Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[C:10]([O:14][C:15]([NH:17][C@@:18]1([C:28]([OH:30])=[O:29])[CH2:23][C:22](=[O:24])[C@@H:21]2[C@H:19]1[C@H:20]2[C:25]([OH:27])=[O:26])=[O:16])([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][O:29][C:28]([C@:18]1([NH:17][C:15]([O:14][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:16])[CH2:23][C:22](=[O:24])[C@@H:21]2[C@H:19]1[C@H:20]2[C:25]([O:27][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[F:1])=[O:26])=[O:30]
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)O)CC(=O)[C@H]2[C@H](C(=O)O)[C@H]21
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@]1(C(=O)OCc2ccccc2F)CC(=O)[C@H]2[C@H](C(=O)OCc3ccccc3F)[C@H]21
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
Add 2-fluorobenzyl bromide (0.21 mL, 1.7 mmol) dropwise to a stirred suspension of (1S,2S,5R,6R)-2-(tert-butoxycarbonylamino)-4-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (0.17 g, 0.57 mmol) and cesium carbonate (0.37 g, 1.14 mmol) in dry N,N-dimethylformamide (1.42 mL). Stir the resulting mixture at room temperature overnight under nitrogen. Quench with water and dilute with ethyl acetate. Extract the aqueous phase with ethyl acetate (3 times) and wash the organic layers with brine and water. Dry over sodium sulfate, filter and concentrate to give the crude material as a pale brown oil. Purify by flash chromatography eluting with ethyl acetate:hexane (20:80 to 30:70) to give the title compound as a pale yellow oil (229 mg, 79%). MS (m/z): 538 (M+23).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:4]([CH:5]=O)[C:3]=1[OH:11].Cl[CH:13](C(OC)=O)[C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:10][C:9]1[CH:8]=[CH:7][C:4]2[CH:5]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[O:11][C:3]=2[C:2]=1[Cl:1]
Reactant: O=Cc1ccc(Cl)c(Cl)c1O
Reactant: COC(=O)C(Cl)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1cc2ccc(Cl)c(Cl)c2o1
Yield: 75.5 %

Procedure:
A suspension of 3,4-dichlorosalicylaldehyde (191 mg, 1.0 mmol), dimethyl chloromalonate (330 mg, 2.0 mmol), and powdery anhydrous potassium carbonate (414 mg, 3.0 mmol) in 4 ml of methyl ethyl ketone is refluxed under heating for 3 hours and evaporated under reduced pressure. The remaining residue is dissolved in ethyl acetate, washed with 10% hydrochloric acid, then water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give a residue, which is chromatographed on a silca gel with methylene chloride as an eluent. The eluates are recrystallized from an ethyl acetate-diethyl ether solution to give 185 mg (Yield 75.2%) of methyl 6,7-dichloro-2-benzofurancarboxylate (D-1), m.p. 161.5°-162° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][C:5]([NH:19][C:20](=[O:23])[CH2:21]Cl)=[C:4]([F:24])[CH:3]=1.[CH2:25]([NH2:27])[CH3:26]>C(O)C>[Cl:1][C:2]1[C:7]([O:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][C:5]([NH:19][C:20](=[O:23])[CH2:21][NH:27][CH2:25][CH3:26])=[C:4]([F:24])[CH:3]=1
Reactant: CCN
Reactant: O=C(CCl)Nc1cc(Oc2ncccc2C(F)(F)F)c(Cl)cc1F
Solvent: CCO
Product: CCNCC(=O)Nc1cc(Oc2ncccc2C(F)(F)F)c(Cl)cc1F

