Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:11][O:12][C:13](=[O:36])[C@H:14]([CH2:22][C:23]1[CH:28]=[C:27]([Cl:29])[C:26]([O:30][CH2:31][CH2:32][CH2:33][NH2:34])=[C:25]([Cl:35])[CH:24]=1)[NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18].C(=O)(O)[O-].[Na+].O>C(OCC)(=O)C>[CH3:11][O:12][C:13](=[O:36])[C@H:14]([CH2:22][C:23]1[CH:24]=[C:25]([Cl:35])[C:26]([O:30][CH2:31][CH2:32][CH2:33][NH:34][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:27]([Cl:29])[CH:28]=1)[NH:15][C:16](=[O:21])[C:17]([F:20])([F:18])[F:19]
Reactant: COC(=O)[C@H](Cc1cc(Cl)c(OCCCN)c(Cl)c1)NC(=O)C(F)(F)F
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1cc(Cl)c(OCCCNC(=O)c2ccccc2)c(Cl)c1)NC(=O)C(F)(F)F
Yield: 105.3 %

Procedure:
A solution of benzoyl chloride (94 mg, 0.669 mmol) in ethyl acetate (2 ml) was added dropwise to a two-layer solution of O-(3-aminopropyl)-3,5-dichloro-N-trifluoroacetyl-L-tyrosine methyl ester hydrochloride (209 mg, 0.461 mmol) and sodium bicarbonate (150 mg, 1.79 mmol) in ethyl acetate (3 ml)-water (2 ml) with stirring under ice cooling and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was diluted with ethyl acetate (20 ml) and the organic layer was separated, washed with brine and dried. The solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography on silica gel (n-hexane/ethyl acetate=2−1) to give O-(3-benzoylaminopropyl)-3,5-dichloro-N-trifluoroacetyl-L-tyrosine methyl ester (253 mg, 100%) as a colorless oil.
Reaction SMILES: [CH2:1]1[O:19][C:4]2([CH2:9][CH2:8][C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)=[CH:6][CH2:5]2)[O:3][CH2:2]1.[H][H]>O1CCCC1.CO.[Pd]>[CH2:2]1[O:3][C:4]2([CH2:9][CH2:8][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:6][CH2:5]2)[O:19][CH2:1]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCC2(C1)OCCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: c1ccc2c(C3CCC4(CC3)OCCO4)c[nH]c2c1
Yield: 100141.7 %

Procedure:
4-(1H-3-indolyl)-3-cyclohexenone ethylene ketal (66.6 g, 0.26 mmol) is dissolved in 500 mL of tetrahydrofuran and 100 mL of methanol, 1.0 g 5% palladium on carbon is added and the mixture is placed under 60 pounds per square inch (psi) of hydrogen. After 2 hours the reaction is filtered and concentrated to give the product as a tan solid (67.0 g). An analytical sample is recrystallized from methanol; mp 163°-5° C.
Reaction SMILES: C1(C(C2C3C(=C(CSC)C=CC=3)NC=2)(C2C=CC3[O:10][C:11]([F:14])([F:13])[O:12]C=3C=2)C)CC1.Cl[C:30]1[CH:35]=[CH:34][C:33]([C:36]([C:41]2[C:49]3[C:44](=[C:45]([CH2:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH:46]=[CH:47][CH:48]=3)[NH:43][CH:42]=2)([CH:38]2[CH2:40][CH2:39]2)[CH3:37])=[CH:32][CH:31]=1>>[CH:38]1([C:36]([C:41]2[C:49]3[C:44](=[C:45]([CH2:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH:46]=[CH:47][CH:48]=3)[NH:43][CH:42]=2)([C:33]2[CH:34]=[CH:35][C:30]3[O:10][C:11]([F:14])([F:13])[O:12][C:31]=3[CH:32]=2)[CH3:37])[CH2:40][CH2:39]1
Reactant: CC(c1ccc(Cl)cc1)(c1c[nH]c2c(CS(C)(=O)=O)cccc12)C1CC1
Reactant: CSCc1cccc2c(C(C)(c3ccc4c(c3)OC(F)(F)O4)C3CC3)c[nH]c12
Product: CC(c1ccc2c(c1)OC(F)(F)O2)(c1c[nH]c2c(CS(C)(=O)=O)cccc12)C1CC1

