Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH2:15][CH3:16])=[C:9]([CH:13]=1)[C:10](Cl)=O)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([CH3:50])[C:28]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)([CH3:29])[NH:27]C(C3C=CC(C(C)(C)C)=CC=3OCC)=[N:25]2)=[CH:20][CH:19]=1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH2:15][CH3:16])=[C:9]([C:10]2[NH:25][C:24]([C:21]3[CH:20]=[CH:19][C:18]([Cl:17])=[CH:23][CH:22]=3)([CH3:50])[C:28]([C:30]3[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=3)([CH3:29])[N:27]=2)[CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Reactant: CCOc1ccc(C(C)(C)C)cc1C(=O)Cl
Product: CCOc1ccc(C(C)(C)C)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1

Procedure:
rac-(4S,5R*)-2-(5-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was prepared from 5-tert-butyl-2-ethoxy-benzoyl chloride (prepared from 5-tert-butyl-2-hydroxy-benzoic acid) and meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (example 1) in an analogous manner as described in example 2 (method 1).
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1.C([O-])([O-])=O.[K+].[K+].Cl>C1COCC1.CN(C=O)C.C(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8](/[CH:9]=[CH:10]/[C:11]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[O:13])=[CH:14][CH:15]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(/C=C/C(=O)O)cc1
Reactant: Nc1cccc(O)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(/C=C/C(=O)Nc2cccc(O)c2)cc1

Procedure:
To a round-bottomed flask equipped with magnetic stirring was added 4-tert-butyl-trans-cinnamic acid (530 mg, 2.43 mmol, EMKA-Chemie), CH2Cl2 (10 mL), and DMF (10 uL, Aldrich) under N2. The solution was treated dropwise with oxalyl chloride (3.0 mL, 6.0 mmol, 2.0 M in CH2Cl2, Aldrich) then stirred at 25° C. for 1 h. The reaction mixture was concentrated in vacuo and treated with 3-aminophenol (265 mg, 2.43 mmol, Aldrich), THF (20 mL) and satd K2CO3 (15 mL). The reaction mixture was stirred at 25° C. overnight, then acidified to pH˜4.5 with 1 N HCl. The mixture was extracted with EtOAc (2×30 mL), the combined organic extract was dried and concentrated in vacuo. Purification by silica gel chromatography (2:1 hexane:EtOAc) provided the title product as an oil. MS (ESI, pos. ion) m/z: 296 (M+1).
Reaction SMILES: C[C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH-].[K+].[CH2:12]([CH2:28]S([O-])(=O)=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24]CCC.O>C1C=CC=CC=1>[CH2:2]([O:3][CH2:4][C@H:5]([CH2:7][OH:8])[OH:6])[CH2:9][CH2:28][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: CCCCCC/C=C\CCCCCCCCCS(=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: CCCCCC/C=C\CCCCCCCCOC[C@@H](O)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
5.32 grams of (R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol, 12.26 grams of powdered potassium hydroxide and 10 grams of cis-9-hexadecenyl-methanesulfonate were stirred in 250 ml benzene and refluxed for 10.5 hours, while removing the water formed by azeotropic distillation. The volume of the solvent was gradually reduced to about 50 ml. The reaction mixture was cooled to room temperature, 50 ml water was added, and the mixture was extracted thrice with 100 ml diethyl ether. The combined organic phase was washed with 100 ml water and the solvent