Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([CH3:13])=[CH:11][N:10]=[C:9]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:8]=1.[F:23][C:24]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:25]=1[CH:26]=[O:27]>CCCCCC.O.C(OCC)C>[Si:16]([O:15][CH2:14][C:9]1[CH:8]=[C:7]([CH:26]([C:25]2[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:24]=2[F:23])[OH:27])[C:12]([CH3:13])=[CH:11][N:10]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: O=Cc1cc(F)ccc1F
Reactant: Cc1cnc(CO[Si](C)(C)C(C)(C)C)cc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: Cc1cnc(CO[Si](C)(C)C(C)(C)C)cc1C(O)c1cc(F)ccc1F
Reaction time: 1 h
Yield: 74.2 %

Procedure:
Under an argon atmosphere, n-butyl lithium (a 1.58M hexane solution, 400 μl, 0.632 mmol) was added to a diethyl ether (3 ml) solution of 4-bromo-2-[(t-butyldimethylsilyloxy)methyl]-5-methylpyridine (200 mg, 0.632 mmol) at −78° C. The resulting mixture was stirred for 1 hour. After 2,5-difluorobenzaldehyde (69 μl, 0.632 mmol) was added dropwise, the reaction mixture was stirred for 1 hour. To the reaction mixture were added water and a saturated aqueous solution of sodium bicarbonate, followed by extraction with diethyl ether. The extract was washed with brine. The organic layer thus obtained was dried over magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=2:1 eluate was concentrated under reduced pressure to give the title compound (178 mg, 0.469 mmol, 74%) as a white powder.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.[NH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[C:22]2[CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38]>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[N:23]=[C:22]4[CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Reactant: COC(=O)CCc1nn(C(=O)OC(C)(C)C)c2ccc(N)cc12
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc3c(c2)c(CCC(=O)OC)nn3C(=O)OC(C)(C)C)ncn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 6-((cyclopropylmethyl)(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 31 mg; 0.13 mmol) in DCM (5 ml) was treated with tert-butyl 5-amino-3-(3-methoxy-3-oxopropyl)-1H-indazole-1-carboxylate (Intermediate 45, 35 mg; 0.11 mmol) and polymer-supported Mukaiyama reagent (300mg). After stirring at RT for 3 hours the mixture was filtered and washed with water. The organic phase was passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give tert-butyl 5-(6-((cyclopropylmethyl)(propyl)amino)pyrimidine-4-carboxamido)-3-(3-methoxy-3-oxopropyl)-1H-indazole-1-carboxylate. The intermediate was redissolved in DCM (2 ml) and treated with TFA (1 ml) and water (1 drop). After stirring at RT for 3 hours the solvent was removed in vacuo. The residue was partitioned between DCM and saturated sodium bicarbonate solution. The separated organic phase was passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.P(Br)(Br)[Br:13].[OH-].[Na+]>C1(C)C=CC=CC=1.CN(C=O)C>[Br:13][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][N:4]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1O
Reactant: BrP(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1cc([N+](=O)[O-])cnc1Br
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 98.7 %

Procedure:
A sample of 3-methyl-5-nitropyridin-2-ol (1.44 g, 9.34 mmol) was placed in 35 mL pressure vessel and dissolved in a mixture of toluene/DMF (10:1 ratio; 15 mL). The vessel was capped with a septum, flushed with Argon and phosphorous tribromide (1.32 mL, 14.0 mmol) was added by syringe. The septum cap was replaced by a Teflon cap and the mixture was stirred for 20 min at 120° C. The mixture was cooled to room temperature, neutralized with a 3M NaOH solution and extracted with toluene (3×). The combined organic phases were dried over anhydrous MgSO4 and concentrated under vacuum to give 2.00 g of the desired 2-bromo-3-methyl-5-nitropyridine product as an orange solid (99%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:15](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C.[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:15])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(F)cc(C(=O)O)c1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Cs+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(F)cc(C)c1[N+](=O)[O-]
Reaction time: 18 h

