Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[F:21][C:22]1[C:27]([F:28])=[C:26]([O:29][CH2:30][CH3:31])[CH:25]=[CH:24][C:23]=1O.C1(N=C=NC2CCCCC2)CCCCC1.O>ClCCl.CN(C)C1C=CN=CC=1>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][C:18]([O:20][C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH3:31])=[C:27]([F:28])[C:22]=3[F:21])=[O:19])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCOc1ccc(O)c(F)c1F
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCC(=O)O)CC2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCC(=O)Oc3ccc(OCC)c(F)c3F)CC2)CC1
Reaction time: 0.5 h

Procedure:
In a 3-L three-neck flask equipped with a stirrer, a thermometer and a dropping funnel, 32.0 g (114.9 mmol) of 3-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)propionic acid and 20.0 g (114.9 mmol) of 2,3-difluoro-4-ethoxyphenol were dissolved in 1000 ml of dichloromethane at room temperature under nitrogen atmosphere, and 15.4 g (126.4 mmol) of 4-dimethylaminopyridine was added thereto. The solution was stirred for 30 minutes thereafter, and then 26.1 g (126.4 mmol) of dicyclohexylcarbodiimide was dissolved in 400 ml of dichloromethane to prepare a solution, which was added dropwise to the reaction mixture at room temperature. After dropwise adding, the solution was stirred at room temperature for 14 hours. 500 ml of water was added to the reaction solution, insoluble materials were filtered, and then the filtrate was washed with 300 ml of 3M hydrochloric acid, 300 ml of water, 300 ml of a saturated aqueous sodium hydrogencarbonate solution and 600 ml of water and dried over anhydrous magnesium sulfate. The solvent was distilled off from the reaction solution under reduce pressure to obtain 56.4 g of a concentrated substance, which was then purified by means of a silica gel column chromatography with a mixed solvent of heptane/ethyl acetate (7/3) used as a developing solvent to obtain 51.4 g of 2,3-difluoro-4-ethoxyphenyl 3-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)propionate as colorless crystals.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:36])=[CH:20][N:19]=1>>[Cl:36][C:21]1[C:22]([NH:24][C:25]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:23][C:18]([NH:14][C:11]2[CH:12]=[CH:13][C:8]3[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:9]=3[CH:10]=2)=[N:19][CH:20]=1
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CCN1CCN(CC)c2cc(Nc3ncc(Cl)c(Nc4c(F)cccc4C(=O)NC)n3)ccc2C1

