Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:13][CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25]CC)=[O:24])=[CH:19][N:18]=2)[C:9]([O:28][CH3:29])=[C:8]2[C:3]=1[C:4](=[O:36])[C:5]([C:33]([OH:35])=[O:34])=[CH:6][N:7]2[CH:30]1[CH2:32][CH2:31]1.[Na+].[Cl-]>CO.[OH-].[Na+].O.[NH4+].[Cl-]>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:13][CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][N:18]=2)[C:9]([O:28][CH3:29])=[C:8]2[C:3]=1[C:4](=[O:36])[C:5]([C:33]([OH:35])=[O:34])=[CH:6][N:7]2[CH:30]1[CH2:31][CH2:32]1
Reactant: CCOC(=O)c1ccc(NCCNc2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2OC)nc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1c(NCCNc2ccc(C(=O)O)cn2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.5 %

Procedure:
To a suspension of 5-amino-1-cyclopropyl-7-[2-[(5-ethoxycarbonyl-2-pyridyl)amino]ethylamino]-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (390 mg, 0.781 mmol) in MeOH (5 mL), 1M aq. NaOH (5 mL) was added. The mixture was stirred at room temperature for 8 h. The reaction mixture was diluted with water (30 mL) and saturated aq NH4Cl (20 mL). The solution was saturated with NaCl and the crude product was extracted with EtOAc (2×100 mL). The organic layers were combined, washed with brine, dried over Na2SO4, and evaporated. The residue was dissolved in a mixture of MeOH (100 mL) and water (30 mL). The solution was concentrated in vacuo until ca. 50 mL and the resulting precipitate was collected by filtration, washed with water and dried to give 5-amino-1-cyclopropyl-6-fluoro 1,4-dihydro-7-[2-[(5-hydroxycarbonyl-2-pyridyl)amino]ethylamino]-8-methoxy-4-oxoquinoline-3-carboxylic acid (86.6 mg, 24%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]([C:24]1[S:25][C:26]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:27]=2[CH:28]=1)[C:20]([O:22][CH3:23])=[O:21].ClC1C=CC2SC(CC(O)=O)=CC=2C=1>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]([C:24]2[S:25][C:26]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:27]=3[CH:28]=2)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)C(N)c1cc2cc(Cl)ccc2s1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: O=C(O)Cc1cc2cc(Cl)ccc2s1
Product: COC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1cc2cc(Cl)ccc2s1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(5-chlorobenzothiophen-2-yl)acetate (prepared from 5-chlorobenzothiophene-2-acetic acid [CAS No. 23799-65-7] using General Procedure G, followed by amination using a procedure essentially the same as that described in Example D4 above), the title compound was prepared as a solid (mp=189-190° C.). The product was purified by titration using Et2O/hexanes.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([C:29](O)=[O:30])=[CH:28][C:23]=2[CH:22]=[CH:21]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:29]([C:27]1[CH:26]=[CH:25][C:24]2[O:20][CH:21]=[CH:22][C:23]=2[CH:28]=1)=[O:30]
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: O=C(O)c1ccc2occc2c1
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc2occc2c1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with benzofuran-5-carboxylic acid. MS: 404.4 (M+H).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([O:38][C:39]1[CH:47]=[CH:46][C:45]([CH:48]2[CH2:50][O:49]2)=[CH:44][C:40]=1[C:41]([NH2:43])=[O:42])C1C=CC=CC=1>>[CH2:21]([NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:50][CH:48]([C:45]3[CH:46]=[CH:47][C:39]([OH:38])=[C:40]([C:41](=[O:42])[NH2:43])[CH:44]=3)[OH:49])=[CH:30][CH:29]=2)[CH2:13][CH2:14]1)=[O:19])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: NC(=O)c1cc(C2CO2)ccc1OCc1ccccc1
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Solvent: O=CO
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNCC(O)c3ccc(O)c(C(N)=O)c3)cc2)CC1
Yield: 23.2 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-octyl-1-piperidinecarboxamide formate (0.50 g, 1.18 mmol) was reacted with 2-(benzyloxy)-5-(2-oxiranyl)benzamide (0.255 g, 0.95 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.143 g, 0.22 mmol).
Reaction SMILES: [O:1]=[C:2]([N:19]1[CH2:31][CH2:30][C:29]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][C:21]=2[CH:20]1[C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)[CH:3]=[CH:4][C:5]1[CH:18]=[CH:17][C:8]([CH2:9][O:10][CH2:11][C:12]([O:14]CC)=[O:13])=[CH:7][CH:6]=1>CCO>[O:1]=[C:2]([N:19]1[CH2:31][CH2:30][C:29]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][C:21]=2[CH:20]1[C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)/[CH:3]=[CH:4]/[C:5]1[CH:6]=[CH:7][C:8]([CH2:9][O:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:17][CH:18]=1
Reactant: CCOC(=O)COCc1ccc(C=CC(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Solvent: CCO
Product: O=C(O)COCc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Yield: 40 %

