Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[CH2:8]=[O:9]>>[OH:9][CH2:8][CH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1cnccn1
Reactant: C=O
Product: OCCc1cnccn1
Yield: 31.5 %

Procedure:
A mixture of 90.0 g (956 mmol) of 2-methylpyrazine and 6.4 g (212 mmol) of paraformaldehyde was heated in a stainless steel autoclave at 165° C. for 5 hours, The residue was distilled under iced aspirator pressure (ca. 10 mmHg) to yield 8.28 g (32%) of a light pink oil.
Reaction SMILES: N[C:2]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].C(O)C.N([O-])=O.[Na+]>Cl.O>[Br:18][C:16]1[CH:15]=[C:14]2[C:3]([C:4](=[O:5])[NH:6][N:7]2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:2][CH:17]=1
Reactant: Nc1cc(Br)ccc1C(=O)NNc1ccccc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=c1[nH]n(-c2ccccc2)c2cc(Br)ccc12
Temperature: 76 °C

Procedure:
Into a 100-mL 3-necked round-bottom flask, was placed a solution of 2-amino-4-bromo-N′-phenylbenzohydrazide (4 g, 13.07 mmol, 1.00 equiv) in 1N HCl:Ethanol=1:1 (40 mL). The resulting solution was heated to 76° C. The solid dissolved to yield red solution. To the resulting mixture was then added a solution of NaNO2 (2.7 g, 39.13 mmol, 3.00 equiv) in water (5 mL) dropwise with stirring at 76° C. The resulting solution was stirred for 1 h at 76° C. in an oil bath. The resulting mixture was cooled to 20° C. with a water bath. The solids were collected by filtration, washed with water (2×40 mL), then dried in an oven under reduced pressure to yield 6-bromo-1-phenyl-1,2-dihydroindazol-3-one as a red solid. MS: 288 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11](=O)[NH:10][C:9]([CH2:14][CH2:15][CH2:16][N:17]1[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]1=[O:27])=[CH:8]2.O=P(Cl)(Cl)[Cl:30]>CC#N>[Cl:30][C:11]1[C:12]2[C:7](=[CH:6][CH:5]=[N:4][C:3]=2[O:2][CH3:1])[CH:8]=[C:9]([CH2:14][CH2:15][CH2:16][N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:27])[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1nccc2cc(CCCN3C(=O)c4ccccc4C3=O)[nH]c(=O)c12
Solvent: CC#N
Product: COc1nccc2cc(CCCN3C(=O)c4ccccc4C3=O)nc(Cl)c12

Procedure:
2-(3-(8-Methoxy-1-oxo-1,2-dihydro-2,7-naphthyridin-3-yl)propyl)isoindoline-1,3-dione (200 mg, 0.55 mmol) is dissolved in CH3CN (2 mL) and POCl3 (59 uL, 0.64 mmol) The mixture is stirred at 80° C. for 3 hours. POCl3 is removed and neutralized with sat. NaHCO3. The compound is extracted with CHCl3 and the organic layer is dried (Na2SO4) and evaporated to yield the crude compound, which is used in the next step without any further purification. MS m/z 382.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH3:23][C:24]1([CH3:27])[CH2:26][O:25]1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24]([OH:25])([CH3:27])[CH3:26])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: CC1(C)CO1
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCNCC3)cn2)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cn1cc(Br)cc(Nc2ccc(N3CCN(CC(C)(C)O)CC3)cn2)c1=O
Temperature: 110 °C

Procedure:
A sealed tube equipped with a magnetic stirrer was charged with 5-bromo-1-methyl-3-(5-(piperazin-1-yl)pyridin-2-ylamino)pyridin-2(1H)-one 101j (500 mg, 1.37 mmol), 2,2-dimethyloxirane (990 mg, 13.7 mmol), Cs2CO3 (1.3 g, 4.11 mmol), and CH3CN (15 mL). After three cycles of vacuum/argon flush, the mixture was heated at 110° C. for 15 h. It was then filtered and the filtrate was evaporated in vacuum. Crude 120a thus obtained was used in the next step without further purification (460 mg, 77%). LCMS: [M+H]+ 437.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1>>[CH:11]1[C:12]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: COc1ccc(Br)cc1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Product: COc1ccc(C2(O)CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)cc1
Yield: 72 %

