Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[C:6]([CH:8]([C:18](=O)[CH3:19])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=O)#[N:2].[CH2:24]([C:26]1[N:27]([NH2:31])[CH:28]=[CH:29][CH:30]=1)[CH3:25]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[C:28]3[N:27]([C:26]([CH2:24][CH3:25])=[CH:30][CH:29]=3)[N:31]=[C:18]([CH3:19])[C:8]=2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:21]=[CH:22][CH:23]=1)#[N:2]
Reactant: CCOC(=O)CCCCC(C(C)=O)C(=O)c1cccc(C#N)c1
Reactant: CCc1cccn1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCc1c(C)nn2c(CC)ccc2c1-c1cccc(C#N)c1
Yield: 83.8 %

Procedure:
To a solution of ethyl 6-(3-cyanobenzoyl)-7-oxooctanoate (3.18 g) in toluene (30 mL) was added 2-ethyl-1H-pyrrol-1-amine (1.17 g) and p-toluenesulfonic acid monohydrate (96 mg) at ambient temperature. The reaction mixture was refluxed for 1 hour. The mixture was evaporated in vacuo. The residue was purified by flash silica gel chromatography (silica gel, 200 mL) eluting with hexane-ethyl acetate=20-1, 15-1, and 10-1 to give ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate (3.29 g, 83.8%) as an yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Li].N>C(O)C>[CH3:11][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH2:10][CH:9]=[CH:8][CH2:7][CH:6]=1
Reactant: CN(C)CCc1ccccc1
Agent: N
Agent: [Li]
Solvent: CCO
Product: CN(C)CCC1=CCC=CC1

Procedure:
45 g. (0.3 moles) of the dimethylphenethylamine is reduced by treatment with 16 g. of lithium (2.3 g. atom) in 1.5 1. of ammonia and 250 ml. of ethanol according to the procedure of Example 1(a) to yield crude 1-[2-(dimethylamino)ethyl]-1,4-cyclohexadiene.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[Cl:12][C:13]1[C:18]([CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[OH:20])=[CH:17][CH:16]=[CH:15][N:14]=1.N1C=CC=CC=1>CCOCC>[C:1]([OH:6])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([OH:20])=[O:5].[Cl:12][C:13]1[C:18]([CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[OH:20])=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: O=C1OC(=O)c2ccccc21
Agent: OC(c1ccccc1)c1cccnc1Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(O)c1ccccc1C(=O)O

Procedure:
0.37 g phthalic anhydride, 0.50 g 2-chloro-α-phenyl-3-pyridinemethanol and 3 ml pyridine are heated at 100° C. for 7 hrs. The reaction mixture is diluted with ether and extracted twice with aqueous sodium carbonate. The aqueous extracts, after washing with ether, are acidified with 2N HCl, affording 0.5 g title product, m.p. 173°-4° C. (ethanol:water); neutralization equivalent: 372 (calculated 367.8); Cl 9.73 (9.64).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23]([OH:25])=O)[CH:19]=[CH:20][CH:21]=1.[Cl:26][C:27]1[S:28][CH:29]=[CH:30][CH:31]=1.ClCCCl>CCOCC>[Cl:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23]([C:29]2[S:28][C:27]([Cl:26])=[CH:31][CH:30]=2)=[O:25])[CH:19]=[CH:20][CH:21]=1
Reactant: Clc1cccs1
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCOCC
Solvent: ClCCCl
Product: O=C(Cc1cccc(Cl)c1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 500-mL round-bottomed flask was added silica gel 60 (21 g, 350 mmol) and the flask was heated with a heat gun under high vacuum for 30 min. The system was cooled to room temperature and phosphorus pentoxide (8.75 mL, 148 mmol) was added. The mixture was stirred at 110° C. (oil bath) under high vacuum for 120 min. The mixture was allowed to cool to room temperature. 3-chlorophenylacetic acid (15.6 g, 91 mmol), 2-chlorothiophene (33.8 mL, 366 mmol) and DCE (50 mL) were added. The reaction mixture was stirred at reflux for 4 hours. LCMS analysis showed the reaction was complete. The reaction mixture was allowed to cool to room temperature. The reaction mixture was diluted with ether (300 mL) and filtered. The organic solution was concentrated under reduced pressure. The residue was triturated with hexane to afford the title compound as an off-white solid. The hexane mother liquid was concentrated and purified by flash chromatography (SiO2, 0 to 30% EtOAc/Hex, a gradient elution) provided another batch of the title compound as a light yellow solid. Mass Spectrum (ESI) m/z=271 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:19]3([OH:32])[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[N:12]=2)=[CH:4][CH:3]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:19]3([OH:32])[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)=[C:11]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2oc(-c3ccc(F)cc3)nc2-c2ccncc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1(c2oc(-c3ccc(F)cc3)nc2-c2ccncc2)CCNCC1

