Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:21])[CH2:17]C(=O)C)=[C:11]([N+:22]([O-])=O)[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[C:9]2[CH:10]=[C:11]3[C:12](=[CH:13][CH:14]=2)[NH:15][C:16](=[O:21])[CH:17]=[N:22]3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CC(=O)Nc1ccc(C(c2cccc(Cl)c2)n2ccnc2)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: O=c1cnc2cc(C(c3cccc(Cl)c3)n3ccnc3)ccc2[nH]1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
A mixture of 12 parts of N-[4-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-2-nitrophenyl]-3-oxobutanamide and 120 parts of sodium hydroxide solution 6.5% was stirred for 15 minutes at 80° C. After cooling, the product was obtained, yielding 10.25 parts (100%) of 6-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-2(1H)-quinoxalinone, N4 -oxide (comp. 175).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[O:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:4][CH:3]=1.Br[CH2:39][C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][CH:47]=1)[C:43]#[N:44]>CC(O)=O.CC(O)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[C:43]([C:42]1[CH:41]=[C:40]([CH:47]=[CH:46][CH:45]=1)[CH2:39][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[O:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:6][CH:7]=1)#[N:44]
Reactant: COCCOc1c(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(O)cc2)ccc2ccccc12
Reactant: N#Cc1cccc(CBr)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: COCCOc1c(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCc3cccc(C#N)c3)cc2)ccc2ccccc12

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-4-(4-allyloxy-phenyl)-3-hydroxy-piperidine-1-carboxylate [Example 86 (b)] with 2-chloromethyl-1-(2-methoxy-ethoxy)-naphthalene there was obtained (3RS,4RS)-4-(4-allyloxy-phenyl)-3-[1-(2-methoxy-ethoxy)-naphthalen-2-ylmethoxy)-piperidine-1-carboxylate, from which after cleavage of the allyl group by means of bis-(triphenylphosphine)-palladium(II) diacetate analogously to Example 152 (e) there resulted tert-butyl (3RS,4RS)-4-(4-hydroxy-phenyl)-3-[1-(2-methoxy-ethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate, alkylation of which analogously to Example 44 (e) with 3-bromomethyl-benzonitrile gave tert-butyl (3RS,4RS)-4-[4-(3-cyano-benzyloxy)-phenyl]-3-[1-(2-methoxy-ethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate as a colourless oil; MS: 623 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:45])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]4[CH:25]=[C:24]([C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=5)[N:23]=[N:22]4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:33])[C:12]=2[C@H:34]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+].[CH2:52](Br)[CH:53]=[CH2:54]>CN(C=O)C>[CH2:1]([O:4][C:5]1([CH3:45])[CH2:6][CH2:7][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]4[CH:25]=[C:24]([C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:54][CH:53]=[CH2:52])[CH:27]=5)[N:23]=[N:22]4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:33])[C:12]=2[C@H:34]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:9][CH2:10]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(Cn4cc(-c5cccc(O)c5)nn4)nn23)CC1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cccc(-c2cn(Cc3cc4nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N5CCC(C)(OCC=C)CC5)n4n3)nn2)c1
Temperature: 60 °C
Yield: 32.9 %

Procedure:
A mixture of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((4-(3-hydroxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.0525 g, 0.085 mmol), K2CO3 (0.047 g, 0.340 mmol) and allyl bromide (0.074 ml, 0.850 mmol) in DMF (3 mL) was heated at 60° C. for 24 h. Then, cooled and purified prep-HPLC to afford (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((4-(3-(allyloxy)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.0184 g, 0.028 mmol, 32.9% yield) as colorless paste. 1H NMR (500 MHz, CDCl3) δ 7.90 (s, 1H), 7.46 (dd, J=1.5, 2.4 Hz, 1H), 7.35-7.38 (m, 1H), 7.29-7.34 (m, 1H), 6.90 (ddd, J=1.0, 2.6, 8.1 Hz, 1H), 6.51 (s, 1H), 5.98-6.14 (m, 2H), 5.88 (br. s., 1H), 5.79 (s, 2H), 5.45 (qd, J=1.6, 17.2 Hz, 2H), 5.31 (qd, J=1.4, 10.4 Hz, 1H), 5.20 (qd, J=1.6, 10.4 Hz, 1H), 4.62 (td, J=1.5, 5.3 Hz, 2H), 4.14-4.28 (m, 2H), 4.00 (d, J=5.0 Hz, 2H), 2.70-3.90 (m, 3H), 2.61 (s, 3H), 1.85-2.03 (m, 3H), 1.64-1.74 (m, 2H), 1.31 (s, 3H), 1.25 (t, J=7.1 Hz, 3H), 1.24 (s, 9H). LCMS (M+H)=658.6.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Ba+2].Cl.[H][H]>C(O)C.[Pd]>[ClH:1].[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NNc1ccc([N+](=O)[O-])cc1)c1ccc(Cl)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1ccc(NNC(=O)c2ccc(Cl)cc2)cc1

