Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:25]([O-])=O)=[C:6]([CH:24]=1)[O:7][C:8]1[CH:9]=[C:10]([C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15])[CH:11]=[CH:12][CH:13]=1>[C].[Pd].C(OCC)(=O)C>[NH2:25][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:24][C:6]=1[O:7][C:8]1[CH:9]=[C:10]([C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15])[CH:11]=[CH:12][CH:13]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(Oc2cc(Cl)ccc2[N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)OC(C)(C)C)c1cccc(Oc2cc(Cl)ccc2N)c1
Reaction time: 1 h
Yield: 99.1 %

Procedure:
5% carbon-palladium (1.1 g) was added to an ethyl acetate (50 ml) solution of tert-butyl(1S)-(-)-1-[3-(5-chloro-2-nitrophenoxy)phenyl]ethylcarbamate (3.5 g, 8.9 mmols). The resulting mixture was hydrogenated at room temperature under atmospheric pressure for 1 hour. The catalyst was removed through filtration, and the filtrate was concentrated under reduced pressure. The residue was purified through silica gel column chromatography to give an oil of tert-butyl(1S)-1-[3-(2-amino-5-chlorophenoxy)phenyl]ethylcarbamate (3.2 g, 99%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[I:17]N1C(=O)CCC1=O.[O-]S([O-])=O.[Na+].[Na+].C([O-])([O-])=O.[Na+].[Na+].P([O-])(O)(O)=O.[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[CH:5]=[C:6]([I:17])[C:7]=1[OH:8]
Reactant: O=C1CCC(=O)N1I
Reactant: N#Cc1ccc(-c2ccc(O)c(F)c2)cc1
Agent: O=C([O-])[O-]
Agent: O=P([O-])(O)O
Agent: O=S([O-])[O-]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2cc(F)c(O)c(I)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
3′-Fluoro-4′-hydroxy-1,1′-biphenyl-4-carbonitrile (320 mg, 1.50 mmol) was dissolved into DMF (7 mL) and treated with N-iodosuccinimide (360 mg, 1.60 mmol). The solution was stirred at room temperature overnight. Then the mixture was poured into an aqueous mixture of Na2SO3 and Na2CO3, adjusted to pH 9 with aqueous potassium dihydrogen phosphate, and extracted with ether. The combined organic phases were dried (Na2SO4) and concentrated to provide the title compound as a pinkish solid (100% yield). MS (ESI APCI negative ion detection) m/z 338 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([OH:24])=O)[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].[CH3:43][N:44](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.CN>CN(C=O)C.C1COCC1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:36][CH2:37][CH:38]([CH3:41])[CH2:39][CH2:40]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:44][CH3:43])=[O:24])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(C)c(-c2nc(N3CCC(N4CCC(C)CC4)CC3)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.3 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and methylamine (41.3 uL, 0.0825 mmol, 2M soln in THF). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (7.2 mg, 22%). LC-MS m/z 587 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4](Cl)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:30][N:31](C=O)[CH3:32]>>[NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4]([N:31]([CH3:32])[CH3:30])[CH:3]=1
Reactant: CN(C)C=O
Reactant: Nc1cc(Cl)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(C)c1cc(N)c([N+](=O)[O-])cc1C(=O)Nc1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution 4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide (1 mmol; see Example 157) in DMF (1 mL) was added with of 10% aqueous K2CO3 solution (0.25 mL). The mixture was then subjected to microwave at 80° C. for 60 min. The contents were cooled to RT and poured into ice-cold water (20 L). The solid formed was collected by filtration, washed with water, and dried in vacuo to provide 4-amino-2-dimethylamino-N-(1H-indazol-6-yl)-5-nitrobenzamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Cu](C#N)[C:12]#[N:13]>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:9][CH3:10])[C:12]#[N:13]
Reactant: N#C[Cu]C#N
Reactant: COc1ccc(Br)cc1F
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C#N)cc1F
Temperature: 25 °C
Yield: 78 %