Procedure:
The same method as employed in the preparation of Example 79 but starting from a solution of (E)-(4-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)propenyl]benzyloxy acetic acid, ethyl ester in EtOH gave after recrystallization from MeOH:H2O the title compound as an off-white solid in a 40% yield.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C@@H:7]([CH3:8])[CH2:6][N:5]([C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH3:20])[N:12]=2)=[O:10])[CH2:4]1.N1C=CC=CC=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>O>[C:27]([NH:2][C@H:3]1[C@@H:7]([CH3:8])[CH2:6][N:5]([C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH3:20])[N:12]=2)=[O:10])[CH2:4]1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H]1CN(C(=O)c2nn(C)c3ccccc23)C[C@H]1N
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)N[C@@H]1CN(C(=O)c2nn(C)c3ccccc23)C[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To 200 mg (0.68 mmol) of cis-3-amino-4-methyl-1-(1-methylindazol-3-ylcarbonyl)pyrrolidine hydrochloride was added 0.7 ml of pyridine, and 0.07 ml (0.75 mmol) of acetic anhydride was added dropwise under ice cooling. Then, after heated to room temperature, the mixture was stirred overnight. To the reaction mixture was added water, and then the solution was extracted with methylene chloride. After washed with saturated saline solution and dried over anhydrous magnesium sulfate, the solution was concentrated under reduced pressure to obtain crude oil. This was subjected to silica gel column chromatographic purification (methylene chloride:acetone=10:1) to obtain 176 mg (86.3%) of aimed compound. m.p. 202°-204° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CC(C)([O-])C.[K+].[Br:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[CH:17][C:18]=1[CH2:19]Br.C1OCCOCCOCCOCCOCCOC1>CCOCC.O>[Br:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[CH:17][C:18]=1[CH2:19][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)C=Cc1ccc(CBr)c(Br)c1
Reactant: c1c[nH]cn1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C=Cc1ccc(Cn2ccnc2)c(Br)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of imidazole (0.25 g, 3.67 mmol), potassium tert-butoxide (0.42 g, 3.75 mmol), ethyl 3-(3-bromo-4-bromomethylphenyl)prop-2-enoate (1.29 g, 3.7 mmol) and 18-crown-6 (0.1 g) in dry ether was stirred at room temperature for 72 h. Water (5 ml) was then added, and the aqueous layer was extracted with ether (3×50 ml). The ether solutions were combined, dried (MgSO4) and then concentrated to afford a pale yellow oil. The oil was `flash` chromatographed using chloroform/methanol 9:1 as eluant. The product fractions were combined, dried (MgSO4) and concentrated to afford ethyl 3-[3-bromo-4-(imidazol-1-ylmethyl)phenyl]prop-2-enoate as a white solid. NMR data was consistent with the assigned structure.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:6][CH:5]([CH3:7])[CH2:4][C:3]1=O.CC1CC(C)(C)CC1=O.S([O-])([O-])(=O)=O.[NH4+].[NH4+].C(N)C=C.ClCC(Cl)=O.C(N(CC)CC)C.C[C:43]1(C)CC(C)[C:45]([N:49](CC=C)[C:50](=[O:53])[CH2:51][Cl:52])=[CH:44]1.CC1CC(C)(C)C(N(CC=C)C(=O)CCl)=C1>C1C=CC=CC=1>[CH3:7][C:5]1[CH2:6][C:2]([CH3:9])([CH3:1])[CH2:3][C:4]=1[N:49]([CH2:45][CH:44]=[CH2:43])[C:50](=[O:53])[CH2:51][Cl:52]
Reactant: C=CCN(C(=O)CCl)C1=CC(C)(C)CC1C
Reactant: CC1CC(=O)C(C)(C)C1
Agent: C=CCN(C(=O)CCl)C1=CC(C)CC1(C)C
Agent: CC1CC(C)(C)CC1=O
Agent: O=C(Cl)CCl
Solvent: C=CCN
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CCN(C(=O)CCl)C1=C(C)CC(C)(C)C1

