Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B1C2CCCC1CCC2.[CH:10]([C:12]1[CH:13]=[CH:14][C:15]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)=[C:16]([CH:19]=1)[C:17]#[N:18])=[CH2:11].[O-:31]S([O-])=O.[Na+].[Na+]>C1COCC1>[OH:31][CH2:11][CH2:10][C:12]1[CH:13]=[CH:14][C:15]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=2)=[C:16]([CH:19]=1)[C:17]#[N:18]
Reactant: C=Cc1ccc(Oc2cccc(C(F)(F)F)c2)c(C#N)c1
Reactant: O=S([O-])[O-]
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cc(CCO)ccc1Oc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.4 %

Procedure:
To a stirred a solution of 9-BBN (10.37 mL, 5.19 mmol) in dry THF (30 mL) was added dropwise a solution of 5-ethenyl-2-{[3-(trifluoromethyl)phenyl]oxy}benzonitrile (1 g, 3.46 mmol) in THF (30 mL) under nitrogen at 0° C. for 0.5 h. The mixture was then allowed to warm to room temperature and stirring continued for 2 h. Na2SO3 was added to quench the reaction. Purification via flash chromatography then afforded the title compound (546 mg, 1.777 mmol, 51.4% yield).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[N:11]2[CH:12]=[C:13]([CH2:15][O:16][C:17]3[CH:24]=[CH:23][C:20]([CH2:21]O)=[CH:19][CH:18]=3)[N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1>O>[Cl:5][C:6]1[N:11]2[CH:12]=[C:13]([CH2:15][O:16][C:17]3[CH:24]=[CH:23][C:20]([CH2:21][Cl:3])=[CH:19][CH:18]=3)[N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1
Reactant: OCc1ccc(OCc2cn3c(Cl)cccc3n2)cc1
Reactant: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: ClCc1ccc(OCc2cn3c(Cl)cccc3n2)cc1
Reaction time: 1 h
Yield: 52 %

Procedure:
Thionyl chloride (0.597 ml) was added dropwise to a mixture of 4-(5-chloroimidazo[1,2-a]pyridine-2-ylmethoxy)benzylalcohol (1.97 g), triethylamine (1.15 ml) and toluene (50 ml) at 0° C. After stirring for 1 hour, water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain 5-chloro-2-(4-chloromethylphenoxymethyl)imidazo[1,2-a]pyridine (1.10 g, yield 52%) as colorless crystals. m.p. 114-115° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[NH:14]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>OS([O-])(=O)=O.[K+]>[N:14]1([C:2]2[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=2)[C:7]([OH:9])=[O:8])[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1CNCCNC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: O=C(O)c1cc(N2CCCNCC2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 73.3 %

Procedure:
5-Chloro-2-nitro-benzoic acid (42.3 g) and homopiperizine (100 g, 4.8 eq.) were mixed without solvent and heated at 110° C. After 10 min, the mixture had melted into an orange, thick solution. After 45 min total reaction time, the mixture turned to a dark black-brown color and become very thick. At this time, the mixture was cooled to room temperature and diluted with 10% KHSO4 (wt/vol) aqueous solution (pH 4). This mixture was stirred at room temperature for ˜1 hour and then filtered. The solid was rinsed with a mixture of hexanes and diethyl ether, diethyl ether and then hexane. The solid was then dried under vacuum. This resulted in 40.8 g (73%) of a dark brown solid. The compound was carried on to the next step without further analysis or purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[O:8])=[CH:5][N:6]=1.[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[C:21]([CH3:26])[N:20]=1.[H-].[Na+]>O1CCCC1>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=1[NH:9][C:7]([C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[C:19]([Cl:18])[N:20]=[C:21]([CH3:26])[N:22]=2)=[N:6][CH:5]=1)=[O:8]
Reactant: Cc1cccc(Cl)c1NC(=O)c1cnc(N)s1
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc(Nc2ncc(C(=O)Nc3c(C)cccc3Cl)s2)n1

Procedure:
The sixth step involves reacting 2-amino-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide (Formula 1c) with 4,6-dichloro-2-methylpyrimidine in the presence of sodium hydride in tetrahydrofuran to obtain N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-1,3-thiazole-5-carboxamide (Formula 1d).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23]Br>C(O)C>[CH3:14][O:15][C:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1)=[O:25]
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: COC(=O)c1ccccc1CBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)c1ccccc1COc1cccc(CC(=O)O)c1
Reaction time: 0.5 h
Yield: 14 %