Procedure:
To a solution of (E1) and cesium carbonate (1.5 eq.) in DMF (0.25 M) at RT was added methyl iodide (1.0 eq.). After the mixture was stirred for 18 h, brine was added and the mixture was extracted with EtOAc. The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The yellow solid was used in the next step without purification. 1H NMR (400 MHz, DMSO, 300K) δ 7.63 (2H, m), 3.83 (3H, s), 2.29 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[C:12]([O:14][CH3:15])=[O:13].[C:16]([CH2:24][C:25](O)=[O:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[C:16]([CH2:24][C:25]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[C:12]([O:14][CH3:15])=[O:13])=[O:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)CC(=O)c1ccccc1
Reactant: COC(=O)c1cccc(N)c1C(=O)OC
Solvent: C1CCOC1
Product: COC(=O)c1cccc(NC(=O)CC(=O)c2ccccc2)c1C(=O)OC
Temperature: 25 °C
Yield: 62.7 %

Procedure:
A mixture of 2.1 grams of dimethyl 3-aminophthalate, 1.4 grams of benzoylacetic acid and 2.9 grams of dicyclohexlcarbodiimide is dissolved in 15 ml of tetrahydrofuran and the mixture is stirred at room temperature for eighteen hours. The insoluble matter are removed by filtration, the filtrate is concentrated, and 1.9 grams of dimethyl 3-benzoylacetylaminophthalate, colorless crystals, melting point 100° to 103° C. is obtained. This (1.9 grams) is dissolved in 30 ml of methanol, heated to reflux for four hours with 0.48 grams of sodium hydride, cooled, adjusted to pH 3 with diluted hydrochloric acid, crystals separated out therefrom are collected by filtration and recrystallized from methanol to give 1.3 grams of methyl 3-benzoyl-4-hydroxy-2-quinolone-5-carboxylate, pale yellow needles, melting point 263° to 265° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][C:23](C5NN=CC=5)=[CH:24][CH:25]=4)[O:20][C:19]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC1(C2C=CC(C3C(=O)C4C(=C(Br)C=CC=4)OC=3C3C=CC=CC=3)=CC=2)CCC1)(C)(C)C.[CH3:77][C:78]1[C:82](B(O)O)=[C:81]([CH3:86])[O:80][N:79]=1>>[C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([C:82]5[C:78]([CH3:77])=[N:79][O:80][C:81]=5[CH3:86])[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1noc(C)c1B(O)O
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(-c5ccn[nH]5)ccc4c3=O)cc2)CCC1
Agent: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Br)cccc4c3=O)cc2)CCC1
Product: Cc1noc(C)c1-c1cccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Yield: 31 %

Procedure:
Following the procedure of (1-{-4-[4-oxo-2-phenyl-7-(2H-pyrazol-3-yl)-4H-chromen-3-yl]phenyl}cyclobutyl)-carbamic acid tert-butyl ester, {1-[4-(8-bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted with 3,5-dimethylisoxazole-4-boronic acid to give the title compound (16 mg, 31%). LCMS (Method G): RT=4.34 min, [M+H]+=563.
Reaction SMILES: CN(C)C=O.[O:6]=[C:7]1[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:9][CH:8]1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[H][H]>ClCCl.C1C=CC=CC=1.C1C=CC=CC=1.Cl[Ru]Cl.Cl[Ru]Cl>[OH:6][C@@H:7]1[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[CH2:9][C@H:8]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: [H][H]
Reactant: CCOC(=O)C1CN(C(=O)OCc2ccccc2)CC1=O
Agent: Cl[Ru]Cl
Solvent: c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 125.4 %

