Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:8][N:7]=[C:6]([N+:9]([O-:11])=[O:10])[N:5]=1.[CH3:12]I.O>CN(C)C=O>[Br:3][C:4]1[N:8]([CH3:12])[N:7]=[C:6]([N+:9]([O-:11])=[O:10])[N:5]=1
Reactant: O=[N+]([O-])c1n[nH]c(Br)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc([N+](=O)[O-])nc1Br
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 59.7 %

Procedure:
1.1 g (28.5 mmol) of 60% sodium hydride are added to a solution of 5 g (25.9 mmol) of 5-bromo-3-nitro-1H-[1,2,4]triazole in 80 ml of dimethylformamide, cooled beforehand to 0° C. The reaction medium is stirred for 20 minutes and 8 ml (129.5 mmol) of methyl iodide are then added. After stirring at room temperature for 18 hours, water is added and the reaction medium is extracted with ethyl acetate. The organic phase is washed thoroughly with water, with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by thin-layer chromatography on silica eluted with a 75/25 heptane/ethyl acetate mixture. 3.2 g (60%) of 5-bromo-1-methyl-3-nitro-1H-[1,2,4]triazole are obtained.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:48])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:47])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:46])[NH:31][C@@H:32]4[CH2:35][C@H:34]([C:36]([N:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)=[O:37])[C:33]4([CH3:45])[CH3:44])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:50])[CH3:49])(=O)C>CO.C1COCC1.[OH-].[Na+]>[CH3:44][C:33]1([CH3:45])[C@@H:34]([C:36]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[O:37])[CH2:35][C@H:32]1[NH:31][C:30]([C@:14]12[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]1[C@@H:16]1[C@@:11]([CH3:47])([CH2:12][CH2:13]2)[C@@:10]2([CH3:48])[C@@H:19]([C@:20]3([CH3:23])[C@@H:7]([CH2:8][CH2:9]2)[C:6]([CH3:49])([CH3:50])[C@@H:5]([OH:4])[CH2:22][CH2:21]3)[CH2:18][CH2:17]1)=[O:46]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)N4CCOCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)N4CCOCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.8 %

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((1R,3S)-2,2-dimethyl-3-(morpholine-4-carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate (Example 16, 0.300 g, 0.43 mmol) in MeOH:THF (2:1) (15 ml), 2N NaOH (5 ml) was added at about 0° C. and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the volatiles were evaporated and the aqueous layer was extracted with ethyl acetate and dried over Na2SO4. The solvent was evaporated and purified by silica gel column (100-200 mesh, elution 15% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.230 g: Yield: 81.8%; 1H NMR (300 MHz, CDCl3): δ 5.83 (d, 1H, J=7.8 Hz), 4.72 (s, 1H), 4.57 (s, 1H), 4.18-4.07 (m, 1H), 3.80-3.41 (m, 8H), 3.22-3.05 (m, 2H), 2.86 (t, 1H, J=8.1 Hz), 2.52-2.23 (m, 3H), 1.99-1.87 (m, 2H), 1.79-1.11 (m, 28H), 0.93, 0.89, 0.81, 0.74 (s, 18H); Mass: [M+1]+ 673 (100); IR (KBr, cm−1): 3419, 2951, 2864, 1624, 1527, 1459, 1374, 1271, 1249, 1112, 1068, 1044, 875, 861; M.R: 213.5° C.-216.5° C.; HPLC: 95.6%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7]/[N:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](/[C:25](=[CH:28]/[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])/[C:26]#[N:27])=[CH:21][CH:20]=1.C(N(CC)CC)C>ClCCCl>[C:1]([O:5][C:6]([CH:7]1[CH:28]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:25]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)([C:26]#[N:27])[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[NH:8]1)=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C/C=C(\C#N)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)C/N=C/c1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)CC1C(C(=O)OC(C)(C)C)NC(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 31.2 %