Procedure:
3-Hydroxyphenylacetic acid (760 mg, (5 mmol) was dissolved in ethanol (99.5%, 20 ml). Potassium hydroxide (560 mg, 10 mmol) was added. The mixture was stirred for 30 minutes. 2-Bromomethylbenzoic acid methyl ester (1.144 g, 5 mmol) was then dropped in. The resulting mixture was heated to reflux for 2 hours and then evaporated in vacuum to dry. Water and ethyl acetate were added into the residue and the phases were separated. The water phase was acidified with 10% hydrochloric acid, pH˜5, and then extracted with ethyl acetate. The organic phase was dried (magnesium sulphate) and evaporated in vacuum to dry. Chromatography of the residue on a column (ISOLUTE® SI, 5 g/25 ml) using DCM, MeOH/DCM (1:99) as eluant gave 213 mg, the desired product, yield 14%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([NH2:10])[CH:7]=[CH:6][CH:5]=1)[CH3:2].C(O[CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([NH:10][CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1cccc(N)n1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1cccc(OCC)n1)C(=O)OCC
Temperature: 95 °C

Procedure:
A mixture of 6-ethoxypyridin-2-amine (8.0 g) and diethyl ethoxymethylenemalonate (12.5 g) was heated at 95° C. under vacuum for 3 hours and then heated at 95° C. at atmospheric pressure for 18 hours. The mixture was cooled to ambient temperature, diluted with petroleum ether b.p. 40°-60° C. and filtered to give diethyl (6-ethoxy-2-pyridylamino)methylenemalonate, m.p. 58°-60° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13].CON(C)[C:17](=[O:27])[CH2:18][O:19][C@@H:20]([CH:25]=[CH2:26])[C:21]([F:24])([F:23])[F:22].[NH4+].[Cl-]>CCCCCC.C1COCC1.[Cl-].[Na+].O>[F:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:17](=[O:27])[CH2:18][O:19][C@@H:20]([CH:25]=[CH2:26])[C:21]([F:23])([F:22])[F:24]
Reactant: C=C[C@H](OCC(=O)N(C)OC)C(F)(F)F
Reactant: Fc1ccccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C[C@H](OCC(=O)c1ccccc1F)C(F)(F)F
Temperature: -60 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
A solution of n-butyllithium in hexane (2.50 M; 90 mL) was added dropwise over 25 mins to a solution of 2-bromofluorobenzene (40.35 g) in THF (250 mL) under a N2 atmosphere at −78° C. The reaction solution was allowed to warm to −60° C. and stir for 60 min. (S)—N-Methoxy-N-methyl-2-((1,1,1-trifluorobut-3-en-2-yl)oxy)acetamide (40 g) in THF (25 mL) was added dropwise to the reaction solution, and after stirring at −60° C. for 2 h, aqueous NH4Cl (100 mL) was added to the reaction solution, followed by warming to RT. Brine (200 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (3×400 mL). The combined organic portions were dried over MgSO4, evaporated, and the residue was purified by silica gel column chromatography (1% to 10% EtOAc in hexanes) to obtain the title compound (33.59 g). 1H-NMR (400 MHz, CDCl3) δ (ppm): 4.40 (pentet, J 6.3 Hz, 1 H) 4.81-4.87 (m, 2H), 5.54-5.69 (m, 2H), 5.86 (ddd, J 17.4, 10.4, 7.3 Hz, 1 H) 7.12-7.22 (m, 1 H) 7.24-7.34 (m, 1 H) 7.54-7.63 (m, 1 H) 7.94-8.02 (m, 1 H).
Reaction SMILES: C([O:8][C:9]1[CH:23]=[CH:22][C:12]([O:13][CH:14]([CH3:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH:14]([CH3:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:22][CH:23]=1
Reactant: [H][H]
Reactant: CCOC(=O)CC(C)Oc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(C)Oc1ccc(O)cc1

Procedure:
To a solution of the product of step i) (4.5 g) in absolute ethanol (200 ml) was added 10% palladium-on-charcoal catalyst (1.2 g) and the resulting suspension hydrogenated at ambient temperature and pressure until uptake of hydrogen ceased. The catalyst was removed by filtration through celite and the filtrate was concentrated in vacuo to give ethyl 3-(4-hydroxyphenoxy)butyrate as a low-melting crystalline solid (3.0 g) NMR (d6DMSO) δ 1.25(3H,t); 1.8-2.0(2H,m); 2.5(2H,t); 3.9(2H,t); 4.1(2H,q); 6.7(4H,m); 8.8)1H,brs); m/e 224 (M)+.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28]N>>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: NNc1ccccc1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Product: O=c1ccn(-c2ccccc2)nc1-c1ccnn1-c1ccccc1F