Procedure:
The title compound was prepared starting from 33 mg (0.08 mmol) of the compound from Example 190 in analogy to the synthesis of the compound from Example 209. 27 mg (76% of theory) of the target compound were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C@@H:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])=[CH:6][CH:5]=1)[CH3:2].Br[C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][CH2:23][C:24]2=[O:27])=[C:20]([F:28])[CH:19]=1.CNCCNC>O1CCOCC1>[CH2:1]([O:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C@@H:11]2[CH2:15][CH2:14][N:13]([C:18]3[CH:26]=[C:25]4[C:21](=[C:20]([F:28])[CH:19]=3)[CH2:22][CH2:23][C:24]4=[O:27])[C:12]2=[O:16])=[CH:6][CH:5]=1)[CH3:2]
Reactant: O=C1CCc2c(F)cc(Br)cc21
Reactant: CCOc1ccc(O[C@@H]2CCNC2=O)cn1
Agent: CNCCNC
Solvent: C1COCCO1
Product: CCOc1ccc(O[C@@H]2CCN(c3cc(F)c4c(c3)C(=O)CC4)C2=O)cn1
Temperature: 100 °C

Procedure:
In a further alternative preparation a mixture of (R)-3-((6-ethoxypyridin-3-yl)oxy)pyrrolidin-2-one (2.00 g), 6-bromo-4-fluoro-2,3-dihydro-1H-inden-1-one (2.30 g), N,N′-dimethyl-ethylene-diamine (10 mL) and 1,4-dioxane (20 mL) was purged with argon and cesium carbonate (3.8 g) and copper(I) iodide (100 mg) were added. The mixture was heated to 100° C. for 1.5 hours. After cooling to r.t. the mixture was diluted with EA and washed with water (5 times) and brine. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by SGC (eluent: heptane with 0 to 70% EA) to provide Example 2-08. 1H-NMR (400 MHz, DMSO) δ 7.99 (1H, dd, J=11.3, 1.8 Hz), 7.97 (1H, d, J=3.1 Hz), 7.77 (1H, d, J=1.8 Hz), 7.53 (1H, dd, J=8.9, 3.1 Hz), 6.76 (1H, d, J=8.9 Hz), 5.22 (1H, dd, J=8.3, 8.3 Hz), 4.24 (2H, q, J=7.0 Hz), 3.96 (1H, m), 3.86 (1H, m), 3.11 (2H, m), 2.72 (2H, m), 2.69 (1H, m), 2.13 (1H, m), 1.30 (3H, t, J=7.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-])=O)=[C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[CH:7]=1.[C:17]([O:20][CH2:21][CH3:22])(=[O:19])C>[Ni]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14][C:17]([O:20][CH2:21][CH3:22])=[O:19])=[C:6]([N:8]([C:17]([O:20][CH2:21][CH3:22])=[O:19])[CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[CH:7]=1
Reactant: CCOC(C)=O
Reactant: CN(C)CCNc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Ni]
Product: CCOC(=O)Nc1ccc(Cl)cc1N(CCN(C)C)C(=O)OCC
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a solution of N-(5-Chloro-2-nitrophenyl)-N',N'-dimethylethylenediamine (1.02 g) in ethyl acetate (10 ml) was added Raney nickel and the reaction mixture was stirred under a hydrogen atmosphere at atmospheric pressure at 5° C. for 1 hour. The reaction mixture was then filtered and the solvent was distilled off under reduced pressure. The residue was dissolved in dichloromethane (15 ml), followed by dropwise addition of triethylamine (1.28 g) and ethyl chloroformate (1.14 g) in turn at 5° C. with stirring. The reaction mixture was further stirred at room temperature for 1 hour and diluted with water (10 ml). The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent:chloroform:methanol=50:1) to give 1.05 g of N-(5-chloro-2-ethoxycarbonylaminophenyl)-N-ethoxycarbonyl-N',N'-dimethylethylenediamine.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:17]2[CH2:20][CH2:19][CH2:18]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:22][CH2:23][CH2:24][O:25][C:26](=[O:28])[CH3:27].C(N(CC)CC)C>CN(C)C=O>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:22][CH2:23][CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH2:15][CH2:16]2)[CH:8]=[C:7]([CH:17]2[CH2:20][CH2:19][CH2:18]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OCCCCl