was removed under reduced pressure. The residue (12.01 grams) was dissolved in 200 ml of a 90:10:3 (v/v) mixture of methanol:water:concentrated hydrochloric acid, and the resulting solution was stirred at room temperature overnight and then refluxed for 1 hour. After cooling to room temperature, 100 ml water was added. The product was extracted thrice with 75 ml diethyl ether, washed consecutively with 100 ml water, 100 ml saturated aqueous solution of sodium bicarbonate, and again with 100 ml water. After drying on Na2SO4, the solvent was removed under reduced pressure, yielding 9.104 grams of crude 1-(cis-9-hexadecenyl)-sn-glycerol. The crude product was purified by chromatography on a silica gel (30 grams) column. 9.07 grams of pure 1-(cis-9-hexadecenyl)-glycerol was eluted by chloroform followed by a mixture of chloroform and 5% methanol. The yield was 91.8%.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][CH2:12][O:13][P:14]([CH2:19][N:20]1[CH:23](S(C)(=O)=O)[CH:22]([N:28]=[N+:29]=[N-:30])[C:21]1=[O:31])([O:16][CH2:17][CH3:18])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Cl:35])(=O)C>>[CH2:1]([O:8][C:9]([CH2:11][CH2:12][O:13][P:14]([CH2:19][N:20]1[CH:23]([Cl:35])[CH:22]([N:28]=[N+:29]=[N-:30])[C:21]1=[O:31])([O:16][CH2:17][CH3:18])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(=O)(CN1C(=O)C(N=[N+]=[N-])C1S(C)(=O)=O)OCCC(=O)OCc1ccccc1
Reactant: CC(=O)Cl
Product: CCOP(=O)(CN1C(=O)C(N=[N+]=[N-])C1Cl)OCCC(=O)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
1-(Benzyloxycarbonyldiethylphosphono)methyl-3-azido-4-methylsulfonyl-2-azetidinone (0.446 g.) is dissolved in acetyl chloride (5 ml.). The mixture is allowed to stand for 10 minutes and the acetyl chloride is removed under reduced pressured to afford 1-(benzyloxycarbonyldiethylphosphono)methyl-3-azido-4-chloro-2-azetidinone.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.O.[OH-].[Li+].Cl>C1COCC1.CO.O>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]=1/[CH:11]=[CH:10]/[C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:24])=[O:2])=[CH:5][N:6]=1
Reactant: COC(=O)c1ccc(/C=C/c2c(-c3ccccc3)noc2C)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1onc(-c2ccccc2)c1/C=C/c1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
To a suspension of 6-[(E)-2-(5-methyl-3-phenyl-isoxazol-4-yl)-vinyl]-nicotinic acid methyl ester (150 mg, 0.47 mmol) in THF (1.5 mL) and methanol (0.5 mL) was added a solution of lithium hydroxide monohydrate (39.2 mg, 0.94 mmol) in water (1.5 mL) added and the resulting mixture stirred at room temperature for 1 h. The mixture was acidified to pH 4 with HCl (1 N) and cooled to 0° C. The precipitate was filtered off and dried to afford the title compound (134 mg, 93%) which was obtained as a white solid. MS: m/e=305.4 [M−H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]([F:26])[C:10]([NH:13][C@@H:14]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]2)=[N:11][CH:12]=1)[CH3:2].Cl>CCO.O1CCOCC1>[F:26][C:9]1[CH:8]=[C:7](/[CH:6]=[CH:5]/[C:4]([O:3][CH2:1][CH3:2])=[O:27])[CH:12]=[N:11][C:10]=1[NH:13][C@@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1
Reactant: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)c(F)c1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCNC2)c(F)c1
Temperature: 24 °C
Reaction time: 3.5 h
Yield: 83.1 %

