Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:32]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:65][C:66]1[CH:74]=[CH:73][C:69]([C:70]([OH:72])=[O:71])=[C:68]([Cl:75])[CH:67]=1>C(Cl)Cl>[CH3:32][O:71][C:70](=[O:72])[C:69]1[CH:73]=[CH:74][C:66]([NH:65][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])=[CH:67][C:68]=1[Cl:75]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: Nc1ccc(C(=O)O)c(Cl)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.34 mmol) in methylene chloride (10 mL), HATU (Aldrich, 235 mg, 0.62 mmol) was added followed by the addition of DIPEA (0.30 mL, 1.72 mmol) and 4-amino-2-chloro-benzoic acid (made above, 128 mg, 0.69 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 5-15% EtOAc/methylene chloride) to give a white solid. 74 mg.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[CH:6]=1.[Li]CCCC.[Si:13]([O:20][CH2:21]/[CH:22]=[N:23]/[S:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>CCOCC.C(Cl)Cl>[Br:7][C:5]1[CH:6]=[C:2]([CH:22]([NH:23][S:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])[CH2:21][O:20][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:15])[CH3:14])[S:3][CH:4]=1
Reactant: CC(C)(C)S(=O)/N=C/CO[Si](C)(C)C(C)(C)C
Reactant: Brc1csc(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)S(=O)NC(CO[Si](C)(C)C(C)(C)C)c1cc(Br)cs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,4-dibromothiophene (3.49 g, 14.41 mmol) was dissolved in Et2O (120 mL) at −78° C., and then n-BuLi (4.32 mL of 2.5 M, 10.8 mmol) was added dropwise and the resulting mixture was stirred for 30 minutes. This solution was cannulated into a solution of N-[(1E)-2-{[tert-butyl(dimethyl)silyl]oxy}ethylidene]-2-methylpropane-2-sulfinamide (2 g, 7.21 mmol) in 120 mL DCM at −78° C. The reaction mixture was quenched with aqueous ammonium chloride and warmed to room temperature. The mixture was extracted with ethyl acetate (3×) and the combined organic fractions were washed with brine, dried (MgSO4), and filtered. The ethyl acetate solvent was then evaporated under reduced pressure, and the resulting product purified on silica gel (EtOAc/hexanes) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>N1C=CC=CC=1>[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Solvent: c1ccncc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(F)cc4)nc23)CC1
Reaction time: 0.17 h
Yield: 87.1 %

Procedure:
A solution of 1.00 gm (4.3 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine in 85 mL pyridine was heated to 55° C. To this solution were added 0.57 mL (4.8 mMol) 4-fluorobenzoyl chloride and the resulting mixture was stirred for 30 minutes at which time an additional 0.10 mL 4-fluorobenzoyl chloride were added. After stirring for an additional 10 minutes the reaction mixture was concentrated under reduced pressure. The residue was treated with 50 mL cold 1N sodium hydroxide followed by 100 mL dichloromethane. The phases were separated and the aqueous phase was extracted 2×50 mL dichloromethane followed by 3×50 mL 3:1 chloroform:isopropanol. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to radial chromatography (4 mm silica gel plate) eluting with dichloromethane containing 10-20% methanol and 1% ammonium hydroxide. Fractions containing product were combined and concentrated under reduced pressure. The residue was crystallized from aqueous ethanol to provide 1.32 gm (87%) of the title compound as ivory crystals.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH2:4][N:3]1[C@@H:8]([C@@H:16]([CH3:19])[CH2:17][CH3:18])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[CH3:20][C:21]1[N:26]=[C:25]([CH2:27]O)[CH:24]=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl.O>[CH3:19][C@@H:16]([CH2:17][CH3:18])[C@H:8]([N:3]1[CH2:4][C:5](=[O:7])[N:6]([CH2:27][C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:20])[N:26]=2)[C:2]1=[O:1])[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10]
Reactant: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CC(=O)NC1=O
Reactant: Cc1cccc(CO)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CC(=O)N(Cc2cccc(C)n2)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.6 %