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCNCC2)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)OCCCN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
5.5 g of 2-tert-butyl-4-piperazin-1-yl-6-cyclobutyl-pyrimidine (20.0 mmol), 3.15 g of acetic acid 3-chloro-propyl ester (23.1 mmol) and 2.76 g of triethylamine (27.3 mmol) were dissolved in 70 ml of dimethylformamide and stirred for 12 h at 80° C. After cooling, the dimethylformamide was evaporated, and the reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the solvent was evaporated. The crude product (7 g) was directly used in the subsequent reaction step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([N:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[C:36]([C:37](Cl)=[O:38])=[C:35]([CH3:40])[O:34][N:33]=1.[OH-].[Na+]>CN(C1C=CN=CC=1)C.ClCCl>[CH3:16][N:15]([CH3:17])[C:8]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:13][CH2:12][CH:11]([NH:14][C:37]([C:36]2[C:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[Cl:25])=[N:33][O:34][C:35]=2[CH3:40])=[O:38])[CH2:10][CH2:9]1
Reactant: CN(C)C1(c2cccc(F)c2)CCC(N)CC1
Reactant: Cc1onc(-c2ccccc2Cl)c1C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1onc(-c2ccccc2Cl)c1C(=O)NC1CCC(c2cccc(F)c2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The non-polar diastereoisomer of 1-(3-fluorophenyl)-N,N-dimethylcyclohexane-1,4-diamine (350 mg) was placed with 220 μI triethylamine (1.05 molar equivalents) and catalytic amounts of DMAP (about 5 mg) in 3.5 ml dichloromethane, 400 mg 3-(2-chlorophenyl)-5-methylisoxazole-4-carbonylchloride (1.05 molar equivalents), dissolved in 2 ml dichloromethane, were added dropwise at −10° C. to and the mixture was stirred overnight while being heated to room temperature. For working up, the mixture was made alkaline (pH>10) with 2-molar sodium hydroxide solution, with ice cooling, the organic phase was separated, the aqueous phase extracted with dichloromethane (20 ml) and the combined organic phases dried over sodium sulphate, filtered and evaporated to dryness. The resultant crude product (690 mg) was chromatographed on silica gel (4.0×15 cm) with methanol/ethyl acetate (V:V=1:1). 530 mg of the non-polar diastereoisomer of 3-(2-chlorophenyl)-5-methylisoxazole-4-carboxylic acid [4-dimethylamino-4-(3-fluorophenyl)cyclohexyl]amide were obtained, which, dissolved in 50 ml 2-butanone were converted overnight into the corresponding hydrochloride by adding 21 μl water and 150 μl chlorotrimethylsilane, then evaporating to dryness, and stirring with 10 ml ethyl acetate (380 mg, Mp. 231-232° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].F[C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][N:19]=1)[C:14]([OH:16])=[O:15]>>[Cl:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:17]1[CH:18]=[N:19][CH:11]=[CH:12][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1ccnc(F)c1
Reactant: Nc1ccc(I)cc1Cl
Product: O=C(O)c1ccncc1Nc1ccc(I)cc1Cl

Procedure:
synthesized as intermediate 1 by reacting 15.7 mmol of 2-chloro-4-iodoaniline with 23,55 mmol 2-fluoroisonicotinic acid. LC/MS [(5.9 min; 376 (M+1)].
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CC(C)=O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][O:1][C:2]2[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[CH:16][CH:17]=1
Reactant: COC(=O)c1cc(I)ccc1O
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(I)ccc1OCc1ccc(F)cc1