Procedure:
Using a procedure similar to that described in example except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing 4-bromoanisole, the hydrochloride salt of the title compound was formed in 72% yield as a white solid, mp 228°-231° C. elemental Analysis for C28H29 NO2.HCl: Calculated: C, 75.07; H, 6.75; N, 3.13 Found: C, 74.93; H, 6.74; N, 3.14
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O[CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[C:9]([O:12][CH2:48][CH2:49][N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15]
Reactant: N#Cc1cnc2cc(F)c(O)cc2c1Cl
Reactant: OCCN1CCOCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: N#Cc1cnc2cc(F)c(OCCN3CCOCC3)cc2c1Cl
Yield: 57 %

Procedure:
Following the procedure used to prepare Reference Example 14, reaction of 4-chloro-7-fluoro-6-hydroxy-3-quinolinecarbonitrile with triphenyl phosphine, diethyl azodicarboxylate and 4-(2-hydroxyethyl)morpholine provides 4-chloro-7-fluoro-6-(2-morpholin-4-ylethoxy)-3-quinolinecarbonitrile in 57% yield. An analytical sample is obtained by preparative thin layer chromatography eluting with 1% methanol in ethyl acetate, mp 163-164° C.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[N:14]([O:16][O-])=[O:15]>P([O-])([O-])([O-])=O>[N+:14]([NH:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)([O-:16])=[O:15]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: O=NO[O-]
Agent: O=P([O-])([O-])[O-]
Product: O=C(O)[C@H](Cc1ccc(O)cc1)N[N+](=O)[O-]

Procedure:
Nitration of L-tyrosine: Peroxynitrite (0.44 μmol) was reacted with 0.16 μmol of L-tyrosine in 2 mL phosphate buffer solution, pH 7.4 at T=24° C. for 5 min. The concentration of such formed nitrotyrosine was estimated by recording the 438 nm absorbance (ε=4200 M−1cm−1) of basified solutions (via the addition of 0.2 ml of 7.8 M NaOH). The same experiments were repeated in the presence of either 0.1 μmol 1-Fe or 1-Mn.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([CH2:19][CH2:20][CH2:21][CH3:22])[C:4](N1[C@@H](CC2C=CC=CC=2)COC1=O)=[O:5].[OH:23]O.O.[OH-].[Li+]>C1COCC1.O.O>[OH:1][CH2:2][C@@H:3]([CH2:19][CH2:20][CH2:21][CH3:22])[C:4]([OH:5])=[O:23]
Reactant: CCCC[C@H](CO)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCC[C@H](CO)C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 107.2 %

Procedure:
To a 2000 mL roundbottom flask was added (4S)-3-[(2R)-2-(hydroxymethyl)hexanoyl]-4-(phenylmethyl)-1,3-oxazolidin-2-one (4) (82 g, 0.268 mol) in THF/water (4:1, 750 mL). The solution was cooled to 0° C. and H2O2 (130 mL, 1.07 mol) was added dropwise, followed by lithium hydroxide monohydrate (22.58 g, 0.537 mol) in water (130 mL). The reaction mixture was warmed up to rt and stirred overnight. THF was removed under vacuum, and the aqueous solution was washed with ethyl acetate. The aqueous solution was then acidified to pH ˜3.0 and extracted with ethyl acetate. The extracts were dried (Na2SO4), filtered and concentrated to provide the title compound (42 g, 107%). LCMS: (2M+H)+: 313.2.
Reaction SMILES: [N+:1]1([O-:10])[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:23][C:24]1[CH:25]=[C:26]([NH2:32])[C:27]([NH2:31])=[CH:28][C:29]=1[Cl:30]>CN(C)C=O.ClCCl>[NH2:32][C:26]1[CH:25]=[C:24]([Cl:23])[C:29]([Cl:30])=[CH:28][C:27]=1[NH:31][C:7]([C:4]1[CH:3]=[CH:2][N+:1]([O-:10])=[CH:6][CH:5]=1)=[O:9]
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: O=C(O)c1cc[n+]([O-])cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1cc(Cl)c(Cl)cc1NC(=O)c1cc[n+]([O-])cc1
Reaction time: 4 h
Yield: 16.4 %