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and 2-fluoro-phenylhydrazine according to the method described for example 1. MS: M=333.2 (M+H)+
Reaction SMILES: [CH:1]12[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.Cl[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=1>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([N:3]2[CH2:4][CH:5]3[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:1]([CH2:7][CH2:6]3)[CH2:2]2)=[N:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Reactant: Clc1ccc(Cl)nc1
Product: CC(C)(C)OC(=O)N1C2CCC1CN(c1ccc(Cl)cn1)C2

Procedure:
tert-Butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate, prepared as described in (J. Med. Chem., (1998) 41, 674), and 2,5-dichloropyridine were processed as described in Example 10A to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[C:5](=O)[NH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[C:5](=[S:22])[NH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)c1[nH]c(=O)c(Nc2ccncn2)cc1Cl
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: CCOC(=O)c1[nH]c(=S)c(Nc2ccncn2)cc1Cl
Temperature: 110 °C

Procedure:
A vial was charged with 3-chloro-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridine-2-carboxylate (3, 0.35, 1.2 mmol) and pyridine (10 mL) was added. To the above mixture phosphorus pentasulfide (0.53 g, 2.4 mmol) was added and reaction was heated at 110° C. for 16 h. TLC showed presence of starting material and phosphorus pentasulfide (0.265 g, 1.2 mmol) was added again and heated the reaction to 115° C. for 24 h. The pyridine was removed under reduced pressure and water (20 mL) was added and extracted with 5% methanol in dichloromethane (100 mL). The organic layer was washed with sodium bicarbonate and brine and layer was concentrated to dryness to afford ethyl 3-chloro-5-(pyrimidin-4-ylamino)-6-thioxo-1,6-dihydropyridine-2-carboxylate (4) as brownish yellow solid and used directly without further purification. Yield: 350 mg, crude; MS (ESI) m/z 310.94 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][F:18]>CN(C)C=O>[F:18][CH2:17][CH2:16][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: FCCBr
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FCCOc1ccccc1Br
Yield: 77.1 %

Procedure:
In a manner similar to that disclosed in German Offenlegungschrift DE No. 3,402,483, the reaction of 5.0 grams (0.029 mole) of 2-bromophenol, 6.0 grams (0.043 mole) of potassium carbonate, and 5.5 grams (0.03 mole) of 1-bromo-2-fluoroethane in 50 ml of N,N-dimethylformamide yielded 4.9 grams of 2-bromophenyl 2-fluoroethyl ether as an oil.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Br:11]N1C(=O)CCC1=O>C(#N)C.CCOCC>[Br:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:1][CH2:2][CH2:3][CH2:4]2
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(c1)CCCN2
Solvent: CC#N
Solvent: CCOCC
Product: Brc1ccc2c(c1)CCCN2
Temperature: 0 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
1,2,3,4-tetrahydroquinoline (1.7 g, 12.8 mmol) was dissolved in acetonitrile (25 mL) and cooled to 0° C. N-Bromosuccinimide (2.16 g, 12.2 mmol) was added in 4 portions over 30 minutes and the mixture was stirred for 3 hours. The mixture was diluted with ether and washed with sodium bisulfite, water, brine, dried over anhydrous magnesium sulfate, and concentrated. Purification via Isco chromatography (the Redisep® column, silica, gradient 5%-30% ethyl acetate in hexane) afforded 6-bromo-1,2,3,4-tetrahydroquinoline (1.5 g). MS (ES) m/z 211.8; HPLC purity 100.0% at 210-370 nm, 10.9 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammonium formate buffer pH=3.5 acetonitrile+MeOH) for 10 minutes, hold 4 minutes.
Reaction SMILES: [CH3:1][C:2]([C:4]([NH:6][CH2:7][CH2:8][CH2:9][N+:10]([CH3:13])([CH3:12])[CH3:11])=[O:5])=[CH2:3].[Cl-:14].O.[CH:16]([OH:19])([CH3:18])C>>[CH3:3][C:2]([C:4]([NH:6][CH2:7][CH2:8][CH2:9][N+:10]([CH3:13])([CH3:11])[CH3:12])=[O:5])=[CH2:1].[Cl-:14].[CH:4]([N:6]1[CH2:7][CH2:8][CH2:18][C:16]1=[O:19])=[CH2:2]
Reactant: CC(C)O
Agent: *CC*
Agent: C=C(C)C(=O)NCCC[N+](C)(C)C
Agent: O=C(O)c1ccc(C(=O)O)cc1
Solvent: O
Product: C=CN1CCCC1=O