Procedure:
tert-Butyl 4-[2-(4-fluorophenyl)-4-(pyridin-4-yl)-1,3-oxazol-5-yl]-4-hydroxypiperidine-1-carboxylate (60 mg, 0.14 mmol) was stirred in 4:1 DCM/TFA (5 ml) at room temperature for 3 h. Then the volatiles were removed under vacuum, and the resulting residue was purified by reverse phase HPLC (0.05% TFA-water-acetonitrile) to give the title compound. LC-MS m/e 340.15 [M+1]+.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].C1COCC1.[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[C:27]([F:29])[CH:28]=1>CCCCCC>[F:22][C:23]1[CH:24]=[C:25]([C:7]2[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=2)[CH:26]=[C:27]([F:29])[CH:28]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CCCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCc1ccc(-c2cc(F)cc(F)c2)cc1
Temperature: 60 °C
Yield: 99.6 %

Procedure:
In a nitrogen atmosphere, a solution prepared by mixing 90.33 g of 4-propylbromobenzene, 2.62 g of tetrakis-triphenylphosphine palladium, 240 mL of an aqueous potassium carbonate solution (2 mol/L), and 450 mL of THF was heated to 60° C., and 71.65 g of 3,5-difluorophenylboronic acid was added to the solution over 30 minutes. The resultant mixture was stirred at 60° C. for 30 minutes and then allowed to cool. Then, hexane was added to the mixture to separate an organic layer, and the organic layer was washed with saturated brine and dried by adding sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to yield 104.92 g of 3,5-difluoro-1-(4-propylphenyl)benzene.
Reaction SMILES: O.NN.OO.[CH2:6]([Li])CCC.[CH2:11]([O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)[CH2:12][C:13]#[CH:14].[Li+].[AlH4-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.BrBr.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1C=CCCC1>[N+]([O-])([O-])=O.[Ag+]>[O:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[O:15][CH2:11][CH2:12][CH2:13][C:14]#[CH:6]
Reactant: [Li]CCCC
Reactant: C#CCCOC1CCCCO1
Agent: [Ag+]
Agent: BrBr
Agent: C1=COCCC1
Solvent: O
Product: C#CCCCOC1CCCCO1

Procedure:
Hydrazine hydrate and hydrogen peroxide (30 wt. % solution in water) were purchased from Mallinckrodt (Chesterfield, Mo.) and Fisher Chemical Co. (Fair Lawn, N.J.), respectively. Butyllithium (1.6M and 2.5M solutions in hexane), 2-(3-butynyloxy)tetrahydro-2H-pyran (1-(tetrahydopyran-2-yloxy)-3-butyne), lithium tetrahydridoaluminate, borane-methylsulfide complex, Cu(I)Br.Me2S complex, and p-toluenesulfonyl chloride from Aldrich Chemical Co. (Milwaukee, Wis.), and bromine and triphenylphosphine from Fluka Chemical Co. (Ronkonkoma, N.Y.), were used as purchased. 1-(Tetrahydopyran-2-yloxy)-4-pentyne was prepared from the corresponding alcohol using the methods described in Robertson, "Adducts of tert-alcohols containing an ethynyl group with dihydropyran. Potentially useful intermediates," J. Org. Chem. 25:931-932 (1960), the disclosure of which is hereby incorporated by reference. Column chromatography was run on silica gel (Merck, H 60), and reactions were monitored by TLC on Baker-flex Silica gel IB2-F plates (J. T. Baker). Silver nitrate column chromatography was done on silica gel impregnated with AgNO3 (20% of AgNO3 on silica gel Merck H 60).
Reaction SMILES: N1N[N:3]=[N:4][C:5]=1[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17]>CC1C=CC=CC=1C>[Br:12][C:13]1[CH:14]=[C:15]([C:16]2[O:17][C:5]([C:6]3[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=3)=[N:4][N:3]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: c1cncc(-c2nn[nH]n2)c1
Reactant: O=C(Cl)c1cccc(Br)c1
Solvent: Cc1ccccc1C
Product: Brc1cccc(-c2nnc(-c3cccnc3)o2)c1