Procedure:
A solution of N-[4-chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenyl]-2-chloroacetamide (1.4 g) and 70% ethylamine (5 ml) in ethanol (25 ml) was heated at reflux for 3 hours and evaporated to dryness. The residue was processed to give a yellow solid (1.0 g). 1H NMR (CDCl3, TMS): 1.16(3H, t, J=7 Hz), 2.72(2H, q, J=7 Hz), 3.39(2H, s), 7.10(1H, dd, J=6,8 Hz), 7.26(1H, d, J=8 Hz), 8.00(1H, m), 8.24(1H, m), 8.45(1H, d, J=8 Hz), 9.86(1H, s).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([S:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:21])=[O:4].C(OC(=O)C)(=[O:24])C.OO>ClCCl>[Br:1][CH2:2][C:3]([C:5]1[C:6]([CH3:21])=[CH:7][C:8]([S:12]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[O:24])=[CH:9][C:10]=1[CH3:11])=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(Sc2cc(C)c(C(=O)CBr)c(C)c2)cc1
Agent: OO
Solvent: ClCCl
Product: COc1ccc(S(=O)c2cc(C)c(C(=O)CBr)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.2 %

Procedure:
A mixture of 2-bromo-1-(4-(4-methoxyphenylthio)-2,6-dimethylphenyl)ethanone (500.0 mg, 1.3 mmol, 1.0 equiv), acetic anhydride (0.14 mL, 1.5 mmol, 1.1 equiv), 30% hydrogen peroxide (55.86 mg, 1.6 mmol, 1.2 equiv) and silica gel (273.75 mg, 230-400 mesh) in dichloromethane (10.0 mL) was stirred at room temperature for 16 h. The solution was concentrated under reduced pressure, and the residue was re-dissolved in EtOAc (50 mL). The solution was washed with saturated aqueous NaHCO3 (30 mL), dried over MgSO4, and concentrated under reduced pressure to give 2-bromo-1-(4-(4-methoxyphenylsulfinyl)-2,6-dimethylphenyl)ethanone (235.4 mg, 0.6 mmol) as pale-yellow oil in 48% yield: 1H NMR (DMSO-d6, 500 MHz) δ 7.65 (d, J=8.8 Hz, 2 H), 7.41 (s, 2 H), 7.09 (d, J=8.8 Hz, 2 H), 4.78 (s, 2 H), 3.79 (s, 3 H), 2.21 (s, 6 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][CH:14]1[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]1[NH:23][CH2:24][C:25]#[N:26])=[O:12])=[CH:5]2.[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+].CCOC(C)=O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@@H:14]1[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C@H:15]1[NH:23][CH2:24][C:25]1[NH:29][N:28]=[N:27][N:26]=1)=[O:12])=[CH:5]2
Reactant: N#CCNC1c2ccccc2CC1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=C(N[C@@H]1Cc2ccccc2[C@H]1NCc1nnn[nH]1)c1cc2cc(Cl)ccc2[nH]1
Yield: 17.2 %

Procedure:
5-Chloro-N-{1-[(cyanomethyl)amino]-2,3-dihydro-1H-inden-2-yl}-1H-indole-2-carboxamide (Example 25; 182 mg, 0.5 mmol), sodium azide (195 mg, 3.0 mmol) and ammonium chloride (163 mg, 3.05 mmol) in DMA (5 mL) were heated in a microwave at 180° C. for 1 min. EtOAc (50 mL) was added and the mixture washed with water (6×10 mL), brine (25 mL), dried (MgSO4) and the volatiles removed by evaporation under reduced pressure. The desired component was isolated by preparative HPLC (CH3CN:water) to give the title compound (35 mg, 14%) as a pale orange powder.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[NH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([F:28])[CH:27]=1>>[NH2:21][C:22]1[CH:23]=[C:24]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: Nc1cc(F)cc(B(O)O)c1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3cc(N)cc(F)c3)ccn2c1=O
Yield: 86.7 %