Procedure:
By the same procedure as in Example 63 using a mixture comprising 2,2,4-trimethylcyclopentanone and 2,4,4-trimethylcyclopentanone (about 1:1) (25.2 parts by weight; 0.2 mole) in 0.2 liter of benzene, 0.1 part by weight of ammonium sulfate, and 11.4 parts by weight (0.2 mole) of allylamine, further reacted with 22.6 parts by weight (0.2 mole) of chloracetyl chloride in 0.05 liter of benzene and 22 parts by weight (0.2 mole) of triethylamine in 0.1 liter of benzene, a mixture of isomers consisting of N-(3,3,5-trimethylcyclopenten-1-yl)-N-allyl-α-chloroacetamide, N-(3,5,5-trimethylcyclopenten-1-yl)-N-allyl-α-chloroacetamide, and N-(2,4,4-trimethylcyclopenten-1-yl)-N-allyl-α-chloroacetamide was obtained. The yield of brown oily distillate (B.P.=88°-93° C. at 1.0 torr) having a refractive index (nD20 =1.4978) was 29 parts by weight. The content of organically combined chlorine was 15.9% (14.7%). The nitrogen content was 6.1% (5.8%).
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]#[CH:6].O1CCCC1.C([Li])CCC.[CH2:28]([C:30]([CH2:32][CH3:33])=[O:31])[CH3:29]>CCCCCC>[CH3:1][N:2]([CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]#[C:6][C:30]([CH2:32][CH3:33])([OH:31])[CH2:28][CH3:29]
Reactant: CCC(=O)CC
Reactant: C#CCCN(C)Cc1cccc2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(O)(C#CCCN(C)Cc1cccc2ccccc12)CC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 2 g N-methyl-N-(1-naphthylmethyl)-3-butyn-amine in abs. tetrahydrofurane (THF) are added dropwise, at -70°, 5.6 ml of a 15% by weight solution of n-butyllithium in hexane and half an hour later, at -70°, 0.95 ml diethylketone. The mixture is stirred for 3 hours at room temperature, poured onto ice and extracted with ether. The organic phase is washed, dried and evaporated in vacuum. The title compound (Compound 25) is obtained as an oil by chromatography over silica gel (with toluene/ethylacetate 3/1).
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:38][CH2:39][C:40](Cl)=[O:41]>ClCCl>[Cl:38][CH2:39][C:40]([NH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1)=[O:41]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N)c3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(NC(=O)CCl)c3ccccc32)cc1
Reaction time: 0.08 h

Procedure:
To a solution of 5-amino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (2.5 g) in dichloromethane (30 ml) is added triethylamine (0.96 ml) and further thereto is added dropwise chloroacetyl chloride (0.55 ml) under ice-cooling. The mixture is stirred for 5 minutes. The reaction solution is concentrated and to the resulting residue is added water. The precipitated crystal is collected by filtration, washed with water, and dried to give 5-(2-chloroacetylamino)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.4 g) as white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][CH3:11])[CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[C:14]1[N:15]2[N:21]=[C:20]([O:22][CH3:23])[C:19]([NH:24][CH2:25][CH2:26][CH3:27])=[C:16]2[S:17][CH:18]=1.Br[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][CH3:11])[CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[C:14]1[N:15]2[N:21]=[C:20]([O:22][CH3:23])[C:19]([N:24]([CH2:25][CH2:26][CH3:27])[C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)=[C:16]2[S:17][CH:18]=1
Reactant: CCCNc1c(OC)nn2c(-c3c(OC)cc(COC)cc3OC)csc12
Reactant: Brc1cccnc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CCCN(c1cccnc1)c1c(OC)nn2c(-c3c(OC)cc(COC)cc3OC)csc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 38.7 %

Procedure:
To a 1,4-dioxane (0.7 mL) solution of 3-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-6-methoxy-N-propylpyrazolo[5,1-b][1,3]thiazole-7-amine (70 mg, 0.179 mmol) were added 3-bromopyridine (33.9 mg, 0.215 mmol), cesium carbonate (99.1 mg, 0.304 mmol), tris(dibenzylideneacetone)dipalladium (8.2 mg, 0.009 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (7.77 mg, 0.0134 mmol), and the mixture was stirred at 100° C. for eight hours. After the reaction mixture was returned to room temperature, water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was purified by medium pressure amino silica gel column chromatography (n-heptane/ethyl acetate: 10% then 60%) to obtain the title compound (32.4 mg, 0.0692 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.[CH3:13]B1OB(C)OB(C)O1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([CH3:13])[CH:3]=1
Reactant: COC(=O)c1cnc(Cl)cc1Cl
Reactant: CB1OB(C)OB(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cnc(C)cc1Cl
Temperature: 110 °C
Yield: 9.3 %