Procedure:
1-(4-Chlorobenzoyl)-2-(4-nitrophenyl)hydrazine (2.92g, 0.01 mole) and 5% palladium or barium sulfate (catalytic amount) were suspended in a mixture of ethanol (350 ml) and concentrated hydrochloric acid (5 ml) in a Parr shaker bottle. The reaction mixture was hydrogenated at room temperature until the theoretical amount of hydrogen had been taken up. The reaction mixture was filtered and the solvent was evaporated from the filtrate leaving a tan solid. Yield 2.9 g (99%), m.p. 209° C (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=3)[C:11]([OH:26])=[C:10]([C:27](OCC)=[O:28])[C:9]2=[O:32])=[CH:4][CH:3]=1.[CH3:33][O:34][CH2:35][CH2:36][NH2:37]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=3)[C:11]([OH:26])=[C:10]([C:27]([NH:37][CH2:36][CH2:35][O:34][CH3:33])=[O:28])[C:9]2=[O:32])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Reactant: COCCN
Solvent: CCO
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Temperature: 140 °C
Yield: 86 %

Procedure:
Ethyl 1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (21 mg, 0.048 mmol) was dissolved in ethanol (1 mL) and [2-(methyloxy)ethyl]amine (0.05 mL) was added. This solution was heated in a microwave at 140° C. for 20 minutes. The resulting suspension was concentrated under reduced pressure and 1 N hydrochloric acid was added to bring the mixture to a pH of 3. The resulting white solid was collected by vacuum filtration to yield 1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[2-(methyloxy)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (19.8 mg, 86%). 1H NMR (CDCl3) δ 10.07 (m, 1 H), 8.52 (s, 1 H), 7.30-7.28 (m, 2 H), 7.22-7.18 (m, 2 H), 7.02-6.92 (m, 4 H), 6.70 (s, 1 H), 3.95 (s, 2 H), 3.65-3.60 (m, 2 H), 3.55-3.52 (m, 2 H), 3.33 (s, 3 H); MS m/z 459 (M+23).
Reaction SMILES: [CH2:1]([N:8]1[CH:17]=[C:16](I)[C:15]2[C:10](=[CH:11][CH:12]=[N:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[C:25](B(O)O)=[C:24]([CH3:29])[O:23][N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[CH:17]=[C:16]([C:25]2[C:21]([CH3:20])=[N:22][O:23][C:24]=2[CH3:29])[C:15]2[C:10](=[CH:11][CH:12]=[N:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c2ccncc2c(I)cn1Cc1ccccc1
Reactant: Cc1noc(C)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1noc(C)c1-c1cn(Cc2ccccc2)c(=O)c2ccncc12
Temperature: 95 °C
Yield: 31.8 %

Procedure:
A mixture of 2-benzyl-4-iodo-2,6-naphthyridin-1(2H)-one (0.070 g, 0.19 mmol), (3,5-dimethylisoxazol-4-yl)boronic acid (0.041 g, 0.29 mmol) and Na2CO3 (0.062 g, 0.58 mmol) in toluene (15 mL), ethanol (15 mL) and water (2 mL) was degassed. Pd(PPh3)4 (0.022 g, 0.19 μmol) was then added and the reaction was heated at 95° C. for 17 h. After that time the reaction was cooled to rt, concentrated under reduced pressure and diluted with ethyl acetate (30 mL). The organic phase was washed with water then brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol) followed by trituration with diethyl ether to give 2-benzyl-4-(3,5-dimethylisoxazol-4-yl)-2,6-naphthyridin-1(2H)-one (0.020 g, 32%) as an off-white solid: mp 159-161° C.; 1H NMR (400 MHz, CDCl3) δ 8.78 (d, J=5.4 Hz, 1H), 8.65 (s, 1H), 8.30 (d, J=5.4 Hz, 1H), 7.30-7.40 (m, 5H), 7.04 (s, 1H), 5.26 (s, 2H), 2.26 (s, 3H), 2.09 (s, 3H); ESI MS m/z 332 [M+H]+.
Reaction SMILES: S(=O)(=O)(O)O.[P:6](=[O:10])([OH:9])([OH:8])[OH:7].[O-2].[Zn+2:12]>O>[P:6]([O-:10])([O-:9])([O-:8])=[O:7].[Zn+2:12].[P:6]([O-:10])([O-:9])([O-:8])=[O:7].[Zn+2:12].[Zn+2:12]
Reactant: O=P(O)(O)O
Agent: O=S(=O)(O)O
Agent: [O-2]
Agent: [Zn+2]
Solvent: O
Product: O=P([O-])([O-])[O-]

