Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[Mg][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[CH:8]12[O:13][CH:12]1[CH2:11][O:10][CH2:9]2>C1COCC1.[Cu]I>[CH2:3]([C@@H:12]1[CH2:11][O:10][CH2:9][C@H:8]1[OH:13])[CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: C=CCCC[Mg]Br
Reactant: C1OCC2OC12
Agent: [Cu]I
Solvent: C1CCOC1
Product: C=CCCC[C@@H]1COC[C@H]1O
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a mixture of CuI (1.66 g, 8.71 mmol) in THF (100 mL) at −5° C., a 0.5M solution of bromo(pent-4-en-1-yl)magnesium (116 mL, 5.81 mmol) was added. The solution was stirred for 1 hour and cooled to −20° C. 3,6-Dioxabicyclo[3.1.0]hexane (5.0 g, 58.1 mmol) was added dropwise, and the reaction mixture was slowly warmed to RT and stirred for 15 hours. The reaction mixture was quenched with NH4Cl(aq.) and extracted with Et2O (3×). The combined organics were washed with H2O and brine, dried over Na2SO4, filtered and concentrated. The crude product was purified on SO2 (gradient elution, 10-100% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3) δ 5.83-5.75 (m, 1H); 5.04-4.95 (m, 2H); 4.14-4.07 (m, 3H); 3.85 (m, 1H); 3.70 (m, 1H); 3.44 (m, 1H); 2.07 (m, 3H); 1.45 (m, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][C:4]=1[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([OH:17])=O)[CH:13]=2)[NH:8][CH:7]=1.ClCCCl.C(N(CC)CC)C.Cl.[F:38][C:39]([F:46])([F:45])[CH2:40][CH:41]([CH3:44])[CH2:42][NH2:43]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:25][O:24][C:22](=[O:23])[C:20]1[CH:19]=[CH:18][C:4]([CH2:5][C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15](=[O:17])[NH:43][CH2:42][CH:41]([CH3:44])[CH2:40][C:39]([F:46])([F:45])[F:38])[CH:13]=3)[NH:8][CH:7]=2)=[C:3]([O:2][CH3:1])[CH:21]=1
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc(C(=O)O)cc23)c(OC)c1
Reactant: CC(CN)CC(F)(F)F
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)c1ccc(Cc2c[nH]c3ccc(C(=O)NCC(C)CC(F)(F)F)cc23)c(OC)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.3 %

Procedure:
To a solution of 3-(2-methoxy-4-methoxycarbonyl-benzyl)-1H-indole-5-carboxylic acid (1.7 grams, 5.00 mmol) in methylene chloride (50 mL), was added 4-dimethylaminopyridine (0.67 grams, 5.50 mmol), 1,2-dichloroethane (1.06 grams, 5.50 mmol), triethylamine (0.73 mL, 5.25 mmol) and 4,4,4-trifluoro-2-methylbutylamine hydrochloride (0.93 grams, 5.25 mmol). The resulting solution was stirred 12 hours, at room temperature, then diluted with methylene chloride. The solution was washed with 1 M hydrochloric acid (aq), then the organics were dried over magnesium sulfate. Concentration in vacuo followed by trituration of the crude product in a 2:1 ratio of ether:hexanes gave 3-methoxy-4-[5-(4,4,4-trifluoro-2-methyl-butylcarbamoyl)-1H-indol-3-ylmethyl]-benzoic acid methylester (1.88 grams, 82% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:5]=1[CH3:17])([O-:3])=[O:2].C[O:19]C(OC)N(C)C>CN(C=O)C.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:5]=1[CH:17]=[O:19])([O-:3])=[O:2]
Reactant: Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-nitro-5-phenoxytoluene (57.3 g, 0.25 mol) prepared in Step A above and dimethylformamide dimethyl acetal (43.1 mL, 0.324 mol) in DMF (259 mL) was heated overnight at 140° C. The mixture was cooled to room temperature, and the solvent was evaporated in vacuo. The residue was dissolved in THF (500 mL) and transferred to a 3L 3-neck flask equipped with an overhead stirrer. The mixture was diluted with 500 mL of water, and NaIO4 (160 g, 0.75 mol) was added in portions (slight exotherm). The mixture was stirred overnight at room temperature. The solids were-filtered and washed well with EtOAc. The filtrate was washed 3× with saturated aqueous NaHCO3 solution, and then dried (MgSO4). The solution was filtered and the solvent was evaporated in vacuo. The crude product was chromatographed (10-40% CH2Cl2:hexane) to yield 2-nitro-5-phenoxy-benzaldehyde as a yellow crystalline solid.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:30][C:31]([F:43])([F:42])[O:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([O:32][C:31]([F:30])([F:42])[F:43])[CH:34]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(OC(F)(F)F)c2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 3-trifluoromethoxybenzene boronic acid. The title compound was obtained in 73% yield as light green foam. MS (m/e): 566.4 (MH+, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](F)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].[OH:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])=[CH:23][CH:22]=1>CS(C)=O>[N+:16]([C:10]1[CH:11]=[CH:12][C:13]([O:20][C:21]2[CH:36]=[CH:35][C:24]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])=[CH:23][CH:22]=2)=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Agent: [K]
Solvent: CS(C)=O
Product: O=C(OCc1ccccc1)c1ccc(Oc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91 %

