ calc'd for C24H24ClFN2O6, 491.13. found 491.2.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:49][C:50]1[CH:51]=[C:52]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([NH2:63])[CH:58]=2)[CH:53]=[C:54]([F:56])[CH:55]=1>CN(C=O)C>[F:49][C:50]1[CH:51]=[C:52]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([NH:63][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:58]=2)[CH:53]=[C:54]([F:56])[CH:55]=1
Reactant: Nc1cccc(-c2cc(F)cc(F)c2)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2cc(F)cc(F)c2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 35.2 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3′,5′-difluoro-biphenyl-3-ylamine (0.013 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.009 g of product in 35% yield: LCMS (ESI) m/z 394 (MH+).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.C([O:36][C@@H:37]([CH3:41])[C:38](Cl)=[O:39])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:38](=[O:39])[C@@H:37]([OH:36])[CH3:41])[CH2:31][CH2:32]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)NC1CCN(C(=O)[C@H](C)O)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f6) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]3[NH:18][C:17]([CH3:19])=[N:16][N:15]=3)=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([CH3:20])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.C1(C2C(C(=O)NC)=CC(C(O)=O)=C(C)C=2)CCC1.Cl.[NH:40]1[CH2:45][CH2:44][CH:43]([C:46]2[CH:47]=[CH:48][C:49]3[N:50]([CH:52]=[CH:53][N:54]=3)[CH:51]=2)[CH2:42][CH2:41]1.N1CCC(C2C=C3C(=CC=2)NN=C3)CC1>>[CH:1]1([C:5]2[C:13]([C:14]3[NH:18][C:17]([CH3:19])=[N:16][N:15]=3)=[CH:12][C:8]([C:9]([N:40]3[CH2:41][CH2:42][CH:43]([C:46]4[CH:47]=[CH:48][C:49]5[N:50]([CH:52]=[CH:53][N:54]=5)[CH:51]=4)[CH2:44][CH2:45]3)=[O:11])=[C:7]([CH3:20])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: c1cn2cc(C3CCNCC3)ccc2n1
Reactant: Cc1nnc(-c2cc(C(=O)O)c(C)cc2C2CCC2)[nH]1
Agent: CNC(=O)c1cc(C(=O)O)c(C)cc1C1CCC1
Agent: Cl
Agent: c1cc2[nH]ncc2cc1C1CCNCC1
Product: Cc1nnc(-c2cc(C(=O)N3CCC(c4ccc5nccn5c4)CC3)c(C)cc2C2CCC2)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 62, except 4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoic acid (compound 78.4, 100 mg) was used in place of 4-cyclobutyl-2-methyl-5-(methylcarbamoyl)benzoic acid (compound 62.3) and 6-(piperidin-4-yl)imidazo[1,2-a]pyridine hydrochloride (compound 78.5, 88 mg) was used in place of 5-(piperidin-4-yl)-1H-indazole (compound 62.5). The title compound was obtained as a white solid (35.6 mg, 21%). m/z (ES+) 455 (M+H)+
Reaction SMILES: [SH:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[O:25]1[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][S:1][C:2]2[N:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:10](=[O:18])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: ClCCN1CCOCC1
Reactant: O=c1c2ccccc2nc(S)n1-c1ccccc1
Product: O=c1c2ccccc2nc(SCCN2CCOCC2)n1-c1ccccc1
Yield: 49.8 %

Procedure:
The title compound was prepared in a yield of 49.8%, using 2-mercapto-3-phenyl-4(3H)-quinazolinone in place of 3- isobutyl-2-mercapto-4(3H)-quinazolinone and N-(2-chloroethyl)morpholine in place of 2-chloromethylpyridine hydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17](Cl)[N:16]=[CH:15][N:14]=2)[CH:10]=[CH:9][C:8]=1[CH3:20])[CH3:2].C([O-])(=O)C.[Na+]>C(O)C.O1CCCC1.[C].[Pd]>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:27])[C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)[CH:10]=[CH:9][C:8]=1[CH3:20])[CH3:26]
Reactant: CCOC(=O)CN(CC(=O)OCC)c1cc(-c2cc(Cl)ncn2)ccc1C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CN(CC(=O)OCC)c1cc(-c2ccncn2)ccc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.2 %

