Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][CH3:16])=[C:6]([C:17]([O:19]CC)=[O:18])[C:5]=1[C:22]([O:24]CC)=[O:23])[CH3:2].[OH-].[Na+]>C(O)C>[CH2:15]([O:14][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:22]([OH:24])=[O:23])[C:6]=1[C:17]([OH:19])=[O:18])[CH3:16]
Reactant: CCOC(=O)c1c(C(=O)OCC)c(OCC)c2ccccc2c1OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1c(C(=O)O)c(C(=O)O)c(OCC)c2ccccc12
Temperature: 0 °C
Yield: 79.6 %

Procedure:
To a stirred solution of diethyl 1,4-bis(ethyloxy)-2,3-naphthalenedicarboxylate (1343 g, 3.73 mol) in ethanol (5.5 L) was added 2M sodium hydroxide solution (5.5 L, 11.0 mol). The reaction mixture was heated to reflux for 8 hours, with the reaction progress monitored by 1H-nmr spectroscopy. The mixture was then cooled to 0° C. for 18 hours before isolation of the crystallised solid by filtration, washing with ethanol (5 L) and drying in a vacuum oven at 60° C. to constant mass gave the desired product as a white solid (903.7 g, ˜11% water remains by Karl-Fischer, 62% yield).
Reaction SMILES: [N:1]1([C:10](=[O:12])[CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Br:13]Br>C(O)(=O)C>[Br:13][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[N:1]([C:10](=[O:12])[CH3:11])[CH2:2][CH2:3]2
Reactant: CC(=O)N1CCc2ccccc21
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(=O)N1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 115.7 %

Procedure:
To a solution of 1-(2,3-dihydro-indol-1-yl)-ethanone (58.0 g, 0.36 mol) in acetic acid (3000 mL) was added Br2 (87.0 g, 0.54 mol) at 10° C. The mixture was stirred at room temperature for 4 h. The precipitate was collected via filtration to give crude 1-(5-bromo-2,3-dihydro-indol-1-yl)-ethanone (100 g, 96%), which was used directly in the next step.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:32])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:29][CH3:30])[C:25](OC)=[O:26])[C:5]1=[O:31])[CH:2]=[CH2:3].[BH4-].[Li+]>CCOCC.C1COCC1>[CH2:1]([C@@:4]1([CH3:32])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@H:24]([CH2:29][CH3:30])[CH2:25][OH:26])[C:5]1=[O:31])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)OC)C1=O
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CC)CO)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-methyl 2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoate and (R)-methyl 2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoate (1.73 g, 3.64 mmol) (mixture of stereoisomers from Example 91, Step A) in 27 mL of Et2O and 9 mL of THF was added a solution of lithium tetrahydroborate in THF (0.238 mL, 7.28 mmol) at 0° C. The resulting solution was stirred at 25° C. for 2 h. The reaction was quenched (10% citric acid), extracted (2×EtOAc) and washed (1×Sat. aq. NaCl solution). The combined organic layers were washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 0-60% EtOAc in hexanes) to give the title compound as the faster eluting isomer.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[C:4]([CH3:15])[N:3]=1.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:6]1[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[C:4]([CH3:15])[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCCc1c(C)nc(N)nc1O
Product: CCCCCCc1c(C)nc(N)nc1Cl
Yield: 18 %