Procedure:
607 g of 97% sulfuric acid and 507 g of 85% phosphoric acid were mixed to 7,000 g of water, and 326 g of zinc oxide was added and dissolved therein to obtain an aqueous zinc phosphate solution having a phosphorus/zinc molar ratio of 1.10.
Reaction SMILES: Cl.[C:2]([O:5][CH2:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:29])[CH:11]2[NH:15][C:16](=[O:28])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]=[N+:26]=[N-:27])=[CH:20][CH:19]=2)[C:8]=1[C:30]([OH:32])=[O:31])(=[O:4])[CH3:3].[C:33]([O:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44]O)=[CH:42][CH:41]=1)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[C:33]([O:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44][O:31][C:30]([C:8]2[N:9]3[CH:12]([S:13][CH2:14][C:7]=2[CH2:6][O:5][C:2](=[O:4])[CH3:3])[CH:11]([NH:15][C:16](=[O:28])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][N:25]=[N+:26]=[N-:27])=[CH:22][CH:23]=2)[C:10]3=[O:29])=[O:32])=[CH:42][CH:41]=1)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccc(CN=[N+]=[N-])cc3)C2SC1
Reactant: CC(C)(C)C(=O)Oc1ccc(CO)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)OCC1=C(C(=O)OCc2ccc(OC(=O)C(C)(C)C)cc2)N2C(=O)C(NC(=O)Cc3ccc(CN=[N+]=[N-])cc3)C2SC1

Procedure:
To a solution of 1.8 g of 3-[(acetyloxy)methyl]-7-[[2-[4-(azidomethyl)phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid hydrochloride in 25 ml of dimethyl formamide is added 0.78 g of ρ-pivalyloxybenzyl alcohol followed by cooling to 0° C. after with 3.7 mole of dicyclohexylcarbodiimide in 7.5 ml of dimethyl formamide is added dropwise with stirring. The reaction mixture is stirred for 1 hours at 0° C. and for an additional 4 hours at room temperature. The formed dicyclohexylurea is removed by filtration. The filtrate is diluted with chloroform and washed with water. The organic layer is then dried over magnesium sulfate filtered and evaporated in vacuo to give an oil which is triturated with ether to give 3-[(acetyloxy)-methyl]-7-[[2-[4-(azidomethyl)phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid ρ-pivalyloxybenzyl ester.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][C:13]1[CH:14]=[C:15]([CH:22]=[CH:23][CH:24]=1)[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.CN(CCN(C)C)C.[CH:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>C1COCC1.O>[N:17]1([CH:16]([C:15]2[CH:14]=[C:13]([CH3:12])[CH:24]=[CH:23][CH:22]=2)[CH:33]([OH:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: Cc1cccc(Cn2ccnc2)c1
Reactant: CC(C)(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: Cc1cccc(C(C(O)C(C)(C)C)n2ccnc2)c1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 8.3 %

