Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]=[C:12]([NH2:15])[S:13][CH:14]=1)([O-:3])=[O:2].Br[CH2:17][C:18](=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(C(C)=O)C>[CH2:22]([O:21][C:19]([C:18]1[N:15]=[C:12]2[N:11]([CH:17]=1)[C:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])=[CH:14][S:13]2)=[O:20])[CH3:23]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1nc(-c2ccccc2[N+](=O)[O-])cs1
Solvent: CCC(C)=O
Product: CCOC(=O)c1cn2c(-c3ccccc3[N+](=O)[O-])csc2n1
Temperature: 25 °C
Yield: 52.5 %

Procedure:
4-(2-Nitro-phenyl)-thiazol-2-ylamine (1.60 g, 7.2 mmol) was mixed with 50 mL of methyl ethyl ketone along 0.90 mL of ethyl bromopyruvate (7.2 mmol) and stirred under reflux for 24 hours. Another equivalent of ethyl bromopyruvate (0.90 mL, 7.2 mmol) was added and the reaction mixture was stirred under reflux for another 8 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by chromatography (Isco, gradient elution, CH2Cl2 to 95% CH2Cl2, 5% MeOH) to afford 1.2 g of 3-(2-nitro-phenyl)-imidazo [2,1-b]thiazole-6-carboxylic acid ethyl ester (52% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[CH:19](Br)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][O:30][C:31]1[N:36]=[CH:35][C:34]([CH2:37][O:38][C:39]2[CH:44]=[CH:43][N:42]=[C:41]([NH2:45])[N:40]=2)=[CH:33][CH:32]=1>CCO>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:45]=[C:41]4[N:40]=[C:39]([O:38][CH2:37][C:34]5[CH:35]=[N:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=5)[CH:44]=[CH:43][N:42]4[C:19]=3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1ccc(COc2ccnc(N)n2)cn1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Solvent: CCO
Product: COc1ccc(COc2ccn3c(-c4ccccc4)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)nc3n2)cn1
Yield: 119.2 %

Procedure:
A mixture of crude {1-[4-(2-bromo-2-phenyl-acetyl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester [Int-1-A] (1.2 g, 82% purity), crude 4-(6-methoxy-pyridin-3-ylmethoxy)-pyrimidin-2-ylamine (0.66 g, 65% purity) and activated 3 Å molecular sieves in EtOH (7.5 mL) was heated at reflux for 2 hours. LC-MS indicated the reaction to be incomplete. A further 0.66 g portion of 4-(6-methoxy-pyridin-3-ylmethoxy)-pyrimidin-2-ylamine was added and the mixture was heated at reflux for 3 hours. On cooling the mixture was partitioned between EtOAc and water, decanted and the separated organic phase washed with brine, dried and concentrated to give the title compound (1.86 g) as a yellow solid which was used in the next step without further purification.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][C:25]([OH:27])=O.[N+:28]([C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:33][CH:32]=1)([O-:30])=[O:29]>C1COCC1.CN(C=O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][C:25]([N:40]1[CH2:41][CH2:42][N:37]([C:34]2[CH:33]=[CH:32][C:31]([N+:28]([O-:30])=[O:29])=[CH:36][CH:35]=2)[CH2:38][CH2:39]1)=[O:27]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: COc1ccc2[nH]cc(CC(=O)O)c2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc2[nH]cc(CC(=O)N3CCN(c4ccc([N+](=O)[O-])cc4)CC3)c2c1
Reaction time: 1 h