Procedure:
Methyl 8-(3-amino-5-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 3-amino-5-fluoro-phenyl-boronic acid (80 mg, 0.51 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (108 mg, 81%).
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9](OC(C)=C)(=[O:11])[CH3:10]>C1(C)C=CC=CC=1>[C:9]([O:8][N:7]=[C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:11])[CH3:10]
Reactant: ON=C1CCCCC1
Reactant: C=C(C)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)ON=C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A mixture of 2.3 g (20 mmole) of cyclohexanone oxime, 2.0 g (20 mmole) of isopropenyl acetate, 0.9 g (2 mmole) of di(η5 -pentamethylcyclopentadienyl)samarium [Cp*2Sm(THF)2 ], and 20 ml of toluene was stirred at room temperature for one hour, and the precipitated crystals were filtered. 3.1 g of acetyloxyiminocyclohexane (O-acetylcyclohexanone oxime) (yield: 100%) was obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([C@@H:7]([CH3:9])[OH:8])[NH2:6].[N+:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)([O-:13])=[O:12].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:2][O:3][C:4](=[O:10])[C@H:5]([C@@H:7]([CH3:9])[OH:8])[NH:6][C:18](=[O:19])[C:17]1[CH:16]=[CH:15][C:14]([N+:11]([O-:13])=[O:12])=[CH:22][CH:21]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](NC(=O)c1ccc([N+](=O)[O-])cc1)[C@@H](C)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 94.1 %

Procedure:
Dichloromethane (80 mL) was added to threonine methyl ester hydrochloride (3.39 g, 20 mmol), 4-nitrobenzoic acid (3.34 g, 20 mmol), WSC hydrochloride (3.83 g, 20 mmol), HOBt (2.87 g, 20 mmol) and N,N-diisopropylethylamine (2.58 g, 20 mmol), and the mixture was stirred at room temperature for three days. The reaction solution was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/2, 1/1, 1/2) to obtain 5.31 g of the title compound as a colorless solid (94%).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:7][C:6]=1[Br:18])(=O)C.[OH-].[Na+].C(O)(=O)C>CO>[Br:18][C:6]1[CH:7]=[C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:9]=[CH:10][C:5]=1[OH:4]
Reactant: CC(=O)Oc1ccc(N2CCN(C)CC2)cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCN(c2ccc(O)c(Br)c2)CC1

Procedure:
2-bromo-4-(4-methylpiperazin-1-yl)phenyl acetate 280 mg (1.03 mmol) were dissolved in methanol and reacted with 2 ml of 1 N NaOH. After two hours the reaction was acidified with glacial acetic acid, evaporated and purified on silica with DCM/MeOH 9/1 0.4% 7M NH3 in MeOH. LC/MS (m/z): 273.2 [M+H]+, HPLC (254 nm) method 3 Rt 2.96 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]2[N:7]=[C:8]([C:10]3[CH:11]=[N:12][C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:14][CH:15]=3)[O:9][C:5]=2[CH:4]=1.[F:26][CH2:27][CH2:28]N(C1C=CC(C2OC3C=C(OC)C=CC=3N=2)=CN=1)C(=O)OC(C)(C)C>>[F:26][CH2:27][CH2:28][N:16]([C:13]1[N:14]=[CH:15][C:10]([C:8]2[O:9][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:25]=[CH:24][C:6]=3[N:7]=2)=[CH:11][N:12]=1)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:20])[CH3:21]
Reactant: COc1ccc2nc(-c3ccc(N(CCF)C(=O)OC(C)(C)C)nc3)oc2c1
Reactant: COc1ccc2nc(-c3cnc(NC(=O)OC(C)(C)C)nc3)oc2c1
Product: COc1ccc2nc(-c3cnc(N(CCF)C(=O)OC(C)(C)C)nc3)oc2c1