Procedure:
43 mL of anhydrous N,N-dimethylformamide was added to 1.15 g of benzene ruthenium (II) chloride dimer (2.30 mmol) and 3.00 g of (R)-(−)-BINAP (4.82 mmol) in a stream of argon gas. The mixture was stirred in an oil bath at an external temperature of 95 to 105° C. for 10 minutes. The mixture was then allowed to cool to room temperature. Volatile materials were evaporated under reduced pressure (using a vacuum pump) in an oil bath at an external temperature of 50 to 70° C. to give a catalyst. 33.5 g of 1-benzyl 3-ethyl 4-oxopyrrolidine-1,3-dicarboxylate (115 mmol) and 68 mL of dehydrated dichloromethane were placed in an autoclave and the air in the autoclave was replaced by argon. The catalyst dissolved in 100 mL of dehydrated dichloromethane was then added and the atmosphere in the autoclave was replaced by hydrogen gas three times. The mixture was stirred under a pressurized hydrogen atmosphere (8.83 MPa) at an external temperature of 50 to 60° C. for 4 hours. Heating/stirring was stopped, and the mixture was left overnight. Subsequently, hydrogen gas was released and the mixture was transferred to a different vessel and washed with 30 mL of dehydrated dichloromethane. The mixture was then concentrated under reduced pressure and dried in vacuo at room temperature for 30 minutes to give 42.3 g of a crude product of the title compound as a dark brown oil. This product was used in the subsequent step without further purification.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6]([N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]3[NH:22][C:23]([CH3:28])=[C:24]([Cl:27])[C:25]=3[Cl:26])=[O:20])[CH2:14][CH2:13]2)(C(OC)=O)[CH:5]=[CH:4][N:3]=1.[N:29]1([CH2:35][CH2:36][NH2:37])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.CN([CH:41]=[O:42])C>CCOC(C)=O.O>[Cl:1][C:2]1[N:3]=[C:4]([C:41]([NH:37][CH2:36][CH2:35][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:42])[CH:5]=[C:6]([N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]3[NH:22][C:23]([CH3:28])=[C:24]([Cl:27])[C:25]=3[Cl:26])=[O:20])[CH2:14][CH2:13]2)[N:7]=1
Reactant: CN(C)C=O
Reactant: NCCN1CCOCC1
Reactant: COC(=O)C1(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)C=CN=C(Cl)N1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)NCCN4CCOCC4)nc(Cl)n3)CC2)c(Cl)c1Cl
Temperature: 25 °C

Procedure:
A solution of methyl 2-chloro-6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)pyrimidine-4-carboxylate (Example 6: 380 mg, 0.85 mmol), 2-morpholin-4-ylethanamine (222 mg, 1.70 mmol) and TEA (0.12 ml, 0.85 mmol) in DMF (3 ml) were stirred at 60° C. under nitrogen for 18 hours. The mixture was cooled to room temperature and diluted with EtOAc (75 ml) and water (10 ml). The organic layer was separated, dried over Na2SO4, filtered and concentrated under vacuum. Purification by reversed-phase HPLC (water/acetonitrile gradient, 5-95%) provided 110 mg of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.[CH3:26][O:27][C:28]1[CH:36]=[C:35]2[C:31]([CH2:32][CH2:33][CH:34]2[NH2:37])=[CH:30][CH:29]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([NH:37][CH:34]2[C:35]4[C:31](=[CH:30][CH:29]=[C:28]([O:27][CH3:26])[CH:36]=4)[CH2:32][CH2:33]2)=[N:9]3)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: COc1ccc2c(c1)C(N)CC2
Product: COc1ccc2c(c1)C(Nc1ccc3c(NS(=O)(=O)c4ccc(F)cc4)cccc3n1)CC2