Procedure:
In a 100 ml flask, 1.62 g (10 mmoles) of 1.1′-carbonyl-diimidazole is added to a solution of 2.05 g (10 mmoles) of 5-methoxyindole-3-acetic acid in 10 ml of THF. After one hour of agitation at ambient temperature, a solution of 1-(4-nitrophenyl)piperazine in 10 ml of DMF is added dropwise. Agitation is continued for 15 hours. The reaction medium is then concentrated under vacuum and the evaporation residue is precipitated from 50 ml of an ethyl acetate/water mixture (1/1). After filtration, the solid is rinsed successively with 50 ml of water, 50 ml of ethyl acetate and 50 the of dichloromethane. After drying under vacuum, a yellow powder is obtained with a yield of wt %. Melting point: 239-240° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]#[N:12].O=[C:14]1[CH2:19][CH2:18][S:17][CH2:16][CH:15]1[C:20](OC)=[O:21].C([O-])(=O)C.[NH4+].O>C(#N)C>[O:21]=[C:20]1[N:3]2[C:2]([NH:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=32)=[C:10]([C:11]#[N:12])[C:14]2[CH2:19][CH2:18][S:17][CH2:16][C:15]1=2
Reactant: COC(=O)C1CSCCC1=O
Reactant: N#CCc1nc2ccccc2[nH]1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: N#Cc1c2c(c(=O)n3c1[nH]c1ccccc13)CSCC2
Temperature: 140 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
A mixture of 1H-benzimidazol-2-ylacetonitrile (13 g), methyl 4-oxotetrahydro-2H-thiopyran-3-carboxylate (15.3 g), and ammonium acetate (33 g) was heated and stirred at 140° C. for 1 hour. The reaction mixture was cooled to room temperature, water and acetonitrile were added, and the resulting precipitate was collected by filtration and dried under reduced pressure to obtain 12-oxo-3,4,6,12-tetrahydro-1H-thiopyrano[4′,3′:4,5]pyrido[1,2-a]benzimidazole-5-carbonitrile (16 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[N:10]([N:21]=[CH:22][C:23]=2[S:24](O)(=[O:26])=[O:25])[C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[CH3:20])=[O:5])[CH3:2].[F:28][C:29]([F:33])([F:32])[CH2:30][NH2:31]>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:11]2[N:10]3[N:21]=[CH:22][C:23]([S:24](=[O:26])(=[O:25])[NH:31][CH2:30][C:29]([F:33])([F:32])[F:28])=[C:9]3[N:8]=[CH:7][C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:14]([CH3:20])[CH:15]=1
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)O)cnn2c1Nc1ccc(F)cc1C
Reactant: NCC(F)(F)F
Product: CCOC(=O)c1cnc2c(S(=O)(=O)NCC(F)(F)F)cnn2c1Nc1ccc(F)cc1C
Yield: 87.6 %

Procedure:
Using 6-ethoxycarbonyl-7-(4-fluoro-2-methylphenylamino)pyrazolo[1,5-a]pyrimidine-3-sulfonic acid (0.970 g, 2.460 mmol) obtained in Example 1 step 2 and 2,2,2-trifluoroethylamine (0.975 g, 9.838 mmol) instead of tert-butylamine, and in the same manner as in Example 1 step 3, the title compound (1.024 g, 87%) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]#[N:21]>CC(C)=O>[CH2:8]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:19][C:20]#[N:21])=[CH:7][CH:6]=1)[C:9]([CH3:10])=[O:11]
Reactant: N#CCCl
Reactant: CC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Cc1ccc(OCC#N)cc1
Reaction time: 4 h

Procedure:
A mixture of 4-hydroxyphenylpropan-2-one, ethylene ketal (4.7 g), potassium carbonate (3.5 g) and chloroacetonitrile (1.83 g) in acetone, was heated under reflux for 5 h, cooled, filtered, and treated with 2N hydrochloric acid (1 ml). The solution was allowed to stand at room temperature for 4 h, the solvent was evaporated in vacuo and the residue partitioned between ethylacetate and water. The organic layer was dried, (magnesium sulphate), filtered and evaporated. The residue was purified by column chromatography on silica using chloroform as eluent to give 4-acetonylphenoxyacetonitrile, (3.0 g)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:30])[N:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-])=O)[CH:14]=1)#[N:2].[H][H]>C(OCC)(=O)C.[C].[Pd]>[NH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:13]1[CH:14]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])[C:10](=[O:30])[N:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:12]=1
Reactant: N#Cc1ccccc1-c1cc(-c2ccccc2[N+](=O)[O-])cn(-c2ccccc2)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1-c1cc(-c2ccccc2N)cn(-c2ccccc2)c1=O
Yield: 67.7 %