Procedure:
By using ethyl 2-acetyloctanoate (6.43 g, 30 mmol) as a starting material and according to the method of Reference-example 2, there was obtained 2-amino-5-hexyl-6-methylpyrimidine-4-ol (4.70 g, 74%). By reacting the obtained 2-amino-5-hexyl-6-methylpyrimidine-4-ol (1 g, 4.78 mmol) and phosphorous oxychloride (12 ml), there was obtained the object compound (196 mg, 18%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[S:5][C:6]=1[C:7]1[N:11]([CH3:12])[N:10]=[CH:9][C:8]=1[Cl:13].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:39])[F:40])[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:16])[S:5][C:6]=1[C:7]1[N:11]([CH3:12])[N:10]=[CH:9][C:8]=1[Cl:13]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1ncc(Cl)c1-c1sc(C(=O)O)cc1Br
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cn1ncc(Cl)c1-c1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
To a 50 mL round-bottomed flask was added 4-bromo-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (224 mg, 0.52 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (201 mg, 0.52 mmol) [prepared according to the procedure of Preparation 6] and PyBrop (295 mg, 0.63 mmol) in chloroform (4 mL). DIEA (0.46 mL, 2.63 mmol) was added and the mixture stirred overnight at room temperature. The reaction mixture was adsorbed onto silica and purified via column chromatography (hexanes/EtOAc) affording the title compound (153 mg, 43%): LC-MS (ES) m/z=651 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br-].[O:14]1CCO[CH:15]1[CH2:19][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOCCN(CCOCCOC)CCOCCOC>ClCCl.C([O-])([O-])=O.[K+].[K+]>[N:1]1[C:10]2[C:5](=[CH:6][C:7](/[CH:11]=[CH:19]/[CH:15]=[O:14])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc2ncccc2c1
Reactant: c1ccc([P+](CC2OCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: ClCCl
Product: O=C/C=C/c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
A mixture of 6-quinolinecarboxaldehyde (1.58 g, 10.05 mmol, prepared as described in U.S. Pat. No. 5,559,256), (1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide (6.45 g, 15.02 mmol), and TDA-1 (3.20 mL, 10.00 mmol) in dichloromethane (50 mL) and sat. aq. K2CO3 (50 mL) was heated to reflux for 5 h. The layers were separated and the aqueous layer was extracted with dichloromethane (2×25 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (MgSO4), and concentrated. THF (25 mL) and 10% HCl (25 mL) were added and the mixture was stirred for 1 h at rt. The reaction mixture was cooled to 0° C., made basic with 10% NaOH, and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (MgSO4), and concentrated. Chromatography (SiO2, 1:1 hexane/ethyl acetate+0.2% triethylamine) provided a yellow solid that was partitioned between ethyl acetate (20 mL) and 10% HCl (15 mL). The aqueous layer was washed with ethyl acetate (2×20 mL) and then made basic with 10% NaOH. The precipitated solids were collected by filtration, washed with water, and dried in vacuo to give 1.20 g (65%) of the title compound as a light yellow solid. MS 184 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH3:11].CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([NH:30][C:31]([C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)=[O:32])[CH:24]=[CH:23]3)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Pd].O>[CH3:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[CH:26]=[C:25]([NH:30][C:31]([C:33]3[CH:37]=[CH:36][S:35][CH:34]=3)=[O:32])[CH:24]=[CH:23]4)[CH:3]=2)[NH:7][N:6]=1
Reactant: Cc1n[nH]c2ccc(Br)cc12
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1n[nH]c2ccc(-c3ccc4cc(NC(=O)c5ccsc5)ccc4c3)cc12
Temperature: 25 °C
Yield: 25.2 %

Procedure:
5-bromo-3-methyl-1H-indazole (30.7 mg, 0.145 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (110.3 mg, 0.291 mmol), Fibercat palladium catalyst (Johnson-Matthey, 59.3 mg), and K2CO3 (2 M in water, 0.50 ml, 1.0 mmol) were combined in a microwave reaction vessel and 1,4-dioxane (1.6 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 60 Watts and 85 C for 20 minutes. The reaction was then cooled to room temperature, diluted with water (5 ml), and extracted with EtOAc (3×10 ml). The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified via silica gel (Biotage instrument, 13% EtOAc/hexanes->100% EtOAc). This crude material was then purified via HPLC (10%->95% MeCN/water with 0.1% TFA) to afford title compound (14.0 mg, 25%). MS (ESI pos. ion) m/z: 384 (M+H). Calc'd Exact Mass for C23H17N3OS: 383.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](Cl)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][O:25][C:26]1[C:27]([CH3:33])=[CH:28][C:29]([NH2:32])=[CH:30][CH:31]=1>>[C:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([O:25][CH2:24][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=4)=[C:27]([CH3:33])[CH:28]=3)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2]
Reactant: Cc1cc(N)ccc1OCc1ccccn1
Reactant: COc1cc2c(Cl)ncnc2cc1OC(C)=O
Product: COc1cc2c(Nc3ccc(OCc4ccccn4)c(C)c3)ncnc2cc1OC(C)=O
Yield: 64 %