Procedure:
In a manner similar to the method described in Example 1c, {[1-(3-chloro-phenyl)-meth-(E)-ylidene]-amino}-acetic acid tert-butyl ester prepared in Example 32a (2.6 g, 11 mmol) was reacted with (Z)-2-(4-chloro-phenyl)-5,5-dimethyl-hex-2-enenitrile (2 g, 7.9 mmol) prepared in Example 32b, AgF (1.3 g, 10 mmol), and triethylamine (2.2 g, 22 mmol) in 1,2-dichloroethane (100 mL) at room temperature for 24 h to give rac-(2R,3R,4R,5S)-5-(3-Chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-3-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.2 g, 31%).
Reaction SMILES: [Cl:1][CH:2]([C:8]([CH3:10])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].BrCC1[CH:20]=[CH:19][C:18]([CH2:21][C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=1.Cl>CN(C)C=O>[CH2:21]([C:18]1[CH:19]=[CH:20][C:10]([CH2:8][CH:2]([Cl:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:16][CH:17]=1)[C:22]([CH3:23])=[O:24]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CC(=O)Cc1ccc(CBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cl)Cc1ccc(CC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of ethyl 2-chloroacetoacetate (8.25 g) in dry dimethylformamide was treated with sodium hydride (1.3 g and stirred at ambient temperature for 0.5 h. A solution of 4-(bromomethyl)phenylpropan-2-one, ethylene ketal (12.0 g) in dry dimethylformamide (20 ml) was then added and the mixture was heated at 70° C. for 4 h. The reaction mixture was cooled, poured into ice/water, acidified with 2N-hydrochloric acid, extracted with ethyl acetate (4×50 ml) and the combined organic extracts dried (magnesium sulphate), filtered and evaporated in vacuo. The residue was dissolved in ethanol and treated at 0°-5° C. with barium hydroxide hydrate (7.7 g). The mixture was stirred for 0.5 h, poured into ice/water, extracted with ethyl acetate (3×50 ml) and the combined organic extracts dried (magnesium sulphate), filtered and evaporated in vacuo to leave a red oil, which was purified by column chromatography on silica using diethyl ether: petroleum ether (60°-80°) (30:70) as eluent to give ethyl 3-(4-acetonylphenyl)-2-chloropropionate, ethylene ketal, (6.0 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Br:14]NC(=O)CCC(N)=O>ClCCl.CN(C)C=O>[NH2:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:9][C:10]=1[Br:14]
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: NC(=O)CCC(=O)NBr
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1c(Br)cc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-amino-3-nitrobenzoic acid (2.50 g, 13.7 mmol) in dichloromethane (65.4 mL) and N,N-dimethylformamide (3.3 mL) was added N-bromosuccinamide (2.69 g, 15.1 mmol). The mixture was stirred at ambient temperature. After 15 min, the mixture was quenched with saturated sodium sulfite. Hydrochloric acid (1.0 M) was added and the mixture was extracted with dichloromethane. The combined organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated (3.65 g). LC-MS [M]=261.0.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[N:12]=[C:11]([NH2:16])[C:10]3[N:17]=[C:18]([CH2:23][O:24][CH3:25])[N:19]([CH2:20][CH2:21][CH3:22])[C:9]=3[C:8]=2[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>CN(C=O)C>[CH3:25][O:24][CH2:23][C:18]1[N:19]([CH2:20][CH2:21][CH3:22])[C:9]2[C:8]3[CH:7]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:41]4[CH2:42][CH2:43][N:38]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=5)[CH2:39][CH2:40]4)[CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:16])[C:10]=2[N:17]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CCCn1c(COC)nc2c(N)nc3ccc(OCCCCl)cc3c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1c(COC)nc2c(N)nc3ccc(OCCCN4CCN(c5ccccn5)CC4)cc3c21
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of 8-(3-chloropropoxy)-2-(methoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (0.20 g, 0.55 mmol, 1 equivalent), potassium carbonate (4 equivalents), and 1-(2-pyridyl)piperazine (1.1 equivalents) in DMF (5 mL) was heated at 70° C. overnight. The reaction mixture was allowed to cool to room temperature and was poured onto ice (50 g). After the mixture was stirred for 3 hours, a brown solid was isolated by filtration. The crude product was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 0-30% CMA in chloroform), followed by recrystallization from acetonitrile to afford 0.065 g of 2-(methoxymethyl)-1-propyl-8-[3-(4-pyridin-2-ylpiperazin-1-yl)propoxy]-1H-imidazo[4,5-c]quinolin-4-amine as off white crystals, mp 196-197° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(O[C:16](=[O:35])[NH:17][C:18]1[S:22][C:21]2[C:23]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:20]=2[CH:19]=1)C1C=CC=CC=1>>[CH3:28][O:27][C:26]1[C:20]2[CH:19]=[C:18]([NH:17][C:16]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:35])[S:22][C:21]=2[C:23]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:24][CH:25]=1
Reactant: COc1ccc(-c2ccccc2)c2sc(NC(=O)OCc3ccccc3)cc12
Reactant: CN1CCNCC1
Product: COc1ccc(-c2ccccc2)c2sc(NC(=O)N3CCN(C)CC3)cc12

