Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:47])[CH2:21][N:22](CC2C=CC=CC=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)C1C=CC=CC=1.C([OH:50])C>C(O)(=O)C.[Pd]>[C:30]([OH:50])(=[O:29])[CH3:31].[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:47])[CH2:21][NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2
Reactant: CCO
Reactant: O=c1ccc2c([C@@H](O)CN(CCCCCCOCCCCc3ccccc3)Cc3ccccc3)ccc(OCc3ccccc3)c2[nH]1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=c1ccc2c([C@@H](O)CNCCCCCCOCCCCc3ccccc3)ccc(O)c2[nH]1

Procedure:
A solution of 8-(benzyloxy)-5-((1R)-2-{benzyl[6-(4-phenylbutoxy)hexyl]amino}-1-hydroxyethyl)quinolin-2(1H)-one (33 mg) in ethanol (15 ml) and acetic acid (0.4 ml) was stirred under hydrogen in the presence of palladium on charcoal (10 mg) for 4 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by chromatography (SPE, gradient from DCM to DCM-MeOH—NH3(aq) 100:10:1) to give the title compound (19.5 mg).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([C:9]([CH2:11]C=O)=N)[CH:6]=[CH:7][CH:8]=1.[NH2:16][C:17]([NH2:19])=[O:18].[CH2:20](O)C>>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[C:5]([C:9]2[CH:11]=[N:16][C:17]([OH:18])=[N:19][CH:20]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: N=C(CC=O)c1cccc(C(F)(F)F)c1
Reactant: CCO
Reactant: NC(N)=O
Product: Oc1ncc(-c2cccc(C(F)(F)F)c2)cn1

Procedure:
By the procedure described in Example 4, (m-trifluoromethylphenyl)formimidoylacetaldehyde is reacted with urea to give the product of the Example (recrystallized from ethanol), m.p. 283°-285° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[N:2]1.Br[C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:15]=1[C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>[Cu]=O>[C:16]([C:15]1[C:19]([O:23][CH3:24])=[CH:20][CH:21]=[CH:22][C:14]=1[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[N:2]1)([OH:18])=[O:17]
Reactant: COc1cccc(Br)c1C(=O)O
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cccc(-n2nc(C(=O)O)c3ccccc32)c1C(=O)O
Yield: 36.5 %

Procedure:
3-Indazolecarboxylic acid (1.16 g), 0.81 g of 2-bromo-6-methoxybenzoic acid [described in Chem. Ber., 107, 3874 (1974)], 0.79 g of potassium carbonate and 0.04 g of copper(II) oxide were subjected to reaction in the same manner as in Example 1 to obtain 0.40 g (25.6%) of 1-(2-carboxy-3-methoxyphenyl)-3-indazolecarboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([C:27]([OH:29])=O)[CH2:23][CH2:22]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][CH:21]4[CH2:26][CH2:25][CH:24]([C:27]([N:59]5[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]5)=[O:29])[CH2:23][CH2:22]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C1CNCCN1
Reactant: O=C(O)[C@H]1CC[C@H](Nc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CCC(Nc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1)N1CCNCC1

Procedure:
Prepared from 4-[(3-chloro-4-fluorophenyl)amino]-6-[trans-4-carboxycyclohexylamino]pyrimido[5,4-d]pyrimidine by reaction with O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, triethylamine and piperazine. Melting point: 178°-182° C.; Rf : 0.47 (alumina; methylene chloride/methanol=10:0.3)
Reaction SMILES: [CH:1]1([Ru:6][CH:7]2[CH:11]=[CH:10][CH:9]=[CH:8]2)[CH:5]=[CH:4][CH:3]=[CH:2]1.P(=O)(O)(O)O.[OH-].[Na+].[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([C:7]1([Ru:6][CH:1]2[CH:2]=[CH:3][CH:4]=[CH:5]2)[CH:11]=[CH:10][CH:9]=[CH:8]1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: C1=CC([Ru]C2C=CC=C2)C=C1
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)C1([Ru]C2C=CC=C2)C=CC=C1
Temperature: 85 °C