Procedure:
A polyethylene terephthalate (PET) surface is coated with an 8% solids solution of MAPTAC/VP/SiAM 15/75/10 of Example 1a (1.5 mL of solution on a 5 cm*5 cm PET sheet, spin coating 1500 rpm, 15 s). The solvent used is a water/isopropyl alcohol mixture (70/30), in order to have a sufficient wetting of the PET sheet by the solution. After 7 days of drying in 75% RH atmosphere, a contact angle of 140° is measured with water.
Reaction SMILES: C(N1C2C(=CC=CC=2)C(CC(O)=O)=C1)(=O)N.C([O:19][C:20](=[O:35])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]([C:31](=[O:33])[NH2:32])[C:23]=1[CH3:34])C>>[C:31]([N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([CH2:21][C:20]([OH:35])=[O:19])=[C:23]1[CH3:34])(=[O:33])[NH2:32]
Reactant: CCOC(=O)Cc1c(C)n(C(N)=O)c2ccccc12
Agent: NC(=O)n1cc(CC(=O)O)c2ccccc21
Product: Cc1c(CC(=O)O)c2ccccc2n1C(N)=O

Procedure:
was prepared in a similar manner as described in Scheme A8 Step B for (1-carbamoyl-1H-indol-3-yl)-acetic acid starting from (1-carbamoyl-2-methyl-1H-indol-3-yl)-acetic acid ethyl ester. The crude product (brownish solid) obtained after extractive work-up was used directly in the next step without purification. MS: 233 [M+H]+; tR (HPLC conditions b) 3.26 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30]>C(O)(C)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)[CH2:27][C:28]([OH:33])([C:29]([F:32])([F:31])[F:30])[N:20]=2)=[CH:4][N:3]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: Cc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1ccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)cn1
Temperature: 82.5 °C
Yield: 46.5 %

Procedure:
To a mixture of the amidine of Step 1 (9.8 g, 33.9 mmol) and sodium bicarbonate (5.7 g, 67.8 mmol) in isopropanol (700 ml), 3-bromo-1,1,1-trifluoroacetone (5.3 ml, 50.8 mmol) was added. After heating at 80-85° C. for 24 hours, the reaction mixture was cooled and filtered. The residue was washed with methylene chloride and the combined organic fractions were dried over sodium sulfate, filtered and concentrated. The crude material (25.7 g) was purified by chromatography (silica gel, ethyl acetate/acetone, 98/2) to give 2-methyl-5-[4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine (6.3 g, 46%) as a white solid: Anal. Calc'd. for C17H16N3SO3F3: C, 50.55, H, 4.12, N, 10.40. Found: C, 50.51, H, 3.91, N, 10.25.
Reaction SMILES: [CH:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([O:13][C:14]3[C:15]([C:48]([F:51])([F:50])[F:49])=[C:16]4[C:21](=[CH:22][CH:23]=3)[CH:20]=[C:19]([C@:24]([NH:40]C(=O)OC(C)(C)C)([CH3:39])[CH2:25][O:26][P:27]([O:34]C(C)(C)C)([O:29]C(C)(C)C)=[O:28])[CH:18]=[CH:17]4)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.Cl.O>>[P:27]([OH:34])([OH:29])([O:26][CH2:25][C@:24]([NH2:40])([C:19]1[CH:18]=[CH:17][C:16]2[C:21](=[CH:22][CH:23]=[C:14]([O:13][C@H:10]3[CH2:11][CH2:12][C@H:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[CH2:8][CH2:9]3)[C:15]=2[C:48]([F:49])([F:51])[F:50])[CH:20]=1)[CH3:39])=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(COP(=O)(OC(C)(C)C)OC(C)(C)C)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C4CCCCC4)CC3)ccc2c1
Agent: Cl
Solvent: CO
Solvent: O
Product: C[C@](N)(COP(=O)(O)O)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C4CCCCC4)CC3)ccc2c1
Temperature: 80 °C