Procedure:
A solution containing the product from Example 36C (0.107 g, 0.396 mmol) in dichloromethane (2 mL) at 0° C. was treated with 6-methyl-2-pyridinemethanol (0.053 g, 0.435 mmol), triphenylphosphine (0.135 g, 0.515 mmol), followed by diethyl azodicarboxylate (0.080 mL, 0.515 mmol), stirred at 25° C. for 16 hours. Water (2 mL) was added and the reaction was stirred for 2 hours at 25° C. The reaction mixture was partitioned between dichloromethane and water, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-30% ethyl acetate/dichloromethane to give the title compound (0.154 g, 94% yield).
Reaction SMILES: [CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH3:2].[Br:28]Br>ClCCl>[Br:28][C:8]1[CH:7]=[CH:6][C:5]2[N:4]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)(=[O:18])=[O:19])[CH:3]([CH2:1][CH3:2])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=1
Reactant: CCC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(OC)cc1
Reactant: BrBr
Solvent: ClCCl
Product: CCC1c2ccccc2-c2cc(Br)ccc2N1S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
A stirred solution of 6-ethyl-5-[(4-methoxyphenyl)sulfonyl]-5,6-dihydrophenanthridine (6.0 g, 15.8 mmol) in dichloromethane (800 mL) was treated drop-wise with excess bromine (2.1 mL, 41 mmol). The reaction mixture was heated to reflux and additional bromine (1.0 mL, 10 mmol) was added. The reaction was cooled and stirred at room temperature overnight. The reaction mixture was washed sequentially with a saturated, aqueous sodium thiosulfate solution, water, and a saturated, aqueous, sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate, filtered through a short column of silica gel, and the solvent was removed in vacuo to afford a crude yellow solid. The crude solid was crystallized from a mixture of ethyl acetate-hexane (1:1), and yielded the title compound (6.3 g, 13.8 mmol, 87%) as a colorless, crystalline solid;
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH2:7])=[O:6])[CH2:2][OH:3].[O:8]=[CH:9][C:10]([Cl:13])([Cl:12])[Cl:11]>>[Cl:11][C:10]([Cl:13])([Cl:12])[CH:9]([NH:7][C:5]([NH:4][CH2:1][CH2:2][O:3][CH:9]([OH:8])[C:10]([Cl:13])([Cl:12])[Cl:11])=[O:6])[OH:8]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: NC(=O)NCCO
Product: O=C(NCCOC(O)C(Cl)(Cl)Cl)NC(O)C(Cl)(Cl)Cl

Procedure:
52 g (0.5 mole) of monoethanolurea was heated to 80° C.; 149.0 g (1.01 mole) of chloral was added dropwise thereto between 80°-90° C. with stirring and heated between 80°-90° C. for an additional hour. On cooling, a clear viscous liquid product was obtained that weighed 200 g.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[C:13]([OH:19])=[CH:14][C:15](=[O:18])[NH:16][CH:17]=1>N1C=CC=CC=1>[Cl:11][C:12]1[C:13]([O:19][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:14][C:15](=[O:18])[NH:16][CH:17]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Solvent: c1ccncc1
Product: O=C(Cc1ccccc1)Oc1cc(=O)[nH]cc1Cl
Yield: 14 %

Procedure:
A 3.63 ml quantity of phenylacetyl chloride was added to a suspension of 2.00 g of 5-chloro-4-hydroxy-2-pyridone in 60 ml of pyridine. The same subsequent procedure as in Example 39 was conducted, thereby producing 500 mg of the title compound in a yield of 14%.
Reaction SMILES: [Na].[NH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[NH2:3].[C:10](#[N:19])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[NH2:19][C:10]1[CH2:11][CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)[N:3]=1
Reactant: NNc1ccccn1
Reactant: N#CC=Cc1ccccc1
Agent: [Na]
Solvent: CCO
Product: NC1=NN(c2ccccn2)C(c2ccccc2)C1

Procedure:
A 1.02 g. amount of sodium metal is dissolved in 250 ml. of absolute ethanol, then 21.82 g. of 2-hydrazinopyridine is added, followed by 25.8 g. of cinnamonitrile. The reaction mixture is refluxed for 16 hours, then the solvent is removed in vacuo. Water is added and the solid is collected by filtration. The solid is recrystallized from 3A ethanol to yield 20.32 g. of the desired product as yellow crystals, m.p. 203°-206° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:25][N:26]([CH2:28][C@H:29]1[C@H:34]([OH:35])[CH2:33][CH2:32][CH2:31][NH:30]1)[CH3:27]>O1CCCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:30]2[CH2:31][CH2:32][CH2:33][C@@H:34]([OH:35])[C@@H:29]2[CH2:28][N:26]([CH3:27])[CH3:25])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C)C[C@@H]1NCCC[C@H]1O
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C)C[C@H]1[C@H](O)CCCN1C(=O)Cc1ccc(Cl)c(Cl)c1
Product: Cl
Reaction time: 16 h
Yield: 112 %

