Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][P:9]([CH2:18][C@H:19]([OH:50])[CH2:20][NH:21][C:22](=[O:49])[C@@H:23]([NH:27][C:28](=[O:48])[C@@H:29]([NH:37]C(OCC1C=CC=CC=1)=O)[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:24]([CH3:26])[CH3:25])([CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10])C1C=CC=CC=1.C(OP(C[C@H](O)CNC(=O)[C@H](NC(=O)[C@@H](NC(OCC1C=CC=CC=1)=O)CC1C=CC=CC=1)C(C)C)(CC1CCCCC1)=O)C1C=CC=CC=1.N(C(OCC1C=CC=CC=1)=O)[C@H](C(N[C@H](C(O)=O)C(C)C)=O)CC1C=CC=CC=1.OC1C2N=NNC=2C=CC=1.N=C=N.C(N(CC)CC)C.Cl.C(OP(C[C@H](O)CN)(CC1CCCCC1)=O)C1C=CC=CC=1>C(Cl)Cl>[NH2:37][C@@H:29]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:28]([NH:27][C@H:23]([CH:24]([CH3:25])[CH3:26])[C:22]([NH:21][CH2:20][C@@H:19]([OH:50])[CH2:18][P:9]([CH2:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)(=[O:8])[OH:10])=[O:49])=[O:48]
Reactant: CC(C)[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Agent: CC(C)[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Agent: CC(C)[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)NC[C@@H](O)CP(=O)(O)CC1CCCCC1
Reaction time: 0.17 h

Procedure:
{(R)-3-[(S)-2-((S)-2-Benzyloxycarbonylamino-3-phenyl-propionylamino)-3-methyl-butyrylamino]-2-hydroxy-propyl}-cyclohexylmethyl-phosphinic acid benzyl ester and {(R)-3-[(R)-2-((S)-2-benzyloxycarbonylamino-3-phenyl-propionylamino)-3-methyl-butyrylamino]-2-hydroxy-propyl}-cyclohexylmethyl-phosphinic acid benzyl ester: To a solution of N-Z-Phe-Val-OH (1.0 g, 2.5 mmol) dissolved in CH2Cl2 (80 mL) under nitrogen was added hydroxybenzotriazole (0.346 g, 2.56 mmol) and PS-Carbodiimide (1.3 g, 3.0 mmol). After stirring for 10 min, triethylamine (1.4 mL, 10 mmol) and ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride (1.36 g, 3.75 mmol) were added. The reaction was stirred for 2 h, then filtered and concentrated in vacuo. The residue was purified by flash chromatography using 0-4% MeOH/CH2Cl2 as the eluent on a 35 g RediSep disposable column to give the title compound (0.806 g, 1.14 mmol) as a glassy solid. 31P NMR (CD3OD, 300 MHz): δ 59.09, 59.09, 58.38, 58.38. LCMS m/z: [M+H]+=707.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:17](=[O:21])[N:18]([CH3:20])[CH3:19])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)(C)(C)C.[ClH:23].O1CCOCC1>>[ClH:23].[ClH:23].[NH2:7][C@@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=1)[C:17]([N:18]([CH3:20])[CH3:19])=[O:21]
Reactant: CN(C)C(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)C(=O)[C@@H](N)Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-[2-(4-Amino-phenyl)-1-dimethylcarbamoyl-ethyl]-carbamicacidtert-butyl ester (214 mg, 0.7 mmol) was dissolved in 4M HCl-dioxane (2 mL) at 0° C. and the solution stirred for 2 hours at 25° C. The mixture was concentrated and the residue triturated with ether. Yield, 294 mg, 102%; PBMS 208 (MH+, 100%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19]2[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=2)[CH:13]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].O>C(COC)OC>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19]2[CH:24]=[C:23]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[O:27][CH3:26])[N:22]=[CH:21][N:20]=2)[CH:13]=1
Reactant: Clc1cc(Nc2cccc(CNc3nc4ccccc4[nH]3)c2)ncn1
Reactant: COc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccccc1-c1cc(Nc2cccc(CNc3nc4ccccc4[nH]3)c2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
235 mg (1H-Benzoimidazol-2-yl)-[3-(6-chloro-pyrimidin-4-ylamino)-benzyl]-amine (prepared in Example 63) (0.70 mmol) was suspended in 30 cm3 dimethoxyethane and the flask was filled with argon properly. 58 mg Tetrakis(thriphenylphosphine) palladium[0] (0.05 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Then 152 mg 2-methoxyphenyl-boronic acid (1 mmol), 318 mg anhydrous Na2CO3 (3 mmol) and 6 ml water was added. The mixture was ferluxed overnight while slow argon flow was being applied. The reaction mixture was poured to 80 cm3 1M NaH2PO4 solution and it was extracted three times with 50-50 cm3 of ethyl-acetate. The combined organic layer was washed with brine, dried over MgSO4, decolorized with activated carbon and evaporated to dryness. The residual solid was recrystallized from minimal amount of acetonitrile and air-dried to give the desired product (158 mg, 55% yield). For analitical results and compound identification see Table 1.
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH2:4][CH2:3][C:2]1=[O:11].C([O-])=O.[Na+].[OH-].[Na+]>C(O)=O>[NH:1]1[C@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][C:2]1=[O:11]
Reactant: O=C1CCC2=C(CCCC2)N1
Agent: O=C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: O=C1CC[C@@H]2CCCC[C@H]2N1
Yield: 74.1 %