Procedure:
The compound (696 mg, 1.78 mmol) obtained in step B was dissolved in a ethanol (25 ml)-tetrahydrofuran (2 ml) mixed solvent. Then, sodium acetate (164 mg, 2.00 mmol) and 10% palladium carbon (containing water) (0.68 g) were added, and the mixture was stirred at room temperature for 5 hr under a hydrogen atmosphere. The insoluble material was filtered off through celite, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (466 mg, yield 73%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[CH3:13][C:14]([CH3:18])([CH3:17])[CH:15]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:13][C:14]([CH3:18])([CH3:17])[CH2:15][NH:7][C:6]1[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: CC(C)(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(NCC(C)(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
4-Methoxy-2-nitroaniline (10 g, 59.5 mmol, 1.0 equiv.) and trimethyl-acetaldehyde (9.73 g, 113 mmol, 1.9 equiv.) were dissolved in anhydrous DCM (100 ml). The resulting solution was treated with acetic acid (18.72 ml, 327 mmol, 5.5 equiv.), followed by sodium triacetoxyborohydride (30.3 g, 143 mmol, 2.4 equiv.). The reaction mixture was stirred at room temperature. When LCMS showed completion of the reaction, the reaction was quenched with saturated aqueous NaHCO3, then extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated to give N-(2,2-dimethylpropyl)-4-methoxy-2-nitroaniline (3), which was used without purification. LRMS m/z (M+H) 239.0 found, 238.1 required.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2.[Br:20]C1C=CC=C2C=1NC=C2>>[Br:20][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2
Reactant: Brc1cccc2cc[nH]c12
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Product: CC1(C)OB(c2cc3cccc(Br)c3[nH]2)OC1(C)C

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 7-bromo-1H-indole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:14]1[C:23]2[C:22](=[O:24])[N:21]([CH3:25])[CH:20]=[N:19][C:18]=2[CH:17]=[C:16]([Cl:26])[N:15]=1>CN(C=O)C>[Cl:26][C:16]1[N:15]=[C:14]([O:8][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:23]2[C:22](=[O:24])[N:21]([CH3:25])[CH:20]=[N:19][C:18]=2[CH:17]=1
Reactant: Cn1cnc2cc(Cl)nc(Cl)c2c1=O
Reactant: COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2nc(Cl)cc3ncn(C)c(=O)c23)cc1
Temperature: 80 °C

Procedure:
To a solution of 4-methoxybenzylalcohol (596 μL, 4.78 mmol) in anhydrous DMF (20 mL) was added NaH (208 mg, 60% dispersion in mineral oil, 5.20 mmol) at 0° C. The mixture was stirred at 0° C. for 10 minutes before 5,7-dichloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (1.00 g, 4.35 mmol) was slowly added. The resulting mixture was heated at 80° C. overnight, cooled down, quenched with H2O (200 mL), and extracted with EtOAc (3×100 mL). The combined organic layer was dried over MgSO4 and evaporated under reduced pressure to afford crude 7-chloro-5-(4-methoxybenzyloxy)-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.C([N:12](CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH2:12])=[O:9])[S:5][CH:6]=1
Reactant: O=C(O)c1cc(Br)cs1
Reactant: CCN(CC)CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Product: NC(=O)c1cc(Br)cs1
Reaction time: 8 h

Procedure:
To a solution of 4-bromothiophene-2-carboxylic acid (15 g), HOBt ammonium salt (16.5 g) and triethylamine (20.08 mL) in acetonitrile (250 mL) was added EDCI hydrochloride (16.87 g), and the mixture was stirred overnight. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (8.0 g).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[F:27][C:28]1[CH:43]=[CH:42][C:31]2[N:32]([CH3:41])[C:33]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)=[N:34][C:30]=2[CH:29]=1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:38]2[CH2:39][CH2:40][N:35]([C:33]3[N:32]([CH3:41])[C:31]4[CH:42]=[CH:43][C:28]([F:27])=[CH:29][C:30]=4[N:34]=3)[CH2:36][CH2:37]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: Cn1c(N2CCNCC2)nc2cc(F)ccc21
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: Cn1c(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)nc2cc(F)ccc21

Procedure:
Prepared analogously to Example 17 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 5-fluoro-1-methyl-2-piperazin-1-yl-1H-benzimidazole
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=O.[CH2:14]([NH2:16])[CH3:15]>>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH2:4][NH:16][CH2:14][CH3:15]
Reactant: CCN
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Product: CCNCc1cc(C(F)(F)F)ccc1Br

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using the following starting materials: 2-bromo-5-(trifluoromethyl)benzaldehyde and ethylamine (2M in THF).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)(O)[O-].[Na+]>ClCCl.C(O)(=O)C>[CH2:10]([NH:17][C:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[OH:1])=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1sccc1O
Reactant: NCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(NCc1ccccc1)c1sccc1O
Temperature: 22 °C
Reaction time: 2 h