Procedure:
A suspension of 4-pyridinecarboxylic acid-1-oxide (2.84 g, 20.4 mmol) and 1,1'-carbonyldiimidazole (3.64 g, 22.4 mmol) in dry dimethylformamide (50 ml) was stirred for 4 hours under an air-lock and the resulting solution added dropwise over 1 hour to a stirred solution of 4,5-dichloro-1,2-benzenediamine (7.23 g, 40.8 mmol) in dichloromethane (50 ml) under air lock. After 2.5 days, the mixture was evaporated in vacuo and the residue purified by chromatography [SiO2 ; dichloromethane-methanoltriethylamine (100:3:1)]. Recrystallisation from ethanol-methanol gave the title compound (1.00 g), m.p. >300°. The compound exhibited infra-red spectral bands at 859, 1182, 1260, 1534, 1671, 3253, 3335 and 3417 cm-1. The NMR spectrum of the compound in DMSO-d6 exhibited the following signals: (δ in ppm from TMS) broad 2 proton signal at 5.5; 1 proton singlet at 6.97; 1 proton singlet at 7.42; 2 proton doublet (J7 Hz) at 7.96; 2 proton doublet (J7 Hz) at 8.37 and broad 1 proton singlet at 9.9.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:8]2[O:12][C:11](=[O:13])[CH:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([O:24][CH2:25]C)=[O:23])=[CH:16][CH:15]=3)[C:9]=2[CH:27]=1)([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([C:5]1[CH:6]=[C:7]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:8]2[O:12][C:11](=[O:13])[CH:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=3)[C:9]=2[CH:27]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)COc1ccc(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)cc1
Solvent: CO
Product: COC(=O)COc1ccc(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)cc1
Yield: 61.9 %

Procedure:
A mixture of 5.0 g (11.8 mmol) of 5,7-di-tert-butyl-3-(4-ethoxycarbonylmethoxyphenyl)benzofuran-2-one (Compound (113), Example 6) and 2 g of strong acidic ion exchanger (Dowex) in 50 ml of methanol is refluxed for 4 hours. The reaction mixture is filtered, and the filtrate is concentrated on a vacuum rotary evaporator. Crystallisation of the residue from ligroin gives 3.0 g (62%) of 5,7-di-tert-butyl-3-(4-methoxycarbonylmethoxyphenyl)benzofuran-2-one, melting point 115°-117° C. (Compound 115), Table 1).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:9][C:10]1[C:18]2[C:13](=[N:14][C:15]([CH3:21])=[CH:16][C:17]=2[CH:19]=[O:20])[S:12][C:11]=1[C:22]([NH2:24])=[O:23].[NH4+].[Cl-]>C1COCC1>[NH2:9][C:10]1[C:18]2[C:13](=[N:14][C:15]([CH3:21])=[CH:16][C:17]=2[CH:19]([OH:20])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[S:12][C:11]=1[C:22]([NH2:24])=[O:23]
Reactant: Br[Mg]c1ccccc1
Reactant: Cc1cc(C=O)c2c(N)c(C(N)=O)sc2n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(C(O)c2ccccc2)c2c(N)c(C(N)=O)sc2n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 314 mg CeCl3 in 3 mL dry THF at −78° C. was added 0.425 mL 3M phenylmagnesium bromide and the reaction was stirred 1.5 h under Ar. Then, 50 mg of 3-amino-4-formyl-6-methyl-thieno[2,3-b]pyridine-2-carboxylic acid amide was added and the reaction was stirred 5 h in the cold and then allowed to warm to room temperature over 0.5 h. Aqueous NH4Cl was added and the reaction was filtered through diatomaceous earth, washing with EtOAc, and the aqueous phase was separated and extracted 3 times with more with EtOAc. The combined organics were dried, and concentrated in vacuo, and the product was purified on a prep plate developed with 5% MeOH—CH2Cl2. Starting material impurity was removed by dissolving the product in EtOAc with a trace MeOH and washing 3 times with aqueous NaHSO3. The organics were dried, concentrated in vacuo, re-dissolved in MeOH—CH2Cl2, filtered, concentrated and dried in vacuo at 60° C. to provide 8.2 mg of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])[C:5]([NH2:8])=[N:6][CH:7]=1.Cl[CH:20]([C:26]([CH3:28])=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:12]([F:18])=[CH:13][CH:14]=[CH:15][C:16]=2[F:17])[C:5]2[N:6]([C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:26]([CH3:28])[N:8]=2)[CH:7]=1
Reactant: Nc1ncc(Cl)cc1OCc1c(F)cccc1F
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(Cl)cn12