Procedure:
To an ice-cooled solution of tert-butyl (3R)-3-({5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-3-fluoro-2-pyridinyl}amino)-1-pyrrolidinecarboxylate (11.6 g) in EtOH (70 ml) was added solution of 4N HCl in dioxane (76.4 ml). The mixture was stirred at 24° C. for 3.5 hr, and evaporated under reduced pressure. The residue was poured into a mixture of water and CH2Cl2. The pH of the aqueous layer was adjusted to ca.9 with NaHCO3. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure to give ethyl (2E)-3-{5-fluoro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylate (7.1 g, 83%) as colorless powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[CH:4][C:3]=1[CH:9]=[N:10]O.C(C1NC=CN=1)(C1NC=CN=1)=O>ClCCl>[Cl:1][C:2]1[C:3]([C:9]#[N:10])=[CH:4][N:5]=[CH:6][C:7]=1[Cl:8]
Reactant: ON=Cc1cncc(Cl)c1Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Product: N#Cc1cncc(Cl)c1Cl
Yield: 7.5 %

Procedure:
To a suspension of 4,5-dichloropyridine-3-carbaldehyde oxime (7.84 g, 41.05 mmol) in dichloromethane (150 ml) was added carbonyl diimidazole (7.99 g, 49.26 mmol). The mixture was then heated to reflux for 1.5 hours before cooling then washing with saturated aqueous sodium bicarbonate (70 ml) and water (70 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuo. Purification of the resultant residue by flash chromatography (Si-PPC, cyclohexane:dichloromethane gradient 20:80 to 0:100) afforded the title compound as a white solid (0.53 g, 72%). LCMS (method B): RT=2.86 min, no ion present.
Reaction SMILES: [C:1]1([N:7]=[N:8][C:9]2[CH:21]=[CH:20][C:12]([O:13][CH2:14][C:15]([O:17]CC)=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CN(C)C=O.O>[C:1]1([N:7]=[N:8][C:9]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:20][CH:21]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)COc1ccc(N=Nc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)COc1ccc(N=Nc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
3.66 g (0.013 mol) of ethyl 2-[4-(phenylazo)phenoxy]-ethanoate was dissolved in a mixture of 160 mL of dimethylformamide and 40 mL of water in a 250 mL one-neck round flask fitted with a magnetic stirring bar and a reflux condenser by heating to 90° C. while stirring on an oil bath. 3.6 g (0.090 mol) of NaOH was added in once through the condenser. Stirring and heating were continued for 1.5 h after which the reaction mixture was left for cooling finally on an ice-bath. The reaction mixture was then added 38 mL of 5.5 N HCl. A yellow precipitate was recovered and 40 mL of water was added. After filtration and vacuum drying 14 h at 50° C. 2.70 g (yield 82%) of 2-[4-(phenylazo)phenoxy]-ethanoic acid was obtained.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[N:15]([C:16]2[S:20][C:19]([CH2:21][NH:22][C:23](=[O:34])[C@@H:24]([NH:26]C(=O)OC(C)(C)C)[CH3:25])=[CH:18][CH:17]=2)[N:14]=[C:13]([C:35]([F:38])([F:37])[F:36])[CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:26][C@@H:24]([CH3:25])[C:23]([NH:22][CH2:21][C:19]1[S:20][C:16]([N:15]2[C:11]([C:9]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])=[CH:12][C:13]([C:35]([F:36])([F:38])[F:37])=[N:14]2)=[CH:17][CH:18]=1)=[O:34]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccc(-n2nc(C(F)(F)F)cc2C(=O)NCc2ccccc2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)C(=O)NCc1ccc(-n2nc(C(F)(F)F)cc2C(=O)NCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.8 %

Procedure:
To a stirred solution of 26a (24 mg, 0.044 mmol) in CH2Cl2 (0.44 mL) was added trifluoroacetic acid (44 μL, 0.571 mmol). The mixture was stirred for 2 h at room temperature. The solvent was then evaporated and the residue was purified by silica gel column chromatography with gradient of MeOH (5-20%) in CH2Cl2. The residue was purified by prep-HPLC using an Aquasil C18 column with gradient of MeOH (5-95%) in water to afford 27a (7.7 mg, 39%) as a white solid. 1H NMR (DMSO-d6) δ(ppm): 9.41 (t, J=5.7 Hz, 1H), 8.69 (m, 1H), 8.28 (s, 1H), 7.41 (s, 1H), 7.33 (d, J=6.8 Hz, 2H), 7.28-7.24 (m, 3H), 7.05 (d, J=3.3 Hz, 1H), 6.86 (d, J=3.9 Hz, 1H), 4.44 (m, 2H), 4.40 (d, J=5.9 Hz, 2H), 3.44 (q, J=6.8 Hz, 1H), 1.20 (d, J=6.8 Hz, 3H). LRMS: calc 451.1; found 452.5 (MH)+.
Reaction SMILES: C1(N2C(=O)C3=CNC4[CH:14]=[C:15]([N:19]5[CH2:24]CN[CH2:21][CH2:20]5)C=CC=4C3=N2)C=CC=CC=1.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]2[C:32]3[C:33]([C:38](=[O:49])[N:39]([C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=4)[N:40]=3)=[CH:34][NH:35][C:36]=2[CH:37]=1.CN1CCNCC1>>[CH3:48][O:47][C:44]1[CH:45]=[CH:46][C:41]([N:39]2[C:38](=[O:49])[C:33]3=[CH:34][NH:35][C:36]4[CH:37]=[C:28]([N:27]5[CH2:21][CH2:20][N:19]([CH3:24])[CH2:15][CH2:14]5)[CH:29]=[CH:30][C:31]=4[C:32]3=[N:40]2)=[CH:42][CH:43]=1
Reactant: COc1ccc(-n2nc3c4ccc(N)cc4[nH]cc-3c2=O)cc1
Reactant: O=c1c2c[nH]c3cc(N4CCNCC4)ccc3c-2nn1-c1ccccc1
Agent: CN1CCNCC1
Product: COc1ccc(-n2nc3c4ccc(N5CCN(C)CC5)cc4[nH]cc-3c2=O)cc1