Procedure:
39 ml (60 mmol) of a 1.55 molar n-butyllithium/hexane solution were added dropwise to a solution of 5.17 g (30 mmol) of N-(3-methylbenzyl)-imidazole and 3.49 g (30 mmol) of TMEDA in 60 ml of absolute THF at -70° C. The mixture was stirred for 30 minutes at about -70° C., after which a solution of 3.80 g (33 mmol) of 75% strength pivalaldehyde in 30 ml of absolute THF was added dropwise at about -70° C. in the course of 20 minutes, stirring was continued for 20 minutes at about -70° C. and the mixture was allowed to warm up to room temperature in the course of 2 hours. Thereafter, water was added, while cooling, and the resulting mixture was extracted with ether. The residue (9.3 g) from the ether extract was crystallized from a diisopropyl ether/hexane mixture. This gave 2.2 g of crystals, which consisted of about 90% of a by-product, 1-(3-methylbenzyl)-2-(1-hydroxy-2,2-dimethylprop-1-yl)-imidazole. The residue from the mother liquor was recrystallized from a diisopropyl ether/acetonitrile solution, and the crystalline product isolated in this procedure was then recrystallized twice from acetonitrile. 0.64 g (=8.3% of theory) of pure 1-(1-imidazolyl)-1-(3-tolyl)-3,3-dimethylbutan-2-ol of melting point 126° C. was obtained in this manner.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH2:5][NH2:6].[CH:14]1[C:23]2[C:18](=[C:19]([CH:24]([CH2:28][CH3:29])[C:25](O)=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:11])([F:12])[F:13])[CH2:5][NH:6][C:25](=[O:26])[CH:24]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[CH:17]=[CH:16][N:15]=[CH:14]2)[CH2:28][CH3:29]
Reactant: NCc1ccc(C(F)(F)F)c(F)c1
Reactant: CCC(C(=O)O)c1cccc2cnccc12
Agent: O=C(O)Cc1cccc2cnccc12
Product: CCC(C(=O)NCc1ccc(C(F)(F)F)c(F)c1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 3-fluoro-4-(trifluoromethyl)benzylamine and 2-(5-isoquinolinyl)butanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 391 (M+H)+; MS (ESI−) m/z 389 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 0.91 (t, J 7.5, 3H), 1.81 (m, 1H), 2.17 (m, 1H), 4.35 (m, 2H), 7.17 (m, 2H), 7.69 (t, J 7.8, 1H), 7.86 (t, J 7.8, 1H), 8.04 (d, J 7.1, 1H), 8.23 (d, J 8.1, 1H), 8.65 (d, J 6.8, 1H), 8.83 (t, J 6.8, 1H), 9.60 (s, 1H); Anal. Calcd for C21H18F4N2O+1HCl: C, 54.77; H, 3.80; N, 5.55. Found: C, 54.62; H, 3.57; N, 5.50.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9]([CH2:11][C:12]([F:15])([F:14])[F:13])=[O:10])=[CH:4][C:3]=1[OH:16].[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27]O)=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[F:17][C:18]([F:29])([F:30])[O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][O:16][C:3]2[CH:4]=[C:5]([S:9]([CH2:11][C:12]([F:14])([F:15])[F:13])=[O:10])[C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])=[CH:24][CH:25]=1
Reactant: Cc1cc(C)c(S(=O)CC(F)(F)F)cc1O
Reactant: OCCc1ccc(OC(F)(F)F)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C)c(S(=O)CC(F)(F)F)cc1OCCc1ccc(OC(F)(F)F)cc1
Reaction time: 16 h
Yield: 40.1 %

Procedure:
In 30 ml of tetrahydrofuran were dissolved 0.3 g (1.19 mmol) of 2,4-dimethyl-5-(2,2,2-trifluoroethylsulfinyl)phenol, 0.29 g (1.41 mmol) of 2-(4′-trifluoromethoxyphenyl)ethanol and 0.41 g (1.56 mmol) of triphenylphosphine. Thereto was added 0.31 g (1.53 mmol) of diisopropyl azodicarboxylate at room temperature, and stirred for 16 hours. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: a mixed solvent of n-hexane:ethyl acetate=5:1), and the residue was washed with n-hexane, to obtain 0.21 g (yield: 40%) of an intended product.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([NH:10][C:11]([C:13]2[C:14]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:12])=[CH:8][CH:7]=[CH:6][N:5]=1.[H][H]>CN(C)C=O.O>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:19]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:11](=[O:12])[NH:10][C:9]3[CH:8]=[CH:7][CH:6]=[N:5][C:4]2=3)=[CH:22][CH:23]=1
Reactant: [H][H]
Reactant: COc1ccc(CNc2ncccc2C(=O)Nc2cccnc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2c3ncccc3NC(=O)c3cccnc32)cc1
Temperature: 110 °C
Yield: 48.1 %