Procedure:
A solution of methyl 4,6-dichloronicotinate (2.0 g, 9.71 mmol) in 1, 4-dioxane (30 mL) and water (1.5 mL), trimethylboroxine (0.731 g, 5.82 mmol), PdCl2(dppf)-CH2Cl2 (0.396 g, 0.485 mmol) and Cs2CO3 (9.49 g, 29.1 mmol) was degassed with argon for 15 min then heated to 110° C. for 16 h. After cooling, the solution was diluted with water (100 mL) and extracted with ethyl acetate (150 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20% EtOAc in pet. ether) to afford methyl 4-chloro-6-methylnicotinate (0.1 g, 0.539 mmol, 22% yield) as a yellow oil. LCMS (ESI) m/e 186.0 [(M+H)+, calcd for C8H9ClNO2 186.02]; LC/MS retention time (Method E): tR=1.75 min. 1H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 7.27 (s, 1H), 3.95 (s, 3H), 2.58 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH:16]([NH:22][C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([NH:33]C(OC(C)(C)C)=O)=[CH:29][CH:28]=2)=[O:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][NH:25][C:23](=[O:24])[NH:22][CH:16]([CH2:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:32][CH:31]=1
Reactant: CCOC(=O)C(Cc1cccc(OCc2ccccc2)c1)NC(=O)NCc1ccc(NC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(Cc1cccc(OCc2ccccc2)c1)NC(=O)NCc1ccc(N)cc1
Reaction time: 1 h
Yield: 91.3 %

Procedure:
161 (469 mg) was dissolved in 4 ml of DCM and 4 ml of TFA was added then the reaction mixture was let 1 h at room temperature. The reaction mixture is concentrated and 50 ml of AcOEt are added. The organic phase are washed with saturated NaHCO3 and brine then dried over Na2SO4, filtered and concentrated to afford 162 as a white solid (350 mg, 91%). 1H NMR (DMSO): δ 1.28 (t, 3H, J=6.5 Hz), 3.04 (m, 2H), 4.13 (d, 2H, J=4.1 Hz), 4.19 (q, 2H, J=6.5 Hz), 4.56 (m, 1H), 5.02 (s, 2H), 5.21 (s, 2H), 6.29 (d, 1H, J=8.3 Hz), 6.45 (m, 1H), 6.62 (d, 2H, J=7.3 Hz), 6.89 (d, 1H, J=7.3 Hz), 7.00 (m, 3H), 7.33 (t, 1H, J=7.3 Hz), 7.53 (t, 1H, J=7.3 Hz), 7.57 (d, 1H, J=6.7 Hz). HPLC method B tr=21.65 nm (97.4%). ESI-MS m/z: 448.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=1)[C:6]([C:24]([O:26]CC)=[O:25])=[C:5]2[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[C:35]([C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1)([CH3:38])([CH3:37])[CH3:36]>>[C:15]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:14]=[CH:13][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([NH:1][C:42]4[CH:43]=[CH:44][C:39]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:40][CH:41]=4)=[CH:10][CH:9]=3)[C:5]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[C:6]2[C:24]([OH:26])=[O:25])=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(N)ccc2n1Cc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: CC(C)(C)c1ccc(Nc2ccc3c(c2)c(-c2ccccc2)c(C(=O)O)n3Cc2ccc(-c3ccccc3)cc2)cc1

Procedure:
The title compound was prepared from ethyl 5-amino-1-(1,1′-biphenyl-4-ylmethyl)-3-phenyl-1H-indole-2-carboxylate and 4-tert-butylbenzeneboronic acid according to the procedure of Example 1 Step 3 as a pale green solid: 1H NMR (CDCl3) δ 1.28 (s, 9 H), 5.85 (s, 2 H), 6.86 (d, J=8.6 Hz, 2 H), 7.15-7.55 (m, 19 H); MS (ESI) m/z 551 (MH+); HRMS calcd. for C38H34N2O2 551.2699; found (ESI+): 551.2681; Anal. calcd. for C38H34N2O2.0.5H2O: C, 81.55; H, 6.30; N, 5.01. Found: C, 81.91; H, 6.39; N, 4.65.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[Cl:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>>[Cl:16][CH2:17][CH2:18][C:19]([N:13]1[CH2:12][CH2:11][N:10]([C:3]2[CH:4]=[C:5]([CH3:9])[C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[CH2:15][CH2:14]1)=[O:20]
Reactant: O=C(Cl)CCCl
Reactant: Cc1cc(C)c(N2CCNCC2)cc1C
Product: Cc1cc(C)c(N2CCN(C(=O)CCCl)CC2)cc1C