Procedure:
16.8 g (114 mmol) of 3-(2H-tetrazol-5-yl)pyridine) according to Synthesis Example 7 and 25 g (114 mmol) of 3-bromobenzoylchloride were dissolved in 180 mL of o-xylene. The solution was reacted at 150° C. for 8 hours. The obtained reactant was purified under a reduced pressure and washed with methanol, obtaining 30 g (Y=87%) of a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23]C(OC(C)(C)C)=O)[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH2:16][C:17]#[CH:18])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.Cl>C(O)C>[CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH2:16][C:17]#[CH:18])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: C#CCc1c(C)nc2c(NCc3c(C)cccc3NC(=O)OC(C)(C)C)cccn12
Agent: Cl
Solvent: CCO
Product: C#CCc1c(C)nc2c(NCc3c(C)cccc3N)cccn12
Reaction time: 6 h
Yield: 64.4 %

Procedure:
To a solution of 8-(2-methyl-6-t-butoxycarbonylaminobenzylamino)-3-(2-propynyl)-2-methylimidazo[1,2-a]pyridine (8.42 g) in ethanol (67 ml) was added dropwise 23%-ethanolic hydrogen chloride (26 g) at room temperature and the mixture was stirred for 6 hours. The resultant solid was siolated by filtration and dispersed into a mixture of an aqueous solution of sodium bicarbonate and chloroform. The chloroform layer was separated and washed with water and dried over magnesium sulfate. Following filtration, the solvent was removed under reduced pressure to give 8-(2-methyl-6-aminobenzylamino)-3-(2-propynyl)-2methylimidazo[1,2-a]pyridine (4.08 g). The crude crystzals (0.5 g) were recrystallized from a mixture of chloroform and n-hexane to give 0.46 g of pure crystals.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][N:9]2[CH2:12][CH2:13][C:14]#[N:15])=[CH:4][CH:3]=1.Cl.[NH:23]1[CH2:26][CH2:25][CH2:24]1.C(N(CC)CC)C>C(#N)C.O>[N:23]1([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][N:9]3[CH2:12][CH2:13][C:14]#[N:15])=[CH:4][CH:3]=2)[CH2:26][CH2:25][CH2:24]1
Reactant: CCOC(=O)c1cn(CCC#N)c2nc(Cl)ccc2c1=O
Reactant: C1CNC1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cn(CCC#N)c2nc(N3CCC3)ccc2c1=O
Reaction time: 1 h

Procedure:
A solution of EXAMPLE 81B (16 g), azetidine hydrochloride (12.2 g) and triethylamine (21.9 mL) in acetonitrile (500 mL) was stirred for 2 hours, treated with triethylamine (900 mg), stirred for one hour, diluted with water (1.5 L), stirred for 1 hour, and filtered.
Reaction SMILES: C(C1C=CC([C:9]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:10]=2[S:11]([O-:14])(=[O:13])=[O:12])=CC=1)#N.C(C1C=C(C(C)(C)C)C=C(C(C)(C)C)C=1[O-])(C)(C)C.[Na+:39].NC1C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.[Fe]>[O:14]([S:11]([C:10]1[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][CH:9]=1)(=[O:13])=[O:12])[Na:39]
Reactant: [Na+]
Reactant: Cc1ccc(S(=O)(=O)[O-])c(-c2ccc(C#N)cc2)c1
Agent: [Fe]
Agent: [Pd]
Agent: CC(C)(C)P([C]1[CH][CH][CH][CH]1)C(C)(C)C
Solvent: Nc1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)O[Na])cc1
Temperature: 110 °C
Yield: 82 %