Procedure:
The title compound was prepared from 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to 712. Product was isolated as a tan solid (0.026 g, 26%); Mp 111-117° C.; LCMS (m/e)-498 (M); 1H-NMR (DMSO, 400 MHz) δ 9.35 (s, 1H), 9.11 (s, 1H), 8.53 (d, 1H), 8.16 (s, 1H), 7.45-7.49 (t, 2H, J=7.07 Hz), 7.38-7.40 (q, 1H, J=6.57 Hz), 7.10-7.12 (d, 1H, J=8.33 Hz), 6.95 (s, 1H), 6.79-6.81 (d, 1H, J=8.08 Hz), 3.54 (s, 1H), 2.97-2.98 (q, 2H, J=6.83 Hz), 2.87 (s, 2H), 2.73-2.74 (s, 6H), 2.39 (m, 2H), 1.07-1.11 (t, 3H, J=6.82 Hz), 1.00-1.03 (t, 3H, J=6.82 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[C:14]3[S:15][CH:16]=[CH:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:3]=1[Cl:22].C(=O)=O.[Br:26]Br>ClCCl>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[C:14]3[S:15][CH:16]=[C:17]([Br:26])[C:13]=3[CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:3]=1[Cl:22]
Reactant: BrBr
Reactant: COC(=O)c1nc(-c2cccc3ccsc23)c(F)c(N)c1Cl
Agent: O=C=O
Solvent: ClCCl
Product: COC(=O)c1nc(-c2cccc3c(Br)csc23)c(F)c(N)c1Cl
Temperature: -5 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
Methyl 4-amino-6-(benzo[b]thiophen-7-yl)-3-chloro-5-fluoropicolinate (0.500 g, 1.485 mmol) was dissolved in dichloromethane (9.90 mL) and cooled to −5° C. in a acetone bath to which was added a few pieces of dry ice. Bromine (114 mL, 2.227 mmol) was dissolved in dichloromethane (9.90 mL) and added dropwise. The reaction mixture was stirred overnight, and then partitioned between ethyl acetate and water. The organic phase was dried and concentrated and the product purified by flash chromatography (SiO2, 5-40% ethyl acetate/hexane gradient) followed by a second purification by reverse phase chromatography to provide the title compound as a grey solid (0.278 g, 45).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=O.[NH4+].O[N:12]1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C=O>[O:6]=[C:5]1[NH:1][C@H:2]([C:7]([NH2:12])=[O:9])[CH2:3][CH2:4]1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [NH4+]
Solvent: CN(C)C=O
Product: NC(=O)[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a stirred solution of L-pyroglutamic acid (II) (75 gm, 0.580 mol, commercially available) in dimethylformamide (750 ml) was added 1-hydroxy benzotriazole ammonium salt (106 gm, 0.696 mol, prepared according the literature procedure described in WO 2006100119) in one lot at 25° C. To this reaction mass, DCC was added in small portions over a period of 30 minutes at 0-5° C. The reaction mixture was allowed to warm to room temperature and stirring continued further for 2 hours. The precipitates were removed by filtration and the filtrate concentrated under reduced pressure. The residue was treated with ethyl acetate (1000 ml) and stirred for 1 hour. The precipitate formed was filtered under suction and washed with additional ethyl acetate (2×75 ml). The combined filtrate was concentrated under reduced pressure to obtain 73 gm of (S)-5-oxopyrrolidine-2-carboxamide (III) as a white solid in 98% yield. The solid thus obtained was used without further purification in the next step.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][C@@H:6]([NH:8][CH3:9])[C@H:5]([OH:10])[CH2:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[N+:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)([O-:19])=[O:18].O>C(Cl)Cl>[CH2:1]([N:3]1[CH2:4][C@@H:5]([OH:10])[C@H:6]([N:8]([CH3:9])[C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=2)[CH2:7]1)[CH3:2]
Reactant: CCN1C[C@@H](O)[C@H](NC)C1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCN1C[C@@H](O)[C@H](N(C)C(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 17.0 g. (118 mmoles) of trans-1-ethyl-4-methylamino-3-pyrrolidinol in 180 ml of methylene chloride was mixed with 15 g of powdered anhydrous potassium carbonate and cooled to -5°. The mixture was kept at or below 0° C. while a solution of 22.0 g (118 mmoles) of p-nitrobenzoyl chloride in 100 ml of methylene chloride was added dropwise. After the mixture was stirred at ambient temperature for 18 hr, it was poured into 100 ml of water. The organic layer was separated, dried, and concentrated. The residue was crystallized from benzene to give 30 g (87%) of white crytals; m.p. 104°-108° C.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][NH:2]1.[CH3:12][CH2:13]C(N)CCCCC>>[CH:10]1([C:1]([NH2:2])=[O:11])[C:5]2[C:6](=[CH:12][CH:13]=[CH:3][CH:4]=2)[CH2:7][CH2:8][CH2:9]1
Reactant: CCCCCC(N)CC
Reactant: O=c1[nH]ccc2ccccc12
Product: NC(=O)C1CCCc2ccccc21

Procedure:
A preferred process for preparing 2-(1-azabicyclo 2.2.2!oct-3-yl)-2,3,3a,4,5,6-hexahydro-1H-benz de!isoquinolin-1-one is that in which L is chloro and the 1-azabicyclo 2.2.2!oct-3-ylamine is (S)-1-azabicyclo 2.2.2!oct-3-ylamine and is reacted with the compound of Formula 5 to give N-(1-azabicyclo 2.2.2!oct-3S-yl)-1,2,3,4-tetrahydronaphthalen-1-ylcarboxamide; and preferably wherein the N-(1-azabicyclo 2.2.2!oct-3S-yl)-1,2,3,4-tetrahydronaphthalen-1-ylcarboxamide is then reduced as N-(1-azabicyclo 2.2.2!oct-3S-yl)-1,2,3,4-tetrahydronaphthalen-1S-ylcarboxamide.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]3[C:13](=[O:14])[N:12]([C:15]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]5[CH:28]=[C:27]([NH:29][C:30]6[CH:35]=[CH:34][C:33]([C:36]([N:38]7[CH2:43][CH2:42][O:41][CH2:40][CH2:39]7)=[O:37])=[CH:32][N:31]=6)[C:26](=[O:44])[N:25]([CH3:45])[CH:24]=5)[C:16]=4[CH:17]=[O:18])[CH2:11][CH2:10][NH:9][C:8]=3[CH:46]=2)[CH2:3][CH2:2]1.C(O)C.[BH4-].[Na+]>C1COCC1>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]3[C:13](=[O:14])[N:12]([C:15]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]5[CH:28]=[C:27]([NH:29][C:30]6[CH:35]=[CH:34][C:33]([C:36]([N:38]7[CH2:43][CH2:42][O:41][CH2:40][CH2:39]7)=[O:37])=[CH:32][N:31]=6)[C:26](=[O:44])[N:25]([CH3:45])[CH:24]=5)[C:16]=4[CH2:17][OH:18])[CH2:11][CH2:10][NH:9][C:8]=3[CH:46]=2)[CH2:2][CH2:3]1
Reactant: Cn1cc(-c2cccc(N3CCNc4cc(C5CC5)ccc4C3=O)c2C=O)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1cc(-c2cccc(N3CCNc4cc(C5CC5)ccc4C3=O)c2CO)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Reaction time: 1 h
Yield: 56.9 %