Procedure:
To a solution of methyl 2-hydroxy-5-iodobenzoate (15 g, 53.9 mmol) in acetone (200 ml) was added 1-(bromomethyl)-4-fluorobenzene (9.95 ml, 81 mmol), potassium carbonate (14.91 g, 108 mmol) and the mixture was refluxed overnight. The mixture was allowed to cool and then filtered to remove the potassium carbonate. The solid potassium carbonate was washed with acetone (100 ml). The organics were combined and evaporated under reduced pressure on a buchi to give a solid. The solid was taken up into ethyl acetate (500 ml) and the organic phase was washed with water (2×200 ml), dried (MgSO4) and evaporated under reduced pressure on a buchi. The solid obtained was recrystallised from cyclohexane to yield the title compound as a white solid. 18.2 g.
Reaction SMILES: CS[C:3]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)=[C:4]([C:7]#[N:8])[C:5]#[N:6].O.[NH2:20][NH2:21]>CCO>[NH2:6][C:5]1[NH:21][N:20]=[C:3]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[C:4]=1[C:7]#[N:8]
Reactant: NN
Reactant: CSC(Nc1ccc([N+](=O)[O-])cc1)=C(C#N)C#N
Solvent: CCO
Solvent: O
Product: N#Cc1c(Nc2ccc([N+](=O)[O-])cc2)n[nH]c1N
Temperature: 0 °C

Procedure:
Dissolved 2-((methylthio)((4-nitrophenyl)amino)methylene)malononitrile in EtOH (100 mL) and added hydrazine hydrate (1 eq., 3.64 mL), then heated to reflux until complete by TLC (absence of starting material, 18 hrs). Poured into ice water and filtered to obtain 5-amino-3-((4-nitrophenyl)amino)-1H-pyrazole-4-carbonitrile as a yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[N:14]1([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:29]=2[CH2:28][NH:27][CH2:26][CH2:25]3)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[C:20]([N:14]5[CH2:19][CH2:18][O:17][CH2:16][CH2:15]5)[CH:21]=[CH:22][CH:23]=4)[CH2:28]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: c1cc2c(c(N3CCOCC3)c1)CNCC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2cccc(N3CCOCC3)c2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: C(O)C.[Cl:4][C:5]1[C:10]([CH3:11])=[C:9](Br)[CH:8]=[C:7]([S:13]([CH3:16])(=[O:15])=[O:14])[C:6]=1[CH3:17].C([O-])(=O)C.[Na+].[H][H]>[Pd].O>[Cl:4][C:5]1[C:6]([CH3:17])=[C:7]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: [H][H]
Reactant: Cc1c(Br)cc(S(C)(=O)=O)c(C)c1Cl
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(C)(=O)=O)c(C)c1Cl
Temperature: 25 °C
Reaction time: 7 h

Procedure:
30 ml of ethanol was added to 1.0 g of the crude 2-chloro-4-bromo-6-methylsulfonyl-m-xylene obtained in Example 3, and 0.1 g of 5% palladium active carbon and 1.0 g of anhydrous sodium acetate were further added thereto. The reactor was sealed, and was substituted with hydrogen, then stirring at room temperature for 7 hours. 30 ml of water was added to the reaction liquor, and was concentrated under reduced pressure. 30 ml of EDC was further added thereto, and the resultant mixture was filtered. The EDC layer was taken out from the filtrate, and was washed with 20 ml of water and then with 10 ml of a saturated aqueous solution of common salt, and was dried over anhydrous sodium sulfate. The EDC layer thus obtained was concentrated under reduced pressure and was dried to a solid to obtain 0.7 g of a crude product of the above-identified aimed compound (purity measured by gas chromatography: 75.6%). The crude product thus obtained was recrystallized by methanol to obtain the above-identified aimed compound.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[CH3:18])[CH2:6]1)=[O:4].[NH:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH:21]=[N:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:17][C:13]1[C:12]([CH3:18])=[C:11]([N:7]2[C:8](=[O:10])[CH2:9][N:5]([C:3](=[O:4])[CH2:2][N:19]3[C:23]4=[N:24][CH:25]=[CH:26][CH:27]=[C:22]4[CH:21]=[N:20]3)[CH2:6]2)[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1c(Cl)cccc1N1CN(C(=O)CCl)CC1=O
Reactant: c1cnc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(Cl)cccc1N1CN(C(=O)Cn2ncc3cccnc32)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(2-Chloro-acetyl)-3-(3-chloro-2-methyl-phenyl)-imidazolidin-4-one (230 mg, 0.8 mmol, 1 eq), 1H-Pyrazolo[3,4-b]pyridine (96 mg, 0.8 mmol, 1 eq), Cesium carbonate (653 mg, 2.0 mmol, 2.5 eq) in DMF (6 ml) was stirred at room temperature overnight. It was diluted with ethyl acetate, washed with water and purified with HPLC to give the desired product. LCMS observed for (M+H)+: 370.1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([CH3:12])[N:4]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17].C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([CH:12]=[CH:15][N:16]([CH3:18])[CH3:17])[N:4]=1
Reactant: COC(OC)N(C)C
Reactant: COc1ccc([N+](=O)[O-])c(C)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(C=CN(C)C)n1
Temperature: 120 °C
Yield: 99.6 %