Procedure:
A solution of 3,4-dichlorophenylacetic acid (2.59 g) and 1,1'-carbonyldiimidazole (2.42 g) in dry tetrahydrofuran (30 ml) was stirred at room temperature under nitrogen for 20 min. A solution of the product of stage (i) (2.0 g) in dry tetrahydrofuran (10 ml) was added and stirring was continued for 16 h before concentrating the reaction mixture in vacuo. The residue was purified by column chromatography on UGI alumina (2.5" diameter×8") with graded elution from dichloromethane/methanol (98:2) to dichloromethane/methanol (9:1) to give the free base of the title compound as an oil (2.7 g). This oil was dissolved in dry diethyl ether (200 ml) and treated with ethereal hydrogen chloride to precipitate the hydrochloride salt which was crystallised from ethyl acetate/methanol to give the title compound as a crystalline solid (0.42 g), m.p. 185°-186°.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])[C:7](=[O:20])[C@H:6]1[NH:21][C:22](=[O:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[N+]=[N-].[CH2:31]([OH:33])[CH3:32]>[Pd]>[C:31]([NH:1][CH2:4][C@H:5]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])[C:7](=[O:20])[C@H:6]1[NH:21][C:22](=[O:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:33])[CH3:32]
Reactant: CCO
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2CN=[N+]=[N-])c(OC)c1
Agent: [Pd]
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2CNC(C)=O)c(OC)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 449 mg of cis-4-azidomethyl-1-(2,4-dimethoxybenzyl)-3-phenylacetamido-2-oxoazetidine in 80 ml of ethanol is added 200 mg of 10% palladium on charcoal, and the mixture is subjected to hydrogenation for 1.5 hours at room temperature and atmospheric pressure. The reaction mixture is filtered to remove the catalyst and the filtrate is concentrated to dryness in vacuo. The residue is taken up in 30 ml of methylene chloride. Under stirring at 0° C., 0.20 ml of triethylamine is added to the resulting methylene chloride solution, and a solution of 0.10 ml of acetyl chloride in methylene chloride is added dropwise over 10 minutes thereto. The reaction mixture is stirred for 40 minutes and then washed with dilute hydrochloric acid, water, an aqueous sodium hydrogen carbonate solution and an aqueous sodium chloride solution in this order, and dried over magnesium sulfate, and the solvent is distilled off in vacuo. Ethyl acetate is added to the residue and the resulting crystals are collected by filtration to give cis-4 -acetamidomethyl-1-(2,4-dimethoxybenzyl)-3-phenylacetamido-2-oxoazetidine, m.p. 205°-207° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:8]=1[F:16])(=O)=O.[I-:19].[Li+].CN1CCCC1=O>O>[I:19][C:7]1[C:8]([F:16])=[CH:9][CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14]
Reactant: [I-]
Reactant: O=[N+]([O-])c1cccc(F)c1OS(=O)(=O)C(F)(F)F
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1cccc(F)c1I
Reaction time: 18 h
Yield: 47 %

Procedure:
A mixture consisting of 2-fluoro-6-nitrophenyl trifluoromethanesulfonate (62.0 g, 0.215 mol), lithium iodide (60 g, 0.451 mol) and 1-methyl-2-pyrrolidinone (400 mL) was heated with stirring at 130°-132° C. (oil bath temperature) for 18 hours. Upon cooling it was poured into water (1200 mL) and extracted with diethyl ether. The combined extracts were washed with 1N NaOH, water and with brine. The solution was dried (MgSO4), filtered, and concentrated in vacuo to give 27.0 g of the title compound as a brown-colored solid title compound (m.p. 54°-57° C.).
Reaction SMILES: Br[C:2]1[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C1COCC1.C([O-])([O-])=O.[Na+].[Na+].[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([F:28])[CH:27]=1>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:22]1[CH:23]=[C:24]([C:2]2[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: O=Cc1ncccc1Br
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: O=Cc1ncccc1-c1cc(F)cc(F)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 60.8 %

