Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[CH:10]=[CH:9][C:8]=1[F:30].Cl.Cl.[NH2:33][CH:34]1[CH2:37][NH:36][CH2:35]1.CN1CCCC1>C(O)C>[NH2:33][CH:34]1[CH2:37][N:36]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[CH:10]=[CH:9][C:8]([F:30])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:35]1
Reactant: NC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)ccc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)ccc1F
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 98.8 %

Procedure:
To 270 mg of N,N-dimethylformamide were added 55 mg of 1-(6-amino-5-fluoropyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 70 mg of 3-aminoazetidine dihydrochloride, and 80 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 15 minutes. After adding 0.3 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 62 mg of the title compound as a colorless powder.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[CH:3]2[CH2:7][CH2:8][CH:9]=[CH:10][CH:2]12.[CH3:12]C12CCCCC1C(=O)OC2=O>>[CH2:12]1[CH:10]2[CH:2]3[C:1](=[O:11])[O:6][C:4](=[O:5])[CH:3]3[CH:7]1[CH:8]=[CH:9]2
Reactant: O=C1OC(=O)C2CCC=CC12
Reactant: CC12CCCCC1C(=O)OC2=O
Product: O=C1OC(=O)C2C3C=CC(C3)C12

Procedure:
tetrahydrophthalic anhydride (referred to as THPA); and methylhexahydrophthalic anhydride (referred to as Me-HHPA).
Reaction SMILES: [N+:1]([C:4](=[CH2:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].[CH3:13][N:14]([CH3:18])[C:15](=[S:17])[S-:16].C[NH2+]C>C(=S)=S>[CH3:13][N:14]([CH3:18])[C:15](=[S:16])[S:17][CH:5]([CH:4]([N+:1]([O-:3])=[O:2])[CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=C(Cc1ccccc1)[N+](=O)[O-]
Reactant: CN(C)C(=S)[S-]
Agent: C[NH2+]C
Solvent: S=C=S
Product: CC(C(SC(=S)N(C)C)c1ccccc1)[N+](=O)[O-]

Procedure:
As in Example 17, reaction of (2-nitro-2-propenyl)benzene with dimethylammonium dimethyldithiocarbamate in the presence of carbon disulfide, gave α-(1-nitroethyl)benzyl dimethyldithiocarbamate melting at 92° C.-94° C. when recrystallized without heating from acetone-ethanol solution.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH2:12]([O:14][C:15](=[O:25])[CH2:16]P(OCC)(OCC)=O)[CH3:13].[Cl:26][C:27]1[N:31]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:29]([CH3:38])[C:28]=1[CH:39]=O>C1COCC1>[CH2:12]([O:14][C:15](=[O:25])[CH:16]=[CH:39][C:28]1[N:29]([CH3:38])[C:30]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[N:31][C:27]=1[Cl:26])[CH3:13]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cn1c(-c2ccccc2)nc(Cl)c1C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C=Cc1c(Cl)nc(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.72 ml of a 1.6 M solution of n-butyllithium in n-hexane (4.4 mmol) were added at 0° C. to a solution of 1.219 g (5.4 mmol) of diethylphosphonoacetic acid ethyl ester in 30 ml of dry THF. After stirring at 0° C. for 30 min, 0.8 g (3.8 mmol) of 5-chloro-3-methyl-2-phenyl-3H-imidazole-4-carbaldehyde in 10 ml of THF were added. The reaction mixture was allowed to stand overnight and then concentrated. The residue was taken up in 100 ml of ethyl acetate, and the solution washed three times with 30 ml each of a sodium hydrogencarbonate solution, dried with magnesium sulfate and evaporated. The obtained crude 3-(5-chloro-3-methyl-2-phenyl-3H-imidazol-4-yl)-acrylic acid ethyl ester was stirred in 5.4 ml of 1 N sodium hydroxide solution and 20 ml of tert-butanol at room temperature for 24 h. After concentration, 10 ml of water were added, and the mixture was acidified to pH=5 with hydrochloric acid. The mixture was stirred for 1 h, and the precipitated product was filtered off with suction and dried.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[C:30]([O:34][C:35](=[O:40])[NH:36][CH2:37][CH2:38][NH2:39])([CH3:33])([CH3:32])[CH3:31]>CC(O)=O>[C:30]([O:34][C:35](=[O:40])[NH:36][CH2:37][CH2:38][NH:39][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 106.9 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (60 mg, 0.16 mmol) and (2-amino-ethyl)-carbamic acid tert-butyl ester (75 mg, 0.47 mmol) was refluxed for 48 h. After cooling to r.t., AcOH (0.2 mL) was added, and the mixture was concentrated to dryness. The residue was dissolved in EtOAc and washed with 0.1 M HCl, saturated NaHCO3, and brine. The organic layer was dried over MgSO4 and concentrated to give 88 mg of the title compound as a pale yellow solid. MS: (+) m/z 515.30 (M+1).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:20][C:19]([C:22](Cl)=[O:23])=[CH:18][CH:17]=1>>[C:16]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:17]=[CH:18][C:19]([C:22]([N:6]2[CH2:7][CH2:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[O:23])=[CH:20][CH:21]=1
Reactant: c1ccc2c(c1)CCNc1ccccc1-2
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: O=C(c1ccc(-c2ccccc2)cc1)N1CCc2ccccc2-c2ccccc21