Procedure:
tert-Butyl (R)-2-(6-(trans-4-cyclohexylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)-1-(di-tert-butoxyphosphoryloxy)propan-2-ylcarbamate was then dissolved in methanol (2 mL, 0.06 mol) followed by 6 M of hydrogen chloride in water (1 mL, 0.007 mol). The reaction mixture was then heated at 80° C. for 3 hours. All is solvents were removed, the crude product was then purified via reverse chromatography (4.3 g, 10-90% acetonitrile with 0.1% TFA/water with 0.1% TFA 7.2 mg, 17%). 1H NMR (MeOD) δ: 8.24 (d, J=8.8 Hz, 1H), 8.11 (d, J=9.3 Hz, 1H), 7.98 (s, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.57 (d, J=9.3 Hz, 1H), 4.43-4.56 (m, 1H), 4.33 (d, J=8.3 Hz, 1H), 4.19 (d, J=7.0 Hz, 1H), 2.18 (d, J=10.5 Hz, 2H), 1.81-1.91 (m, 5H), 1.71-1.79 (m, 4H), 1.67 (d, J=11.5 Hz, 1H), 1.40-1.57 (m, 2H), 1.10-1.32 (m, 7H), 0.97-1.08 (m, 2H). MS (M+1): 530.0
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N:4]=1.[CH3:32][NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1>COCCO>[CH3:27][O:26][C:20]1[CH:19]=[C:18]([C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=3)[N:4]=[C:3]([CH2:2][N:33]([CH3:32])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: CNc1ccccn1
Solvent: COCCO
Product: CCOC(=O)c1c(CN(C)c2ccccn2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Yield: 8.6 %

Procedure:
A mixture of ethyl 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (1.0 g), 2-(methylamino)pyridine (0.95 g) and 2-methoxyethanol (30 ml) was stirred under reflux for 17 hours. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with hexane - ethyl acetate (3:2, v/v) gave ethyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-[N-methyl-N-(2-pyridyl)aminomethyl]quinoline-3-carboxylate (0.1 g, 9%). This compound was recrystallized from dichloromethane-ethanol. Pale yellow prisms, mp. 174°-175° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33]([NH:35][CH:36]4[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]4)=[O:34])=[C:22]([CH3:32])[N:23](COCC[Si](C)(C)C)[C:16]=23)[CH2:3][CH2:2]1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(N)CN>O1CCCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33]([NH:35][CH:36]4[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]4)=[O:34])=[C:22]([CH3:32])[NH:23][C:16]=23)[CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c2nccc(-c3c(OCC4CC4)ccc4c3OCO4)c2n1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: NCCN
Solvent: C1CCOC1
Product: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ccnc2c1C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A solution of tert-butyl 4-{[(7-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridin-3-yl)carbonyl]amino}piperidine-1-carboxylate from example D.d1 (3.74 g; 5.5 mmol), tetrabutylammonium fluoride trihydrate (5.21 g; 16.5 mmol) and ethane-1,2-diamine (0.50 g; 8.25 mmol) in tetrahydrofurane (40 mL) is heated to gentle reflux until the starting material is completely consumed according to LC-MS. The crude is purified by column chromatography on silica gel (ethyl acetate/cyclohexane—1:1 to 2:1) to yield the title compound as colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH2:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH:20]1[C:32]2[CH:31]([CH2:33][O:34][C:35](N3C(=O)CCC3=O)=[O:36])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1.C(OCC)(=O)C>O1CCCC1>[C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:35]([O:34][CH2:33][CH:31]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:24]3[C:32]2=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:36])[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN)cs1
Reactant: O=C1CCC(=O)N1C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNC(=O)OCC2c3ccccc3-c3ccccc32)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a solution of 2-{[4-(2-aminoethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (19 g) synthesized in Example 7 in tetrahydrofuran (60 mL) was added N-(9H-fluorene-9-ylmethyloxycarbonyl)succinimide (23 g), and the mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated brine. The precipitate was filtered and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1) to give the title compound (33 g) as a pale-brown oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)[CH3:2].C([O:12][CH:13]=[C:14]([C:20](OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>>[CH2:18]([O:17][C:15]([C:14]1[C:13](=[O:12])[C:8]2[C:6](=[CH:5][CH:4]=[C:3]([CH2:1][CH3:2])[CH:9]=2)[NH:7][CH:20]=1)=[O:16])[CH3:19]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCc1ccc(N)cc1
Product: CCOC(=O)c1c[nH]c2ccc(CC)cc2c1=O
Yield: 35.6 %

Procedure:
p-Ethylaniline (5.0 g) and diethyl ethoxymethylenemalonate (10.7 g) were reacted in the same manner as in Experimental Example 1 to give 3-ethoxycarbonyl-6-ethyl-4(1H)-quinolone (3.6 g). The compound (2.8 g) was N-ethylated with potassium carbonate (2.3 g) and ethyl iodide (2.1 g) in the same manner as in Experimental Example 9 to give 1,6-diethyl-3-ethoxycarbonyl-4(1H)-quinolone (compound 85, 1.55 g).