Procedure:
The title compound, MS: m/e=464.1 (M+H+), was prepared in accordance with the general method of example 13 from 5-nitro-2-chloroquinoline, 4-fluorobenzenesulfonyl chloride and 6-methoxyindan-1-ylamine (CAS 103028-81-5).
Reaction SMILES: I[C:2]1[C:3]([F:25])=[C:4]([F:24])[C:5]([F:23])=[C:6]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:7]=1.[CH:26]#[C:27][CH:28]([OH:32])[CH2:29][CH2:30][CH3:31].S([O-])([O-])(=O)=S.[Na+].[Na+]>[Cu](I)I.CN(C=O)C.C(N(CC)CC)C>[OH:32][CH:28]([CH2:29][CH2:30][CH3:31])[C:27]#[C:26][C:2]1[C:3]([F:25])=[C:4]([F:24])[C:5]([F:23])=[C:6]([C@H:8]2[CH2:9][CH2:10][C@H:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]3)[CH2:12][CH2:13]2)[CH:7]=1
Reactant: C#CC(O)CCC
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3cc(I)c(F)c(F)c3F)CC2)CC1
Agent: I[Cu]I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC(O)C#Cc1cc([C@H]2CC[C@H]([C@H]3CC[C@H](CCC)CC3)CC2)c(F)c(F)c1F
Temperature: 55 °C
Reaction time: 3 h

Procedure:
In a nitrogen atmosphere, 25 g of 5-iodo-2,3,4-trifluoro-1-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]benzene was dissolved into 300 mL of DMF, to which 21 mL of triethylamine, 0.19 g of copper iodide (I), and 0.58 g of tetrakistriphenylphosphine palladium (0) were added, followed by heating to 55° C. Into this, the DMF (30 mL) solution containing 5.9 g of 1-hexine-3-ol was added dropwise for 20 minutes, and stirred for 3 hours. After the reaction mixture was poured into a sodium thiosulfate aqueous solution, and stirred for a while, an organic layer was separated and an aqueous layer was extracted with toluene. After the extract and the organic layer were mixed together, washed using water, 10% hydrochloric acid twice, water, a saturated sodium hydrogen carbonate aqueous solution, and a saturated saline solution in that order, and dried using anhydrous magnesium sulfate, the solvent was evaporated under a reduced pressure. The residue was purified by sequentially carrying out column chromatography (silica gel, toluene) twice, activated carbon treatment (acetone), and column chromatography (silica gel, hexane/acetone), to obtain 20 g of 5-(3-hydroxy-1-hexynyl)-2,3,4-trifluoro-1-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]benzene.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:3]=1.[Li]CCCC.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([O:30][CH2:31][C:32]2([CH2:39][O:40][S:41]([C:44]3[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=3)(=[O:43])=[O:42])[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]2)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C1COCC1>[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([O:30][CH2:31][C:32]2([CH2:39][O:40][S:41]([C:44]3[CH:45]=[CH:46][C:47]([CH3:50])=[CH:48][CH:49]=3)(=[O:43])=[O:42])[CH2:33][CH2:34][C:35]([OH:38])([C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:3]=3)[CH2:36][CH2:37]2)(=[O:28])=[O:29])=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2(COS(=O)(=O)c3ccc(C)cc3)CCC(=O)CC2)cc1
Reactant: Brc1cccc(Oc2ccccc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCC2(COS(=O)(=O)c3ccc(C)cc3)CCC(O)(c3cccc(Oc4ccccc4)c3)CC2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 57.2 %

Procedure:
To a solution of 1-bromo-3-phenoxybenzene (0.320 g, 1.29 mmol) in anhydrous THF (10 mL) at −78° C. was added n-BuLi (0.804 mL of a 1.6 M solution in hexanes; 1.286 mmol). The reaction was stirred at −78° C. for 0.5 h and a solution of (4-oxocyclohexane-1,1-diyl)bis(methylene) bis(4-methylbenzenesulfonate) (0.5 g, 1.07 mmol) in THF (5 mL) was then added dropwise. The reaction mixture was slowly warmed to rt and stirred overnight. The reaction was quenched with sat′d aq NH4Cl and diluted with water. The mixture was extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated in vacuo. The crude oil was purified by flash chromatography on SiO2 (0 to 50% EtOAc:hexanes) to afford the title compound (0.39 g, 57% yield) as a white foam. 1H NMR (500 MHz, CDCl3) δ 7.78 (t, J=8.6 Hz, 4H), 7.41-7.33 (m, 6H), 7.29 (dd, J=11.4, 5.0 Hz, 1H), 7.16-7.10 (m, 1H), 7.08-6.99 (m, 4H), 6.89-6.84 (m, 1H), 4.01 (s, 2H), 3.81 (s, 2H), 2.49 (s, 3H), 2.45 (s, 3H), 1.75-1.47 (m, 8H).
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:20])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Br.[CH3:53][O:54][C:55](=[O:69])[CH2:56][CH2:57][C:58]1[O:62][N:61]=[C:60]([CH:63]([NH2:68])[CH2:64][CH:65]([CH3:67])[CH3:66])[CH:59]=1>C(Cl)Cl.O>[CH3:53][O:54][C:55](=[O:69])[CH2:56][CH2:57][C:58]1[O:62][N:61]=[C:60]([CH:63]([NH:68][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:8]([NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:21])=[O:20])=[CH:15][CH:14]=2)[CH2:64][CH:65]([CH3:67])[CH3:66])[CH:59]=1
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)O)cc1
Reactant: COC(=O)CCc1cc(C(N)CC(C)C)no1
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCc1cc(C(CC(C)C)NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)cc2)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.1 %