Procedure:
A mixture of 1 g (6.62 mmol) of 3,4,5,6,7,8,-hexahydro-2(1H)-quinolinone, 2.8 g (41 mmol) of sodium formate and 5 mL of formic acid was heated to reflux for 1 day The reaction mixture was then cooled and 20% sodium hydroxide solution was added to make it basic. This mixture was then extracted with ethyl acetate. The combined ethyl acetate extracts were dried over anhydrous magnesium sulfate and the solvent was removed to give a crude product. This was purified on silica gel using ethyl acetate as solvent to provide 752 mg of the desired product with about 10% of the cis-isomer. Recrystallization of this material from cyclohexane did not improve the ratio of the isomers.
Reaction SMILES: [CH:1]1([N:4]2[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](OS(C(F)(F)F)(=O)=O)=[N:7][C:6]3[C:23]([CH3:27])=[CH:24][CH:25]=[N:26][C:5]2=3)[CH2:3][CH2:2]1.[OH-].[NH4+:29]>O1CCOCC1.C(OCC)(=O)C>[NH2:29][C:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[N:11][C:10]=2[N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]2[N:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:6]=2[N:7]=1
Reactant: [NH4+]
Reactant: Cc1ccnc2c1N=C(OS(=O)(=O)C(F)(F)F)c1cccnc1N2C1CC1
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccnc2c1N=C(N)c1cccnc1N2C1CC1
Temperature: 100 °C
Yield: 30 %

Procedure:
To a solution of 11-cyclopropyl-4-methyl-6-trifluoromethanesulfonyloxy-11H-dipyrido[3,2-b:2',3'-e][1,4]diazepine (0.22 g, 0.55 mmol) in 1,4-dioxane (3 mL) was added 30% ammonium hydroxide (3 mL). The mixture was heated at 100° C. for 15 min. After cooling to room temperature the mixture was diluted with ethyl acetate, washed with water, dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was chromatographed over silica gel (eluted with 1:1:1 ethyl acetate/hexane/methylene chloride→50% ethyl acetate/hexane) to give the title compound (0.045 g, 0.17 mmol, 30%) which crystallized from ethyl acetate/hexane, m.p. 242°-244° C.
Reaction SMILES: [NH2:1][C@@H:2]([C@H:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:9]=1)[CH3:7])[C:3]([OH:5])=[O:4].C(=O)(O)[O-].[Na+].O=C1CCC(=O)N1[C:36]([O:38][CH2:39][CH:40]1[C:52]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[C:46]2[C:41]1=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37].[Cl-].[NH4+]>O.C1COCC1>[CH:51]1[C:52]2[CH:40]([CH2:39][O:38][C:36]([NH:1][C@@H:2]([C@H:6]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH:9]=3)[CH3:7])[C:3]([OH:5])=[O:4])=[O:37])[C:41]3[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:47]=2[CH:48]=[CH:49][CH:50]=1
Reactant: O=C1CCC(=O)N1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: C[C@@H](c1cn(C(=O)OC(C)(C)C)c2ccccc12)[C@H](N)C(=O)O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](c1cn(C(=O)OC(C)(C)C)c2ccccc12)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reaction time: 16 h