Procedure:
As described for Example 26, 6,7-dihydro-5H-dibenz[b,d]azepine is reacted with [1,1'-biphenyl]-4-carbonyl chloride to give the product as a solid.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:11])=[CH:6][C:5]=1[CH3:21].C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[OH-].[Li+]>O1CCCC1.CO.O>[OH:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][NH:12][C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:22])=[O:2])=[C:5]([CH3:21])[CH:6]=1)=[O:11]
Reactant: COC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1C
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)NCc2cccc(O)c2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 34 %

Procedure:
A solution of 4-(methoxycarbonyl)-3-methylbenzoic acid (Example 89; 4.83 g, 24.9 mmol) and triphenylphosphine (7.37 g, 28.1 mmol) in dichloromethane (100 mL) was cooled to ˜0° C. and N-chlorosuccinimide (3.75 g, 28.1 mmol) was added portionwise. The solution was allowed to warm to room temperature and stirred for 30 min. 3-Hydroxybenzylamine (Example 69; 4.00 g, 33.0 mmol) and diisopropylethylamine (4.00 g, 30.9 mmol) were added and the solution was allowed to stir at room temperature for 72 h. The solution was washed with 1N hydrochloric acid solution, water and brine (200 mL each), dried (MgSO4), filtered and evaporated to give a colorless solid (13.34 g) which contained 4-[[(3-hydroxybenzyl)amino]carbonyl]-2-methylbenzoic acid methyl ester and triphenylphosphine oxide. The solid was taken up in tetrahydrofuran/methanol (3:1; 200 mL) and a solution of lithium hydroxide monohydrate (4.00 g, 95.3 mmol) in water (50 mL) was added. The solution was stirred at room temperature for 4 h and then the solvent was evaporated under reduced pressure. The residual material was taken up in a mixture of 1N sodium hydroxide and diethyl ether (200 mL each) and the mixture was filtered to remove undissolved solids. The diethyl ether layer was discarded and the aqueous basic layer of the filtrate was acidified with conc. hydrochloric acid solution to ˜pH 1. The mixture was extracted with ethyl acetate (2×100 mL) and the combined organic layers were washed with brine (200 mL), dried (MgSO4), filtered and evaporated to give 4-[[(3-hydroxybenzyl)amino]carbonyl]-2-methylbenzoic acid as a colorless solid (2.40 g, 34% yield).
Reaction SMILES: OC[C:3]([CH2:8][OH:9])(CO)CO.C([CH:12]=[C:13]([CH3:20])[C:14]([O:16][N:17]=[C:18]=[O:19])=[O:15])C>>[C:14]([OH:16])(=[O:15])[C:13]([CH3:20])=[CH2:12].[C:14]([OH:16])(=[O:15])[C:13]([CH3:20])=[CH2:12].[C:14]([OH:16])(=[O:15])[C:13]([CH3:20])=[CH2:12].[C:14]([OH:16])(=[O:15])[C:13]([CH3:20])=[CH2:12].[NH2:17][C:18]([O:9][CH2:8][CH3:3])=[O:19]
Reactant: OCC(CO)(CO)CO
Reactant: CCC=C(C)C(=O)ON=C=O
Product: C=C(C)C(=O)O
Product: CCOC(N)=O