Procedure:
To 2-methoxy-5-nitro-6-methylpyridine (29.39 g, 175 mmol) dissolved in 300 mL of N,N-dimethylformamide was added dimethylformamide dimethylacetal (120 mL, 896 mmol) and triethylamine (1 mL). The bright red reaction mixture was heated at 120° C. for 2 hours, then concentrated in vacuo to provide 38.90 g of the title compound as a red solid, which was used in Preparation 13 without further purification.
Reaction SMILES: C([CH2:4][SiH:5](Cl)[Cl:6])C=C.[CH2:8]([Mg]Cl)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].CCCCCC>O1CCCC1>[CH3:4][SiH:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[Cl:6]
Reactant: CCCCCCCCCCCCCCCCCC[Mg]Cl
Reactant: C=CCC[SiH](Cl)Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCCCC[SiH](C)Cl

Procedure:
was prepared as follows. Allylmethyldichlorosilane (0.69 moles, available from the Aldrich Chemical Co., Milwaukee, Wis., USA) was put into a reaction flask with 250 milliliters of tetrahydrofuran (THF). One molar octadecylmagnesium chloride (0.65 moles) in THF was added portionwise to the flask while the mixture was stirred and cooling to a temperature range of about -10° to +5°. The temperature of this mixture was allowed to increase to 24°. Hexane was added to the mixture, and the solid filtered off. The filtrate was evaporated on a rotary evaporator to leave an oil. The oil was vacuum-distilled, providing 134.7 g (55.8% relative to the theoretical yield) of ally methyl octadecyl-chlorosilane (compound A) as a clear, colorless oil. The boiling point of compound A was 188°/0.1-191°/0.2 mm, and gas chromatography/mass spectrometry (GC/MS) showed 100% compound A.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][C:23](C5NN=CC=5)=[CH:24][CH:25]=4)[O:20][C:19]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC1(C2C=CC(C3C(=O)C4C(=C(Br)C=CC=4)OC=3C3C=CC=CC=3)=CC=2)CCC1)(C)(C)C.[CH3:77][C:78]1[C:82](B2OC(C)(C)C(C)(C)O2)=[CH:81][NH:80][N:79]=1>>[C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([C:82]5[C:78]([CH3:77])=[N:79][NH:80][CH:81]=5)[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(-c5ccn[nH]5)ccc4c3=O)cc2)CCC1
Agent: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Br)cccc4c3=O)cc2)CCC1
Product: Cc1n[nH]cc1-c1cccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Yield: 70 %