Procedure:
40 g of 5-chloro-3-[(2,6-difluorobenzyl)oxy]pyridine-2-amine (Example 14A; 147.8 mmol; 1 equivalent) were initially charged in 800 ml of ethanol, 30 g of powdered molecular sieve 3A and 128 g of ethyl 2-chloroacetoacetate (739 mmol, 5 equivalents) were added and the mixture was heated at reflux overnight. The reaction mixture was concentrated and the residue was taken up in ethyl acetate and filtered. The ethyl acetate phase was washed with water, dried, filtered and concentrated. This gave 44 g (78% of theory) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][CH:5]=1)([O-:3])=[O:2].II.[I:22]([O-])(=O)=O.[K+].O>S(=O)(=O)(O)O>[I:22][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][N:11]2[C:14](=[O:19])[C:15]([F:18])([F:16])[F:17]
Reactant: O=C(N1CCCc2ccc([N+](=O)[O-])cc21)C(F)(F)F
Reactant: [O-][I+2]([O-])[O-]
Agent: II
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=C(N1CCCc2c(I)cc([N+](=O)[O-])cc21)C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 36.2 %

Procedure:
A solution of 7-nitro-1-trifluoroacteyl-1,2,3,4-tetrahydroquinoline (D4) (2 g, 7.3 mmol) in conc. sulfuric acid (10 ml) was cooled to 0° C. and treated with iodine (1.11 μg, 4.4 mmol) and potassium iodate (0.625 g, 2.9 mmol). The reaction was stirred at 0° C. for 3 h then room temperature for 2 h. The reaction mixture was slowly poured into water (150 ml) at 0° C. and extracted with DCM. This was washed with aq. sodium metabisulfite and water then dried over MgSO4 and concentrated in vacuo to give the crude product. Purification by column chromatography gave the title compound (420 mg). 1H NMR (250 MHz, CDCl3) δ (ppm): 8.59 (m, 2H), 3.86 (m, 2H), 2.90 (t, 2H), 2.17 (m, 2H).
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12](=[S:14])[NH2:13])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:15]I>CC(C)=O>[CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]([S:14][CH3:15])=[NH:13])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCNc1nc[nH]c1C(N)=S
Reactant: CI
Solvent: CC(C)=O
Product: CCCCCNc1nc[nH]c1C(=N)SC
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.8 %

Procedure:
To a solution of 4-(pentylamino)-1H-imidazole-5-carbothioamide (1.0 g, 4.7 mmol) in acetone (40 mL) was added methyl iodide (0.80 g, 5.6 mmol) dropwise. The mixture was stirred at room temperature overnight. The solvent was removed and the residue was diluted with water and ethyl acetate. The organic layer was washed with water and brine, dried and concentrated to yield the crude product (1.2 g), which was used for next step without further purification. LCMS calculated for C10H19N4S (M+H): 227.1; found: 227.1.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH2:6][NH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:30])[C:14]=2[C:18](=[O:29])[NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][C:24]([F:28])([F:27])[CH2:23][CH2:22]2)[N:9]=1)C.O.[OH-].[Li+]>C1COCC1.O>[Cl:30][C:13]1[C:14]([C:18](=[O:29])[NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][C:24]([F:27])([F:28])[CH2:23][CH2:22]2)=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:31])=[O:3])[CH:17]=[CH:16]2
Reactant: CCOC(=O)CCNc1ccc2c(C(=O)NCC3CCC(F)(F)CC3)c(Cl)ccc2n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCNc1ccc2c(C(=O)NCC3CCC(F)(F)CC3)c(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.1 %