Procedure:
To 5000 g (0.31 mol) of dried macrotetrol (e.g., polycaprolactone, MW 16.000 g/mol, pentaerythritol initiated), 193.8 g (1.25 mol) of isocyanato ethylmethacrylate IEM (Karenz Moi) was added dropwise at 110° C. during 0.5 hour. The reaction was carried out at 110° C. until absorption by an isocyanate group at a wavelength of 2250 cm−1 in the infrared absorption spectrum was no longer observed in order to obtain an urethane tetramethacrylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=2[CH3:19])=[CH:5][CH:4]=1.OOS([O-])=O.[K+].[K+].[Br-:27]>C(#N)C.O>[Br:27][C:8]1[CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=2[CH3:19])[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)c1ccc(-c2ccc(OC)cc2)c(C)c1
Reactant: [Br-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc(-c2ccc(OC)c(Br)c2)c(C)c1
Reaction time: 2.5 h

Procedure:
To a solution of methyl 4′-methoxy-2-methylbiphenyl-4-carboxylate (71.5 g, 0.279 mol) in acetonitrile (1.43 L) and water (572 mL) was added oxone (180.1 g, 0.293 mol). Then a solution of KBr (38.2 g, 0.321 mol) in water (143 mL) was slowly added over 30 minutes. The reaction was stirred for 2.5 hours, then water (715 mL) was added and the mixture was left standing for 1 hour. The solids were filtered and washed as follows: with a solution of MeCN/water (1:1, 350 mL, twice), water (700 mL, twice, then 350 mL) and dried to afford methyl 3′-bromo-4′-methoxy-2-methylbiphenyl-4-carboxylate. 1H NMR (CDCl3, 400 MHz) δ 7.94 (s, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.53 (d, J=2.2 Hz, 1H), 7.3-7.2 (m, 2H), 6.97 (d, J=8.4 Hz, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: CO.[OH-].[Na+].[NH2:5][C:6]1[C:11]([C:12]2[O:16][N:15]=[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[CH:13]=2)=[CH:10][CH:9]=[CH:8][N:7]=1.Cl[CH2:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][N:28]=1>CN(C)C=O>[CH3:33][C:31]1[CH:30]=[CH:29][N:28]=[C:27]([CH2:26][O:24][C:21]2[CH:22]=[CH:23][C:18]([CH2:17][C:14]3[CH:13]=[C:12]([C:11]4[C:6]([NH2:5])=[N:7][CH:8]=[CH:9][CH:10]=4)[O:16][N:15]=3)=[CH:19][CH:20]=2)[CH:32]=1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Reactant: Cc1ccnc(CCl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccnc(COc2ccc(Cc3cc(-c4cccnc4N)on3)cc2)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 29.7 %

Procedure:
Methanol (3 mL) and 1 N aqueous sodium hydroxide solution (0.18 mL) were added to 4-(5-(2-amino-pyridine-3-yl)isoxazole-3-ylmethyl)-phenol (50 mg, 0.19 mmol) described in Manufacturing Example 5-1-1, which was then dissolved by irradiating ultrasonic wave. This solution was concentrated under a reduced pressure. To the resulting residue were added 2-chloromethyl-4-methyl-pyridine (31.8 mg, 0.22 mmol) described in Manufacturing Example 11-1-4 and N,N-dimethylformamide (2 mL), which was stirred for 10 minutes at 60° C. The reaction solution was partitioned into water and ethyl acetate. The organic layer was separated, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (21 mg, 30.2%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].CN(C)C=O.[F:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([N+:35]([O-:37])=[O:36])[CH:29]=1>O>[F:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:8][CH2:9][CH2:10][N:11]2[C:15](=[O:16])[C:14]3[C:13](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]2=[O:21])=[C:30]([N+:35]([O-:37])=[O:36])[CH:29]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: O=[N+]([O-])c1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCOc1ccc(F)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 4 h
Yield: 100.4 %