Procedure:
Bis(cyclopentadienyl)ruthenium (3 g), acetic anhydride (10 ml), and 85% phosphoric acid (2.0 ml) were placed in a round-bottom flask, and the mixture was heated at 85° C. for one hour. The formed reaction product was neutralized by use of sodium hydroxide, recrystallized, and subjected to extraction by use of hexane, thereby yielding 1.8 g of (acetylcyclopentadienyl)cyclopentadienylruthenium.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][OH:29])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:30](Cl)([CH3:33])(=[O:32])=[O:31]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=2)=[O:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1ccc(NC(=O)C(CO)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: CS(=O)(=O)Cl
Product: COC(=O)CCc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The procedure described in Example 65 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-3-hydroxypropanamide (882 mg) was reacted with mesyl chloride to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(4-(2-methoxycarbonylethyl)phenyl)propanamide (246 mg).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]=[CH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.[N+:16]([CH:19]([CH3:21])[CH3:20])([O-:18])=[O:17].C1CCN2C(=NCCC2)CC1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([C:19]([CH3:21])([N+:16]([O-:18])=[O:17])[CH3:20])[CH2:9][C:8]2=[O:13])=[CH:14][CH:15]=1
Reactant: CC(C)[N+](=O)[O-]
Reactant: O=C1C=CCCN1Cc1ccc(F)cc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C1CCN(Cc2ccc(F)cc2)C(=O)C1)[N+](=O)[O-]
Reaction time: 48 h

Procedure:
To a solution 1-(4-fluorobenzyl)-5,6-dihydropyridin-2(1H)-one (see Step 3 of Example 1) (0.75 g, 3.65 mmol) in 2-nitropropane (9.77 g, 109 mmol) was added DBU (0.56 g, 3.65 mmol). After stirring for 48 hours, the reaction mixture was concentrated under vacuum. The residual material was purified using silica gel column chromatography eluting with CH2Cl2. The appropriate fractions were combined and concentrated to afford the title compound. 1H NMR (400 MHz, CDCl3) δ 7.44 (m, 2H), 7.04 (t, J=9 Hz, 2H), 4.64 (d, J=15 Hz, 1H), 4.43 (d, J=15 Hz, 1H), 3.23 (m, 2H), 2.56 (m, 2H), 2.22 (m, 1H), 1.73 (m, 1H), 1.56 (s, 6H), 1.51 (m, 1H) ppm. ES MS M+1=295.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.[N:15]([O-:17])=[O:16].[Na+]>O>[N+:15]([N:2]([CH3:1])[C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)([O-:17])=[O:16]
Reactant: O=N[O-]
Reactant: CN[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CN([C@@H](Cc1ccccc1)C(=O)O)[N+](=O)[O-]
Temperature: 5 °C

Procedure:
N-Methyl-L-phenylalanine (2.50 g) was suspended in water (25 ml) and conc. HCl (1 ml) was addded, with stirring. The solution was cooled to 5° C. and solid sodium nitrite (1.35 g) was added to the stirred solution. After stirring at 5° C. for 1 h, the reaction mixture was partitioned between dichloromethane and water. The organic solution was washed with brine and dried (MgSO4). After filtration the solvent was evaporated to yield N-nitro-N-methyl-L-phenylalanine as a white solid.
Reaction SMILES: O=[C:2]1[C:11]2[CH2:12][CH2:13]O[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:4]=2[NH:3]1.[CH2:21]([O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[C:31]([CH3:36])[CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)COCCO.O>[CH3:36][C:31]1[CH:30]=[C:29]([O:28][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:35]=[CH:34][C:32]=1[N:33]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:4]=3[N:3]=[C:2]([NH:3][CH2:4][CH2:5][OH:15])[C:11]=2[CH2:12][CH2:13]1
Reactant: Cc1cc(OCc2ccccc2)ccc1N
Reactant: O=c1[nH]c2c(OCC(F)(F)F)cccc2c2c1CCO2
Solvent: O
Solvent: OCCOCCO
Product: Cc1cc(OCc2ccccc2)ccc1N1CCc2c(NCCO)nc3c(OCC(F)(F)F)cccc3c21
Temperature: 250 °C
Yield: 86 %