Procedure:
(2S,3S)-2-amino-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)butanoic acid (2197 mg, 6.9 mmol) was dissolved in a mixture of Water (35 mL) and THF (100 mL). Sodium bicarbonate (2174 mg, 25.9 mmol) and (9H-fluoren-9-yl)methyl 2,5-dioxopyrrolidine-1-carboxylate (4434 mg, 13.80 mmol) were added to the solution and the reaction was stirred for 16 h. Saturated ammonium chloride solution (200 mL) was added to the reaction and the solvent was then removed under vacuum. The remaining aqueous layer was extracted with EtOAc. The organic layer was then collected, dried over sodium sulfate, and concentrated under vacuum. The crude material was purified by rev. phase BIOTAGE® C-18 column using a gradient of 20-80% ACN/water with 0.1% TFA modifier over 20 min. The product fractions were collected, diluted with water and extracted with EtOAc. The organic layer washed with water, then brine, dried over sodium sulfate, and concentrated under vacuum to give (2S,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)butanoic acid, 500 mg (13%). ESI-MS(+) m/z 541.5 (M+H). 1H NMR (500 MHz, DMSO-d6) δ 12.79 (br. s., 1H), 8.03 (d, J=8.2 Hz, 1H), 7.90-7.85 (m, 2H), 7.73 (dd, J=8.1, 4.7 Hz, 2H), 7.62 (d, J=7.4 Hz, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.53 (s, 1H), 7.39 (td, J=7.4, 4.0 Hz, 2H), 7.35-7.30 (m, 1H), 7.28-7.18 (m, 3H), 4.45 (t, J=8.2 Hz, 1H), 4.30-4.25 (m, 1H), 4.21-4.15 (m, 1H), 4.15-4.09 (m, 1H), 3.48 (quin, J=7.2 Hz, 1H), 1.57 (s, 9H), 1.34 (d, J=7.3 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1NC(=O)CC(=O)c1cccc(-c2ccccn2)c1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J24) (466 mg, 1.5 mmol) and 3-oxo-3-(3-pyridin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K3) (446 mg, 1.5 mmol) according to the general procedure M. Obtained as an orange oil (310 mg, 39%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:5]=1[C:6](OCC)=[O:7])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>C1COCC1>[CH2:1]([O:3][C:4]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:5]=1[CH2:6][OH:7])[CH3:2]
Reactant: CCOC(=O)c1cccc(C)c1OCC
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCOc1c(C)cccc1CO
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.7 %

Procedure:
at 20°-25° C., a solution of 125.8 g of ethyl 2-ethoxy-3-methylbenzoate is dripped into 24.3 g of lithiumaluminum hydride in 500 ml of absolute THF. The mixture is stirred for 15 hours at room temperature, ice water is dripped in, and the mixture is acidified with concentrated hydrochloric acid and extracted with ether. The combined organic phases are washed with water, dried and concentrated. There is obtained 97.1 g of 2-ethoxy-3-methylbenzyl alcohol.
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:25][C:26]([NH:28][C@H:29]2[CH2:34][CH2:33][C@H:32]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:31][CH2:30]2)=[O:27])[C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=2)=[CH:6][CH:5]=1.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[F:18][C:17]([F:19])([F:20])[C:15]1[CH:16]=[C:11]([CH:10]([NH:25][C:26]([NH:28][C@H:29]2[CH2:30][CH2:31][C@H:32]([C:35]([CH3:36])([CH3:37])[CH3:38])[CH2:33][CH2:34]2)=[O:27])[C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:39])=[O:2])=[CH:9][CH:8]=2)[CH:12]=[C:13]([C:21]([F:22])([F:23])[F:24])[CH:14]=1
Reactant: COC(=O)c1ccc(C(NC(=O)N[C@H]2CC[C@H](C(C)(C)C)CC2)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)[C@H]1CC[C@H](NC(=O)NC(c2ccc(C(=O)O)cc2)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1