Procedure:
To a solution of 3-bromo-pyridine-2-carbaldehyde (1.2 g, 6.45 mmol) dissolved in ethylene glycol dimethyl ether (25 mL), THF(10 mL) and saturated solution of Na2CO3 (9 mL) was added 3,5 difluorophenyl boronic acid (1.12 g, 7.10 mmol). Purge the mixture with Ar gas (10 min). To this mixture was added Pd(PPh3)4 (373 mg, 0.33 mmol) and stir under a positive pressure of Ar at 90° C. for 16 hours. The reaction mixture was quenched with a solution of saturated NaHCO3 (50 mL). Extract with CH2Cl2 (2×50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to afford a light yellow oil. Purification via column chromatography on silica gel (CH2Cl2:MeOH: 80:20, v/v/v) afforded 3-(3,5-difluoro-phenyl)-pyridine-2-carbaldehyde as a white solid (0.86 g, 61%). 1H NMR (CDCl3) δ 6.59 (m, 1H), 6.92 (m, 2H), 7.60 (m, 1H), 7.76 (d, 1H, J=7.5 Hz), 8.88 (d, 1H, J=3.5 Hz), 10.11 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5](=[C:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:6]#[N:7])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([CH:8]1[CH:13]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]2)[CH2:9]1)[C:6]#[N:7])[CH3:2]
Reactant: CCOC(=O)C(C#N)=C1CN2CCC1CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C#N)C1CN2CCC1CC2

Procedure:
A solution of ethyl(1-azabicyclo[2.2.2]octan-3-ylidene)cyanoacetate (73 g, 0.33 mol) in absolute ethanol (1 l) was treated with 10% palladium on charcoal (10 g) and hydrogen in a parr shaker at 20 psi for 5 h. Filtration and evaporation gave the wanted product in 68 g yield.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:46])[NH:11][C:12]1[N:16]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH2:23][N:22](C(OC(C)(C)C)=O)[CH:21]([C:34]([O:36]CC)=[O:35])[CH2:20]3)[N:15]=[C:14]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])[CH:13]=1.Cl>C1COCC1>[ClH:1].[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:46])[NH:11][C:12]1[N:16]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH2:23][NH:22][CH:21]([C:34]([OH:36])=[O:35])[CH2:20]3)[N:15]=[C:14]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])[CH:13]=1
Reactant: CCOC(=O)C1Cc2cc(-n3nc(-c4ccccc4F)cc3NC(=O)Nc3cccc(Cl)c3Cl)ccc2CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: O=C(Nc1cccc(Cl)c1Cl)Nc1cc(-c2ccccc2F)nn1-c1ccc2c(c1)CC(C(=O)O)NC2
Temperature: 50 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
To a solution of 2-t-butyl 3-ethyl 6-(5-(3-(2,3-dichlorophenyl)ureido)-3-(2-fluorophenyl)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate (0.050 g, 0.075 mmol) in THF (2 mL) was added 6N HCl (2 mL) and the solution was stirred at 50° C. overnight. The organic solvent was evaporated and the precipitate was collected to yield 6-(5-(3-(2,3-dichlorophenyl)ureido)-3-(2-fluorophenyl)-1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride as a white solid (15 mg, 35% yield). 1H-NMR (acetone-d6): δ 8.01-7.96 (m, 2H), 7.62-7.60 (m, 2H), 7.47 (d, 1H, J=8.0 Hz), 7.42-7.37 (m, 1H), 7.27-7.19 (m, 4H), 6.92 (d, 1H, J=3.6 Hz), 4.59 (d, 1H, J=16.0 Hz), 4.50 (d, 1H, J=16.0 Hz), 4.48 (dd, 1H, J=11.4, 5.0 Hz), 3.61 (dd, 1H, J=18.0, 5.2 Hz), urea, acid and amine protons not visible, one proton is buried under the methanol peak. LC-MS (EI) m/z: 540.0 542.0 (M+H+).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][N:6]([C:16](=[O:32])[C@H:17]([CH:29]([CH3:31])[CH3:30])[NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1)C.[OH-].[K+]>C(O)C>[C:19]([NH:18][C@H:17]([C:16]([N:6]([CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1)[CH2:5][C:4]([OH:33])=[O:3])=[O:32])[CH:29]([CH3:30])[CH3:31])([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: CCOC(=O)CN(C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C1Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=O)O)C1Cc2ccccc2C1
Reaction time: 8 h
Yield: 70.3 %

Procedure:
N-CBZ-L-Valyl-N-(2-indanyl)glycine ethyl ester (13.8 g, 0.0305 mol) was dissolved in ethanol (200 mL) and treated with 1N KOH (30 mL) in 5 mL portions. After the mixture was allowed to sit at room temperature overnight, the ethanol was removed under vacuum, and the residue treated with water. The aqueous mixture was washed three times with ethyl acetate and the layers separated. The aqueous layer was acidified to pH 3 with 1N HCl. The product was extracted into ethyl acetate and washed with saturated aqueous NaCl-solution. After drying over MgSO4, filtration and evaporation under reduced pressure afforded the product as a white semi-solid (9.1 g).
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:22]=[CH:21][C:16]([C:17](OC)=[O:18])=[CH:15][CH:14]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[NH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>ClCCl>[OH2:18].[O:29]1[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][NH:23][C:17](=[O:18])[C:16]2[CH:15]=[CH:14][C:13]([C:3]3[C:4]4[CH2:12][C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:5]=4[NH:1][N:2]=3)=[CH:22][CH:21]=2)[CH2:27][CH2:28]1
Reactant: NCCN1CCOCC1
Reactant: COC(=O)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Solvent: ClCCl
Product: O
Product: O=C(NCCN1CCOCC1)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Temperature: 150 °C