Procedure:
4-Oxo-6-β,β,β-trifluoroethoxy-2,3,4,5-tetrahydrofuro[3,2-c]quinoline(5.7 g, 20.0 mmol) was dissolved in diethylene glycol(70 ml) and crude 4-benzyloxy-2-methyl aniline(5.6 g, 26.0 mmol) was added. The reaction mixture was refluxed at 250° C. for 15 hours. The reaction mixture was dissolved in water, extracted with dichloromethane, and the organic layer was washed with water for 3 times. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography(ethyl acetate:dichloromethane=1:1) to obtain 4.5 g of desired compound as solid in 47% of yield.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@H:4]1[C:13]2[C:8](=[C:9]([O:16]C)[C:10]([O:14]C)=[CH:11][CH:12]=2)[CH2:7][C@@H:6]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:5]1.B(Br)(Br)[Br:25].CO>C(Cl)Cl>[BrH:25].[NH2:2][CH2:3][C@H:4]1[C:13]2[C:8](=[C:9]([OH:16])[C:10]([OH:14])=[CH:11][CH:12]=2)[CH2:7][C@@H:6]([CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:5]1
Reactant: COc1ccc2c(c1OC)C[C@@H](C1CCCCC1)C[C@H]2CN
Reactant: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Br
Product: NC[C@@H]1C[C@H](C2CCCCC2)Cc2c1ccc(O)c2O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
[1R,3S]1-Aminomethyl-3-cyclohexyl-5,6-dimethoxy-1,2,3,4-tetrahydro-naphthalene hydrochloride (0.7 g, 2.3 mmol), from Step 1, was suspended in 20 mL of methylene chloride at -78° C. Boron tribromide (9.7 mL of a 1M solution in methylene chloride, 9.7 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. After stirring at ambient temperature for 1 h, the reaction mixture was cooled to -78° C. and 10 mL of methanol was added. The reaction mixture was again allowed to warm to ambient temperature and stirred at ambient temperature for 1 h. The solvent was removed in vacuo and methanol was added to the residue. The methanol solution was concentrated and the residue dissolved in a minimal amount of methanol and added dropwise to a large excess of diethyl ether. The precipitate was filtered and recrystallized from ethanol/diethyl ether to give 0.48 g (65% yield) of [1R,3S]1-aminomethyl-3-cyclohexyl-5,6-dihydroxy-1,2,3,4-tetrahydro-naphthalene hydrobromide, m.p. 203°-204° C. 1H NMR (d6 -DMSO) delta 0.9-1.5 (m, 8H), 1.6-1.9 (m, 5H), 2.0-2.1 (m, 2H), 2.7-3.0 (m, 3H), 3.3-3.4 (m, 1H), 6.5-6.7 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:5][C:6]([CH3:19])=[CH:7][C:8](=[O:18])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O[CH:21](C1OC(C)=CC(=O)C=1OCC1C=CC=CC=1)[CH2:22]C>>[CH3:1][O:2][CH:3]([C:4]1[O:5][C:6]([CH3:19])=[CH:7][C:8](=[O:18])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:21][CH3:22]
Reactant: CCC(O)c1oc(C)cc(=O)c1OCc1ccccc1
Reactant: COCc1oc(C)cc(=O)c1OCc1ccccc1
Product: CCC(OC)c1oc(C)cc(=O)c1OCc1ccccc1
Yield: 90.3 %