Procedure:
4-Cyanodiphenylamine (Takeuchi, H.; Takano, K. J. Chem. Soc. Perkin Trans. 1 1986, 611-618. 4-Cyanophenyltosylate (271 mg, 1.02 mmol), Pd(DBA)2 (11.7 mg, 0.02 mmol), DBtPF (14.5 mg, 0.03 mmol) and sodium 2,4,6-tri-t-butylphenoxide (346 mg, 1.22 mmol) were suspended in 2 mL of toluene in a screw-capped vial. The vial was sealed with a cap containing a PTFE septum and removed from the dry box. Aniline (102 μL, 1.12 mmol) was added to the reaction mixture by syringe. The vial was heated in a 110° C. oil bath for 16 hours. Over this time, a large amount of solid (presumably NaOTs) formed. The reaction was cooled to room temperature. The crude reaction was diluted with toluene (50 mL) and washed with water (50 mL, 1×) followed by brine (50 mL, 1×). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purified product was obtained in 82% yield after silica gel chromatography using 10% EtOAc in hexanes. 1H NMR: (CDCl3) δ 7.41 (d, J=8.7 Hz, 214), 7.33 (m, 2H) 6.08 (m, 3H), 6.96 (d, J=8.7 Hz, 2H), 6.43 (bs, 1H); 13C{1H} NMR: (CDCl3) δ 148.01, 139.64, 133.50, 129.38, 123.56, 120.87, 120.01, 114.64, 100.63.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][C:10]([NH:12][C:13]2[S:14][C:15]3[CH:21]=[C:20]([O:22][S:23]([C:26]4[CH:31]=[CH:30][C:29]([NH:32][CH2:33][CH2:34][NH:35][CH:36]([CH3:38])[CH3:37])=[CH:28][CH:27]=4)(=[O:25])=[O:24])[CH:19]=[CH:18][C:16]=3[N:17]=2)=[O:11])[CH2:4][CH2:3]1.[C:39]([O:43][C:44](N1CCC(CCC(=O)NC2SC3C=C(OS(C4C=CC(F)=CC=4)(=O)=O)C=CC=3N=2)CC1)=[O:45])([CH3:42])([CH3:41])[CH3:40].C(NC(C)C)(C)C>>[C:39]([O:43][C:44]([N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][C:10](=[O:11])[NH:12][C:13]2[S:14][C:15]3[CH:21]=[C:20]([O:22][S:23]([C:26]4[CH:27]=[CH:28][C:29]([NH:32][CH2:33][CH2:34][NH:35][CH:36]([CH3:38])[CH3:37])=[CH:30][CH:31]=4)(=[O:24])=[O:25])[CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:4][CH2:3]1)=[O:45])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)NCCNc1ccc(S(=O)(=O)Oc2ccc3nc(NC(=O)CCC4CCNCC4)sc3c2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)Nc2nc3ccc(OS(=O)(=O)c4ccc(F)cc4)cc3s2)CC1
Agent: Cl
Solvent: CC(C)NC(C)C
Product: CC(C)NCCNc1ccc(S(=O)(=O)Oc2ccc3nc(NC(=O)CCC4CCN(C(=O)OC(C)(C)C)CC4)sc3c2)cc1

Procedure:
According to the method of example 18, 4-(2-isopropylaminoethylamino)-benzenesulfonic acid 2-(3-piperid-4-ylpropionylamino)benzothiazol-6-yl ester hydrochloride is prepared by combining 4-{2-[6-(4-fluorobenzenesulfonyloxy)-benzothiazol-2-ylcarbamoyl]ethyl}piperidine-1-carboxylic acid tert-butyl ester (intermediate 23) with N,N-diisopropylamine. The compound obtained from the first step (4-(2-{6-[4-(2-isopropylaminoethylamino)benzenesulfonyloxy]-benzothiazol-2-ylcarbamoyl}ethyl)piperidine-1-carboxylic acid tert-butyl ester) is purified on a flash cartridge of 5 g of silica of porosity 15-35μ, with a gradient of from 1% to 10% of methanol in dichloromethane.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.O[C:9]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12].N1CCOCC1>CO.C(OCC)(=O)C>[CH3:18][C:15]1[CH:16]=[CH:17][C:9]2[O:7][C:4]3([CH2:5][CH2:6][NH:1][CH2:2][CH2:3]3)[NH:13][C:11](=[O:12])[C:10]=2[CH:14]=1
Reactant: O=C1CCNCC1
Reactant: Cc1ccc(O)c(C(N)=O)c1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1COCCN1
Product: Cc1ccc2c(c1)C(=O)NC1(CCNCC1)O2