Procedure:
Potassium carbonate (10.8 g, 78.1 mmol) and N-(3-bromopropyl)phthalimide (12.1 g, 45.1 mmol) were added to a N,N-dimethylformamide (DMF) solution (80 ml) of 4-fluoro-2-nitrophenol (6.0 g, 38.2 mmol), and the mixture was stirred at 60° C. for 4 hours. After the reaction mixture was cooled to room temperature, water (200 ml) was added, and the reaction mixture was then cooled with ice. The precipitated insoluble matter was collected by filtration. After being washed with water (50 ml×3), the substance remaining in the filter was air-dried, giving 13.2 g of powdery pale yellow 2-[3-(4-fluoro-2-nitrophenoxy)propyl]isoindole-1,3-dione (yield: 100%).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[CH2:5][CH2:6][CH2:7][C:8]([O-:10])=[O:9].[Na+].F[C:20]1[CH:27]=[C:26]([O:28][CH2:29][C:30]2[CH:34]=[CH:33][S:32][CH:31]=2)[CH:25]=[CH:24][C:21]=1[C:22]#[N:23]>O1CCCC1>[C:22]([C:21]1[CH:24]=[CH:25][C:26]([O:28][CH2:29][C:30]2[CH:34]=[CH:33][S:32][CH:31]=2)=[CH:27][C:20]=1[O:3][CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])#[N:23]
Reactant: N#Cc1ccc(OCc2ccsc2)cc1F
Reactant: Cc1ccccc1C(O)CCCC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1C(CCCC(=O)O)Oc1cc(OCc2ccsc2)ccc1C#N
Temperature: 57.5 °C

Procedure:
To a stirred suspension of sodium hydride (0.69 g, 60% dispersion in mineral oil) in dry tetrahydrofuran (50 mL) is added a solution of sodium (RS)-5-hydroxy-5-(2-methylphenyl)pentanoate (1.23 g) in dry tetrahydrofuran (100 mL). The mixture is stirred at room temperature for 1.5 hours when 2-fluoro-4-(3-thienylmethoxy)benzonitrile (1.57 g) is added in one portion. The reaction mixture is heated at 55-60° C. for 18 hours and evaporated. The residue is dissolved in water (100 mL), the solution acidified to pH 1 with 1 N hydrochloric acid and the mixture extracted three times with ethyl acetate (100 mL). The combined extracts are washed with brine (100 mL), dried over magnesium sulphate and evaporated to give (RS)-5-[2-cyano-5-(3-thienylmethoxy)phenoxy]-5-(2-methylphenyl)pentanoic acid as a white waxy solid (0.4 g), mp.p.106-108° C. [Elemental analysis:- C,67.15; H,5.84; N,2.75; S,6.99%. Calculated for C24H23NO4S.0.5EtOAc:- C,66.66; H,4.66; N,6.48%].
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:17][C:18]1[CH:22]=[C:21]([CH2:23]Cl)[O:20][N:19]=1>CS(C)=O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:23][C:21]2[O:20][N:19]=[C:18]([CH3:17])[CH:22]=2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: Cc1cc(CCl)on1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(COc2ccc(Oc3ccccc3)cc2)on1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
At 10° to 20° C., 18.6 g of p-phenoxyphenol in 50 ml of dimethyl sulfoxide is dripped into 3.1 g of sodium hydride (85% strength in paraffin) in 100 ml of dimethyl sulfoxide. The mixture is stirred for 30 minutes at 50° C. and then 3-methyl-5-chloromethylisoxazole is dripped in at 15°-20° C. The mixture is worked up in the usual manner after 8 hours at 70° C. There is obtained 26.7 g of compound no. 31.25 of m.p. 48°-51° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([CH3:12])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH:13]1(Br)[CH2:16][CH2:15][CH2:14]1.[C:18](=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]([CH2:18][CH:13]2[CH2:16][CH2:15][CH2:14]2)[C:10](=[O:11])[CH3:12])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(=O)Cc1cccc(C#N)c1
Reactant: BrC1CCC1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(=O)C(CC1CCC1)c1cccc(C#N)c1
Temperature: 60 °C