Procedure:
In an analogous procedure in the preparation of 2-methoxymethyl-3-benzyloxy-6-methyl-pyran-4(1 H)-one using 2-(1-hydroxypropyl)-3-benzyloxy-6-methyl-pyran-4(1H)-one (5.48 g, 20 mmol, 1 eq.) yielded the title compound (5.2 g, 90.3%) as an orange oil which solidified on cooling. Recrystallisation from CH2Cl2/Pet. ether 40/60 afforded the pure product as a white crystalline solid. m.p. 63-65 ° C.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH3:16][N:17]1[CH2:22][CH2:21][CH2:20][CH:19]([C:23]2[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=2)[NH2:26])[CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:16][N:17]1[CH2:22][CH2:21][CH2:20][CH:19]([C:23]2[CH:24]=[C:25]([NH:26][C:2]3[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=3[N+:13]([O-:15])=[O:14])[CH:27]=[CH:28][CH:29]=2)[CH2:18]1
Reactant: CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN1CCCC(c2cccc(N)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1ccc(Nc2cccc(C3CCCN(C)C3)c2)c([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
A mixture of 1c (5.7 g, 25 mmol), 2j (3.8 g, 20 mmol) and potassium carbonate (3.45 g, 25 mmol) was heated to 70° C. under a stream of nitrogen. The resulting melt was stirred at 70° C. overnight. The reaction mixture was partitioned between water and ethyl acetate and the organic phase was extracted with diluted hydrochloric acid (4M). The aqueous phase was rendered alkaline by addition of aqueous sodium hydroxide (4M) and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure to leave ethyl 4-(3-(1-methylpiperidin-3-yl)phenylamino)-3-nitrobenzoate (7.5 g, 98%) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[O:4][N:3]=1.[Cl:11]N1C(=O)CCC1=O>CN(C)C=O>[Cl:11][C:6]1[C:2]([OH:1])=[N:3][O:4][C:5]=1[CH2:7][C:8]([OH:10])=[O:9]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(O)Cc1cc(O)no1
Solvent: CN(C)C=O
Product: O=C(O)Cc1onc(O)c1Cl
Reaction time: 15 h
Yield: 60.1 %

Procedure:
To a solution of 4.3 g (30 mmoles) of 3-hydroxyisoxazol-5-ylacetic acid in 10 ml of N,N-dimethylformamide were added 4.81 g (36 mmole) of N-chlorosuccinimide, with ice-cooling and stirring. The mixture was left to stand at room temperature for 15 hours, after which the N,N-dimethylformamide was distilled off under reduced pressure and ethyl acetate was added. The mixture was then extracted with an aqueous solution of sodium hydrogen carbonate and then the pH of the extract was adjusted to a value below 1.0 by addition of concentrated hydrochloric acid. After drying the solution, the solvent was distilled off and the residue was recrystallized from a 1:5 by volume mixture of ethyl acetate and cyclohexane, to give 3.2 g (60%) of the title compound, melting point 155° C.
Reaction SMILES: CC[N:3]=C=NCCCN(C)C.[Cl:12][C:13]1[S:39][C:16]2[NH:17][C:18]([C:20]([NH:22][CH:23]3[CH2:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]([CH2:33][CH:34](O)CO)[C:24]3=[O:38])=[O:21])=[CH:19][C:15]=2[CH:14]=1.ClC1SC2NC(C(NC3CC4C(=CC=CC=4)N(C[C@@H](O)CO)C3=O)=O)=CC=2C=1>C(Cl)Cl>[Cl:12][C:13]1[S:39][C:16]2[NH:17][C:18]([C:20]([NH:22][CH:23]3[CH2:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]([CH2:33][C:34]#[N:3])[C:24]3=[O:38])=[O:21])=[CH:19][C:15]=2[CH:14]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(NC1Cc2ccccc2N(CC(O)CO)C1=O)c1cc2cc(Cl)sc2[nH]1
Agent: O=C(NC1Cc2ccccc2N(C[C@@H](O)CO)C1=O)c1cc2cc(Cl)sc2[nH]1
Solvent: ClCCl
Product: N#CCN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Reaction time: 18 h
Yield: 21 %