Procedure:
Using an analogous procedure to that described in Example 1 except that the reaction mixture was heated to reflux for 3 hours, 7-acetoxy-4-chloro-6-methoxyquinazoline was reacted with 5-amino-2-tolyl 2-pyridylmethyl ether to give 7-acetoxy-6-methoxy-4-[3-methyl-4-(2-pyridylmethoxy)anilino]quinazoline in 64% yield;
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:20][O:21][C:22]([C:24]1[CH:29]=[C:28]([CH3:30])[C:27](=[O:31])[N:26]([CH3:32])[C:25]=1Cl)=[O:23].O.Cl.[Cl-].[Na+]>C1COCC1>[CH3:20][O:21][C:22]([C:24]1[CH:29]=[C:28]([CH3:30])[C:27](=[O:31])[N:26]([CH3:32])[C:25]=1[NH:4][C:3]1[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=1[F:1])=[O:23]
Reactant: COC(=O)c1cc(C)c(=O)n(C)c1Cl
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(C)c(=O)n(C)c1Nc1ccc(I)cc1F
Temperature: -13 °C
Reaction time: 0.47 h
Yield: 83.3 %

Procedure:
To a stirred solution of 2-fluoro-4-iodoaniline (182 g, 0.77 mol) in THF (5.25 L) at −45° C. under nitrogen was added 1M lithium bis(trimethylsilyl)amide solution in hexanes (1260 g), over 28 minutes at −43 to −41.6° C. After 1 hour, 2-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (155 g, 0.72 mol) in THF (1.05 L) was added over 43 minutes. The mixture was held for 1 hour 55 minutes at −46° C., then allowed to warm to −13° C. and quenched with water (186 mL, 10.3 mol) over 5 minutes, maintaining the temperature between −13° C. and −11° C. The mixture was then allowed to warm to 0° C. over 30 minutes. 2M HCl was then added over 1 hour until pH 7-8 was achieved (1855 mL added). After standing overnight the mixture was allowed to warm to ambient temperature, and sodium chloride solution (1 L, 15% w/v) was added. The lower (aqueous layer) was discarded and the THF layer was concentrated by distillation to approx 1.4 L. Iso-hexane (4.65 L) was added to the mixture at approximately 52° C. over 1 hour 15 minutes, and then the mixture was cooled to 20° C. over 3 hours. After 1 hour at 20° C., the mixture was cooled to 0° C. and held at this temperature overnight. The reaction mixture was then filtered, and the solid was washed with chilled iso-hexane (5° C.) (2×1.25 L). The solid was dried in a vacuum oven at 45° C. to provide 2-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (248 g, 0.60 mol, 83% yield). 1H NMR (D6-DMSO): δ 7.75 (d, 1H, J 1 Hz, ArH), 7.68 (dd, 1H, J 11, 2 Hz, ArH), 7.42 (d, 1H, J 8.5 Hz, ArH), 6.62 (˜t, 1H, J 8.5 Hz, ArH), 3.69 (s, 3H, OCH3), 3.22 (s, 3H, NCH3), 2.03 (s, 3H, ArCH3).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:9]=O)=[N:5][CH:6]=[CH:7][N:8]=1.Cl.[NH2:12][OH:13].C(N(CC)CC)C>C(O)C>[CH3:1][O:2][C:3]1[C:4]([CH:9]=[N:12][OH:13])=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: NO
Reactant: COc1nccnc1C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1nccnc1C=NO
Temperature: 60 °C
Yield: 32.2 %