Procedure:
20 g of the 2-fluoro-4-bromoanisole thus obtained and 9.8 g of copper cyanide were dissolved in 100 ml of dimethyl formamide and heated under reflux for ten hours. To the reaction mixture, was added an aqueous solution of 20 g of ferric chloride in 100 ml of water. The reaction mixture was allowed to cool to room temperature and the reaction product was extracted with toluene. The organic layer was successively washed with water, a saturated aqueous solution of sodium carbonate and a saturated aqueous solution of common salt. Then the organic layer was separated. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=10:1) and further recrystallized from ethanol. Thus 10.0 g of 3-fluoro-4-methoxybenzonitrile was obtained. Yield: 68%.
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(C)(C)C.C([CH2:14][NH2:15])O.C=O.P(=O)(O)(O)O>C(O)C.O>[OH:11][C:8]1[CH:7]=[CH:6][CH:5]=[CH:10][C:9]=1[CH2:14][NH2:15]
Reactant: NCCO
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: C=O
Agent: O=P(O)(O)O
Solvent: CCO
Solvent: O
Product: NCc1ccccc1O

Procedure:
An o-hydroxybenzylamine compound of the present invention composition was prepared according to the procedure of Example 1, except that 50 g of 4-t-butylphenol was employed in place of the Bisphenol-A, 20.1 g of ethanolamine was employed in place of the 2-(methylamino)ethanol, and that heating of the reactants was only begun after the formaldehyde addition was completed. A 0.5 g sample of the product was dissolved in 500 ml of ethanol/water (1:4 by volume) and the pH of the solution was adjusted to 3.0 with phosphoric acid.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]([CH2:16][CH2:17][O:18]C(=O)C)[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)(=O)C.C[O-].[Na+].C(O)(=O)C>CN(C)C=O.CO>[OH:4][CH2:5][CH2:6][N:7]([CH2:16][CH2:17][OH:18])[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1
Reactant: CC(=O)OCCN(CCOC(C)=O)c1ccc(C=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=Cc1ccc(N(CCO)CCO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
To a solution of 293 g of 4-di-(2-acetoxyethyl) aminobenzaldehyde (see under Example 2b) in 500 ml of dimethyl formamide was added a solution of 54 g of sodium methanolate in 500 ml of methanol. After stirring for 30 minutes at room temperature the reaction mixture was neutralized with acetic acid and concentrated to a small volume. The residue was taken up in 500 ml of water and 500 ml of ethyl acetate. The water layer was separated and extracted six times, each time with a portion of 500 ml of ethyl acetate. The combined organic layers were dried on magnesium sulphate and evaporated. The residue was crystallized from 500 ml of ethyl acetate to yield 156 g of 4-di(2-hydroxyethyl)aminobenzaldehyde with a melting point of 63°-64° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:12][C:13](=[O:15])[CH3:14]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CC(=O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)CSc1ccc(Br)cc1
Reaction time: 0.75 h
Yield: 104.5 %

Procedure:
To a stirred solution of 4-bromothiophenol (5.09 g, 26.9 mmol) in NaOH (1.08 g, 26.9 mmol) and water (32 ml) was added chloroacetone (2.17 ml, 27.3 mmol) and the mixture was stirred under nitrogen for 45min before extracting with ether, washing with water, drying (Na2SO4) and evaporating in vacuo, leaving 6.89 g (100%) of the title compound as a white solid, δ (CDCl3) 2.27 (3H, s), 3.65 (2H, s), 7.20 (2H, d, J=8.5 Hz), 7.41 (2H, d, J=8.5 Hz).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].N1C=CC=CC=1.[OH:13][C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20](=[O:22])[CH:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]=2[CH:29]=1>ClCCl>[O:22]=[C:20]1[CH:19]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:18]2[CH:29]=[C:14]([O:13][C:1](=[O:5])[C:2]([Cl:4])=[O:3])[CH:15]=[CH:16][C:17]=2[O:21]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C1Oc2ccc(O)cc2C1c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cl)C(=O)Oc1ccc2c(c1)C(c1ccccc1)C(=O)O2