Procedure:
A target compound (925 mg, 3.137 mmol, 62.5%) was yielded as liquid in the same manner as Reference Example 13 by reacting 1-(2,4,5-trimethylphenyl)piperazine (1.03 g, 5.041 mmol) with 3-chloropropionyl chloride (484.9 mg, 5.041 mmol) and purifying by separation through column chromatography (EtOAc/hexane, 1:2).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([S:11][CH2:12][C:13](=O)[CH3:14])[CH:8]=[C:7]([CH3:16])[CH:6]=1)[CH3:2].Cl.[Cl:19][C:20]1[CH:21]=[C:22]([NH:26]N)[CH:23]=[CH:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:6]=[C:7]([CH3:16])[CH:8]=[C:9]([S:11][C:12]2[C:23]3[C:22](=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=3)[NH:26][C:13]=2[CH3:14])[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(C)cc(SCC(C)=O)c1
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Product: CCOC(=O)c1cc(C)cc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: 3-Methyl-5-(2-oxo-propylsulfanyl)-benzoic acid ethyl ester and 3-chlorophenylhydrazine hydrochloride.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:37]([CH3:38])=[CH:36][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([N:23]4[CH2:28][CH2:27][N:26]5[C:29](C(F)(F)F)=[N:30][N:31]=[C:25]5[CH2:24]4)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].Cl.N1N=CN2CCNCC=12>>[C:1]([O:5][C@@H:6]([C:10]1[C:37]([CH3:38])=[CH:36][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([N:23]4[CH2:28][CH2:27][N:26]5[CH:29]=[N:30][N:31]=[C:25]5[CH2:24]4)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:39]1[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2nc(-c3ccnc(N4CCn5c(nnc5C(F)(F)F)C4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Agent: Cl
Agent: c1nnc2n1CCNC2
Product: Cc1cc2nc(-c3ccnc(N4CCn5cnnc5C4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetic acid was prepared in a similar manner as (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)acetic acid except starting with 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride instead of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride. LCMS-ESI+: calc'd for C30H30ClN6O3S: 589.2 (M+H+); Found: 589.3 (M+H+); 1H NMR (400 MHz, CD3OD) δ 9.11 (s, 1H), 8.28 (d, J=5.4 Hz, 1H), 7.85 (s, 1H), 7.67 (dd, J=8.5, 1.7 Hz, 1H), 7.63-7.51 (m, 4H), 7.34 (d, J=5.3 Hz, 1H), 5.25 (s, 1H), 5.15 (s, 2H), 4.40 (t, J=5.3 Hz, 2H), 4.22 (t, J=5.4 Hz, 2H), 2.60 (s, 3H), 0.96 (s, 9H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[F:23][C:24]([F:32])([F:31])[C@@H:25]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]1>>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([N:27]5[CH2:28][CH2:29][CH2:30][C@@H:25]([C:24]([F:32])([F:31])[F:23])[CH2:26]5)=[O:20])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1
Reactant: FC(F)(F)[C@@H]1CCCNC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCC[C@@H](C(F)(F)F)C1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (R)-3-(trifluoromethyl)piperidine (1.2 equiv) to give 201 (M+1 449.0)
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[CH2:7]([NH:9][CH2:10][CH2:11][OH:12])C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.O>[CH3:7][N:9]([CH3:2])[CH2:10][CH2:11][OH:12].[Br:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCNCCO
Agent: [Cu]I
Agent: Brc1cccs1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: CN(C)CCO
Temperature: 80 °C
Reaction time: 72 h

Procedure:
2-Bromothiophene (16.3 g, 0.1 mol), 2-(ethylamino)ethanol (100 ml), Cu metal (0.32 g), CuI (0.85 g), K3PO4(42.4 g) were added to a flask fitted with a magnetic stir bar, a condenser and sealed with a septum. The reaction mixture was stirred at 80° C. for 72 hour under nitrogen position pressure. After the reaction cooled to room temperature, 600 ml water was added and mixture was extracted with ethyl ether (3*200 ml). The combined organic layers were then washed with brine and dried over MgSO4. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel eluted with hexane/EtoAc (1:1). The product was obtained as a liquid. Examples of Amination of 2-bromothiophene are shown in Table 7.