Procedure:
The title compound was prepared following the procedure for 14a using 13c and 1-methylpiperazine. 1H-NMR (CD3OD) δ (ppm): 2.32 (3H, s), 2.67 (4H, brm), 3.40 (4H, brm), 3.85 (3H, s), 6.88 (2H, m), 7.02 (1H, d, J=2.47 Hz), 7.31 (1H, dd, J=9.06, 2.20 Hz), 7.66 (2H, m), 8.16 (1H, d, J=9.06 Hz), 8.52 (1H, s). m/z 390.4 (MH+).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:34]=[CH:33][C:10]([CH2:11][N:12]2[CH2:16][C:15]([CH3:18])([CH3:17])[CH:14]([O:19][C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=3)[C:13]2=[O:32])=[CH:9][CH:8]=1.O>ClCCl>[OH:6][C:7]1[CH:34]=[CH:33][C:10]([CH2:11][N:12]2[CH2:16][C:15]([CH3:18])([CH3:17])[CH:14]([O:19][C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:31])([F:29])[F:30])[CH:21]=3)[C:13]2=[O:32])=[CH:9][CH:8]=1
Reactant: COc1ccc(CN2CC(C)(C)C(Oc3ccc(C#N)c(C(F)(F)F)c3)C2=O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC1(C)CN(Cc2ccc(O)cc2)C(=O)C1Oc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
Boron tribromide (3 eq.) was added dropwise to a −78° C. solution of 4-[1-(4-methoxy-benzyl)-4,4-dimethyl-2-oxo-pyrrolidin-3-yloxy]-2-trifluoromethyl-benzonitrile (220 mg, 1_eq. in dichloromethane, i.e. the product of example 7). The reaction was allowed to gradually warm to ambient temperature overnight. Water was carefully added to the reaction and the product was extracted into dichloromethane. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate, filtered and concentrated. The crude material was purified by flash column chromatography. (Procedure of example 8 will be referred to as a “demthylation reaction hereinafter”) MS (APCl, M+1) 405.0 LCMS: 50-2% H2O, 214 nm, 2.390 min, 100%
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[C:10](=[O:11])[CH:9]=[C:8]([CH3:12])[O:7][C:6]1=[O:13])C>[OH-].[NH4+]>[CH3:12][C:8]1[NH:2][CH:4]=[C:5]([C:6]([OH:7])=[O:13])[C:10](=[O:11])[CH:9]=1
Reactant: CC1=CC(=O)C(=CN(C)C)C(=O)O1
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cc(=O)c(C(=O)O)c[nH]1
Temperature: 70 °C
Yield: 53.7 %

Procedure:
A mixture of 3-(dimethylaminomethylene)-4-oxo-6-methyl-2-pyrone (85.0 g) and ammonium hydroxide (500 ml) is slowly heated to 70° C. with the condenser outlet open. The mixture is heated at 70°-80° C. for 3 hours, concentrated to a volume of about 100 ml and acidified with 3N HCl to pH 5. The product is filtered and washed with water and diethyl ether to give 38.6 g of the title compound. Physical characteristics are as follows:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]4[C:16]([CH3:22])=[N:17][N:18]([CH2:20][CH3:21])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:25][O:26][C:27]1[N:32]=[C:31]([O:33][CH3:34])[C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[CH3:25][O:26][C:27]1[N:32]=[C:31]([O:33][CH3:34])[C:30]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]5[C:16]([CH3:22])=[N:17][N:18]([CH2:20][CH3:21])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:29][N:28]=1
Reactant: CCn1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)c(C)n1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Product: CCn1cc(-n2c(=O)n(C)c3cnc4ccc(-c5cnc(OC)nc5OC)cc4c32)c(C)n1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate F, 0.101 mmol) and 2,4-dimethoxypyrimidine-5-boronic acid pinacol ester (Frontier Scientific, Logan, USA, 0.119 mmol) to give the title compound as a white foam. (HPLC: tR 2.51 min (Method A); M+H=446 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.32 (s, 1H), 8.11 (s, 1H), 8.07-8.04 (m, 1H), 7.78-7.74 (m, 1H), 7.56-7.54 (m, 1H), 4.14 (q, 2H), 3.92 (s, 1H), 3.92 (s, 3H), 3.57 (s, 3H), 1.95 (s, 3H), 1.33 (t, 3H))
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:11]1[N:16]=[C:15]2[O:17][C:18]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)=[C:19]([C:20]([NH:22][CH3:23])=[O:21])[C:14]2=[CH:13][C:12]=1I)[S:7]([CH3:10])(=[O:9])=[O:8].CO[C:34]1C=CC=C(OC)[C:39]=1[C:40]1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C(=O)([O-])[O-].[Na+].[Na+].C1(B(O)O)CC1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:11]1[N:16]=[C:15]2[O:17][C:18]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)=[C:19]([C:20]([NH:22][CH3:23])=[O:21])[C:14]2=[CH:13][C:12]=1[CH:40]1[CH2:39][CH2:34]1)[S:7]([CH3:10])(=[O:9])=[O:8]
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCCCBr)S(C)(=O)=O)c(I)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCCCBr)S(C)(=O)=O)c(C3CC3)cc12