Procedure:
Oxalyl chloride (17.5 parts) and pyridine (0.5 parts) were added to a suspension of 5-hydroxy-2-oxo-3-phenyl-2,3-dihydrobenzfuran (22.6 parts) in dichloromethane (200 parts). After six hours reflux, chloro-oxo-acetic acid 2-oxo-3-phenyl-2,3-dihydro-benzofuran-5-yl ester was isolated and phenol (9.9 parts) added and the mixture refluxed for eighteen hours. Removal of the solvent gave the crude product oxalic acid (2-oxo-3-phenyl-2,3-dihydro-benzofuran-5-yl)ester phenyl ester (33.3 parts; 89%). Trituration in methanol and recrystallisation from ethyl acetate gave a pure product. Analysis C,70.4; H,3.7; C22H13O6 requires C,70.8; H,3.5%. M.pt.134° C., 1H and 13Cnmr gave spectra consistent with structure.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:38][C:39]3[CH:44]=[C:43]([CH3:45])[C:42]([OH:46])=[C:41]([CH3:47])[CH:40]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:48]=[CH:49][CH:50]=[CH:51][C:4]=2[NH:3]1.O[CH2:53][C:54]([N:56]([CH3:58])[CH3:57])=[O:55]>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:38][C:39]3[CH:44]=[C:43]([CH3:45])[C:42]([OH:46])=[C:41]([CH3:47])[CH:40]=3)[C:19]([N:21]3[CH2:22][CH2:23][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][C:35]([O:37][CH2:53][C:54](=[O:55])[N:56]([CH3:58])[CH3:57])=[O:36])[CH2:29][CH2:28]4)[CH2:25][CH2:26]3)=[O:20])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:48]=[CH:49][CH:50]=[CH:51][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CCC(=O)O)CC3)CC2)cc(C)c1O
Reactant: CN(C)C(=O)CO
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CCC(=O)OCC(=O)N(C)C)CC3)CC2)cc(C)c1O

Procedure:
Prepared analogously to Example 1i from 100 mg (0.14 mmol) (R)-2-[1′-(2-carboxy-ethyl)-4,4′-bipiperidinyl-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 16 mg (0.16 mmol) 2-hydroxy-N,N-dimethyl-acetamide.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][N:5]1[CH:9]=[C:8]([N:10]2[C:22]3[C:21]4[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=4[N:15]=[CH:14][C:13]=3[N:12]([CH3:24])[C:11]2=[O:25])[C:7]([CH3:26])=[N:6]1.[N:28]1([C:33]2[N:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][N:34]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH3:26][C:7]1[C:8]([N:10]2[C:22]3[C:21]4[CH:20]=[C:19]([C:36]5[CH:37]=[N:38][C:33]([N:28]6[CH2:29][CH2:30][CH2:31][CH2:32]6)=[N:34][CH:35]=5)[CH:18]=[CH:17][C:16]=4[N:15]=[CH:14][C:13]=3[N:12]([CH3:24])[C:11]2=[O:25])=[CH:9][N:5]([CH2:4][C:3]([OH:2])=[O:27])[N:6]=1
Reactant: COC(=O)Cn1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)c(C)n1
Reactant: CC1(C)OB(c2cnc(N3CCCC3)nc2)OC1(C)C
Product: Cc1nn(CC(=O)O)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc(N5CCCC5)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using [4-(8-bromo-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-3-methyl-pyrazol-1-yl]-acetic acid methyl ester (stage 247.1.2) and 2-(pyrrolidin-1-yl)pyrimidine-5-boronic acid pinacol ester (Frontier Scientific, Logan, USA) to give the title compound as a yellow hydrochloride salt after evaporation of the fractions containing pure product and exchange of the trifluoroacetate to the chlorure. (HPLC: tR 2.29 min (Method A); M+H=485, M−H=483 MS-ES)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:20]([C:32]#[N:33])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+].[ClH:51]>C(O)C.O1CCOCC1>[ClH:51].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:20]([C:32]#[N:33])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CCCCCCCOc1ccc(CCC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: CCO
Product: CCCCCCCOc1ccc(CCC(N)(CO)CO)cc1C#N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Compound 5-1 (255 mg) was dissolved in ethanol (2 ml), p-toluenesulfonic acid (19 mg) was added, and the mixture was stirred at room temperature for 4 hr. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give an oil. To the oil was added dioxane containing hydrogen chloride (4 mol/l), and the mixture was stirred at room temperature for 3 hr. The precipitate was collected by filtration and dried to give the object product (45 mg) as a white powder.
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[CH:27]=[C:26]([C:28]([NH:30][C@@H:31]([C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][CH:34]=2)[CH3:32])=[O:29])[CH:25]=[C:24]([Cl:43])[C:6]=1[C:7]([NH:9][C@H:10]([C:20]([O:22]C)=[O:21])[CH2:11][NH:12][C:13]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)=[O:14])=[O:8]>O.O1CCCC1.CO>[Cl:4][C:5]1[CH:27]=[C:26]([C:28]([NH:30][C@@H:31]([C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][CH:34]=2)[CH3:32])=[O:29])[CH:25]=[C:24]([Cl:43])[C:6]=1[C:7]([NH:9][C@H:10]([C:20]([OH:22])=[O:21])[CH2:11][NH:12][C:13]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)=[O:14])=[O:8]
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1c(Cl)cc(C(=O)N[C@H](C)c2cccc3ccccc23)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@@H](NC(=O)c1cc(Cl)c(C(=O)N[C@@H](CNC(=O)c2cccs2)C(=O)O)c(Cl)c1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
A solution of lithium hydroxide monohydrate (100 mg, 2.38 mmol) in water (5 mL) was added to a solution of N-[2,6-dichloro-4-[[[(1R)-1-(1-naphthalenyl)ethyl]amino]carbonyl]benzoyl]-3-[(thiophene-2-carbonyl)amino]-L-alanine, methyl ester (260 mg, 0.434 mmol) in tetrahydrofuran (15 mL) and methanol (5 mL), and the resulting mixture was stirred at room temperature overnight. The solution was evaporated, and the residue was partitioned between ethyl acetate (40 mL) and 1 M HCl (10 mL). The organic layer was evaporated and the residue was dissolved in methanol (˜1 mL), purified by HPLC, and lyophilized to give N-[2,6-dichloro-4-[[[(1R)-1-(1-naphthalenyl)ethyl]amino]carbonyl]benzoyl]-3-[(thiophene-2-carbonyl)amino]-L-alanine (170 mg, 67%).
Reaction SMILES: [C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[N+]([O-])(O)=O.[N+]([O-])([O-])=O.[Ag+:23]>C(OCCCC)(=O)C>[C:1]([O-:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Ag+:23]
Reactant: CCCCCCCCCCCC(=O)O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O=[N+]([O-])O
Solvent: CCCCOC(C)=O
Product: CCCCCCCCCCCC(=O)[O-]