Procedure:
24.7 g of 5-fluoro-2-nitrophenyl benzyl ether (0.1 mol) are dissolved in 250 ml of dimethyl sulfoxide, and a solution of 26.6 g of the potassium salt of benzyl 4-hydroxybenzoate (0.1 mol) in 250 ml of dimethyl sulfoxide is then slowly added drop wise with stirring at room temperature. The mixture is then stirred first at room temperature for 1 hour and then at 50° C. for 24 hours. The reaction solution is then allowed to cool to room temperature and is filtered through a fluted filter, the filtrate is diluted with 700 ml of water, and the crude product is extracted by shaking with 300 ml of ethyl acetate. The organic phase is then washed three times with water, dried over sodium sulfate and evaporated in a rotary evaporator until the reaction product precipitates out. The reaction product is stirred in petrol ether (boiling range 40 to 60° C.) for 2 hours, filtered off via a Büchner funnel and then dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 91%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[C:2]1([NH:1][S:15]([CH3:14])(=[O:17])=[O:16])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of 250 g (2.68 mole) of aniline and 233.2 g (2.95 mole) of pyridine in 1.25 L of methylene chloride and 319.6 g (2.79 mole) of methanesulfonyl chloride dropwise. Stir the resulting solution at 0° C. for about 30 minutes then warm to ambient temperature for about 16 hours. Extract the mixture with 2N aqueous sodium hydroxide (4×1 L). Combine the aqueous extracts and wash with 1 L of methylene chloride. Cool the aqueous layer to about 0° C. and acidify with concentrated hydrochloric acid until about pH 1. Collect the precipitate and dry to give the title compound.
Reaction SMILES: [C:1]([C:5]1[N:6]=[N:7][N:8]([CH2:10][C@H:11]([N:18]2[CH2:23][C:22]3[CH:24]=[C:25]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:26]=[CH:27][C:21]=3[N:20]=[C:19]2[NH2:35])[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:43][O:44][CH2:45][C:46](Cl)=[O:47]>C(Cl)Cl>[C:1]([C:5]1[N:6]=[N:7][N:8]([CH2:10][C@@H:11]([N:18]2[CH2:23][C:22]3[CH:24]=[C:25]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:26]=[CH:27][C:21]=3[N:20]=[C:19]2[NH:35][C:46](=[O:47])[CH2:45][O:44][CH3:43])[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cn(C[C@@H](C2CCCCC2)N2Cc3cc(Oc4ccccc4)ncc3N=C2N)nn1
Reactant: COCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)NC1=Nc2cnc(Oc3ccccc3)cc2CN1[C@H](Cn1cc(C(C)(C)C)nn1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound #152 (0.115 g, 0.24 mmol), prepared, for example, as described in Example 44 above, was taken up into DCM (5 mL) and then triethylamine (34 μL, 0.24 mmol) was added. Methoxy-acetyl chloride (22 μL, 0.24 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was purified using normal phase chromatography (heptanes:EtOAc) to yield the title compound as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:7][CH:6]1[C:8]([OH:10])=O)=[O:4].O1CCCC1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:23][C:24]1[N:25]=[C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:34]=[CH:35][C:36]([CH3:49])=[C:37]([NH:39][C:40]([C:42]4[N:46]([CH3:47])[N:45]=[C:44]([CH3:48])[CH:43]=4)=[O:41])[CH:38]=3)=[N:28][N:27]2[CH:50]=1>CN(C)C=O.CN(C)C(=O)C>[CH3:47][N:46]1[C:42]([C:40]([NH:39][C:37]2[CH:38]=[C:33]([CH:34]=[CH:35][C:36]=2[CH3:49])[O:32][C:29]2[CH:30]=[CH:31][C:26]3[N:27]([CH:50]=[C:24]([NH:23][C:8]([CH:6]4[CH2:7][CH:5]4[C:3]([O:2][CH3:1])=[O:4])=[O:10])[N:25]=3)[N:28]=2)=[O:41])=[CH:43][C:44]([CH3:48])=[N:45]1
Reactant: COC(=O)C1CC1C(=O)O
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2C)n(C)n1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C1CC1C(=O)Nc1cn2nc(Oc3ccc(C)c(NC(=O)c4cc(C)nn4C)c3)ccc2n1
Yield: 24.8 %