Procedure:
To 6-(N-(4-bromobutyl)methylsulfonamido)-5-iodo-N-methyl-2-(p-tolyl)furo[2,3-b]pyridine-3-carboxamide (57 mg, 0.092 mmol) was added a premixed solution of S-Phos (3.77 mg, 9.19 μmol) and Pd(OAc)2 (0.825 mg, 3.68 μmol) in toluene (300 μL). Added a premixed solution of 2N SODIUM CARBONATE (919 μL, 1.838 mmol) and cyclopropylboronic acid (118 mg, 1.378 mmol) in toluene (900 μL). Degassed with N2 for 60 minutes.
Reaction SMILES: C([O:4][C@@H:5]([C:30]([NH:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=1)=[O:31])[C@@H:6](CC([O-])=O)[C:7]([N:9]([C:17]1[CH:25]=[C:24]2[C:20]([CH:21]=[CH:22][NH:23]2)=[CH:19][CH:18]=1)[CH2:10][CH2:11][O:12]S(C)(=O)=O)=[O:8])(=O)C.C([O-])([O-])=O.[K+].[K+].Cl.O>CO.CCOCC>[C:39]([C:36]1[CH:37]=[CH:38][C:33]([NH:32][C:30](=[O:31])[C@H:5]([OH:4])[C@H:6]2[O:12][CH2:11][CH2:10][N:9]([C:17]3[CH:25]=[C:24]4[C:20]([CH:21]=[CH:22][NH:23]4)=[CH:19][CH:18]=3)[C:7]2=[O:8])=[CH:34][CH:35]=1)#[N:40]
Reactant: CC(=O)O[C@@H](C(=O)Nc1ccc(C#N)cc1)[C@@H](CC(=O)[O-])C(=O)N(CCOS(C)(=O)=O)c1ccc2cc[nH]c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: N#Cc1ccc(NC(=O)[C@H](O)[C@H]2OCCN(c3ccc4cc[nH]c4c3)C2=O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 17.2 %

Procedure:
To a solution of compound 18-2 (0.34 g) in MeOH (10.2 mL), was added K2CO3 (272 mg) at 0° C. The reaction mixture was stirred at 0° C. overnight. Then 1N HCl (2 mL), H2O (5 mL) and Et2O (15 mL) were added into the reaction mixture. The precipitate was collected by filtration and was rinsed with H2O and Et2O to obtain compound 18-3 (40 mg) as a colorless amorphous solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([CH2:13][C:14]([CH3:22])([CH3:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][C:7]=1[Br:23].CN1CCOCC1.F[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>>[Br:23][C:7]1[CH:8]=[C:9]([CH2:13][C:14]([CH3:22])([CH3:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:10]=[C:11]([F:12])[C:6]=1[O:5][CH2:4][CH2:3][CH2:2][NH:1][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1
Reactant: CCOC(=O)CC(C)(C)Cc1cc(F)c(OCCCN)c(Br)c1
Reactant: Fc1ccccn1
Solvent: CN1CCOCC1
Product: CCOC(=O)CC(C)(C)Cc1cc(F)c(OCCCNc2ccccn2)c(Br)c1
Temperature: 115 °C