Procedure:
To a solution of 1.45 g (9.07 mmol) of 1-(3-cyanophenyl)acetone in 18 mL acetonitrile, 1.1 mL (9.5 mmol) cyclobutyl bromide and 5.91 g (18.1 mmol) cesium carbonate were added. After heating the solution in a 60° C. bath overnight, it was cooled and filtered. The filtrate was partitioned between water and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried and concentrated. The residue was purified on a flash column using a gradient of 5-10% EtOAc/hexane to isolate the title compound. 1H NMR: (500 MHz, CDCl3): δ 1.5-2.2 (m, 9H), 2.13 (s, 3H), 3.64 (m, 1H), 7.4-7.7 (m, 4H)
Reaction SMILES: C([S:4][CH2:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([NH2:14])=[O:13])=[C:8]([Cl:17])[CH:7]=1)(=O)C.[OH-].[Na+]>CO.O>[Cl:17][C:8]1[CH:7]=[C:6]([CH2:5][SH:4])[CH:16]=[CH:15][C:9]=1[O:10][CH2:11][C:12]([NH2:14])=[O:13]
Reactant: CC(=O)SCc1ccc(OCC(N)=O)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC(=O)COc1ccc(CS)cc1Cl
Reaction time: 48 h

Procedure:
To a solution of the product from example 15 step c) (1.0 g) in methanol (50 ml) was added sodium hydroxide pellets (0.15 g) and the mixture stirred for 2 days. The mixture was diluted with water and the subtitle compound collected by filtration. (0.7 g).
Reaction SMILES: C([O:3][C:4]([CH:6](C(OCC)=O)[C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][C:10]([F:16])=[CH:9][N:8]=1)=O)C.C(OCC)(=O)CC(OCC)=O.NC1C(C(C(OCC)=O)C(OCC)=O)=NC=C(F)C=1>C(O)C.[Ni].O.Cl>[F:16][C:10]1[CH:11]=[C:12]2[C:7]([CH2:6][C:4](=[O:3])[NH:13]2)=[N:8][CH:9]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ncc(F)cc1[N+](=O)[O-]
Agent: [Ni]
Agent: CCOC(=O)C(C(=O)OCC)c1ncc(F)cc1N
Agent: Cl
Solvent: O
Solvent: CCOC(=O)CC(=O)OCC
Solvent: CCO
Product: O=C1Cc2ncc(F)cc2N1

Procedure:
The mixture of 2-bis(ethoxycarbonyl)methyl-5-fluoro-3-nitropyridine and diethyl malonate was dissolved in ethanol (100 mL) and added to a suspension of 50% Raney nickel in water (7.8 g) diluted with ethanol (150 mL). The mixture was hydrogenated in a Parr shaker at 3 atmospheres pressure overnight and then filtered through diatomaceous earth (Celite (trademark)) to remove the catalyst. The solvent was removed in vacuo to leave a mixture of 3-amino-2-bis(ethoxycarbonyl)methyl-5-fluoropyridine and diethyl malonate as an oil. The mixture containing 3-amino-2-bis(ethoxycarbonyl)methyl-5-fluropyridine and diethyl malonate was taken up in 6N HCl solution (280 mL) and heated at reflux for 3 hours. After removing the aqueous acid in vacuo, the residue was taken up in water and again concentrated to leave a solid. This was taken up in dry ethanol and concentrated two times to obtain the title compound as a light green solid (4.07 g) which was triturated with hot ethyl acetate and dried in the air. Although somewhat impure by NMR this material was used in directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH2:12])=[C:10]([NH:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH:18](Cl)(Cl)Cl>C(OC(OCC)OCC)C>[Cl:1][C:2]1[C:11]2[N:12]=[CH:18][N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: ClC(Cl)Cl
Reactant: CC(C)CNc1c(N)c(Cl)nc2ccccc12
Solvent: CCOC(OCC)OCC
Product: CC(C)Cn1cnc2c(Cl)nc3ccccc3c21
Temperature: 25 °C