Procedure:
To a mixture of 2-(8-Cyclopropyl-5-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-benzaldehyde (350 mg, 0.566 mmol) in 40 mL 1:1 absolute ethanol and THF cooled to 0 C was added sodium borohydride (22 mg, 0.566 mmol, 1 eq) and the reaction was stirred for 1 hour at 0 C. The reaction was quenched with water and 2 drops glacial acetic acid, and stirred for 5 min. The mixture was concentrated in vacuo to remove THF and Ethanol, neutralized with a few drops of aqueous saturated sodium bicarbonate, then concentrated to dryness. The residue was loaded directly on an analogix 40 g column using 10% methanol in CH2Cl2, and eluted with a gradient of 5% to 10% methanol in CH2Cl2 to give a solid. Repurification using HPLC gave 200 mg 8-Cyclopropyl-4-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one, as a solid, 63% yield.
Reaction SMILES: [Na].[P:2]([O-:9])([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5].[F:10][CH:11]([F:32])[C:12]1[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:14](F)[C:13]=1[C:28]([O:30][CH3:31])=[O:29].O>C1COCC1>[F:32][CH:11]([F:10])[C:12]1[N:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[C:15]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:14]([P:2]([O:6][CH2:7][CH3:8])([O:3][CH2:4][CH3:5])=[O:9])[C:13]=1[C:28]([O:30][CH3:31])=[O:29]
Reactant: CCOP([O-])OCC
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1F
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.4 %

Procedure:
To a mixture of 0.26 g (0.011 mol) of sodium metal in 35 ml of dry THF was added 3.14 g (0.023 mol) of diethyl phosphite. This solution was stirred at room temperature under a N2 atmosphere for 18 hours. To this salt solution was added 2.0 g (0.006 mol) of product of Example 107. This mixture was stirred at reflux for 18 hours. The mixture was cooled to room temperature and poured into H2O. The H2O mixture was extracted twice with diethyl ether. The combined ether phases were then washed with H2O, dried (MgSO4), and concentrated in vacuo affording 2.18 g of an orange oil. This oil was kugelrohr distilled at 80 and collected at 150°-151° C. pot temperature yielding 1.68 g (63%) of a clear oil, n25D 1.4536.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH:13]=[O:14])=O)(C)(C)C.[CH:15]1([Mg]Cl)[CH2:17][CH2:16]1.C(=O)([O-])O.[Na+].ClCCl>O1CCCC1>[CH:15]1([C@H:13]([CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[OH:14])[CH2:17][CH2:16]1
Reactant: Cl[Mg]C1CC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O[C@H](C1CC1)C1CCCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.2 %

Procedure:
To a solution of (R)-2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 1 mmol) in tetrahydrofuran at −78° C. was added a 1 M solution of cyclopropylmagnesium chloride (1.3 ml, 1.3 mmol). After stirring for 1 h at room temperature and addition of aqueous sodium hydrogencarbonate, extraction (3 times with dichloromethane), drying of the combined organic layers over sodium sulfate and evaporation of the solvents the crude product was heated with aqueous sodium hydroxide at 100° C. for 3 days to give 20 mg of crude cyclopropyl-(R)-pyrrolidin-2-yl-methanol which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.Cl[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([NH:19][CH3:20])=[O:18])[CH:12]=1>>[CH3:20][NH:19][C:17]([C:13]1[CH:12]=[C:11]([O:8][C:6]2[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=2[CH3:9])[NH2:1])[CH:16]=[CH:15][N:14]=1)=[O:18]
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: Cc1ccc(N)cc1O
Product: CNC(=O)c1cc(Oc2cc(N)ccc2C)ccn1