Procedure:
The title intermediate was synthesized from tert-butyl [5-(6-methoxy-1,3-benzoxazol-2-yl)pyrimidin-2-yl]carbamate according to the procedure described for tert-butyl (2-fluoroethyl)[5-(6-methoxy-1,3-benzoxazol-2-yl)pyridin-2-yl]carbamate to give 128 mg. 1H NMR 400 MHz, Chloroform-d) δ ppm 9.33 (s, 2H) 7.66 (d, 1H) 7.14 (d, 1H) 7.00 (dd, 1H) 4.79 (t, 1H) 4.67 (t, 1H) 4.42 (t, 1H) 4.37 (t, 1H) 3.90 (s, 3 H) 1.57 (s, 9H) MS m/z 389 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cl)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)N2CCOCC2)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
Under an atmosphere of argon protective gas, 5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonyl chloride (50 mg, 101 μmol) was dissolved in absolute THF (2.5 ml), morpholine (26 μl, 303 μmol; 3 eq.) and triethylamine (10.2 mg, 101 μmol; 1 eq.) were added at room temperature and the mixture was stirred overnight. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Kromasil C-18, 5 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave a colorless amorphous solid (44 mg, 80% of theory).
Reaction SMILES: [CH2:1]=[CH2:2].[CH2:3]=[CH:4][CH2:5][CH3:6]>>[CH2:4]1[CH:3]2[CH:5]3[CH:4]=[CH:3][CH:2]([CH:1]2[CH:6]=[CH:5]1)[CH2:6]3
Reactant: C=C
Reactant: C=CCC
Product: C1=CC2C3C=CC(C3)C2C1

Procedure:
When the copolymerization reaction was performed under the conditions described above, a copolymer of ethylene, 1-butene and dicyclopentadiene was obtained as a uniform solution. A small amount of methanol was added to the polymer solution withdrawn from the bottom of the polymerization vessel to stop the polymerization reaction. The polymer was separated from the solvent by steam stripping, and dried under reduced pressure at 80° C. for one day.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([CH3:15])[CH3:14])=[CH:9][CH:8]=2)=[CH:5][NH:4][N:3]=1.C([O:24][CH:25]=[C:26]([C:32](OCC)=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28])C.C[O-].[Na+]>C(O)C>[CH2:30]([O:29][C:27]([C:26]1[CH:32]=[N:1][C:2]2[N:3]([N:4]=[CH:5][C:6]=2[C:7]2[CH:8]=[CH:9][C:10]([C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)([CH3:15])[CH3:14])=[CH:11][CH:12]=2)[C:25]=1[OH:24])=[O:28])[CH3:31]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)(c1ccccc1)c1ccc(-c2c[nH]nc2N)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc2c(-c3ccc(C(C)(C)c4ccccc4)cc3)cnn2c1O
Reaction time: 24 h
Yield: 94.6 %

Procedure:
To a suspention of 3-amino-4-[4-(2-phenylpropan-2-yl)phenyl]pyrazole (920 mg) in ethanol (10 ml) was added diethyl ethoxymethylenemalonate (1.34 ml), and the mixture was heated and refluxed for 3 days. To the mixture was added sodium methoxide (540 mg) under ice-cooling, and the mixture was stirred for 1 day. Ethanol was distilled away under reduced pressure, and thereto was added water (50 ml) under ice-cooling. The mixture was adjusted to acid with 10% hydrochloric acid, and the precipitate was separated by filtration, washed with water to give the title compound (1.26 g, 94.6%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:16][CH2:15]2)=[CH:10][C:9]=1[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:14]1([C:11]2[CH:10]=[C:9]3[C:8](=[CH:13][CH:12]=2)[NH:7][C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:17]3)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2CC2)cc1CC(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2cc3cc(C4CC4)ccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 85.1 %