Procedure:
To a stirred solution of [4-(3-o-tolyl-ureido)-phenyl]-acetic acid (305 mg, 1.07 mmol), DIEA (1.3 ml), HOBT (120 mg, 0.89 mmol) and EDCI (170 mg, 0.89 mmol) in CH2Cl2 (8 ml) at room temperature was added a solution of 3-[3-(1-amino-3-methyl-butyl)-isoxazol-5-yl]-propionic acid methyl ester hydrobromide (272 mg, 0.85 mmol) in CH2Cl2 (12 ml). After stirring for 16 h at room temperature the mixture was diluted with CH2Cl2 (20 ml) and poured into water. The layers were separated and the aqueous layer was extracted with CH2Cl2 (20 ml×3). The combined organics were dried over MgSO4; filtered; and concentrated under reduced pressure. The residue was purified by Flash 40 chromatography using a silica gel column and eluting with 65% EtOAc/hexane to give 220 mg of the title compound as a white amorphous solid. MP 153-4° C.; MS [+1]+507.2; 1H nmr (400 MHz, CDCl3) δ0.88 (d, J=6.4 Hz, 6H), 1.53-1.66 (m, 3H), 2.21 (s, 3H), 2.66 (t, J=7.6 Hz, 2H), 3.00 (t, J=7.6 Hz, 2H), 3.49 (s, 2H), 3.68 (s, 3H), 5.15 (dt, J=6.2 and 8.7 Hz, 1H), 5.85 (s, 1H), 6.11 (d, J=8.5 Hz, 1H), 6.65 (s, 1H), 7.00 (s, 1H), 7.05-7.24 (m, 7H), 7.53 (d, 1H); Anal. calcd. for C28H34N4O5: C (66.39), H (6.76), N (11.05). Found: C (66.29), H (7.11), N (11.11).
Reaction SMILES: [N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:31]=[C:32]([C:34](=[O:43])[NH:35][C:36]4[CH:41]=[N:40][C:39]([CH3:42])=[CH:38][N:37]=4)[CH:33]=3)[O:17][CH:18]([CH2:24][CH2:25]OS(C)(=O)=O)[C:19]([O:21]CC)=O)=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[I-].[Na+].[CH:46]1([NH2:50])[CH2:49][CH2:48][CH2:47]1>C(#N)C>[N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:33]=[C:32]([CH:31]=[C:16]([O:17][CH:18]4[CH2:24][CH2:25][N:50]([CH:46]5[CH2:49][CH2:48][CH2:47]5)[C:19]4=[O:21])[CH:15]=3)[C:34]([NH:35][C:36]3[CH:41]=[N:40][C:39]([CH3:42])=[CH:38][N:37]=3)=[O:43])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCC1
Reactant: CCOC(=O)C(CCOS(C)(=O)=O)Oc1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(C(=O)Nc2cnc(C)cn2)c1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(OC3CCN(C4CCC4)C3=O)c2)cn1
Temperature: 120 °C
Yield: 42.7 %