Procedure:
EDCI (1.09 g, 5.65 mmol) was added to a suspension of 5-Carboxy-2-chloro-6H-thieno[2,3-b]pyrrole (Method 9, 1.04 g, 5.13 mmol) and (3-amino-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetonitrile (Method 13; 1.29 g, 5.13 mmol) in DCM (30 mL) and the reaction stirred for 18 hours. The reaction was evaporated and the residue was partitioned between DCM:MeOH (9:1) (100 mL) and aqueous K2CO3 (25 mL). The organic layer was then separated, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (DCM to DCM:MeOH (9:1)) to give a brown solid. The solid was triturated with refluxing Et2O (25 mL) and the solid filtered, washed with Et2O (25 mL) then hexane (25 mL) to afford the title compound (414 mg, 21%) as a pale brown solid.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH:7]([C:11](O)=O)[CH2:6]2)OCC1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:29]1([C:35]2[CH2:36][CH2:37][NH:38][CH2:39][CH:40]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl>[C:29]1([C:35]2[CH2:40][CH2:39][N:38]([CH2:11][CH:7]3[CH2:8][CH2:9][CH2:10][C:5](=[O:1])[CH2:6]3)[CH2:37][CH:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(O)C1CCCC2(C1)OCCO2
Reactant: C1=C(c2ccccc2)CCNC1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCCC(CN2CC=C(c3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
A solution of 1,4-dioxaspiro[4.5]decane-7-carboxylic acid (Step A) (99.3 g) and triethylamine (80.8 g) in 1000 mL of dichloromethane is cooled in an ice bath, and treated dropwise with isobutyl chloroformate (80.1 g), dropwise, under nitrogen. After 30 minutes, a solution of 4-phenyl-1,2,3,6-tetrahydropyridine (84.7 g) in 500 mL of dichloromethane is added dropwise over a 2-hour period. The mixture is stirred at room temperature for 2 additional hours. The solvent is removed in vacuo. The residue is suspended in 1000 mL of ethyl acetate, cooled to 0° C., and sequentially washed with ice-cold 1N aqueous hydrochloric acid solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The crude product is purified by flash chromatography (silica; hexane:ethyl acetate, 3:1) to give 107.1 g of the title compound as a yellow oil (silica; Rf =0.4; 1% methanol, 99% chloroform); Mass Spectrum (Electron Ionization) (MS (EI)) 327 (M, 26.1%), 141 (100%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:3]=1.[I:25]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:16])([F:15])[F:17])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:3]=1[I:25]
Reactant: Nc1cc(-c2ccccc2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: Nc1c(I)c(-c2ccccc2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
To a stirred solution of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-phenylpyrazole (0.12 g) and N-iodosuccinirnide (0.08 g) in acetonitrile (5 ml) were left at room temperature overnight. The mixture was evaporated to dryness and the residue partitioned between dichloromethane (15 ml) and water (10 ml). The organic layer was separated and washed with water (20 ml, ×2), brine (15 ml) and dried (MgSO4) and evaporated. The residue was triturated with hexane to give the title compound as a yellow solid, m.p. 162-164° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:23][C:24](=[O:35])[C:25]1[CH:30]=[C:29](Cl)[CH:28]=[CH:27][C:26]=1[N+:32]([O-:34])=[O:33].[CH3:36][NH:37][CH2:38][CH2:39][CH2:40][NH:41][CH3:42]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:23][C:24](=[O:35])[C:25]1[CH:30]=[C:29]([N:37]([CH2:38][CH2:39][CH2:40][NH:41][CH3:42])[CH3:36])[CH:28]=[CH:27][C:26]=1[N+:32]([O-:34])=[O:33]
Reactant: CNCCCNC
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Product: CNCCCN(C)c1ccc([N+](=O)[O-])c(C(=O)Nc2cc(NC(=O)c3ccnc(N4CCOCC4)c3)ccc2C)c1