Procedure:
A mixture of 3-methoxypyrazine-2-carboxaldehyde (Tetrahedron (1999), 56(2), 265-273) (2.1 g, 15 mmol), hydroxylamine hydrochloride (1.27 g, 18 mmol), ethanol (20 ml) and triethylamine (4.17 ml, 30 mmol) was heated at 60° C. for 90 minutes. The volatiles were removed by evaporation and residue was purified by column chromatography on silica gel eluting with hexane/EtOAc (100:0 increasing in polarity 0:100) to give the title compound (740 mg, 32%) as a white solid.
Reaction SMILES: N(C[C@@H](C1C=CC(OCC2C=CC=CC=2)=C2C=1C=CC(=O)N2)O)=[N+]=[N-].[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([C@@H:40]([O:77][Si](C(C)(C)C)(C)C)[CH2:41][NH:42][C:43]([CH3:76])([CH3:75])[CH2:44][C:45]2[CH:46]=[C:47]([CH:72]=[CH:73][CH:74]=2)[C:48]([NH:50][CH2:51][C:52]2[C:53]([NH:65][CH:66]3[CH2:71][CH2:70][O:69][CH2:68][CH2:67]3)=[C:54]3[CH:62]=[N:61][N:60]([CH2:63][CH3:64])[C:55]3=[N:56][C:57]=2[CH2:58][CH3:59])=[O:49])=[CH:36][C:35]=1[CH2:85][O:86][Si](C(C)(C)C)(C)C)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([C@@H:40]([OH:77])[CH2:41][NH:42][C:43]([CH3:75])([CH3:76])[CH2:44][C:45]2[CH:46]=[C:47]([CH:72]=[CH:73][CH:74]=2)[C:48]([NH:50][CH2:51][C:52]2[C:53]([NH:65][CH:66]3[CH2:67][CH2:68][O:69][CH2:70][CH2:71]3)=[C:54]3[CH:62]=[N:61][N:60]([CH2:63][CH3:64])[C:55]3=[N:56][C:57]=2[CH2:58][CH3:59])=[O:49])=[CH:36][C:35]=1[CH2:85][OH:86])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CC(C)(C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Agent: [N-]=[N+]=NC[C@H](O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CC(C)(C)NC[C@H](O)c2ccc(OCc3ccccc3)c(CO)c2)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 3, using Intermediate 51 as a substrate. ES/MS calcd. for C43H55N6O5+ 735.2. found m/z=735.5 (M+H)+.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([CH3:23])[N:9]=[C:10]([NH:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)O1.C([O-])([O-])=O.[K+].[K+].O.O(C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[OH:38][C:35]1[CH:36]=[CH:37][C:32]([C:2]2[N:6]3[CH:7]=[C:8]([CH3:23])[N:9]=[C:10]([NH:11][CH2:12][C:13]4[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=4)[C:5]3=[N:4][CH:3]=2)=[CH:33][CH:34]=1
Reactant: Cc1cn2c(Br)cnc2c(NCc2ccc(S(N)(=O)=O)cc2)n1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cn2c(-c3ccc(O)cc3)cnc2c(NCc2ccc(S(N)(=O)=O)cc2)n1
Temperature: 88 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
A mixture of 4-[(3-bromo-6-methyl-imidazo[1,2-a]pyrazin-8-ylamino)-methyl]-benzenesulfonamide (0.1 g, 0.252 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (0.061 g, 0.277 mmol), K2CO3 1.5M in water (0.34 mL, 0.504 mmol), Pd(OAc)2 (3.0 mg, 0.013 mmol), and (oxidi-2,1-phenylene)bis(diphenylphosphine) (14 mg, 0.026 mmol) in DMF 1 mL was stirred at 88° C. overnight. Then the reaction mixture is filtered through cotton, diluted with AcOEt, washed with water, the organic layer dried with MgSO4 (anhydrous), filtered and evaporated. The crude mixture is purified by prep. HPLC under acid conditions using a gradient of 0.1% formic acid in H2O/0.1% formic acid in acetonitrile (95/5:5 min, 9/1:13 min, 0/1:4 min) to give 4-{[3-(4-hydroxy-phenyl)-6-methyl-imidazo[1,2-a]pyrazin-8-ylamino]-methyl}-benzenesulfonamide as a brown oil (30.2 mg) LC-MS m/z 410 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:21])[C:11]([O:13][C:14]2([CH3:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+]([C:25]1[CH:30]=CC(C(C)C(O)=O)=C[CH:26]=1)([O-])=O.C1C2CC3(O)CC(C2)CC1C3>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH3:21])[C:11]([O:13][C:14]23[CH2:20][CH:25]4[CH2:30][CH:18]([CH2:17][CH:16]([CH2:26]4)[CH2:15]2)[CH2:19]3)=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C(=O)OC1(C)CCCCC1)c1ccc([N+](=O)[O-])cc1
Agent: OC12CC3CC(CC(C3)C1)C2
Product: CC(C(=O)OC12CC3CC(CC(C3)C1)C2)c1ccc([N+](=O)[O-])cc1
Yield: 92 %