Procedure:
To a solution of ethyl 2-[3-[6-(azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(5-methylpyrazin-2-yl)carbamoyl]phenoxy]-4-methylsulfonyloxy-butanoate (Intermediate 27) (250 mg, 0.41 mmol) in acetonitrile (5 mL), was added sodium iodide (62 mg, 0.41 mmol) and cyclobutylamine (70 μL, 0.81 mmol). The resulting mixture was heated in a microwave at 120° C. for 60 minutes. The solvent was evaporated under reduced pressure and the residue purified by flash chromatography eluting with 0-40% methanol in DCM to afford the product (95 mg, 43%). 1H NMR δ (300 MHz, CDCl3) 1.69-1.78 (2H, m), 2.13-2.23 (5H, m), 2.30-2.40 (2H, m), 2.55-2.64 (4H, m), 3.39-3.47 (1H, m), 3.57-3.64 (1H, m), 4.24 (2H t), 4.62-4.72 (3H, m), 4.91-4.96 (1H, m), 6.96 (1H, t), 7.22 (1H t), 7.36-7.40 (1H, m), 7.45 (1H, t), 8.09-8.13 (2H, m), 8.32 (1H, d), 8.61 (1H, s), 9.51 (1H, d); m/z 543 (M+H)+.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].O=[C:14]([CH2:21][CH2:22][CH3:23])[CH2:15][C:16]([O:18]CC)=[O:17].C[O-].[Na+].[OH-].[Na+]>CO>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([N:1]2[C:14]([CH2:21][CH2:22][CH3:23])=[C:15]([C:16]([OH:18])=[O:17])[N:3]=[N:2]2)=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: [N-]=[N+]=Nc1ccc([N+](=O)[O-])cc1
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(C(=O)O)nnn1-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
To a solution of 1-azido-4-nitrobenzene (16.4 g) obtained in Example 1a) and ethyl 3-keto-n-hexanoate (17.0 ml) in methanol (200 ml) was added 28% sodium methoxide in methanol solution (21 ml) under ice-cooling, and the mixture was stirred for 30 min and then at 50° C. overnight. Then, 1N aqueous sodium hydroxide solution (100 ml) was added, and the mixture was stirred at 50° C. for 1.5 hr, and cooled to room temperature. The solvent was evaporated under reduced pressure, and the residual aqueous solution was diluted with water and washed with ethyl acetate. Then, the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a brown solid (13.4 g, 49%). The obtained crude product was used for the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17](=O)[C:16]3[C:15]([C:19]([O:21]CC)=O)=[CH:14][CH:13]=[CH:12][C:11]=3[NH:10][CH:9]2[C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.O.[NH2:37][NH2:38]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:17]3=[N:37][NH:38][C:19](=[O:21])[C:15]4[CH:14]=[CH:13][CH:12]=[C:11]([C:16]=43)[NH:10][CH:9]2[C:24]2[CH:25]=[CH:26][C:27]([CH2:30][N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[CH:28][CH:29]=2)=[CH:6][CH:7]=1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(Cl)cc1)C(c1ccc(CN(CC)CC)cc1)N2
Solvent: CO
Solvent: O
Product: CCN(CC)Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(Cl)cc2)cc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A mixture of ethyl 3-(4-chlorophenyl)-2-(4-((diethylamino)methyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (268 mg) in 85% hydrazine monohydrate (0.5 mL) and methanol (2 mL) was stirred at 23° C. for overnight. Methanol was removed under reduced pressure. The crude was purified by prep-HPLC to give the title compound (93 mg, yield 37%). LC-MS (ESI) m/z: 459 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 0.93 (t, 6H), 2.38 (q, 4H), 3.44 (s, 2H), 4.35 (d, 1H), 4.73 (d, 1H), 7.13-7.19 (m, 5H), 7.22-7.25 (m, 4H), 7.38 (d, 2H), 7.41 (s, 1H), 7.56-7.59 (m, 1H).