Procedure:
1.44 g of 3-hydroxy-thiophene-2-carboxylic acid were dissolved in 100 ml of dichloromethane, and 2.18 ml of benzylamine and 5.00 ml of a 50% strength 1-propanephosphoric anhydride solution in acetic acid were added. The reaction mixture was stirred at 22° C. for 2 h and, after addition of 100 ml of saturated sodium bicarbonate solution, extracted twice with 100 ml of dichloromethane each time. The combined organic phases were washed with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The product with the molecular weight of 233.3 (C12H11NO2S), MS (ESI): 234 (M+h+) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[CH3:19][S:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1)(=[O:22])=[O:21].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:28][CH2:27][C:26]2[CH:25]=[CH:24][C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[CH:30][CH:29]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CS(=O)(=O)c1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)cc1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 4-methanesulfonylbenzylamine hydrochloride and DBU in DME. ES-MS m/e (%): 370 (M+H+, 100).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]=[C:21]([Cl:23])[Cl:22])[CH:15]=[C:14]([Cl:24])[C:13]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]=[C:21]([Cl:22])[Cl:23])[CH:15]=[C:14]([Cl:24])[C:13]=1[O:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([CH:2]=[O:1])=[CH:4][CH:5]=1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: O=Cc1ccc(CO)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=Cc1ccc(COc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Yield: 46.8 %

Procedure:
To a mixture of 3.40 g of p-(hydroxymethyl)benzaldehyde obtained in the same manner as described above, 7.2 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 6.56 g of triphenylphosphine, and 50 ml of tetrahydrofuran was slowly added dropwise 5.05 g of diisopropyl azodicarboxylate with stirring under ice cooling. After stirring at room temperature for 12 hours, the reaction mixture was concentrated to give a residue. This residue was subjected to silica gel chromatography, which afforded 4.75 g (yield, 46%) of 4-((2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)methyl)benzaldehyde, m.p., 93.9° C.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]([N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH2:19][CH2:18]3)=[N:15][CH:16]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl.C(N(CC)CC)C>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]([N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([C:28]([Cl:27])=[O:30])[CH2:19][CH2:18]3)=[N:15][CH:16]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)N1CCN(c2ccc(N3CCNc4ccccc43)nc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)N1CCN(c2ccc(N3CCN(C(=O)Cl)c4ccccc43)nc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.430 g of 1-[5-(4-tert-butyl-piperazin-1-yl)pyridin-2-yl]-1,2,3,4-tetrahydroquinoxaline is put in 12.23 ml of dichloromethane and 0.51 ml of triethylamine, then 0.181 g of triphosgene is added at 0° C. The reaction mixture is stirred at room temperature under nitrogen atmosphere for 15 minutes to form 4-[5-(4-tert-butyl-piperazin-1-yl)pyridin-2-yl]-3,4-dihydro-2H-quinoxaline-1-carbonyl chloride. 0.378 g of trans N-(4-amino-adamantan-1-yl)-methanesulfonamide is prepared in 10 ml of dimethyl formamide and 0.51 ml of triethylamine under nitrogen atmosphere which is heated to dissolve it. The hot mixture is added to the reaction mixture containing 4-[5-(4-tert-butyl-piperazin-1-yl)pyridin-2-yl]-3,4-dihydro-2H-quinoxaline-1-carbonyl chloride and it is stirred for two hours. Water and sodium chloride are added, and it is extracted three times with dichloromethane; the organic phases are combined and then dried over magnesium sulfate, then concentrated under reduced pressure. The 0.829 g of raw product is chromatographed on silica gel, eluting with a gradient of a dichloromethane/(dichloromethane-methanol 90:10) mixture from 0 to 100%. 0.4184 g of trans (5-methanesulfonylamino-adamantan-2-yl)amide of 4-[5-(4-tert-butyl-piperazin-1-yl)pyridin-2-yl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid is obtained.
Reaction SMILES: [N:1]1[NH:2][CH:3]=[C:4]2[C:9]=1[CH2:8][CH2:7][CH2:6][C:5]2=[O:10].[Br:11]Br>CCOCC.CC(O)=O>[Br:11][CH:6]1[CH2:7][CH2:8][C:9]2[C:4](=[CH:3][NH:2][N:1]=2)[C:5]1=[O:10]
Reactant: BrBr
Reactant: O=C1CCCc2n[nH]cc21
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C1c2c[nH]nc2CCC1Br
Yield: 80 %