Procedure:
Entry 50: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline to afford the urea.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:32]([CH2:40][C:41](=O)[CH3:42])(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:42]/[C:41](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])=[CH:40]/[C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CC(=O)CC(=O)c1ccccc1
Product: C/C(=C/C(=O)c1ccccc1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 40 mg (0.092 mmol) of Intermediate 50 and 15 mg (0.092 mmol) of benzoylacetone to yield 32 mg of Example 7: TLC (DCM/MeOH, 4/1): Rf=0.48; 1H NMR (DMSO-d6, 300 MHz) δ11.49 (d, 1H, J=9.8), 8.17 (d, 2h, J=8.9), 7.9 (d, 2H, J=8.9), 7.85 (m, 2H), 7.44 (m, 3H), 7.19 (d, 2H, J=8.8), 6.89 (d, 2H, J=8.8), 5.60 (s, 1H), 4.23 (t, 2H, J=6.0), 4.16 (m, 1H), 3.21 (m, 2H), 2.99 (t, 2H, J=6.0), 2.82 (dd, 1H, J=14.2, 9.8), 2.42 (s, 3H), 1.78 (s, 3H); low resolution MS (ES+)m/e 579.0 (MH+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[C:15]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][CH:18]=[C:17]([C:21](Cl)=[O:22])[CH:16]=1.C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([C:17]1[CH:16]=[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)=[O:22]
Reactant: O=C(Cl)c1cccc(-c2ccccc2)c1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(-c2ccccc2)c1
Yield: 35.5 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide was obtained following Method C starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g, 0.424 mmol), biphenyl-3-carbonyl chloride (0.0965 g; 0.445 mmol), and triethylamine (0.145 mL; 1.06 mmol) in dichloromethane (5 mL). Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.0565 g (36%) of N-(2-(5-Chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide as a white solid.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:20]([N:22]([CH2:31][CH3:32])[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[CH3:21]>>[CH2:31]([N:22]([CH2:20][CH3:21])[C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:25][CH:24]=1)[CH3:32]
Reactant: CCN(CC)c1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: CCN(CC)c1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-diethylaminobenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give N,N-diethyl-4-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]aniline.
Reaction SMILES: [NH:1]([C:5]1[CH:22]=[CH:21][C:8]([C:9]([O:11]C2C=CC([N+]([O-])=O)=CC=2)=O)=[CH:7][CH:6]=1)[C:2]([NH2:4])=[NH:3].[ClH:23].[NH2:24][CH2:25][CH2:26][CH2:27][N:28]1[CH2:32][C:31](=[O:33])[N:30]([CH:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:35]([O:37][CH3:38])=[O:36])[C:29]1=[O:45].C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C>CN(C)C=O>[ClH:23].[NH:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:24][CH2:25][CH2:26][CH2:27][N:28]2[CH2:32][C:31](=[O:33])[N:30]([CH:34]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:35]([O:37][CH3:38])=[O:36])[C:29]2=[O:45])=[O:11])=[CH:21][CH:22]=1)[C:2]([NH2:4])=[NH:3]
Reactant: COC(=O)C(c1ccccc1)N1C(=O)CN(CCCN)C1=O
Reactant: N=C(N)Nc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: CCN1CCOCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccccc1)N1C(=O)CN(CCCNC(=O)c2ccc(NC(=N)N)cc2)C1=O

Procedure:
384 mg (1.14 mmol) of 4-nitrophenyl 4-guanidinobenzoate, 390 mg (1.14 mmol) of methyl (3-(3-aminopropyl)-2,5-dioxoimidazolidin-1-yl)phenylacetate hydrochloride, 55 mg (0.4 mmol) of HOBt and 140 mg (1.2 mmol) of N-ethylmorpholine are stirred at room temperature for 5 h in 10 ml of dimethylformamide. Following concentration, chromatography takes place, for purification, on silica gel using a mixture of methylene chloride, methanol, glacial acetic acid and water=85:15:2:2. The fractions containing the pure substance are concentrated and freeze dried.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:24]3[C:19](=[CH:20][C:21]([C:25]([NH:27][C@H:28]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]([CH3:38])[CH3:37])[CH:31]=4)[CH3:29])=[O:26])=[CH:22][CH:23]=3)[C:18]([CH3:39])=[C:17]2[CH3:40])=[CH:11][CH:10]=1)#[N:2].[N:41]([Si](C)(C)C)=[N+:42]=[N-:43].C([Sn](CCCC)=O)CCC>C1(C)C=CC=CC=1>[N:2]1[NH:41][N:42]=[N:43][C:1]=1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]2[C:24]3[C:19](=[CH:20][C:21]([C:25]([NH:27][C@H:28]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]([CH3:37])[CH3:38])[CH:31]=4)[CH3:29])=[O:26])=[CH:22][CH:23]=3)[C:18]([CH3:39])=[C:17]2[CH3:40])=[CH:13][CH:14]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C#N)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(C)C)c3)cc12
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3-c3nn[nH]n3)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(C)C)c3)cc12
Temperature: 110 °C