Procedure:
The title compound MS: m/e=380.2 (M−H) was obtained as a light yellow foam (46% yield) by the reaction of N-methyl-piperizine with (4-methoxy-7-phenyl-benzo[b]thiophen-2-yl)-carbamic acid benzyl ester according to the method described above for example 1.
Reaction SMILES: [N+:1]1([O-:8])[C:2]([CH3:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.C([O-])(C)(C)C.[K+].[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O>>[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=[CH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N+:1]=1[O-:8]
Reactant: Cc1cccc[n+]1[O-]
Reactant: O=Cc1ccccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: [O-][n+]1ccccc1C=Cc1ccccc1F

Procedure:
Following the general method described in example 2a, 2-picoline-1-oxide was reacted with potassium tert.-butanolate and 2-fluoro-benzaldehyde. After extraction and chromatography the title compound was obtained as a yellow solid material. MS: m/e=215 (M+).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=O)[N:6]=1.[NH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[C:20](=O)[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=1>>[CH2:27]([C:24]1[CH:23]=[CH:22][C:21]([C:20]2[C:13]3[C:12](=[CH:19][CH:18]=[C:15]([C:16]#[N:17])[CH:14]=3)[NH:11][C:8](=[O:10])[C:7]=2[C:5]2[N:6]=[C:2]([CH3:1])[S:3][CH:4]=2)=[CH:26][CH:25]=1)[CH3:28]
Reactant: Cc1nc(CC(=O)O)cs1
Reactant: CCc1ccc(C(=O)c2cc(C#N)ccc2N)cc1
Product: CCc1ccc(-c2c(-c3csc(C)n3)c(=O)[nH]c3ccc(C#N)cc23)cc1
Yield: 27 %

Procedure:
Synthesized from (2-methyl-thiazol-4-yl)-acetic acid and 4-Amino-3-(4-ethyl-benzoyl)-benzonitrile according to general procedure 2. Yield 27%.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:28])[C:15]2[CH:20]=[C:19]([C:21]#[C:22][Si](C)(C)C)[CH:18]=[CH:17][C:16]=2[OH:27])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]([F:29])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:28])[C:15]2[CH:20]=[C:19]([C:21]#[CH:22])[CH:18]=[CH:17][C:16]=2[OH:27])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C[Si](C)(C)C#Cc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-[(trimethylsilyl)ethynyl]benzamide (233 mg, 0.5 mmol) was dissolved in methanol (1 mL). 2 N sodium hydroxide (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 2 N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine one after another, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was crystallized from ethanol-water to give the title compound (67 mg, 35.9%) as a light gray crystal.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[H][H]>[Ni].C(O)C>[CH2:9]([O:8][C:6]([CH:5]1[CH2:11][CH2:12][CH:2]([OH:1])[CH2:3][CH2:4]1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)C1CCC(O)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 79.1 %

Procedure:
In an autoclave made of stainless steel having a volume of 1 liter were placed 142 g (0.86 mole) of ethyl para-hydroxybenzoate, 10 g of Raney Ni catalyst (activity W-7) and 400 ml of ethanol, and reacted with stirring at a pressure of hydrogen of 100 kg/cm2 and a reaction temperature of 150° C. for 20 hours. After the autoclave was allowed to cool to room temperature, the hydrogen in the vessel was released, and the Raney Ni catalyst was then removed by suction filtration. The filtrate was concentrated by means of a rotary evaporator and then distilled under reduced pressure to obtain 117 g (0.68 mole, yield 79%) of 4-ethoxycarbonylcyclohexanol having a boiling point of 98° to 104° C./4 mmHg.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C>>[CH3:26][O:25][C:4]1[CH:3]=[C:2]([NH:34][CH:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)[CH:7]=[CH:6][C:5]=1[C:8]1[O:9][C:10]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:11][N:12]=1
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NC2CCN(C)CC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 22.1 %