Procedure:
Trans-4-[1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-tert-butylcyclohexyl)ureidomethyl]benzoic acid methyl ester (1.4 g) was suspended in absolute ethanol (20 mL), sodium hydroxide (2N, 11 mL) was added and the reaction mixture was gently refluxed for 2 hours. The ethanol was removed in vacuo, additional water (40 mL) was added, pH was adjusted with hydrochloride (4 N) to acidic reaction and then ethyl acetate (200 mL) was added. The organic phase was isolated, washed with water (4×50 mL), dried with magnesium sulphate, filtered and evaporated in vacuo, affording 1.1 g (85%) trans-4-[1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-tert-butylcyclohexyl)ureidomethyl]benzoic acid as a solid.
Reaction SMILES: CON(C)[C:4](=[O:28])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH3:26])=[CH:16][C:15]=3[CH:27]=2)[CH:6]=1.[F:30][C:31]1[CH:32]=[C:33]([Mg]Br)[CH:34]=[CH:35][CH:36]=1>>[F:30][C:31]1[CH:32]=[C:33]([C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]3[CH:12]=[CH:13][C:14]4[O:18][C:17]([CH2:19][CH2:20][N:21]5[CH2:25][CH2:24][CH2:23][C@H:22]5[CH3:26])=[CH:16][C:15]=4[CH:27]=3)[CH:6]=2)=[O:28])[CH:34]=[CH:35][CH:36]=1
Reactant: Fc1cccc([Mg]Br)c1
Reactant: CON(C)C(=O)c1cccc(-c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)c1
Product: C[C@@H]1CCCN1CCc1cc2cc(-c3cccc(C(=O)c4cccc(F)c4)c3)ccc2o1
Yield: 46 %

Procedure:
The product from Example 145 and 3-fluorophenylmagnesium bromide were processed as described in Example 146 to provide the title compound (46% yield). MS (ESI APCI) m/z 428 (M+H)+; 1HNMR (300 MHz, CD3OD) δ 1.17 (d, 3 H), 1.36-1.53 (m, 1 H), 1.72-1.86 (m, 2 H), 1.94-2.07 (m, 1 H), 2.22-2.33 (m, 1 H), 2.39-2.58 (m, 2 H), 2.93-3.14 (m, 2 H), 3.18-3.3 (m, 2 H), 6.62 (s, 1 H), 7.37-7.45 (m, 1 H), 7.49-7.52 (m, 2 H), 7.52-7.66 (m, 4 H), 7.72 (ddd, 1 H), 7.77 (dd, 1 H), 7.94 (ddd, 1 H), 8.02 (dd, 1 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][N:36]=2)[CH2:31][CH2:30]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O.C(=O)(O)[O-].[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:25][C:24]1[CH:23]=[C:22]([CH3:26])[NH:21][C:20](=[O:27])[C:19]=1[CH2:18][NH:17][C:15]([C:4]1[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=[C:2]([C:38]2[CH:37]=[N:36][C:35]([N:32]3[CH2:31][CH2:30][N:29]([CH3:28])[CH2:34][CH2:33]3)=[CH:40][CH:39]=2)[CH:3]=1)=[O:16]
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2c(C)nn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCN(C)CC4)nc3)cc3c2c(C)nn3C(C)C)c(=O)[nH]1
Reaction time: 0.08 h