Procedure:
In an analogous procedure to that described in the fifth paragraph of the portion of Note a) which is concerned with the preparation of starting materials, N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-5-chloro-2-nitrobenzamide was reacted with N-(3-methylaminopropyl)-N-methylamine to give N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl)-5-[N-(3-methylaminopropyl)-N-methylamino]-2-nitrobenzamide; NMR Spectrum: (DMSOd6) 1.61-1.74 (m, 2H), 2.35 (s, 3H), 2.26. (m, 3H), 2.38-2.44 (m, 2H), 3.09 (s, 3H), 3.5-3.55 (m, 6H), 3.7-3.74 (m, 4H), 6.78 (s, 1H), 6.84 (d, 1H), 7.14 (d, 1H), 7.21 (d, 1H), 7.27 (s, 1H), 7.6 (d, 1H), 7.9 (s, 1H), 8.04 (d, 1H), 8.27 (d, 1H), 9.83 (s, 1H), 10.55 (s, 1H); Mass Spectrum: M+H+ 562.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH:4]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][I:32])=[CH:29][CH:28]=1>>[I-:32].[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH:4]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[CH2:5][N+:6]1[CH:10]=[CH:9][N:8]([CH2:31][C:30]2[CH:33]=[CH:34][C:27]([F:26])=[CH:28][CH:29]=2)[CH:7]=1
Reactant: Fc1ccc(CI)cc1
Reactant: Clc1ccc(COC(Cn2ccnc2)c2ccc(Cl)cc2Cl)c(Cl)c1
Product: Fc1ccc(Cn2cc[n+](CC(OCc3ccc(Cl)cc3Cl)c3ccc(Cl)cc3Cl)c2)cc1
Product: [I-]

Procedure:
mp. 151° -153° C., by the reaction of 1-[2,4-dichloro-β-(2,4-dichlorobenzyloxy)phenethyl]-imidazole and p-fluorobenzyl iodide.
Reaction SMILES: [F:1][CH:2]([F:35])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH3:34])=[C:21]([NH:23][C:24]([N:26]4[CH2:33][C:30]5([CH2:32][CH2:31]5)[NH:29][CH2:28][CH2:27]4)=[O:25])[CH:22]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.[CH2:36]=O.[O-]S([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[F:35][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH3:34])=[C:21]([NH:23][C:24]([N:26]4[CH2:33][C:30]5([CH2:32][CH2:31]5)[N:29]([CH3:36])[CH2:28][CH2:27]4)=[O:25])[CH:22]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: C=O
Reactant: Cc1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1NC(=O)N1CCNC2(CC2)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1NC(=O)N1CCN(C)C2(CC2)C1
Reaction time: 12 h

Procedure:
A solution of N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4,7-diazaspiro[2.5]octane-7-carboxamide D8 (0.05 mmol), HCHO (0.15 mmol, 30% aqueous) and anhydrous Na2SO4 (1.5 mmol) in DCM (2 mL) is stirred at rt for 30 min. Then NaHB(OAc)3 (0.3 mmol) is added and the resulting mixture is stirred for 12 h. Purification by prep-HPLC (ACN gradient 10-70%) affords N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-methyl-4,7-diazaspiro[2.5]octane-7-carboxamide D9. 1H NMR (400 MHz, d6-DMSO) δ 9.67 (s, 1H), 8.79 (s, 2H), 7.98 (s, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.60 (s, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.27 (d, J=8.4 Hz, 2H), 7.26 (t, J=76.0 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 2.78 (m, 2H), 2.51 (m, 4H), 2.31 (s, 3H), 2.10 (s, 3H), 0.62 (m, 2H), 0.50 (m, 2H). MS (m/z) (M+1)+: 537.1.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl[C:25]1[CH:30]=[N:29][C:28]([CH3:31])=[CH:27][N:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:25]3[CH:30]=[N:29][C:28]([CH3:31])=[CH:27][N:26]=3)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: Cc1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)cn1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
A mixture of N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide (600 mg), 2-chloro-5-methyl-pyrazine (100 mg), and cesium carbonate (300 mg) in N,N-dimethylformamide (10 mL) is stirred for 3 days at 80° C. After cooling to room temperature ethyl acetate and water are added. The organic phase is separated, washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (ethyl acetate/methanol 7:3) to give the title compound. LC (method 1): tR=1.08 min; Mass spectrum (ESI+): m/z=404 [M+H]+.