Procedure:
As described for example 26, 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.57 mmol) was converted using 1-methylpiperidin-4-amine (195 mg, 1.71 mmol) and N,N-diisopropylethylamine (147 mg, 1.14 mmol) instead of thiomorpholine to the title compound (SiO2, heptane:ethyl acetate:dichloromethane:methanol=40:40:20:0 to 0:75:20:5, 56 mg, 22%) which was obtained as an off-white solid. MS: m/e=446.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:25])[C:13]([N:15]([CH3:24])[N:16]=CC1C=CC=CC=1)=[O:14])[CH3:2]>[Pd].COCCOC>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:25])[C:13]([N:15]([CH3:24])[NH2:16])=[O:14])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=Cc1ccccc1
Agent: [Pd]
Solvent: COCCOC
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 25 mL volume two-necked flask, 1.47 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(phenylmethylidene)hydrazine ((40-b)-(15)-5), 5.1 ml of 1,2-dimethoxyethane and 147 mg of 5 wt % Pd—C were added. The mixture was stirred under a hydrogen atmosphere at room temperature for 8 hours. An unsolved substance was removed by filtration and washed with 1,2-dimethoxyethane. The filtrates were combined and concentrated under reduced pressure to give 1.06% g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)=[N:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:27]([O:34][C:35]1[CH:36]=[N:37][C:38]2[C:43]([CH:44]=1)=[N:42][CH:41]=[CH:40][C:39]=2Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[CH2:27]([O:34][C:35]1[CH:44]=[C:43]2[C:38]([C:39]([O:26][C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:12]4[C:13]5[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=5)[C:9]([C:6]5[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=5)=[N:10][N:11]=4)=[CH:25][CH:24]=3)=[CH:40][CH:41]=[N:42]2)=[N:37][CH:36]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Oc1ccc(Nc2nnc(-c3ccc(Cl)cc3)c3ccccc23)cc1
Reactant: Clc1ccnc2cc(OCc3ccccc3)cnc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Clc1ccc(-c2nnc(Nc3ccc(Oc4ccnc5cc(OCc6ccccc6)cnc45)cc3)c3ccccc23)cc1
Temperature: 100 °C

Procedure:
A pyrex reaction tube was charged with 4-(4-(4-chlorophenyl)phthalazin-1-ylamino)phenol hydrochloride (344 mg, 894 μmol), 3-(benzyloxy)-8-chloro-1,5-naphthyridine (220 mg, 813 μmol), cesium carbonate (662 mg, 2032 μmol) and 4.1 mL DMSO. The tube was sealed and the mixture was heated at 100° C. for 4 h. Water was added and the resulting precipitate was filtered, washed with water and dried. The crude material was purified by silica gel chromatography, 90/10/1 DCM/MeOH/NH4OH in DCM to provide N-(4-(7-(benzyloxy)-1,5-naphthyridin-4-yloxy)phenyl)-4-(4-chlorophenyl)phthalazin-1-amine. MS: [M+H]=583.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:11].[CH2:25]([O:27][CH2:28][CH2:29]Br)[CH3:26].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:26][CH2:25][O:27][CH2:28][CH2:29][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([CH:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]1)=[O:11]
Reactant: CCOCCBr
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3[nH]2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCn1c(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Temperature: 90 °C

Procedure:
Mix [1H-benzimidazol-2-yl][1-(t-butyloxycarbonyl)-4-piperidinyl]methanone (4.25 g, 12.91 mmol), 2-bromoethyl ethyl ether (2.34 g, 15.3 mmol), potassium carbonate (5.29 g, 38.25 mmol) and dimethylformamide (100 mL). Stir and heat and at 90° C. overnight. Allow to cool to room temperature, dilute with water and extract with ethyl acetate (2×). Wash the combined organic phases with water (3×), then brine and dry (MgSO4). Evaporate the solvent in vacuo and purify by chromatography to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][O-].[Na+].CI.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: C[O-]
Reactant: Sc1cccc(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CI
Product: CSc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-bromobenzenethiol (5 g, 26.44 mmol) was added to a solution of sodium methoxide (1.43 g, 26.48 mmol) in 20 ml of anhydrous methanol. The mixture was stirred for 30 min under nitrogen at room temperature and a solution of methyl iodide (4.51 g, 31.77 mmol) in 20 ml anhydrous methanol was then added. The reaction mixture was stirred overnight at room temperature, poured into 2 M aqueous NaOH solution (30 ml) and extracted three times with ether (60 ml×3). The combined organic layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After removal of solvent, the product was purified by distillation at 80° C. (0.3 mmHg) and isolated in 86.1% (4.62 g) yield. 1H NMR(CDCl3, 500 MHz) δ ppm: 2.44 (s, 3H, CH3), 7.1-7.4(m, 4H, Ar—H)GC-MS(relative intensity %): 202, 204(1:1, 100, M+), 187, 189(1:1, 11, 3-BrPhS+).
Reaction SMILES: C(C(CCCCCC)C[OH:5])C.[CH2:12]([CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:16][OH:17])[CH2:13][CH3:14].[Mn]([O-])(=O)(=O)=O.[K+].S(=O)(=O)(O)O>>[CH2:12]([CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:16]([OH:5])=[O:17])[CH2:13][CH3:14]
Reactant: CCCCCCCCC(CO)CCC
Reactant: CCCCCCC(CC)CO
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCCCCCCCC(CCC)C(=O)O