Procedure:
Using a method similar to that used in the preparation of 1-methylcyclohexyl 2-(p-nitrophenyl)propionate, 14.6 g of 2-(p-nitrophenyl)propionic acid, but using 1-adamantol instead of 1-methylcyclohexanol, were reacted to obtain 22.74 g (92% yield) of 1-adamantyl 2-(p-nitrophenyl)propionate as a light yellow viscous liquid.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:13]=[C:12]([Cl:14])[C:11]2[CH2:10][CH2:9][C:8]([Cl:16])([Cl:15])[C:7](=[O:17])[C:6]=2[C:5]=1[CH2:18][CH2:19][C:20]([O-:22])=[O:21].[CH2:23](O)[CH3:24]>[BH4-].[Na+]>[OH:17][CH:7]1[C:6]2[C:5]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:4]([CH3:3])[CH:13]=[C:12]([Cl:14])[C:11]=2[CH2:10][CH2:9][C:8]1([Cl:16])[Cl:15]
Reactant: CCO
Reactant: Cc1cc(Cl)c2c(c1CCC(=O)[O-])C(=O)C(Cl)(Cl)CC2
Agent: [BH4-]
Agent: [Na+]
Product: CCOC(=O)CCc1c(C)cc(Cl)c2c1C(O)C(Cl)(Cl)CC2
Reaction time: 0.25 h

Procedure:
Sodium borohydride (0.19 g, 5.02 mmoles) was added to a solution of 3-(2-methyl-8-oxo-5,6,7,8-tetrahydro-4,7,7-trichloronaphthalen-1-yl)propanoate (7.38 g, 20.3 mmoles) in ethanol (60 ml) which had been cooled in an ice-water bath. The reaction was allowed to stir for 15 minutes. Tlc (silica-CH2Cl2) showed reaction not complete. Add 20 mg of sodium borohydride first stirred in the cold for 15 minutes. Repeat addition of 20 mg of sodium borohydride with 15 minutes stirring in the cold twice more at which time tlc showed reaction complete. The reaction was then partitioned between ether (150 ml) and water (300 ml). The water was extracted with ether two times. The combined ether extracts were washed with water two times, dried (MgSO4), filtered, and the solvent evaporated in vacuo to leave 7.25 g of title compound as a gum.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20].O>CC(C)=O>[CH2:20]([O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1)[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C=CCOc1ccc(C(=O)OC)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
To a solution of 15.0 g (98.6 mmol) of methyl p-hydroxybenzoate and 13.0 g (94.1 mmol) of potassium carbonate mixed in 150 ml of acetone were added 13 ml (150 mmol) of allyl bromide and the whole was stirred at 80° C. for 2 hours under an argon gas atmosphere. Water was added to the solution and the whole was extracted with ethyl acetate. Then, the organic phase was washed with 5% aqueous solution of sodium hydroxide and saturated saline solution. After removal of the solvent by distillation, the residue was purified by silica gel column chromatography to obtain 18.6 g of methyl p-allyloxybenzoate (11) (yield: 96.6%).
Reaction SMILES: C(=O)(OC(C)(C)C)N.[NH2:9][C@H:10]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:11][C:12]([N:14]1[CH2:34][CH2:33][CH2:32][C@H:15]1[C:16]([NH:18][CH2:19][C:20]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:21]=1[O:22][CH2:23][C:24]([OH:26])=O)=[O:17])=[O:13].[CH:42]1([NH2:45])[CH2:44][CH2:43]1>CN(C=O)C>[NH2:9][C@H:10]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:11][C:12]([N:14]1[CH2:34][CH2:33][CH2:32][C@H:15]1[C:16]([NH:18][CH2:19][C:20]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:21]=1[O:22][CH2:23][C:24]([NH:45][CH:42]1[CH2:44][CH2:43]1)=[O:26])=[O:17])=[O:13]
Reactant: NC1CC1
Reactant: N[C@@H](CC(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1OCC(=O)O)Cc1ccccc1
Agent: CC(C)(C)OC(N)=O
Solvent: CN(C)C=O
Product: N[C@@H](CC(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1OCC(=O)NC1CC1)Cc1ccccc1