Procedure:
To a solution of 3-{6-Chloro-5-[(4,4-difluoro-cyclohexylmethyl)-carbamoyl]-quinolin-2-ylamino}-propionic acid ethyl ester (80 mg, 0.17 mmol, 1.00 eq) in THF (8.00 mL, 100 V) and Water (2.00 mL, 25 V) was added Lithium Hydroxide Monohydrate (14.72 mg, 0.35 mmol, 2.00 eq). The reaction mixture was stirred for overnight at room temperature. The reaction mixture was concentrated under vacuum. The aqueous solution was adjusted to pH 2 and then extracted with ethyl acetate and combined organic layer was collected and dried over anhydrous sodium sulphate, filtered, concentrated under vacuum. The crude was purified by preparative HPLC to afford the title compound (35 mg, 0.08 mmol, 45.3%) as a off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.69 (t, J=6.01 Hz, 1H), 7.60 (d, J=9.22 Hz, 1H), 7.46-7.52 (m, 2H), 7.31-7.33 (m, 1H), 6.84 (d, J=9.24 Hz, 1H), 3.57 (q, J=6.43 Hz, 2H), 3.22 (t, J=6.40 Hz, 2H), 2.54-2.57 (m, 2H), 2.03-2.00 (m, 2H), 1.72-1.89 (m, 5H), 1.22-1.31 (m, 2H). m/z: 426.0 [M+H]+
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]([C:5]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:8]2([CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH2:7][CH:6]=1)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][N:2]([CH3:27])[C:3]([C:5]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:8]2([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:7][CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)C1=CCC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)C1=CCC2(CCNCC2)c2ccccc21
Yield: 118.6 %

Procedure:
A solution of the dimethylamide (B2) (156 mg) in dichloromethane (5 ml) was treated with TFA (1 ml) for 1 h. After concentration and co-evaporation with acetonitrile, the residue was dissolved in dichloromethane, washed with a mixture of brine and 1 ml 6N NaOH, dried (Na2SO4), and concentrated to give N,N-dimethyl-2H-spiro[naphthalene-1,4′-piperidine]-4-carboxamide (B3) (135 mg). LC-MS: m/e=271.0 (M+H). Rt=1.30 min.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:17]([OH:19])=[O:18])=[CH:8][N:9]2[CH:14]2[CH2:16][CH2:15]2)=[CH:4][C:3]=1[F:21].[C@H:22]12[CH2:30][NH:29][CH2:28][C@@H:27]1[NH:26][CH2:25][CH2:24][O:23]2.C(N(CC)CC)C>C(#N)C>[C:12]([C:11]1[C:2]([C@:22]23[CH2:30][NH:29][CH2:28][C@@H:27]2[NH:26][CH2:25][CH2:24][O:23]3)=[C:3]([F:21])[CH:4]=[C:5]2[C:10]=1[N:9]([CH:14]1[CH2:16][CH2:15]1)[CH:8]=[C:7]([C:17]([OH:19])=[O:18])[C:6]2=[O:20])#[N:13]
Reactant: N#Cc1c(Cl)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: C1CO[C@H]2CNC[C@@H]2N1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1c([C@]23CNC[C@@H]2NCCO3)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
1.00 g (3.26 mmol) of 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid are stirred under argon at 40-45° C. for 25 hours with 501 mg (3.91 mmol) of (1S,6S)-2-oxa-5,8-diazabicyclo[4.3.0]nonane and 0.9 ml of triethylamine in 30 ml of acetonitrile. All volatile components are removed in vacuo and the residue is recrystallized from ethanol.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([CH3:7])[C@H:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1.N1C=CN=C1.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18]>ClCCl>[Si:21]([O:1][C@H:2]1[CH2:6][N:5]([CH3:7])[C@H:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C
Reaction time: 12 h