Procedure:
To a stirred solution of 6-bromo-N-((1,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1-isopropyl-3-methyl-1H-indazole-4-carboxamide (0.3 g, 0.69 mmol) in DMF (15 mL) was added 1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (0.25 g, 0.82 mmol) followed by PdCl2(PPh3)2 (0.097 g, 0.13 mmol) and the mixture stirred 5 min. Sodium carbonate (0.184 g, 1.73 mmol) dissolved in water (2 mL) was added and the resulting reaction mixture was stirred at 110° C. for 4 h. The contents were then diluted with sodium bicarbonate solution and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine solution (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford the crude product. The crude compound was purified by silica gel chromatography (eluent: 5% MeOH\DCM). The desired product was isolated as an off white solid with trace impurities. The impure compound was washed several times with cold water and triturated with hexane to afford the title compound as an off-white solid (80 mg, 22%). 1H NMR (DMSO-d6, 400 MHz): δ 1.447 (d, J=6.4 Hz, 6H), 2.112 (s, 3H), 2.235 (s, 6H), 2.411 (s, 7H), 3.551 (s, 4H), 4.363 (d, J=4.4 Hz, 2H), 4.991-5.054 (m, 1H), 5.870 (s, 1H), 6.942 (d, J=9.2 Hz, 1H), 7.321 (s, 1H), 7.880 (s, 1H), 7.99 (d, J=8.8 Hz, 1H), 8.403 (s, 1H), 8.569 (s, 1H), 11.483 (brs, 1H). LCMS (ES+) m/z: 528.29.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.O[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=[O:24])[CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[CH:18]([N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)[C:17](=[O:24])[C:12]3[CH:11]=[CH:16][CH:15]=[CH:14][C:13]=3[O:7]2)=[CH:4][CH:3]=1
Reactant: O=C(Cn1cncn1)c1ccccc1O
Reactant: O=Cc1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: O=C1c2ccccc2OC(c2ccc(Cl)cc2)C1n1cncn1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
4-Chlorobenzaldehyde (1.18 g) was added to 2'-hydroxy-2-(1,2,4-triazol-1-yl)acetophenone, obtained in Example 6 (1.7 g), in dry dimethylformamide (20 ml). The mixture was stirred at 90° C. for 24 hours. It was then poured into ice/water, extracted with dichloromethane and the extract dried and evaporated. The residual oil was triturated with diisopropyl ether to give 2-(4-chlorophenyl)-2,3-dihydro-3-(1,2,4-triazol-1-yl)-benzopyran-4-one, m.p. 140°-141° C. (Compound 15).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)=[O:4].[CH3:24][O:25][C:26]([C:28]1[CH:38]=[CH:37][C:31]([O:32]CC(O)=O)=[CH:30][CH:29]=1)=[O:27].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[S:11]([N:8]1[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][O:32][C:31]2[CH:30]=[CH:29][C:28]([C:26]([O:25][CH3:24])=[O:27])=[CH:38][CH:37]=2)[CH2:6][CH2:7]1)(=[O:13])=[O:12]
Reactant: COC(=O)c1ccc(OCC(=O)O)cc1
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
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: ClCCl
Product: COC(=O)c1ccc(OCC(=O)N2CCN(S(=O)(=O)c3ccc4ccccc4c3)CC2)cc1
Reaction time: 8 h
Yield: 63 %

Procedure:
To a stirred solution of 2-chloro-1-(4-(naphthalen-2-yl-sulfonyl)piperazin-1-yl)ethanone (compound 4, 0.2 g, 0.64 mmol) and 2-(4-(methoxycarbonyl)phenoxy)acetic acid (134 mg, 0.64 mmol) taken in dry DCM (20 mL), DIPEA (495 mg, 3.86 mmol) followed by HATU (486 mg, 1.27 mmol) was added at room temperature and stirred overnight. The mixture was then diluted with DCM washed with water (2×10 mL) and brine (2×10 mL) The organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield the title compound (0.189 g, 63.21%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:28]=[CH:29][CH:30]=1)[C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:15]=[C:16]([CH:19]=[C:20]([NH:22][C:23]3[S:24][CH:25]=[CH:26][N:27]=3)[N:21]=2)[C:17]#[N:18])[CH2:9][CH2:8]1)=[O:6].[N-:32]=[N+:33]=[N-:34].[Na+].Cl.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:28]=[CH:29][CH:30]=1)[C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[N:21]=[C:20]([NH:22][C:23]3[S:24][CH:25]=[CH:26][N:27]=3)[CH:19]=[C:16]([C:17]3[N:32]=[N:33][NH:34][N:18]=3)[CH:15]=2)[CH2:9][CH2:8]1)=[O:6]
Reactant: N#Cc1cc(CN2CCN(C(=O)c3cccc(Cl)c3F)CC2)nc(Nc2nccs2)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1cccc(Cl)c1F)N1CCN(Cc2cc(-c3nn[nH]n3)cc(Nc3nccs3)n2)CC1
Temperature: 110 °C
Reaction time: 13 h