Procedure:
3-(2-Cyanophenyl)-5-(2-nitrophenyl)-1-phenyl-1,2-dihydropyridin-2-one (32 mg) was dissolved in 15 ml of ethyl acetate, 5 mg of 10% palladium-carbon (water-containing substance) were added and the mixture was stirred at room temperature in a hydrogen atmosphere for 15 minutes. The catalyst was filtered off and the solvent was evaporated in vacuo to give 20 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10](/[N:12]=[C:13]2\[NH:14][CH2:15][C:16]3([CH2:23][CH:22]4[NH:24][CH:19]([CH2:20][CH2:21]4)[CH2:18]3)[NH:17]\2)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:49]1[C:57]2[CH:56]=[CH:55][CH:54]=[C:53]([C:58](O)=[O:59])[C:52]=2[CH:51]=[CH:50]1.CN1CCOCC1>CN(C=O)C>[NH:49]1[C:57]2[CH:56]=[CH:55][CH:54]=[C:53]([C:58]([N:24]3[CH:22]4[CH2:21][CH2:20][CH:19]3[CH2:18][C:16]3([CH2:23]4)[CH2:15][NH:14]/[C:13](=[N:12]\[C:10]([C:3]4[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=4)=[O:11])/[NH:17]3)=[O:59])[C:52]=2[CH:51]=[CH:50]1
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CC4CCC(C3)N4)N2)nc1Cl
Reactant: O=C(O)c1cccc2[nH]ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Nc1nc(N)c(C(=O)/N=C2\NCC3(CC4CCC(C3)N4C(=O)c3cccc4[nH]ccc34)N2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(E)-3,5-diamino-6-chloro-N-(8-azaspiro[bicyclo[3.2.1]octane-3,4′-imidazolidine]-2′-ylidene)pyrazine-2-carboxamide (170 mg, 0.49 mmol) is dissolved in DMF (10 ml) along with HATU (184 mg, 0.49 mmol) and 4-indole-carboxylic acid (78 mg, 0.49 mmol). N-Methyl morpholine (160 ml, 1.45 mmol) is added and the solution stirred at room temperature overnight. The mixture is then concentrated in vacuo. EtOAc (100 ml) is added and the solution washed with water (100 ml). The organic phase is dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (SiO2, DCM/MeOH) gives the title compound as a yellow solid; [M+H]+ 494.15, 496.27 for Cl isotopes.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([C:16](=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].Cl[C:23]1C(Cl)=C(C(=O)CCC)C=CC=1OCCCC(O)=O>>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([C:16](=[O:21])[C:17](=[CH2:23])[CH2:18][CH2:19][CH3:20])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: CCCC(=O)c1ccc(OCCCC(=O)O)c(Cl)c1Cl
Reactant: CCCCC(=O)c1ccc(OCCCC(=O)O)c(Cl)c1Cl
Product: C=C(CCC)C(=O)c1ccc(OCCCC(=O)O)c(Cl)c1Cl

Procedure:
By conducting the reaction as described in Example 2, Step B, except that an equimolar amount of 4-(2,3-dichloro-4-valerylphenoxy)butyric acid was substituted for the 4-(2,3-dichloro-4-butyrylphenoxy)-butyric acid, there was obtained 4-[2,3-dichloro-4-(2-methylenevaleryl)phenoxy]butyric acid, m.p. 85°-87° C.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:13]=[C:12]([NH:14][C:15](=[O:28])[NH:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25]([OH:27])=O)[CH2:21][CH2:20]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[CH3:29][NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C>[CH3:29][N:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]([CH:22]1[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][NH:16][C:15]([NH:14][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:3])[CH:13]=2)=[O:28])[CH2:20][CH2:21]1)=[O:27]
Reactant: CNc1ccccc1
Reactant: Cc1cc(NC(=O)NCCN2CCC(C(=O)O)CC2)c2ccccc2n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)NCCN2CCC(C(=O)N(C)c3ccccc3)CC2)c2ccccc2n1
Reaction time: 15 h