Procedure:
Following the procedure of (1-{4-[4-oxo-2-phenyl-7-(2H-pyrazol-3-yl)-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, {1-[4-(8-bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted with 3-methyl-1H-pyrazole-4-boronic acid pinacol ester to give the title compound as a gum (35 mg, 70%). LCMS (Method G): RT=3.81 min, [M+H]+=548.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[NH:21][C:22](=[O:25])[CH2:23]Cl.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[NH:21][C:22](=[O:25])[CH2:23][N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(CCl)Nc1cccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CN1CCN(c2ccccn2)CC1)Nc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.4 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(2,3-dichlorophenyl)-2-chloroacetamide (48 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure the residue purified by preparative HPLC to provide 9 mg (16%) of the desired product as a trifluoroacetic acid salt. 1H NMR (500 MHz, DMSO-d6) δ 2.62 (t, J=4 Hz, 4H), 3.23 (s, 2H), 3.58 (t, J=4 Hz, 4H), 6.63 (t, J=5 Hz, 1H), 6.83 (d, J=6 Hz, 1H), 7.55 (t, J=6 Hz, 1H), 7.68 (m, 2H), 7.88 (m, 2H), 8.12 (d, J=5 Hz, 1H), 10.12 (s, 1H); MS (ESI/APCI+) m/e 365 (M+H)+.
Reaction SMILES: C([S:4][C@@H:5]1[CH2:9][N:8]([CH3:10])[C@H:7]([CH2:11][N:12]2[CH2:16][CH2:15][NH:14][C:13]2=[O:17])[CH2:6]1)(=O)C.C[O-].[Na+].C(O)(=O)C>CO>[SH:4][C@@H:5]1[CH2:9][N:8]([CH3:10])[C@H:7]([CH2:11][N:12]2[CH2:16][CH2:15][NH:14][C:13]2=[O:17])[CH2:6]1
Reactant: CC(=O)S[C@H]1C[C@@H](CN2CCNC2=O)N(C)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN1C[C@@H](S)C[C@H]1CN1CCNC1=O
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
To a solution of (2S,4S)-4-acetylthio-1-methyl-2-(2-oxoimidazolidin-1-yl)methylpyrrolidine (1.83 g) in methanol (20 ml) was added 28% sodium methoxide in methanol solution (1.50 ml) at -10°~-5° C. and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added acetic acid (0.45 ml) at the same temperature and the mixture was evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (9:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-4-mercapto-1-methyl-2-(2-oxoimidazolidin-1-yl)methylpyrrolidine (0.60 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:5][CH:4]([CH:6]([NH:16][C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][C:23]([F:27])=[CH:22][CH:21]=3)[C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.Cl.[CH2:30]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH2:36])[CH3:31].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1([CH3:28])[CH2:3][CH:4]([CH:6]([NH:16][C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][C:23]([F:27])=[CH:22][CH:21]=3)[C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:36][CH2:35][CH2:34][C:33]([O:32][CH2:30][CH3:31])=[O:37])=[O:12])=[CH:9][CH:8]=2)[CH2:5]1
Reactant: CCOC(=O)CCN
Reactant: CC1(C)CC(C(Nc2cnc3ccc(F)cc3c2)c2ccc(C(=O)O)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ccc(C(Nc2cnc3ccc(F)cc3c2)C2CC(C)(C)C2)cc1
Reaction time: 18 h
Yield: 53.4 %

Procedure:
To a vial containing 4-((3,3-dimethylcyclobutyl)(6-fluoroquinolin-3-ylamino)methyl)benzoic acid (11.0 mg, 0.0290 mmol), was added 3-aminopropionic acid ethyl ester hydrochloride (4.90 mg, 0.0320 mmol), 1-Hydroxy-7-azabenzotriazole (4.80 mg, 0.0350 mmol) and 1-ethyl-3-(3-dimethylamino propyl)carbodiimide hydrochloride (6.70 mg, 0.0350 mmol). Anhydrous methylene chloride (0.290 mL) was added followed by triethylamine (0.005 mL, 0.0380 mmol). After 18 h, the reaction was diluted with methylene chloride and quenched with a saturated solution of ammonium chloride. The aqueous layer was extracted three times with methylene chloride. The combined organic layers were dried with sodium sulfate, filtered, and concentrated to give 28.6 mg of crude material. Purification by silica gel flash chromatography (0-70% ethyl acetate in heptane) provided ethyl 3-(4-((3,3-dimethylcyclobutyl)(6-fluoroquinolin-3-ylamino)methyl)benzamido)propanoate (7.40 mg, 54% yield) as an oil. 1H NMR (400 MHz, CDCl3, δ): 7.86 (s, 1H), 7.72 (d, J=8.2 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.14-7.06 (m, 1H), 7.05-6.96 (m, 1H), 6.80 (t, J=5.9 Hz, 1H), 6.60 (s, 1H), 4.45 (s, 1H), 4.24 (dd, J=9.3, 4.4 Hz, 1H), 4.19-4.08 (m, 2H), 3.70 (q, J=6.0 Hz, 2H), 2.62 (t, J=6.0 Hz, 2H), 2.58-2.44 (m, 1H), 2.06-1.96 (m, 1H), 1.75-1.67 (m, 2H), 1.67-1.55 (m, 2H), 1.28-1.22 (m, 3H), 1.13 (s, 3H), 1.09 (s, 3H). (M+1): 478.3.