Procedure:
Instead of (-)-2-ethyl-1-octanol in Example 8, 5.07 g (25.3 mmol) of (-)-2-propyl-1-decanol was used and then oxidized with potassium permanganate under the same acidic state of sulfuric acid as in Example 6 to obtain 2-propyl decanoic acid. 2.19 g (10.2 mmol) of this compound was reacted with 1.75 g (14.7 mmol) of thionyl chloride under the same conditions as in Example 8 to obtain 2.39 g of a light brown liquid of (+)-2-propyldecanoic acid chloride having a specific rotation [α]25 of +1.63.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:13]O)[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34](Br)(Br)(Br)[Br:35]>C(Cl)Cl>[Br:35][CH2:34][CH2:13][C:4]1[CH:3]=[C:2]([Cl:1])[C:11]([Cl:12])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(Cl)c(Cl)cc1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)c(Cl)cc1CCBr
Reaction time: 16 h
Yield: 47.6 %

Procedure:
To a solution of 169 mg (0.72 mmol) of the product of Step B in 3 mL of CH2Cl2 at 0° C. was added 283 mg (1.08 mmol, 1.5 eq) of triphenylphosphine and 360 mg (1.08 mmol, 1.5 eq) of carbon tetrabromide. The mixture was stirred for 16 hours and quenched with methanol. The reaction was concentrated in vacuo and the resultant oil was flash chromatographed with 2:1 hexane/ethyl acetate to afford the titled compound (107 mg, 50%) as a brownish orange oil.
Reaction SMILES: [CH2:1]([C:3]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18](F)[C:4]=1[C:5]([C:7](=[CH:13][NH:14][CH:15]1[CH2:17][CH2:16]1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6])[CH3:2].[H-].[Na+]>>[CH:15]1([N:14]2[C:18]3[C:4](=[C:3]([CH2:1][CH3:2])[C:21]([F:22])=[C:20]([F:23])[C:19]=3[F:24])[C:5](=[O:6])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13]2)[CH2:17][CH2:16]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)c(F)c(F)c(F)c1CC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(CC)c2c1=O
Yield: 60.8 %

Procedure:
Employing ethyl 2-(2-ethyl-3,4,5,6-tetrafluorobenzoyl)-3-cyclopropylaminoacrylate (8.71 g) and 60% sodium hydride (1.09 g), the procedure of Reference Example 22 is repeated to give ethyl 1-cyclopropyl-6,7,8-trifluoro-5-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (5 g), as white powder, m.p. 139°-140° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[Br:18][C:19]1[C:20](Cl)=[C:21]([C:27](=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:22]([CH3:26])=[N:23][C:24]=1[CH3:25]>CC#N>[Br:18][C:19]1[C:20]([N:5]2[CH2:6][CH2:7][C:2]([CH3:8])([CH3:1])[CH2:3][CH2:4]2)=[C:21]([C:27](=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:22]([CH3:26])=[N:23][C:24]=1[CH3:25]
Reactant: CCOC(=O)C(=O)c1c(C)nc(C)c(Br)c1Cl
Reactant: CC1(C)CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(=O)c1c(C)nc(C)c(Br)c1N1CCC(C)(C)CC1
Reaction time: 22 h
Yield: 71.6 %

Procedure:
To a solution of 4,4-dimethylpiperidine (1.245 g, 11.00 mmol) and DIEA (3.49 ml, 20.00 mmol) in anhydrous CH3CN (40 mL) was added ethyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (3.21 g, 10 mmol) at rt. The resulting mixture was placed in a pre-heated oil bath (80° C.). After 22 h, the reaction mixture was concentrated and the residue was purified by flash chromatography using 1-lit each 2.5, 5, 7.5 and 10% EtOAc/Hex to afford ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate (2.846 g, 7.16 mmol, 71.6% yield) as yellow solid. 1H NMR (500 MHz, CDCl3) δ 4.37 (q, J=7.1 Hz, 2H), 3.67-2.75 (br.s., 4H), 2.71 (s, 3H), 2.44 (s, 3H), 1.42 (t, J=7.1 Hz, 3H), 1.38 (t, J=5.6 Hz, 4H), 1.00 (s, 6H). LCMS (M+H)=399.4.