Procedure:
To a suspension of 1-{2-[3-(2-methyl-quinolin-4-yl)-ureido]-ethyl}-piperidine-4-carboxylic acid dihydrochloride (64.25 mg, 0.15 mmol), TEA (0.07 mL, 0.5 mmol) and N-methylaniline (11 mg, 0.1 mmol) in DMF (0.6 mL) is is added T3P (50% in EtOAc, 0.07 mL, 0.12 mmol) at room temperature. The mixture is stirred for 15 h, quenched with sat. Na2CO3 (5 mL) and extracted with CH2Cl2 (3×10 mL). The organic phases are dried (Na2SO4), filtered, evaporated and the residue purified by preparative HPLC to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]([C:20](O)=[O:21])[CH:14]=2)=[CH:9][CH:8]=1)=[O:5].[CH2:28]([O:30][CH:31]([O:34][CH2:35][CH3:36])[CH2:32][NH2:33])[CH3:29].CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH2:28]([O:30][CH:31]([O:34][CH2:35][CH3:36])[CH2:32][NH:33][C:20]([C:15]1[CH:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:26][CH:25]=[CH:24][C:23]=3[F:27])=[CH:8][CH:9]=2)[C:18]([CH3:19])=[CH:17][CH:16]=1)=[O:21])[CH3:29]
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc(NC(=O)c2c(F)cccc2F)cc1
Reactant: CCOC(CN)OCC
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(CNC(=O)c1ccc(C)c(-c2ccc(NC(=O)c3c(F)cccc3F)cc2)c1)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Compound 1 was hydrolyzed by heating it in a solution of LiOH to yield 4′-(2,6-difluoro-benzoylamino)-6-methyl-biphenyl-3-carboxylic acid. A mixture of 4′-(2,6-difluoro-benzoylamino)-6-methyl-biphenyl-3-carboxylic acid (800 mg, 2.2 mmol), 2,2-diethoxy-ethylamine (0.32 mL, 2.2. mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (5 mmol) in dry DMF (5 mL) was stirred at room temperature for 24 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (EtOAc) (2×20 mL). The organic extract was washed with water and dried. The oil obtained on concentration of the organic layer was purified by flash chromatograghed on silica gel to give 4′-(2,6-difluoro-benzoylamino)-6-methyl-biphenyl-3-carboxylic acid (2,2-diethoxy-ethyl)-amide as colorless oil (0.68 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].[CH:30]([NH:33][CH:34]([CH3:41])[CH2:35][CH2:36][O:37][C:38](=[O:40])[CH3:39])([CH3:32])[CH3:31]>>[CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([N:33]([CH:30]([CH3:32])[CH3:31])[CH:34]([CH3:41])[CH2:35][CH2:36][O:37][C:38](=[O:40])[CH2:39][C:7]4[CH:6]=[CH:5][C:4]([O:3][CH3:1])=[C:27]([O:28][CH3:29])[CH:26]=4)=[O:23])=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCN(C)C[C@H]21
Reactant: CC(=O)OCCC(C)NC(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C(C)C)C(C)CCOC(=O)Cc3ccc(OC)c(OC)c3)cc1)=N[C@@H]1CCN(C)C[C@H]21

Procedure:
Prepared from 4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]-naphthyridin-6yl)benzoic acid and rac-3,4-dimethoxy-phenyl)-acetic acid 3-isopropylamino-butyl ester as described for example 1.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27]([C:29]1[NH:30][CH:31]=[C:32]([Br:34])[CH:33]=1)=[O:28])=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27]([C:29]3[NH:30][CH:31]=[C:32]([Br:34])[CH:33]=3)=[O:28])[CH:13]=2)[N:6]=1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reactant: [N-]=[N+]=NCCNC(=O)c1cc(Br)c[nH]1
Product: CC(C)(C)OC(=O)n1cc(CCCCCc2cn(CCNC(=O)c3cc(Br)c[nH]3)nn2)nc1N