Procedure:
A mixture of 26 mg (0.083 mmol) of N-[4,8-dimethoxyquinoline-2-yl)carbonyl]-4-piperidone (prepared as described in Example 44), 12.5 mg (0.083 mmol) of 2-hydroxy-5-methylbenzamide, and 0.020 mL of morpholine in 2 mL of methanol is refluxed for 20 hr. The reaction mixture is diluted with ethyl acetate, and washed with water, brine, and dried over Na2SO4. After solvent removal by rotoevaporation, the crude product is purified by preparative TLC to give 20 mg (0.045 mmol, 54% yield) of 1′-[4,8-dimethoxyquinoline-2-yl)carbonyl]-6-methylspiro-[2H-1,3-benzoxazin-2,4′-piperidin]-4-(3H)-one (Compound 137): 1H NMR (DMSO-d6): δ 2.28 (s, 3H), 3.95 (s, 3H), 4.06 (s, 3H), 6.98 (d, 1H), 7.19 (s, 1H), 7.23 (d of d, 1H), 7.33 (d of d, 1H), 7.52 (d of d, 1H), 7.56 (d, 1H), 7.68 (d of d, 1H), and 8.77 ppm (s, 1H). MS m/z: 448.1 (M+H)+, 470.0 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[CH2:10][C@H:9]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]3[C:21]([F:37])=[CH:22][C:23]([C:33]#[C:34][CH2:35][OH:36])=[C:24]([N:26]4[C:30](=[O:31])[N:29]([CH3:32])[N:28]=[N:27]4)[CH:25]=3)[N:13]=2)[CH2:8][C@H:7]2[N:3]1[CH2:4][CH2:5][CH2:6]2>CO.[Pd]>[CH3:1][C:2]1([CH3:38])[CH2:10][C@H:9]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]3[C:21]([F:37])=[CH:22][C:23]([CH2:33][CH2:34][CH2:35][OH:36])=[C:24]([N:26]4[C:30](=[O:31])[N:29]([CH3:32])[N:28]=[N:27]4)[CH:25]=3)[N:13]=2)[CH2:8][C@H:7]2[N:3]1[CH2:4][CH2:5][CH2:6]2
Reactant: Cn1nnn(-c2cc(Nc3ncc(F)c(N[C@@H]4C[C@@H]5CCCN5C(C)(C)C4)n3)c(F)cc2C#CCO)c1=O
Agent: [Pd]
Solvent: CO
Product: Cn1nnn(-c2cc(Nc3ncc(F)c(N[C@@H]4C[C@@H]5CCCN5C(C)(C)C4)n3)c(F)cc2CCCO)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
1-(5-(4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-5-fluoropyrimidin-2-ylamino)-4-fluoro-2-(3-hydroxyprop-1-ynyl)phenyl)-4-methyl-1H-tetrazol-5(4H)-one (77.9 mg, 0.15 mmol) was dissolved in 10 mL methanol. After purging with nitrogen, the flask was charged with 32.7 mg (0.015 mmol) 10% palladium on carbon (50 wt % water for safety). The reaction was then evacuated and back-filled with nitrogen three times before one final evacuation and introduction of a hydrogen balloon. This was stirred overnight at room temperature under one atmosphere of hydrogen. After filtration of the catalyst, the methanol was evaporated to give 72.6 mg (93% crude recovery). 63.0 mg was subjected to column chromatography. After drying, 39.6 mg was obtained of the title compound (63% yield).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Cl[C:9]1[CH:10]=[CH:11][C:12]([N+:31]([O-:33])=[O:32])=[C:13]([CH:30]=1)[C:14]([NH:16][C:17]1[CH:22]=[C:21]([C:23]([NH:25][CH:26]2[CH2:28][CH2:27]2)=[O:24])[CH:20]=[CH:19][C:18]=1[CH3:29])=[O:15]>>[CH:26]1([NH:25][C:23]([C:21]2[CH:20]=[CH:19][C:18]([CH3:29])=[C:17]([NH:16][C:14](=[O:15])[C:13]3[CH:30]=[C:9]([N:6]4[CH2:5][CH2:4][NH:3][C@@H:2]([CH3:1])[CH2:7]4)[CH:10]=[CH:11][C:12]=3[N+:31]([O-:33])=[O:32])[CH:22]=2)=[O:24])[CH2:28][CH2:27]1
Reactant: C[C@H]1CNCCN1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(N2CCN[C@@H](C)C2)ccc1[N+](=O)[O-]