Procedure:
In the same manner as in Example 279 and using 2-(methoxycarbonyl)cyclopropanecarboxylic acid (140 mg, 0.78 mmol), tetrahydrofuran (1.5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (69 μL, 0.8 mmol), N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide hydrochloride (250 mg, 0.6 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (75 mg, 25%) was obtained as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:45]=[CH:44][C:16]([CH2:17][CH:18]2[S:22][C:21](=[O:23])[N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:19]2=[O:43])=[CH:15][CH:14]=1>[Pd].O1CCOCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][CH:18]2[S:22][C:21](=[O:23])[NH:20][C:19]2=[O:43])=[CH:44][CH:45]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)cc2ccccc21
Agent: [Pd]
Solvent: C1COCCO1
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)cc2ccccc21
Yield: 76.4 %

Procedure:
A procedure similar to that described in Example 6 was repeated, except that 3.24 g of 5-[4-(1-methylindol-2-ylmethoxy)benzyl]-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 24), 4.86 g of 10% w/w palladium-on-charcoal and 100 ml of dioxane were used, to give 1.49 g of the title compound, melting at 174.3-175.5° C.
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].[Li]CCCC.[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13]>C1COCC1>[CH3:1][C:2]([OH:6])([CH3:3])[C:4]#[C:5][CH:19]([C:18]1[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:22][CH:21]=1)[OH:20]
Reactant: C#CC(C)(C)O
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(O)C#CC(O)c1ccc([N+](=O)[O-])cc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 64.3 %

Procedure:
To a stirred −78° C. solution of 2-methylbut-3-yn-2-ol (6.1 mL, 63.5 mmol, 1.2 eq) in dry THF (250 mL), n-BuLi (62 mL, 2.3 M in hexane, 142 mmol, 2.7 eq) was added dropwise over 10 minutes under an inert atmosphere. After being stirred for 40 min at −78° C., a solution of 4-nitrobenz aldehyde (8 g, 52.9 mmol, 1 eq) in dry THF (50 mL) was added to the reaction mixture and stirring was continued for an additional 1 h at −78° C. The reaction mixture was then quenched with a saturated NH4Cl solution and extracted with EtOAc (2×200 mL). The combined organic layers were washed with water (200 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography (30% ethyl acetate in hexanes) to afford 4-methyl-1-(4-nitrophenyl)pent-2-yne-1,4-diol (8 g, 65%) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=1.[NH2:20][C:21]1[C:25]([C:26]#[N:27])=[CH:24][NH:23][N:22]=1>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:22]3[N:23]=[CH:24][C:25]([C:26]#[N:27])=[C:21]3[N:20]=2)=[CH:5][CH:4]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)cc1
Reactant: N#Cc1c[nH]nc1N
Product: N#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Yield: 38.5 %

Procedure:
Reaction of 1-(4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (284 mg, 1.0 mmol), prepared from commercially available 4-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as an off-white solid (137 mg, 38%). MS (ISP) 357.0 [(M+H)+]; mp 176° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[C:24]([CH3:25])=[C:23]([CH3:26])[S:22][C:13]=2[N:14]=[C:15]([C:17]2[O:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[O:21]1[C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[C:24]([CH3:25])=[C:23]([CH3:26])[S:22][C:13]=3[N:14]=2)=[CH:18][CH:19]=[N:20]1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1sc2nc(-c3ccno3)nc(Cl)c2c1C
Product: Cc1sc2nc(-c3ccno3)nc(NCc3ccc(F)cc3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(isoxazol-5-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(4-fluorobenzylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([OH:3])=O.C(N(C(C)C)CC)(C)C.CN(C(ON1N=[N:47][C:42]2[CH:43]=[CH:44][CH:45]=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.C1(CN)CC1>CN(C)C=O>[CH:43]1([CH2:42][NH:47][C:1]([C:4]2[CH:5]=[CH:6][C:7]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:12][CH2:11]3)=[CH:8][CH:9]=2)=[O:3])[CH2:45][CH2:44]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NCC1CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)NCC3CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.8 %