Procedure:
A mixture of methyl 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzoate (100 mg) and N-(2-aminoethyl)morpholine (0.5 ml) was stirred and heated at 150° C. for 5 hours. The mixture was cooled and washed with petroleum ether, b.p. 40-60° C. (20 ml). The mixture was dissolved in a mixture of dichloromethane/IMS/triethyl-amine (25:2:1) and purified by flash column chromatography on silica using the same solvent mixture as the mobile phase. Appropriate fractions were collected, combined and evaporated to give a gum which was dissolved in dichloromethane, washed with water, then dried, filtered and evaporated to give a solid which was triturated with ether and filtered to give N-(2-morpholinoethyl)-4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide monohydrate, m.p. 210-214° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([O:24][CH2:25][CH3:26])[CH:15]=3)[CH:11]=[C:10]([C:27]([F:30])([F:29])[F:28])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:31][C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1>>[CH2:25]([O:24][C:16]1[CH:15]=[C:14]([C:12]2[CH:11]=[C:10]([C:27]([F:30])([F:29])[F:28])[N:9]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:35]4[CH:34]=[N:33][C:32]([NH2:31])=[CH:37][CH:36]=4)[CH:7]=3)[N:13]=2)[CH:19]=[CH:18][C:17]=1[C:20]([F:23])([F:22])[F:21])[CH3:26]
Reactant: CCOc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)ccc1C(F)(F)F
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: CCOc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(-c4ccc(N)nc4)c3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-(2-chloro-pyridin-4-yl)-4-(3-ethoxy-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example E.33) (0.224 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.155 g, 61%). MS (ISP) 506.1 [(M+H)+]; mp 222° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:18][N:19]([CH3:21])[CH3:20])[C:15]([O-:17])=O)=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[K+].CCN=C=NCCCN(C)C.[CH:34]1[CH:35]=[CH:36][C:37]2N(O)N=[N:40][C:38]=2[CH:39]=1.NC1C=CC=CC=1>CN(C=O)C>[NH:40]([C:15](=[O:17])[CH:14]([C:11]1[CH:10]=[CH:9][C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:13][CH:12]=1)[CH2:18][N:19]([CH3:21])[CH3:20])[C:38]1[CH:39]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: On1nnc2ccccc21
Reactant: CN(C)CC(C(=O)[O-])c1ccc(C(=O)OC(C)(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Nc1ccccc1
Product: CN(C)CC(C(=O)Nc1ccccc1)c1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 0.08 h

Procedure:
Crude potassium 2-[4-(tert-butoxycarbonyl)phenyl]-3-(dimethylamino)propanoate (925 mg, ˜2.79 mmol), EDCI (803 mg, 4.19 mmol), and HOBT (491 mg, 3.63 mg) were combined in DMF (15 mL) and stirred for 5 minutes before adding aniline (331 μL, 3.63 mmol). The reaction was stirred at room temperature for 3 h. Additional EDCI (200 mg) was added, and the reaction was stirred for another 3 h. The mixture was concentrated and purified by reverse phase HPLC (50-95% MeCN/water). The resulting residue was dissolved in EtOAc, neutralized with sat. NaHCO3, washed with brine, dried (MgSO4), and concentrated to give tert-butyl 4-{2-anilino-1-[(dimethylamino)methyl]-2-oxoethyl}benzoate as a white solid. 1H NMR (CDCl3) δ 7.97 (d, J=8.5 Hz, 2H), 7.33 (d, J=8.5 Hz, 2H), 7.21 (dd, J=8.5, 7.3 Hz, 2H), 6.77 (t, J=7.3 Hz, 1H), 6.72 (d, J=7.9 Hz, 2H), 4.22 (dd, J=8.8, 5.0 Hz, 1H), 3.80 (dd, J=13.8, 9.1 Hz, 1H), 3.40 (dd, J=13.6, 4.8 Hz, 1H), 2.95 (s, 3H), 2.74 (s, 3H), 1.58 (s, 9H). MS (ESI) calcd [M+H]+ 369.2, found 369.2.