Procedure:
Methyl (2S,4R)-4-hydroxy-1-methyl-pyrrolidine-2-carboxylate 3b (6 g, 37 mmol) was dissolved in 100 mL of dichloromethane, followed by addition of imidazole (7.70 g, 113 mmol) and tert-butyl dimethylchlorosilane (6.80 g, 45 mmol) successively. After stirring for 12 hours, the reaction mixture was diluted with 100 mL of dichloromethane, washed with water (50 mL) and saturated brine (50 mL) successively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound methyl (2S,4R)-4-(tert-butyl(dimethyl)silyl)oxy-1-methyl-pyrrolidine-2-carboxylate 3c crude product as a colourless oil, which was directly used in the next step without purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[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](Br)=[CH:24][CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[C:41](B(O)O)=[CH:40][CH:39]=[N:38]1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:36])[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]([C:41]5[NH:37][N:38]=[CH:39][CH:40]=5)=[CH:24][CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccn[nH]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(Br)ccc4c3=O)cc2)CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(-c5ccn[nH]5)ccc4c3=O)cc2)CCC1
Temperature: 150 °C
Yield: 45 %

Procedure:
{1-[4-(7-Bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (81 mg, 0.15 mmol), 1H-pyrazole-5-boronic acid (22 mg, 0.2 mmol), tetrakis(triphenylphosphine)palladium (0) (17 mg, 0.015 mmol) and sodium carbonate (32 mg, 0.30 mmol) were suspended in DME (2 mL) and water (1 mL) in a microwave vial. The vial was sealed, evacuated and flushed twice with nitrogen. The mixture was heated in a microwave at 150° C. for 25 min. The resulting mixture was partitioned between ethyl acetate (40 mL) and water (20 mL) and the phases were separated. The organic layer was washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was subjected to flash chromatography (SiO2, 40% ethyl acetate in cyclohexane) to give the title compound as a pale brown oil (36 mg, 45%). LCMS (Method B): RT=4.82 min, [M+H]+=534.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][NH:12][CH2:13][CH:14]([C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][CH:19]=2)[CH2:15][CH:16]=[CH2:17])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1N=CN([C:30](N2C=NC=C2)=[O:31])C=1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:10][CH2:11][N:12]([CH2:13][CH:14]([C:18]3[CH:19]=[CH:20][C:21]([I:24])=[CH:22][CH:23]=3)[CH2:15][CH:16]=[CH2:17])[C:30]2=[O:31])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C=CCC(CNCCNc1cc(Cl)cc(Cl)c1)c1ccc(I)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCC(CN1CCN(c2cc(Cl)cc(Cl)c2)C1=O)c1ccc(I)cc1
Temperature: 100 °C
Yield: 31.5 %

Procedure:
To a stirred solution of N-(3,5-dichloro-phenyl)-N′-[2-(4-iodo-phenyl)-pent-4-enyl]-ethane-1,2-diamine (0.386 g, 0.81 mmol) in toluene (10 mL) was added CDI (0.18 g, 1.1 mmol, 1.4 eq). The mixture was heated to 100° C. for 16 h, then cooled to room temperature, diluted with EtOAc (25 mL) and washed twice with saturated aqueous NaCl (25 mL). The organic extracts were dried over sodium sulfate, filtered and concentrated by rotary evaporation to give a dark brown oil. The crude product was purified by flash column chromatography eluting with 10% EtOAc/hexanes to give 1-(3,5-dichloro-phenyl)-3-[2-(4-iodo-phenyl)-pent-4-enyl]-imidazolidin-2-one (0.128 g, 0.255 mmol, 30%) as a pale foam. 1H NMR (300 MHz, CDCl3): δ 7.74 (d, 2H), 7.54 (d, 2H), 7.20 (m, 3H), 5.75 (m, 1H), 5.10 (m, 2H), 3.74 (m, 3H), 3.38 (m, 2H), 3.22 (m, 1H), 3.08 (m, 1H), 2.50 (m, 2H).