Procedure:
The mixture of (S)-1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide (0.1 g, 0.19 mmol), azidotrimethylsilane 90.05 mL, 0.38 mmol) and dibutylstannanone (0.005 g, 0.019 mmol) in toluene (3 mL) was heated at 110° C. oil bath for 16 hr. The solvent was removed and the residue was purified by preparative-HPLC to obtain the title compound. ESI-MS (m/z): 569 [M+H]+.
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][CH2:8][NH2:9])[CH:6]=1.[F:10][C:11]([F:23])([F:22])[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH:20]=O)=[CH:14][CH:13]=1>>[I:1][C:2]1[N:3]=[CH:4][N:5]2[CH2:7][CH2:8][NH:9][CH:20]([CH2:19][CH2:18][C:15]3[CH:16]=[CH:17][C:12]([C:11]([F:10])([F:22])[F:23])=[CH:13][CH:14]=3)[C:6]=12
Reactant: O=CCCc1ccc(C(F)(F)F)cc1
Reactant: NCCn1cnc(I)c1
Product: FC(F)(F)c1ccc(CCC2NCCn3cnc(I)c32)cc1

Procedure:
According to the general procedure (GP10), the microwave-assisted Pictet-Spengler reaction (70 W; 130° C.; 10 bars; 10 min.) between 2-(4-iodo-imidazol-1-yl)-ethylamine (4.326 g; 18.253 mmol) and 3-(4-trifluoromethyl-phenyl)-propionaldehyde (3.690 g; 18.253 mmol) afforded 1-iodo-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine which was Boc-protected and finally purified by FC (DCM/MeOH=25/1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:5]2=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[F:27][C:28]1[CH:51]=[CH:50][C:31]([CH2:32][NH:33][C:34]2[CH:35]=[C:36]([CH:48]=[O:49])[N:37]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)[N:38]=2)=[CH:30][CH:29]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:48]([C:36]3[N:37]([CH2:39][C:40]4[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=4)[N:38]=[C:34]([NH:33][CH2:32][C:31]4[CH:30]=[CH:29][C:28]([F:27])=[CH:51][CH:50]=4)[CH:35]=3)[OH:49])=[CH:9][N:8]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(Cn2nc(NCc3ccc(F)cc3)cc2C=O)cc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cc(Cl)cnc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(NCc3ccc(F)cc3)cc2C(O)c2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncc(Cl)cc23)cc1
Temperature: -20 °C

Procedure:
In a round bottom flask, 5-chloro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (4, 1.7 g, 3.9 mmol) was combined with 1.3 mL of tetrahydrofuran and cooled to −20° C. Isopropylmagnesium chloride (2.0 mL, 2 M in tetrahydrofuran, 4.0 mmol) was added dropwise and the reaction stirred at −5° C. The reaction was cooled to −20° C. and 5-(4-fluoro-benzylamino)-2-(4-methoxy-benzyl)-2H-pyrazole-3-carbaldehyde (113, 0.622 g, 1.83 mmol) in 2 mL of tetrahydrofuran was added and the reaction stirred at 0° C. The reaction was concentrated under vacuum, diluted with ethyl acetate and washed with sodium bicarbonate and brine. The organic layer was dried with sodium sulfate and purified by silica gel column chromatography, eluting with 5-80% ethyl acetate in hexanes. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound. MS (ESI) [M+H+]+=648.38 and 649.74.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].C(OC([N:28]1[CH2:33][CH2:32][CH:31]([C:34]2[CH:35]=[N:36][C:37]([NH2:40])=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=O)(C)(C)C>>[CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10]([NH:40][C:37]3[N:36]=[CH:35][C:34]([CH:31]4[CH2:32][CH2:33][NH:28][CH2:29][CH2:30]4)=[CH:39][CH:38]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)nc2)CC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C4CCNCC4)cn3)nc2n1C1CCCC1
Yield: 47.5 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (300 mg, 1.03 mmol) and 6-amino-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (313 mg, 1.13 mmol), followed by deprotection using General Procedure A to give 7-cyclopentyl-2-(1′,2′,3′,4′,5′,6′-hexahydro-[3,4′]bipyridinyl-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (212 mg, 48%). MS (ESI) m/z 434.3 (M+H)+