Procedure:
To a solution of 2,5,6,7-tetrahydro-indazol-4-one (5.28 mmol), optionally protected as the trityl derivative, in Et2O (20 mL) and AcOH (15 mL), at 0° C., a solution of Br2 (10.56 mmol) in AcOH (20 mL) was slowly added dropwise. The solution was then heated at 60° C. for 1h then the organic solvents were evaporated to dryness and the white precipitate was suspended in Et2O, filtered and dried. The title compound was obtained in 80% yield. ESI (+) MS: m/z 216 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:35]I)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:35][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: Oc1ccc(-c2ccc(F)cc2)cc1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(OC)cc2)C1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCN(C(=O)c2ccc(OC)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 4′-fluoro-biphenyl-4-ol and 3-iodomethyl-1-(4-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 14) to afford the racemate as a white solid (162 mg, 73.2%)
Reaction SMILES: [CH2:1]([C@H:8]([NH:30][C:31](=[O:50])[C@H:32]([CH:47]([CH3:49])[CH3:48])[NH:33][C:34]([N:36]([CH2:38][C:39]1[N:40]=[C:41]([CH:44]([CH3:46])[CH3:45])[S:42][CH:43]=1)[CH3:37])=[O:35])[CH2:9][C@H:10]([OH:29])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:51]([S:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH2:52][CH2:53][CH3:54].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(#N)C.C(OCC)(=O)C>[CH2:1]([C@H:8]([NH:30][C:31](=[O:50])[C@H:32]([CH:47]([CH3:49])[CH3:48])[NH:33][C:34]([N:36]([CH2:38][C:39]1[N:40]=[C:41]([CH:44]([CH3:45])[CH3:46])[S:42][CH:43]=1)[CH3:37])=[O:35])[CH2:9][C@H:10]([O:29][CH:51]([S:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH2:52][CH2:53][CH3:54])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCSCCCC
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCCSC(CCC)O[C@@H](C[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(C(C)C)n1)C(C)C)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of the compound of Example 1 (3.0 g, 4.2 mmol) and butyl sulfide (18 mL) in acetonitrile (24 mL) at 0° C. was added benzoyl peroxide (2.0 g) in three portions over 3 hours, and the reaction was stirred at 0° C. for 1 hour and then at room temperature for 1 hour. Additional benzoyl peroxide (4.0 g) was added in two portions over 2 hours at room temperature. The reaction was diluted with ethyl acetate and washed with 10% Na2CO3 and brine. The organic phase was dried over MgSO4, filtered and evaporated. The concentrate was chromatographed on silica gel eluting with a gradient starting with 50% ethyl acetate in chloroform and ending with ethyl acetate to give the title compound (2.43 g, 68% yield).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[CH:8][N:7]([C:10]2[CH:19]=[C:18]([O:20][CH:21]3[CH2:38][CH:37]4[CH:23]([C:24](=[O:44])[N:25]([CH3:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]5[C:34]([C:40](O)=[O:41])([NH:35][C:36]4=[O:39])[CH2:33]5)[CH2:22]3)[C:17]3[C:12](=[C:13]([CH3:47])[C:14]([O:45][CH3:46])=[CH:15][CH:16]=3)[N:11]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:48]1([S:51]([NH2:54])(=[O:53])=[O:52])[CH2:50][CH2:49]1.ClC1C(OC)=CC=C2C=1N=C(C1SC=C(C(C)C)N=1)C=C2OC1CC2C(C(=O)N(C)CCCCC=CC3C(C(NS(C4CC4)(=O)=O)=O)(NC2=O)C3)C1>>[C:1]([C:5]1[CH:9]=[CH:8][N:7]([C:10]2[CH:19]=[C:18]([O:20][CH:21]3[CH2:38][CH:37]4[CH:23]([C:24](=[O:44])[N:25]([CH3:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]5[C:34]([C:40]([NH:54][S:51]([CH:48]6[CH2:50][CH2:49]6)(=[O:53])=[O:52])=[O:41])([NH:35][C:36]4=[O:39])[CH2:33]5)[CH2:22]3)[C:17]3[C:12](=[C:13]([CH3:47])[C:14]([O:45][CH3:46])=[CH:15][CH:16]=3)[N:11]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-n3ccc(C(C)(C)C)n3)nc2c1C
Reactant: NS(=O)(=O)C1CC1
Agent: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-n3ccc(C(C)(C)C)n3)nc2c1C

Procedure:
The title compound was prepared from 17-[2-(3-tert-butylpyrazol-1-yl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04′6]octadec-7-ene-4-carboxylic acid (127) and cyclopropylsulfonamide following the procedure reported for the preparation of N-[17-[8-chloro-2-(4-isopropylthiazole-2-yl)-7-methoxyquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]-octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (56): m/z=747 (M+H)+. 1H NMR (CDCl3): 0.95-1.12 (m, 2H), 1.13-1.30 (m, 2H), 1.31-1.55 (m, 11H), 1.63-2.05 (m, 4H), 2.20-2.55 (m, 9H), 2.80-2.98 (m, 1H), 3.03 (s, 3H), 3.36-3.47 (m, 2H), 3.61-3.70 (m, 1H), 3.97 (s, 3H), 4.60 (t, J=12.2 Hz, 1H), 5.04 (t, J=10.3 Hz, 1H), 5.26-5.46 (m, 1H), 5.61-5.69 (m, 1H), 6.35 (d, J=2.5 Hz, 1H), 6.42 (br s, 1H), 7.13 (d, J=9.1 Hz, 1H), 7.32 (s, 1H), 7.95 (d, J=9.1 Hz, 1H), 8.67 (d, J=2.5 Hz, 1H), 10.9 (br s, 1H).