Procedure:
A mixture of the product of STEP 8 (0.725 g, 1.24 mmol), 4-methylmorpholine (1.01 g, 10 mmol), and 2-fluoropyridine (10 ml) was heated at 115° C. for 18 h under N2. The cooled reaction was concentrated. The residue was purified by chromatography (on silica gel, CH2Cl2/CH3OH/NH4OH=97/2/1) to give a brown oil in 0.251 g. NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH2:9])[N:3]=1.[CH2:10]1[C:14]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:13][CH:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:11]1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].CCN(CC)CC>C(O)(C)C>[NH2:9][C:4]1[N:3]=[C:2]([Cl:1])[N:7]=[C:6]([N:17]2[CH2:16][CH2:15][C:14]3([CH2:10][N:11]([C:25]([O:27][CH2:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[O:26])[CH:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13]3)[CH2:19][CH2:18]2)[N:5]=1
Reactant: CCOC(=O)C1CC2(CCNCC2)CN1C(=O)OCc1ccccc1
Reactant: Nc1nc(Cl)nc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCOC(=O)C1CC2(CCN(c3nc(N)nc(Cl)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 4,6-dichloro-1,3,5-triazin-2-amine (1.6 g) in isopropanol (14 mL) was added 2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (1.28 g, 3.7 mmol) and Et3N (7 mL). The solution was heated to reflux for 72 h, then cooled to RT, and concentrated in vacuo. Purification by normal phase chromatography (CH2Cl2/MeOH=50/1) afforded 2-benzyl 3-ethyl 8-(4-amino-6-chloro-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[C:8]([O:15][CH3:16])[C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH:4]=1)#[N:2].CO.C(OCC)C.[C-:24]#[N:25].[K+]>O>[C:1]([CH:3]1[C:12]2[C:7](=[C:8]([O:15][CH3:16])[C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH:4]1[C:24]#[N:25])#[N:2]
Reactant: [C-]#N
Reactant: COc1ccc2c(c1OC)CCC=C2C#N
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: COc1ccc2c(c1OC)CCC(C#N)C2C#N
Reaction time: 48 h
Yield: 41.3 %

Procedure:
A suspension of the compound of example 1 (29.2 g, 0.14 mole), 315 mL MeOH, and 110 mL diethyl ether was stirred mechanically, just below reflux temperature as a 45° solution of KCN (34 g, 0.52 mole) in 94 mL water was added dropwise, quickly. The reaction mixture was stirred at reflux for 1.5 hr. After cooling briefly a solution of NH4OAc (21 g, 0.27 mole) in 34 mL water was added. Water was added until cloudy and the solution was stored at 0° for 2 days. The solid was filtered, washed with 60° water, cold 50% aqueous MeOH, and dried (high-vacuum) to yield 14.0 g tan solid (41%); mp 107°-8°; M+ 242.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:29])[C:13](/[CH:23]=[CH:24]/[P:25](=[O:28])([OH:27])[OH:26])=[CH:14][N:15]3[CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:10][C:9]=2[F:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Na+].C1CCN2C(=NCCC2)CC1.[C:44]([O:50][CH2:51]Cl)(=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46].[Cl-].[NH4+]>C(#N)C.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:44]([O:50][CH2:51][O:28][P:25](/[CH:24]=[CH:23]/[C:13]1[C:12](=[O:29])[C:11]2[C:16](=[CH:17][C:8]([NH:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:9]([F:30])[CH:10]=2)[N:15]([CH:18]([CH2:19][CH3:20])[CH2:21][CH3:22])[CH:14]=1)([OH:27])=[O:26])(=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CCC(CC)n1cc(/C=C/P(=O)(O)O)c(=O)c2cc(F)c(NC3CCCCC3)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Cl-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCC(CC)n1cc(/C=C/P(=O)(O)OCOC(=O)C(C)(C)C)c(=O)c2cc(F)c(NC3CCCCC3)cc21
Temperature: 80 °C
Reaction time: 8 h

Procedure:
500 mg of {(E)-2-[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]vinyl}phosphonic acid was dissolved in 10 ml of acetonitrile, and 86 mg of sodium iodide, 0.51 ml of 1,8-diazabicyclo[5.4.0]-7-undecene, 194 mg of tetrabutylammonium hydrogensulfate and 0.53 ml of chloromethyl pivalate were added in that order, followed by overnight stirring at 80° C. Aqueous saturated ammonium chloride was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then evaporated under a reduced pressure. By purifying the resulting residue by silica gel column chromatography, 400 mg of bis{[(2,2-dimethylpropanoyl)oxy]methyl}{(E)-2-[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]vinyl}phosphonate (Example 25) and 190 mg of {[{(E)-2-[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydro-3-quinolinyl]vinyl}(hydroxy)phosphoryl]oxy}methyl pivalate (Example 26) were obtained.