Procedure:
To a solution of tert-butyl[4-cyclopropyl-2-(2-oxo-2-phenylethyl)phenyl]carbamate (561 mg) in dichloromethane (8 mL) was added dropwise trifluoroacetic acid (1.6 mL) under ice-cooling. The mixture was heated to room temperature, and then stirred for 23 hours. The reaction mixture was concentrated under reduced pressure. To the residue were added ethyl acetate and saturated aqueous sodium hydrogen carbonate solution to separate the organic layer. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (317 mg). 1H-NMR (CDCl3) δ ppm: 0.65-0.75 (2H, m), 0.85-1.00 (2H, m), 1.95-2.10 (1H, m), 6.70-6.80 (1H, m), 6.90-7.00 (1H, m), 7.25-7.50 (5H, m), 7.60-7.70 (2H, m), 8.24 (1H, br s).
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl.[NH:19]1[CH2:22][CH:21]([O:23][CH2:24][C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[CH2:20]1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[O:17]=[C:15]([N:19]1[CH2:22][CH:21]([O:23][CH2:24][C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[CH2:20]1)/[CH:14]=[CH:13]/[C:8]1[CH:7]=[C:6]2[C:11](=[N:10][CH:9]=1)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]2
Reactant: c1csc(COC2CNC2)n1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CCc2cc(/C=C/C(=O)N3CC(OCc4nccs4)C3)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.6 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (60 mg, 0.24 mmol), DMF (5.8 mL), 2-[(azetidin-3-yloxy)methyl]-1,3-thiazole hydrochloride (99 mg, 0.48 mmol; which may be prepared as described in Step 3), DIPEA (119 μL, 0.72 mmol), DMAP (2.4 mg, 0.02 mmol) and EDAC (56 mg, 0.29 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was precipitated in methanol/water and then filtered. The resulting solid was purified on column chromatography (eluent: 96/4 dichloromethane/MeOH) then triturated in pentane and MeOH to give the title compound (21 mg, 24%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[C:6]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:5][S:4]1.[CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[C:23]=1[N:31]=[C:32]=[O:33])([CH3:21])[CH3:20]>[Cl-]>[CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:29])[CH3:30])[C:23]=1[NH:31][C:32]([NH:1][CH2:2][CH:3]1[CH2:8][C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[C:6]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:5][S:4]1)=[O:33])([CH3:20])[CH3:21]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCCC1=C(CCCCC)CC(CN)SC1
Agent: [Cl-]
Product: CCCCCC1=C(CCCCC)CC(CNC(=O)Nc2c(C(C)C)cccc2C(C)C)SC1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Part D. The amine product from Part C above (ca. 1.8 mmol) was dissolved inmethylene chloride (10 mL), and cooled to 0° C. The solution was treated with 2,6-diisopropylphenyl-isocyanate (0.50 mL, 2.10 mmol) by syringe. The mixture was allowed to stir for 12 hours, then evaporated, and the residue was separated by flash chromatography (7:93 ethyl acetate-hexane) to afford the title product as a solid, mp 65°-67° C. (490 mg, 1.04 mmol, 58%). 1H NMR (CDCl3): δ 7.40-7.07 (3H, m); 6.06 (1H, br s); 5.30 (1H, br s);3.61-3.46 (2H, m); 3.29 (2H, heptet, J=6.6 Hz); 3.19-2.87 (3H, m); 2.39-2.29 (1H, m); 2.08-1.96 (5H, m); 1.40-1.15 (24H, m); 0.88 (6H, t, J=6Hz); 0.87 (6H, t, J=6 Hz). 13C NMR (CDCl3): δ 157.9, 148.1, 131.1, 128.4, 128.0, 124.0, 123.4, 43.7, 40.0, 34.1, 33.9, 33.2, 32.0, 31.9, 28.6, 28.4, 28.3, 28.0, 25.6, 24.1, 23.9, 22.6, 14.1, 14.0. IR(KBr): 3320, 2960, 2928, 1638, 1590, 1556, 1466, 1362, 1256 cm-1. Massspectrum (NH3 -CI/DDIP): m/z 475 (10%); 474 (34%); 473 (100%); 381 (99%); 252 (2%). High-resolution mass spectrum: for C29H49N2OS, calculated 473.3566, measured 473.3566, difference 0 ppm.
Reaction SMILES: [OH:1][C@H:2]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:3]([CH3:21])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18](O)=[O:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[CH:30]1([NH2:33])[CH2:32][CH2:31]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:30]1([NH:33][C:18](=[O:19])[CH2:17][C:14]2[CH:13]=[CH:12][C:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][C@@H:3]([CH3:21])[C@H:2]([OH:1])[CH2:22][CH2:23][C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[CH:10][CH:9]=3)=[CH:16][CH:15]=2)[CH2:32][CH2:31]1
Reactant: C[C@H](Oc1ccc(-c2ccc(CC(=O)O)cc2)cc1)[C@H](O)CCc1cccnc1
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C[C@H](Oc1ccc(-c2ccc(CC(=O)NC3CC3)cc2)cc1)[C@H](O)CCc1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.8 %