Procedure:
500 mg tert-butyl 4-(4-carboxyphenyl)-piperidine-1-carboxylate are placed in 28 ml dimethylformamide, then 1.14 ml diisopropylethylamine and 747 mg HATU are added. The reaction mixture is stirred for 15 min at ambient temperature, then 194 mg cyclopropylmethylamin hydrochloride are added. The reaction mixture is stirred overnight at ambient temperature. Then the product is purified by preparative HPLC (method A). 480 mg product are obtained as an oil. Analytical HPLC-MS (method B): RT=1.64 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[Cl:15][C:16]1[C:24]([Cl:25])=[C:23]([CH3:26])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>ClCCl>[Cl:15][C:16]1[C:24]([Cl:25])=[C:23]([CH3:26])[CH:22]=[CH:21][C:17]=1[C:18]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:19]
Reactant: Cc1ccc(C(=O)Cl)c(Cl)c1Cl
Reactant: O=C1CNCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N2CCNC(=O)C2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-piperazinone (1 g, 9.99 mmol, commercially available from e.g. Sigma-Aldrich) and triethylamine (2.78 mL, 19.98 mmol) were dissolved in Dichloromethane (DCM) (25 mL) at 0° C. 2,3-dichloro-4-methylbenzoyl chloride (I71) (2.232 g, 9.99 mmol) dissolved in Dichloromethane (DCM) (25 mL) was added dropwise and the solution stirred to room temperature overnight. Solvents were removed in vacuo and the residue was partitioned between ethyl acetate (50 mL) and saturated sodium bicarbonate solution (25 mL). The aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water (2×50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated to a crude solid. A 100 mg sample was purified by MDAP to afford product in 69 mg.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[CH2:9][CH2:8][C:7]2([C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][CH2:20][C:21](OCC)=[O:22])[CH:16]=3)[N:11]([C:26](=[O:35])[NH:27][C:28]3[CH:33]=[N:32][C:31]([CH3:34])=[CH:30][N:29]=3)[CH2:10]2)[CH2:6]1)=[O:4].Cl.[NH:37]1[CH2:40][CH2:39][CH2:38]1>>[N:37]1([C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C:15]2[CH:16]=[C:17]3[C:7]4([CH2:8][CH2:9][N:5]([C:3]([NH:2][CH3:1])=[O:4])[CH2:6]4)[CH2:10][N:11]([C:26]([NH:27][C:28]4[CH:33]=[N:32][C:31]([CH3:34])=[CH:30][N:29]=4)=[O:35])[C:12]3=[CH:13][CH:14]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: C1CNC1
Reactant: CCOC(=O)CCCc1ccc2c(c1)C1(CCN(C(=O)NC)C1)CN2C(=O)Nc1cnc(C)cn1
Agent: Cl
Product: CNC(=O)N1CCC2(C1)CN(C(=O)Nc1cnc(C)cn1)c1ccc(CCCC(=O)N3CCC3)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Examples 29 and 85, with the exceptions that the ethyl 4-(1′-(methylcarbamoyl)-1-((5-methylpyrazin-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidin]-5-yl)butanoate obtained in Example 420 was used instead of 2-((2-(1′-acetyl-5-bromospiro[indoline-3,3′-pyrrolidin]-1-ylcarboxamido)thiazol-5-yl)thio)acetate, and that azetidine hydrochloride was used instead of dimethylamine hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:16]3[CH:17]=[CH:18][C:19]4[N:23]=[CH:22][N:21]([CH2:24][CH2:25][CH2:26][O:27]C5CCCCO5)[C:20]=4[CH:34]=3)=[C:10]3[CH2:15][CH2:14][CH2:13][N:11]3[N:12]=2)[CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.O1CCCC1.O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:16]3[CH:17]=[CH:18][C:19]4[N:23]=[CH:22][N:21]([CH2:24][CH2:25][CH2:26][OH:27])[C:20]=4[CH:34]=3)=[C:10]3[CH2:15][CH2:14][CH2:13][N:11]3[N:12]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(-c2nn3c(c2-c2ccc4ncn(CCCOC5CCCCO5)c4c2)CCC3)n1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc(-c2nn3c(c2-c2ccc4ncn(CCCO)c4c2)CCC3)n1
Yield: 75 %