Procedure:
A solution of 11g of lauric acid in 100ml of butyl acetate was maintained at 10° C, and with stirring with a stirrer 100ml of a dilute aqueous solution of nitric acid (having a pH of 2.0 at 25° C) was mixed with the above solution. With continued stirring, 50ml of an aqueous solution (cooled to 0° C) of a silver nitrate.ammonium complex salt containing 8.5g of silver nitrate was added over the course of 1 minute to allow the lauric acid to react with the silver ion. Silver laurate crystals were obtained in the form of spindles each of which measured about 1 micron along its long side and about 0.05 micron along its short side. The silver salt obtained was washed with water, and then with methanol, and 3.0g of polyvinyl butyral and 20ml of isopropyl alcohol, both based on 2.7g of the silver laurate, were added. The mixture was processed in a ball mill to form a polymer dispersion of the silver salt.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([Cl:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].O(C(C)(C)C)[K].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[C:5]([Cl:12])[CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1ccc2cccc(Cl)c2n1
Agent: [Pd]
Agent: CC(C)(C)O[K]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc3cccc(Cl)c3n2)CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a degassed solution of 2,8-dichloro-quinoline (3.00 g, 15.15 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (3.64 g, 18.18 mmol, 1.2 equiv; commercially available) in toluene (35 mL) was added KOtert-Bu (2.38 g, 21.21 mmol, 1.4 equiv), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (0.38 g, 0.61 mmol, 0.04 equiv) and tris(dibenzylideneacetone)-dipalladium(0) (0.31 g, 0.30 mmol, 0.02 equiv). The reaction mixture was stirred at 80° C. for 18 h, concentrated by evaporation under reduced pressure and the residue purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane (+1% triethylamine)/ethyl acetate providing 1.73 g (31%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.37-1.51 (m, 2H), 1.48 (s, 9H), 2.17-2.22 (m, 2H), 2.96-3.04 (m, 2H), 4.07-4.17 (m, 3H), 4.76 (d, J=7.0 Hz, 1H), 6.64 (d, H=8.9 Hz, 1H), 7.11 (t, J=7.8 Hz, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.80 (d, J=8.9 Hz, 1H). MS (ISP): 362.5 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.[K+].[CH3:14][O:15][C:16](=[O:21])[CH2:17]C([O-])=O>>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](=[O:12])[CH2:17][C:16]([O:15][CH3:14])=[O:21]
Reactant: Cc1ccc(CC(=O)O)c(F)c1
Reactant: COC(=O)CC(=O)[O-]
Agent: [K+]
Product: COC(=O)CC(=O)Cc1ccc(C)cc1F