Procedure:
Using an analogous procedure to that described paragraph (B) in the portion of Example 1 which is concerned with the preparation of starting material (S)-2-methylpiperazine was reacted with 5-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-nitrobenzamide to give N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-[(3S)-3-methylpiperazine-1-yl)-2-nitrobenzamide; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.67 (m, 2H), 1.05 (d, 3H), 2.29 (s, 3H), 2.53 (m, 2H), 2.79 (m, 4H), 3.00 (d, 1H), 3.93 (t, 2H), 7.05 (m, 2H), 7.27 (d, 1H), 7.56 (d, 1H), 7.97 (s, 1H), 8.03 (d, 1H), 8.35 (d, 1H), 9.88 (s, 1H); Mass Spectrum: M+H+ 438.
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[N:14]([CH3:17])[CH:15]=[CH:16][C:3]=12.N1C=CC=CC=1.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[Na+].[I-:40].Cl.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(#N)C.C(OCC)(=O)C>[I:40][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[N:14]([CH3:17])[CH:15]=[CH:16][C:3]=12
Reactant: [I-]
Reactant: CCOC(=O)c1c(C)nc2c(ccn2C)c1O
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=S([O-])([O-])=S
Solvent: CC#N
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)nc2c(ccn2C)c1I
Temperature: 70 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A 0° C. solution of ethyl 4-hydroxy-1,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (10.0 g, 42.7 mmol) in acetonitrile (200 mL) and pyridine (4.13 mL, 51.2 mmol) was treated dropwise with Tf2O (8.65 mL, 51.2 mmol). After 1 h, the reaction mixture was treated with NaI (19.20 g, 128 mmol) followed by dropwise addition of 3M HCl (17.08 mL, 51.2 mmol) and warmed to 70° C. After 3 h, the reaction mixture was cooled to ambient temperature and added to a sat. aq. solution of Na2S2O3. After stirring for 15 min, ethyl acetate was added and the layers partitioned. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford ethyl 4-iodo-1,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (14.7 g).
Reaction SMILES: Cl.[CH2:2]([N:9]1[C:13]([C:14]([F:17])([F:16])[F:15])=[C:12]([CH3:18])[C:11]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:10]1[C:26]([N:28]([CH2:30][CH2:31][NH:32]C(=O)OC(C)(C)C)[CH3:29])=[O:27])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCOCC1>[ClH:25].[NH2:32][CH2:31][CH2:30][N:28]([CH3:29])[C:26]([C:10]1[N:9]([CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:13]([C:14]([F:16])([F:17])[F:15])=[C:12]([CH3:18])[C:11]=1[C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)=[O:27]
Reactant: Cc1c(-c2ccc(Cl)cc2)c(C(=O)N(C)CCNC(=O)OC(C)(C)C)n(Cc2ccccc2)c1C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(-c2ccc(Cl)cc2)c(C(=O)N(C)CCN)n(Cc2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 120 h
Yield: 154.2 %

Procedure:
4 M HCl in dioxane (1.067 mL, 4.27 mmol) was added dropwise to a solution of tert-butyl 2-(1-benzyl-3-(4-chlorophenyl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamido)ethylcarbamate (587 mg, 1.067 mmol) in dry dioxane (5 mL) under a N2 atmosphere. The mixture was stirred at room temperature for 5 d. The mixture was evaporated to dryness and the residue was stirred in Et2O. The solids were filtered off to obtain 400 mg (77%) of the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:7])=[CH:4][CH:3]=1.Cl[C:17]1C=CC(C=O)=C[CH:18]=1.C(OC)(=O)C=CCC.[C-]#N.[Na+]>CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]([CH2:17][CH3:18])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:7])=[CH:14][CH:15]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COC(=O)CCC(=O)c1ccc(Cl)cc1
Agent: CCC=CC(=O)OC
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC(CC(=O)OC)C(=O)c1ccc(Cl)cc1
Yield: 21 %

Procedure:
By the procedure described for the preparation of methyl 3-(4-chlorobenzoyl)propanoate (see Example 1), 4-chlorobenzaldehyde (22.48 g), methyl pent-2-enoate (13.65 g), and sodium cyanide (3.92 g) in dry dimethylformamide (DMF: 250 ml), followed by column chromatography on silica gel using dichloromethane: 40°-60° petrol (1:2) as eluent, gave methyl 3-(4-chlorobenzoyl)pentanoate (6.5 g, 21%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([Cl:25])=[C:20]([CH:24]=3)[C:21]([OH:23])=[O:22])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.Cl.[CH3:27]O>O1CCOCC1>[NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([Cl:25])=[C:20]([CH:24]=3)[C:21]([O:23][CH3:27])=[O:22])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc2ccc(S(=O)(=O)Nc3ccc(Cl)c(C(=O)O)c3)cc2c1
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc3ccc(N)cc3c2)ccc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 10.1 g (0.027 mol) of compound 133 dissolved in 250 mL of methanol was added 50 mL of 4 N HCl in dioxane. This solution was allowed to stir at ambient temperature for 18 hours. The reaction was incomplete, so it was heated at reflux for an additional 5 hours. Then, the volatiles were removed by rotary evaporation and the resulting solid was extracted with ethyl acetate and 0.4 N sodium bicarbonate, water, and brine. The organic layer was dried (MgSO4), filtered, and the volatiles removed by rotary evaporation to yield 8.71 g of compound 134.