Procedure:
A solution of 2-chloro-N4 -(2-methylpropyl)-3,4-quinolinediamine (3 g) in triethylorthoformate (2.8 g) was heated at 80° C. for 15 h. The resulting solution was cooled to ambient temperature and 20 mL of chloroform was added. The solution was washed with water. The product 4-chloro-1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinoline was obtained by concentrating the solution.
Reaction SMILES: C1(=O)OC(=O)C=C1.NC1C=CC=CC=1O.CN(C)C=O.[OH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29](=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=O>C1(C)C(C)=CC=CC=1.C1(C)C=CC=CC=1>[OH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[C:29](=[O:35])[CH:30]=[CH:31][C:32]1=[O:34]
Reactant: O=C(O)/C=C\C(=O)Nc1ccccc1O
Agent: Nc1ccccc1O
Agent: O=C1C=CC(=O)O1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: O=C1C=CC(=O)N1c1ccccc1O

Procedure:
A maleic anhydride copolymer and an aminophenol are heated in an organic solvent such as dimethylformamide to 0°-150° C., preferably 10°-100° C., more preferably 50°-100° C. for 1-20 hours to convert a portion or whole of the maleic anhydride units into N-(hydroxyphenyl)maleamic acid unit. To the reaction mixture is added a tertiary amine catalyst, and is further added an azeotropic agent (i.e., azeotropic solvent) such as toluene or xylene for removing water produced upon cyclization-dehydration reaction. The resulting mixture is then heated to 80°-200° C., preferably 100°-150° C., for 1-20 hours for performing a cyclization-dehydration reaction, to obtain the desired N-(hydroxyphenyl)maleimide copolymer.
Reaction SMILES: [CH3:1][C:2]([C:7]1[S:11][C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH2:15][CH2:16][CH3:17])=[N:9][N:8]=1)([CH3:6])[CH2:3][CH:4]=O.[CH:31]([NH2:34])([CH3:33])[CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(Cl)Cl>[CH:31]([NH:34][CH2:4][CH2:3][C:2]([C:7]1[S:11][C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH2:15][CH2:16][CH3:17])=[N:9][N:8]=1)([CH3:6])[CH3:1])([CH3:33])[CH3:32]
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)(C)CC=O)s1
Reactant: CC(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)(C)CCNC(C)C)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of -[2-(2-(3,5-difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1,1-dimethyl-3-oxo-propyl)-[1,3,4]thiadiazol-2-yl]-amide (88 mg, 0.2 mmol), isopropylamine (0.09 ml) in dichloroethane (1 ml) and methylene chloride (1 ml) was stirred at r.t. for 10 min, sodium triacetoxyborohydride (76 mg) was added and the resulting mixture was stirred at r.t. overnight. The mixture was quenched with water, diluted with sodium hydroxide, and extracted with methylene chloride. The organic layer was separated, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography using 3-5% methanol in methylene chloride, then 5% methanol/0.5% ammonium hydroxide in methylene chloride as eluent to give the title compound as a free base form. The free base was treated with 4 N HCl in doxane (0.1 ml) in methylene chloride (1 ml) and concentrated to dryness. The residue was triturated with hexane, pumped to dryness to give a white solid, LC-MS RT=1.8 min, M+1=481.9.