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.104 g, 0.375 mmol) was reacted with N-(2-azidoethyl)-4-bromo-1H-pyrrole-2-carboxamide (0.131 g, 0.375 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(4-bromo-1H-pyrrole-2-carboxamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 11.44 (s, 1H), δ 7.84 (s, 1H), δ 7.28 (s, 1H), δ 6.84 (s, 1H), δ 6.74 (s, 1H), δ 6.46 (s, 1H), δ 4.89 (s, 2H), δ 3.82 (s, 2H), δ 2.57 (s, 2H), δ 2.28 (s, 2H), δ 1.55 (m, 13H), δ 1.29 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 186.8, 161.4, 150.7, 149.3, 148.2, 137.6, 126.3, 122.5, 122.1, 113.1, 100.4, 96.9, 85.4, 49.6, 29.1, 28.7, 28.2, 27.7, 25.5 ppm; HRMS (ESI) calcd for C22H31BrN8O3 (M+) 534.1703. Found 534.1705, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-4-bromo-1H-pyrrole-2-carboxamide hydrochloride (0.129 g, 73% yield). 1H NMR (400 MHz, CD3OD) δ 8.42 (s, 1H), δ 6.93 (s, 1H), δ 6.82 (s, 1H), δ 6.47 (s, 1H), δ 4.76 (s, 2H), δ 3.87 (s, 2H), δ 2.79 (s, 2H), δ 2.45 (s, 2H), δ 1.69 (s, 2H), δ 1.60 (s, 2H), δ 1.37 (s, 2H) ppm; 13C NMR (100 MHz, CD3OD) δ 161.4, 159.5, 159.1, 147.3, 147.2, 127.6, 125.8, 122.3, 122.1, 112.8, 108.6, 108.5, 96.4, 51.9, 38.9, 28.0, 27.9, 27.6, 24.1, 23.6 ppm; HRMS (ESI) calcd for C17H23BrN8O (M+) 434.1178. Found 434.1171.
Reaction SMILES: IC.[C:3]([C@H:10]([CH:14]([NH2:22])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)C(O)=O)([O:5][C:6](C)(C)C)=[O:4].[C:23](=[O:26])([O-])[O-:24].[K+].[K+]>CN(C=O)C>[C:15]([O:24][C:23]([NH:22][C@@H:14]([C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)[CH2:10][C:3]([O:5][CH3:6])=[O:4])=[O:26])([CH3:20])([CH3:16])[CH3:14]
Reactant: CC(C)(C)OC(=O)[C@@H](C(=O)O)C(N)c1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 199.1 %

Procedure:
Iodomethane (0.987 mL, 15.85 mmol) was added in one portion to boc-(R)-3-amino-3-(4-chloro-phenyl)-propionic acid (950 mg, 3.17 mmol) and potassium carbonate (876 mg, 6.34 mmol) in DMF (15 mL). The resulting suspension was stirred at 80° C. for 24 hours. The reaction mixture was concentrated and diluted with EtOAc (25 mL) with water (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford (R)-methyl 3-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoate (990 mg, 100%) as a orange solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:25][CH3:26])[C:16]2[C:21]([NH:22][CH2:23][CH3:24])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:25]([N:15]([CH2:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:16]1[C:21]([NH:22][CH2:23][CH3:24])=[CH:20][CH:19]=[CH:18][N:17]=1)[CH3:26]
Reactant: [H][H]
Reactant: CCNc1cccnc1N(CC)CC1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCNc1cccnc1N(CC)CC1CCNCC1

Procedure:
1-Benzyl-4-[N-ethyl-N-(3-ethylamino-2-pyridinyl)amino]methylpiperidine (EXAMPLE 187, 2.38 g, 6.75 mmol) and palladium hydroxide on carbon (1.5 g) in 100 ml ethanol is hydrogenated under 40 p.s.i. hydrogen for 42 hr. Filtration and evaporation of the solvent gives 4-[N-ethyl-N-(3-ethylamino-2-pyridinyl)aminomethyl]piperidine.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH2:17][C:18]([O:20]C)=[O:19])[CH:12]=2)[CH:7]=1)[CH3:5].Cl>[OH-].[Na+]>[C:18]([CH2:17][O:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH:7]=[C:6]([CH:4]([CH3:5])[C:3]([OH:22])=[O:2])[CH:15]=[CH:14]2)([OH:20])=[O:19]
Reactant: COC(=O)COc1ccc2cc(C(C)C(=O)OC)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C(=O)O)c1ccc2cc(OCC(=O)O)ccc2c1
Temperature: 90 °C
Yield: 71.8 %