Procedure:
A mixture of 25.2 mg of 2-((4-(3-chloro-2-fluorobenzoyl)piperazin-1-yl)methyl)-6-(thiazol-2-ylamino)isonicotinonitrile obtained in Example 104, 17.9 mg of sodium azide, 38.0 mg of triethylamine hydrochloride and 2 ml of N,N-dimethylformamide was stirred at 110° C. for 13 hours, and then the reaction solution was concentrated. The resulting residue was purified by a thin-layer chromatography for fractionation (eluent: chloroform/methanol=5/1) to give the title compound.
Reaction SMILES: [CH2:1]([N:5]([CH3:22])[C:6]([C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([C:17]2[O:18][CH:19]=[CH:20][N:21]=2)[CH:16]=1)[C:11]([OH:13])=O)=[O:7])[CH2:2][CH2:3][CH3:4].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:58][C@@H:59]([CH2:73][C:74]1[CH:79]=[C:78]([F:80])[CH:77]=[C:76]([F:81])[CH:75]=1)[C@H:60]([OH:72])[CH2:61][NH:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[C:66]([CH2:70][CH3:71])[CH:65]=1>CN(C=O)C.C(Cl)(Cl)Cl>[CH2:1]([N:5]([CH3:22])[C:6](=[O:7])[C:8]1[CH:16]=[C:15]([C:17]2[O:18][CH:19]=[CH:20][N:21]=2)[CH:14]=[C:10]([C:11]([NH:58][C@@H:59]([CH2:73][C:74]2[CH:75]=[C:76]([F:81])[CH:77]=[C:78]([F:80])[CH:79]=2)[C@H:60]([OH:72])[CH2:61][NH:62][CH2:63][C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([CH2:70][CH3:71])[CH:65]=2)=[O:13])[CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C)C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCCCN(C)C(=O)c1cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)cc(-c2ncco2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-{[Butyl(methyl)amino]carbonyl}-5-(1,3-oxazol-2-yl)benzoic acid (237 mg, 0.78 mmol) is dissolved in DMF (5 mL), and diisopropylethylamine (546 μL, 3.1 mmol), HATU (358 mg, 0.94 mmol), and (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride prepared by the method of EXAMPLE SP-272 (319 mg, 0.78 mmol) are added. The reaction stirred at room temperature 5 h. The reaction mixture is diluted with chloroform, washed with water, 1N hydrochloric acid (aq), saturated sodium bicarbonate, saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 9% methanol/methylene chloride) provides the title compound. ESI MS m/z 619.3 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:8][O:9][C:10]1[C:18]2[C:17]3[CH:19]=[C:20]([C:23]#[N:24])[N:21]=[CH:22][C:16]=3[N:15](COCC[Si](C)(C)C)[C:14]=2[N:13]=[CH:12][CH:11]=1.Br.[OH-].[Na+].Cl>O1CCOCC1>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:8][O:9][C:10]1[C:18]2[C:17]3[CH:19]=[C:20]([C:23]#[N:24])[N:21]=[CH:22][C:16]=3[NH:15][C:14]=2[N:13]=[CH:12][CH:11]=1
Reactant: CN1CCCC[C@@H]1COc1ccnc2c1c1cc(C#N)ncc1n2COCC[Si](C)(C)C
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CN1CCCC[C@@H]1COc1ccnc2[nH]c3cnc(C#N)cc3c12
Temperature: 75 °C
Yield: 27.6 %

Procedure:
(R)-4-((1-methylpiperidin-2-yl)methoxy)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (197 mg, 0.44 mmol) was dissolved in 1,4-dioxane (0.5 mL) and then treated with 48% HBr(aq) (0.5 mL) and heated at 75° C. for 15 minutes. The cooled reaction mixture was then basified to pH ˜12 by dropwise addition of 6N sodium hydroxide and then immediately acidified to pH ˜8-9 by dropwise addition of concentrated hydrochloric acid, producing a cloudy precipitate. The solid was collected by centrifugation, dissolved in dimethylsulfoxide (2 mL), and purified by preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) over 30 min, 35 mL/min] to afford the title compound as a white solid (39 mg, 28%). 1H NMR (400 MHz, d6-DMSO) δ 12.80 (s, 1H), 8.98 (d, J=0.9, 1H), 8.55 (d, J=5.7, 1H), 8.47 (d, J=0.9, 1H), 7.07 (d, J=5.8, 1H), 4.39 (ddd, J=35.9, 10.4, 4.4, 2H), 2.84 (m, 1H), 2.34 (s, 3H), 2.16 (td, J=11.4, 3.3, 1H), 1.92-1.82 (m, 1H), 1.76 (m, 1H), 1.62 (m, 1H), 1.58-1.43 (m, 2H), 1.43-1.29 (m, 1H), 1.23 (s, 1H). LCMS (Method D): RT=7.48 min, M+H+=322.1.