Procedure:
Prepared according to the method described in Example 66. (1S,2R)-[4′-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy)-biphenyl-4-yl]acetic acid (Example 55, 0.07 g), cyclopropylamine (0.011 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.038 g) and 1-hydroxybenzotriazole (0.027 g) were dissolved in dimethylformamide (2 ml) and stirred for 16 hours at room temperature. The dimethylformamide was removed by vacuum distillation, the residue was dissolved in dichloromethane, filtered and purified by normal-phase HPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as a solid (0.063 g).
Reaction SMILES: [C:1]1(=[O:29])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:13]([O:22][CH3:23])[CH:12]=2)[CH2:7][C:8](O)=[O:9])[C:4](=[O:24])[C:3]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:2]12.C(N1C=CN=C1)([N:32]1C=CN=C1)=O>>[C:1]1(=[O:29])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:13]([O:22][CH3:23])[CH:12]=2)[CH2:7][C:8]([NH2:32])=[O:9])[C:4](=[O:24])[C:3]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:2]12
Reactant: CCCCOc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Product: CCCCOc1ccc(C(CC(N)=O)N2C(=O)c3ccccc3C2=O)cc1OC

Procedure:
By following the procedure of Example 65 utilizing 3-phthalimido-3-(4-butoxy-3-methoxyphenyl)propionic acid and carbonyldiimidazole, there is obtained 0.742 g (74%) of crude product as a pale yellow powder. The crude product was recrystallized from ethyl acetate (16 mL) to afford 0.517 (52%) of 3-phthalimido-3-(4-butoxy-3-methoxyphenyl)propionamide as fine fluffy white needles: HPLC 99.1%; 1H NMR (DMSO-d6) δ 7.95-7.75 (m, 4 H, Ar), 7.54 (br s, 1 H, CONH), 7.04 (s, 1 H, Ar), 7.0-6.75 (m, 2 H), 6.86 (br s, 1 H, CONH), 5.67 (t, 1 H, J=8 Hz), 3.90 (t, 2 H, J=6 Hz), 3.73 (s, 3 H), 3.20 (d, 1 H, J=8 Hz, CH2CO), 1.8-1.55 (m, 2 H) 1.5-1.3 (m, 2 H) 0.91 (t, 3 H, J=7 Hz); 13C NMR (DMSO-d6) δ 171.2, 167.6, 148.8, 147.7, 134.5, 131.6, 131.2, 123.0, 119.4, 112.8, 111.4, 67.8, 55.5, 50.3, 36.9, 30.7, 18.6, 13.6.
Reaction SMILES: [C:1]([C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].[CH:12]1([C:15]2[CH:16]=[C:17]([NH:29][C:30](=[O:39])[C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[C:33](I)[CH:32]=3)[CH:18]=[CH:19][C:20]=2[CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)[CH2:14][CH2:13]1.CC(O)=O>CO>[CH:12]1([C:15]2[CH:16]=[C:17]([NH:29][C:30](=[O:39])[C:31]3[CH:32]=[CH:33][C:34]([CH3:37])=[C:35]([C:2]#[C:1][C:3]4[N:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]5=[N:5][CH:4]=4)[CH:36]=3)[CH:18]=[CH:19][C:20]=2[CH2:21][N:22]2[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]2)[CH2:14][CH2:13]1
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C3CC3)c2)cc1I
Reactant: C#Cc1cnc2cccnn12
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C3CC3)c2)cc1C#Cc1cnc2cccnn12

Procedure:
The title compound was synthesized from 3-ethynylimidazo[1,2-b]pyridazine and N-(3-cyclopropyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-iodo-4-methylbenzamide in a manner similar to that described for Example 14 (nitro reduction performed in a manner similar to that described for Example 17; 0.25M in MeOH/10%AcOH). The product was obtained as a solid: 505 m/z (M+H).