Procedure:
A mixture of 2-(6-Methoxycarbonylmethoxy-naphthalen-2-yl)-propionic acid methyl ester 31 (23 grams, 76.16 mmol) in 4 N—NaOH solutions (230 mL) was heated on a water bath at 90° C. for 8 hours. The reaction mass was cooled to room temperature and the pH adjusted to 2 with concentrated hydrochloric acid. Crude 89 was filtered, dried, and recrystallized from a mixture of ethyl acetate:hexane (1:6) to give pure 89 (15 grams, 71.9%) as a white powder. Mp: 185-188° C. IH NMR (DMSO-d6) δ 1.54 (d, 3H, CH3), 3.80 (q, 1H, CH), 4.74 (s, 2H, OCH2), 7.08 (s, 1H, Ar), 7.22 (m, 1H, Ar), 7.42 (m, 1H, Ar), 7.66 (m, 3H, Ar).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([NH2:26])=[C:12]([O:14][CH:15]([C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]([F:24])[C:18]=3[Cl:25])[CH3:16])[CH:13]=2)=[CH:4][CH:3]=1.[N:27]1([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:31][CH2:30][CH2:29][CH2:28]1>CN1CCCC1=O>[Cl:25][C:18]1[C:19]([F:24])=[CH:20][CH:21]=[C:22]([Cl:23])[C:17]=1[CH:15]([O:14][C:12]1[CH:13]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([N:35]3[CH2:36][CH2:37][CH:32]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:33][CH2:34]3)=[N:7][CH:6]=2)[CH:9]=[N:10][C:11]=1[NH2:26])[CH3:16]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: CC(Oc1cc(-c2ccc(Br)nc2)cnc1N)c1c(Cl)ccc(F)c1Cl
Solvent: CN1CCCC1=O
Product: CC(Oc1cc(-c2ccc(N3CCC(N4CCCC4)CC3)nc2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 80 °C
Yield: 50 %

Procedure:
A tube was charged with 6′-bromo-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-6-ylamine (92 mg, 0.20 mmol), 4-pyrrolidin-1-yl-piperidine (0.62 g, 4.0 mmol) and N-methylpyrrolidinone (0.8 mL). The tube was sealed and the mixture was heated at 80° C. overnight. The temperature was increased to 100° C. for 5.5 hours and then heating was ceased. The reaction was partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated by rotary evaporation. The residue was purified by silica gel chromatography using gradient elution of dichloromethane, methanol, ammonium hydroxide to afford 5″-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-4-pyrrolidin-1-yl-3,4,5,6-tetrahydro-2H-[1,2′;5′,3″]terpyridin-6″-ylamine (53 mg, 50%).
Reaction SMILES: [CH:1]1([S:4]([NH2:7])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[H-].[Na+].[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:32])=[C:15]([CH:17]2[C:26]([CH3:28])([CH3:27])[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:29](O)=[O:30])[CH:23]=3)[NH:18]2)[CH:16]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:32])=[C:15]([CH:17]2[C:26]([CH3:27])([CH3:28])[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:29]([NH:7][S:4]([CH:1]4[CH2:3][CH2:2]4)(=[O:6])=[O:5])=[O:30])[CH:23]=3)[NH:18]2)[CH:16]=1
Reactant: Cc1ccc(F)cc1C1Nc2ccc(C(=O)O)cc2CC1(C)C
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1C1Nc2ccc(C(=O)NS(=O)(=O)C3CC3)cc2CC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.9 %

Procedure:
To a suspension of cyclopropanesulfonic acid amide (250 mg, 2.1 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (84 mg, 2.1 mmol). The resulting mixture was stirred at 25° C. for 1 hour. A solution of 2-(5-fluoro-2-methyl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (130 mg, 0.42 mmol) and 1,1′-carbonyldiimidazole (130 mg, 0.84 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h. Then the above suspension of cyclopropanesulfonic acid amide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [2-(5-fluoro-2-methyl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (40 mg, 23%) as a white solid: LC/MS m/e calcd for C22H25FN2O3S (M+H)+: 417.5, observed: 417.3.