Procedure:
The title compound was prepared from 2-(2-fluoro-4-methylphenyl)acetic acid and 3-methoxy-3-oxopropanoic acid potassium salt according to the procedure for the preparation of Example 170, part A. 1H NMR (300 MHz, CDCl3): δ 2.35 (3H, s), 3.52 (2H, s), 3.74 (3H, s), 3.83 (2H, s), 6.89-6.95 (2H, m), 7.05-7.08 (1H, m).
Reaction SMILES: C1([I:7](OC(=O)C(F)(F)F)OC(=O)C(F)(F)F)C=CC=CC=1.[CH3:22][N:23]1[C:27]2[N:28]=[N:29][CH:30]=[C:31]([OH:32])[C:26]=2[C:25]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:24]1.II.N1C=CC=CC=1>C(Cl)Cl>[I:7][C:30]1[N:29]=[N:28][C:27]2[N:23]([CH3:22])[N:24]=[C:25]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:26]=2[C:31]=1[OH:32]
Reactant: Cn1nc(-c2ccccc2)c2c(O)cnnc21
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Agent: II
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1nc(-c2ccccc2)c2c(O)c(I)nnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 105.7 %

Procedure:
Phenyl[bis(2,2,2-trifluoroacetoxy)]-λ3-iodane (190 mg, 0.43 mmol) was added to a suspension of 1-methyl-3-phenyl-pyrazolo[3,4-c]pyridazin-4-ol (166 mg, 0.73 mmol) in CH2Cl2 (3.7 mL), followed by the addition of iodine (111 mg, 0.43 mmol) and pyridine (71 μL). The reaction mixture was stirred at room temperature for 16 h, then filtered. The collected solid was washed with CH2Cl2 and dried, to yield the title compound (160 mg).
Reaction SMILES: [CH:1]1([C:4](=O)/[CH:5]=[CH:6]/N(C)C)[CH2:3][CH2:2]1.[C:11]1([NH:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[CH:1]1([C:4]2[CH:5]=[CH:6][N:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:18]=2)[CH2:3][CH2:2]1
Reactant: NNc1ccccc1
Reactant: CN(C)/C=C/C(=O)C1CC1
Solvent: CCO
Product: c1ccc(-n2ccc(C3CC3)n2)cc1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
(2E)-1-cyclopropyl-3-(dimethylamino)prop-2-en-1-one (327 mg, 2.35 mmol) and phenylhydrazine (0.35 ml, 3.5 mmol) were added to ethanol (5 ml). The reaction mixture was heated to 150° C. in the Biotage Initiator Series microwave reactor. After 30 minutes, the reaction mixture was cooled and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/hexanes gradient) to afford 3-cyclopropyl-1-phenyl-1H-pyrazole (faster eluting isomer) and 5-cyclopropyl-1-phenyl-1H-pyrazole (slower eluting isomer).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([F:13])[CH2:11][CH2:10][CH2:9][NH:8][C:7]1=[O:12])=[O:5])[CH3:2]>C(O)C>[F:13][C@@:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10][CH2:9][NH:8][C:7]1=[O:12]
Reactant: CCOC(=O)C1(F)CCCNC1=O
Solvent: CCO
Product: CCOC(=O)[C@]1(F)CCCNC1=O

Procedure:
Samples were prepared in batches according to the following method: ethyl-3-fluoro-2-oxo-3-piperidinecarboxylate (25 g) was dissolved in ethanol (450 ml) with gentle heating and sonication. The solution was then filtered through a Pall Acrodisc 37 mm syringe filter with 1 μm glass fibre membrane to remove fines and undissolved material. The filtered solution was adjusted to a total volume of 500 ml with ethanol to give a solution with nominal concentration of 50 mg/mL.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>O.CN(C)C=O.C1C=CC=CC=1>[CH3:3][S:4]([NH:7][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:6])=[O:5]
Reactant: CCOC(=O)CCCCCCBr
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCNS(C)(=O)=O
Temperature: 25 °C

Procedure:
A stirred suspension of sodium hydride (57%) (2.33 g., 0.055 mole) in a solvent mixture of benzene (50 ml.) and dimethylformamide (50 ml.) is treated, over 30 minutes with methanesulfonamide (4.75 g., 0.055 mole). This mixture is heated on the steam bath for 1.5 hours, then cooled to room temperature. At this temperature is added ethyl 7-bromoheptanoate (13 g., 0.055 mole) and the reaction is heated at 90° C. for twenty hours. The reaction is poured into water (200 ml.), neutralized with hydrochloric acid and extracted with ethyl acetate (2 × 100 ml.). The ethyl acetate layer is washed with brine, dried over sodium sulfate, then concentrated in vacuo. The yield of ethyl 7-(methanesulfonamido)heptanoate is 7.1 g. (51%) boiling 165°-168°/0.1 mm.