Procedure:
A solution of 46 mg (0.08 mmol) of the tert butyl carbamate of {2-[({1-[(3R)-3-amino-4-phenylbutanoyl]-L-prolyl}amino)methyl]-4-chlorophenoxyacetic acid and 0.0055 mL (0.096 mmol) of cyclopropylamine in DMF were coupled and deprotected as described for Example 1, Step C and D to give 25 mg of the title compound. 1H NMR (400 MHz, CD3OD) δ 7.32–7.10 (m, 7H), 6.95 (d, 0.2H, J=8 Hz), 6.85 (d, 0.8H, J=8 Hz), 4.55–4.22 (m, 5H), 3.61–3.35 (m, 3H), 2.82–2.50 (m, 4H), 2.38–2.10 (m, 2H), 2.07–1.80 (m, 3H), 0.75–0.58 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.ClC1C=C(C[C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[O:18])C=CN=1>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:17](=[O:18])[CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=2)=[CH:20][CH:21]=1
Reactant: Cc1ccnc(F)c1
Reactant: O=C(Cc1ccnc(Cl)c1)c1ccc(F)cc1
Product: O=C(Cc1ccnc(F)c1)c1ccc(F)cc1

Procedure:
21b was prepared from 2-fluoro-4-methylpyridine (13.9 g; 125 mmol) using the method described in the synthesis of 21a.
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(OCC)(=O)C>[CH3:23][S:24]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)(=[O:26])=[O:25]
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CS(=O)(=O)N1CCNCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Benzyl 1-piperazinecarboxylate (2.03 g, 9.22 mmol) was dissolved in pyridine (23.0 mL, 9.22 mmol) and cooled to 0° C. before methanesulfonyl chloride (2.85 mL, 36.9 mmol) was added. The reaction mixture was stirred at 0° C. for 30 minutes and warmed to RT for 2 h. The reaction mixture was diluted with 75 mL of ethyl acetate, added to a separation funnel, partitioned with 3 N HCl (aqueous), washed 3× with 50 mL of 3 N HCl (aqueous), and separated, before the aqueous layer was extracted 3× with chloroform/isopropanol, then dried over sodium sulfate, and concentrated in vacuo to give the title compound. Benzyl 4-(methylsulfonyl)piperazine-1-carboxylate (2.80 g, 9.4 mmol) was dissolved in ethanol (0.43 g, 9.4 mmol) before palladium, 10 wt. % on activated carbon (2.0 g) was added and a hydrogen balloon attached. The reaction mixture was stirred at RT for 2 h before it was filtered through a pad of Celite®, washed with methanol, and concentrated in vacuo to give the title compound. MS (ES+): 165 (M+H)+.