Procedure:
Heat a solution of (6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1H-benzoimidazole (Example 54; 368 mg mg, 0.8 mmol) in 4:2:1 acetic acid/tetrahydrofuran/water (20 mL) to 80° C. for 18 h. Remove the solvent in vacuo and dissolve the residue in excess 3:1 chloroform/isopropyl alcohol. Wash the organic layer with saturated sodium bicarbonate, dry over sodium sulfate, filter, and concentrate in vacuo. Purify the residue by column chromatography on silica gel eluting with dichloromethane to 10% methanol/90% dichloromethane to give the desired product as a white solid (225 mg, 75%). MS ES+ m/e 374.3 (M+1).
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:11]2[C@@H:7]([CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10]2)[CH2:6][CH2:5]1)=[N+]=[N-].[H][H]>[Ni].C(O)C>[CH2:12]([N:9]1[CH2:10][C@@H:11]2[C@@H:4]([NH2:1])[CH2:5][CH2:6][C@@H:7]2[CH2:8]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: [N-]=[N+]=N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Reaction time: 24 h

Procedure:
(3aR,4S,6aS)-4-Azido-2-benzyloctahydrocyclopenta[c]pyrrole (1.70 g, 7.02 mmol), Raney®-nickel (0.46 g, 20% wt), and ethanol (47 mL) were combined in a Parr stirrer reactor. The reactor was pressured with hydrogen gas to 30 psi and the reaction mixture was agitated for 24 hours. The slurry was filtered to provide (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in ethanol.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2([C:17]3[N:21]([CH3:22])[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])=[N:19][N:18]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1.[CH3:30]I>CN(C=O)C.C(OCC)(=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:30])[C:11]([C:13]2([C:17]3[N:21]([CH3:22])[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])=[N:19][N:18]=3)[CH2:14][CH2:15][CH2:16]2)=[O:12])=[CH:6][CH:5]=1
Reactant: Cn1c(-c2ccccc2Cl)nnc1C1(C(=O)Nc2ccc(Cl)cc2)CCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C(=O)C1(c2nnc(-c3ccccc3Cl)n2C)CCC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (55% oily, 13 mg) was suspended in DMF (3 ml) and then N-(4-chlorophenyl)-1-[5-(2-chlorophenyl)-4-methyl-1,2,4-triazol-3-yl]cyclobutanecarboxamide was added thereto under ice cooling, followed by stirring at room temperature for 30 minutes. Methyl iodide (17 μl) was added thereto under ice cooling, followed by stirring at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate (30 ml) and washed with a saturated sodium bicarbonate solution (10 ml×2). The organic layer was dried over anhydrous sodium sulfate and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting residue was purified by column chromatography (methanol:chloroform=2:98) to obtain 83 mg of N-(4-chlorophenyl)-1-[5-(2-chlorophenyl)-4-methyl-1,2,4-triazol-3-yl]-N-methylcyclobutanecarboxamide (white solid).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10](OC)=[O:11])[CH:2]=1.[NH2:17][NH2:18].C(OCC)C>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([NH:17][NH2:18])=[O:11])[CH:2]=1
Reactant: NN
Reactant: COC(=O)c1cccc(-c2cccnc2)c1
Solvent: CO
Solvent: CCOCC
Product: NNC(=O)c1cccc(-c2cccnc2)c1
Yield: 35 %

Procedure:
To a stirred solution of methyl 3-(pyridin-3-yl)benzoate (190 mg, 0.89 mmol) in anhydrous methanol (1 mL) was added hydrazine (0.07 mL,). The solution was stirred at RT overnight before ethyl ether was added. The solid was filtered and washed with ethyl ether to give 67 mg (35% yield) of 3-(pyridin-3-yl)benzohydrazide as a white solid. An additional 120 mg of the product was recovered from the filtrate. (M+H)+=214.13