Procedure:
1.44 g of a 50% dispersion of sodium hydride in mineral oil was added to a solution of 3.69 g (0.010 mol) N-(2-chloro-3-pyridinyl)-2-[[(4-methoxyphenyl)methyl]amino]-3-pyridinecarboxamide in 100 ml of dimethylformamide. After the evolution of hydrogen stopped, the mixture was heated (110° C.) for 16 hours and then refluxed for eight hours. After the mixture had cooled, the excess sodium hydride was decomposed by the slow addition of ice. The mixture was further diluted with water, and the product was extracted with ether and concentrated. The crystallized residue was filtered and washed with ether to give 1.60 g of 5,11-dihydro-11-[(4-methoxyphenyl)methyl]-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (50% of theory) as an off-white powder, m.p. 209°-210° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:13](=[O:14])[N:12]3[C:15](=[O:22])[C:16]([CH3:21])([CH:18]([CH3:20])[CH3:19])[N:17]=[C:11]3[C:7]2=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[H-].[Na+].[CH2:25]([OH:31])[C:26]1[O:30][CH:29]=[CH:28][CH:27]=1.C(O)(=O)C>O1CCCC1>[C:1]([C:4]1[C:9]([CH3:10])=[N:8][C:7]([C:11]2[NH:12][C:15](=[O:22])[C:16]([CH:18]([CH3:19])[CH3:20])([CH3:21])[N:17]=2)=[C:6]([CH:5]=1)[C:13]([O:31][CH2:25][C:26]1[O:30][CH:29]=[CH:28][CH:27]=1)=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc2c(nc1C)C1=NC(C)(C(C)C)C(=O)N1C2=O
Reactant: OCc1ccco1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)c1cc(C(=O)OCc2ccco2)c(C2=NC(C)(C(C)C)C(=O)N2)nc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.0 g of 7-acetyl-2,8-dimethyl-2-isopropyl-5H-imidazo[1',2':1,2]pyrrolo[3,4-b]-pyridine-3(2H),5-dione in 50 mL tetrahydrofuran is added dropwise to a preformed mixture of 0.03 g sodium hydride and 0.35 mL furfuryl alcohol in 50 mL tetrahydrofuran. The reaction mixture is stirred at room temperature overnight, acidified with acetic acid, and concentrated in vacuo. The residue is chromatographed on silica gel using 5% ethyl acetate in methylene chloride as eluant to afford the desired product. Recrystallization from methylene chloride-hexanes gives a solid, mp 133°-136°.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([CH:12]=[C:13]([CH:16]=[O:17])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[CH2:27](O)[CH2:28][OH:29].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1COCC1>[O:17]1[CH2:27][CH2:28][O:29][CH:16]1[C:13]1[C:14]([F:15])=[C:2]([F:1])[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([CH:12]=1)[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: OCCO
Reactant: O=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NOCCO)c1cc(C2OCCO2)c(F)c(F)c1Nc1ccc(I)cc1F
Reaction time: 14 h

Procedure:
To a solution of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide (15.99 g, 33.3 mmol) prepared in Step F in anhydrous THF (150 ml) were added ethylene glycol (70 ml) and p-toluenesulfonic acid monohydrate (316.6 mg, 1.66 mmol) at room temperature, and the mixture was stirred for 14 hours. Then ethylene glycol (100 ml) was added, and the reaction mixture was stirred for additional 8 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 5-[1,3]dioxolan-2-yl-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide (21.69 g) as a crude product.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH:5]([CH2:22][S:23]C(=O)C)[CH2:6][C:7]1[CH:8]=[N:9][C:10]([NH:14]C(OC(C)(C)C)=O)=[C:11]([Cl:13])[CH:12]=1)C>Cl>[NH2:14][C:10]1[N:9]=[CH:8][C:7]([CH2:6][CH:5]([CH2:22][SH:23])[C:4]([OH:27])=[O:3])=[CH:12][C:11]=1[Cl:13]
Reactant: CCOC(=O)C(CSC(C)=O)Cc1cnc(NC(=O)OC(C)(C)C)c(Cl)c1
Agent: Cl
Product: Nc1ncc(CC(CS)C(=O)O)cc1Cl
Yield: 110.5 %

Procedure:
A solution of 2-acetylsulfanylmethyl-3-(6-tert-butoxycarbonylamino-5-chloro-pyridin-3-yl)-propionic acid ethyl ester (55mg, 0.132 mmol) in concentrated HCl (4 mL) was refluxed for 90 min. The reaction was cooled and concentrated under reduced pressure to give the title compound as the HCl salt (36mg, 96.4%)
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][OH:11].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=O.O>C1COCC1>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:19]2[O:11][CH2:10][C:9]([CH3:13])([CH3:12])[N:8]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: CC(C)(N)CO
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cccc(C2=NC(C)(C)CO2)c1
Temperature: 0 °C
Reaction time: 24 h
Yield: 73.1 %

Procedure:
Triethylamine (23.0 mL) was added to a solution of 2-amino-2-methyl-1-propanol (14.4 g) in THF (200 mL), 3-methoxybenzoyl chloride (25.0 g) was dropped thereinto at 0° C. and the mixture was stirred at room temperature for 1 day. After water was added to the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over sodium sulfate, filtered and concentrated in vacuo. Thionyl chloride (25 mL) was dropped into the resulting residue at 0° C. and stirred at room temperature for 3 hours. An aqueous solution of sodium hydroxide was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was evaporated in vacuo to give the aimed compound (22.0 g, 81%) as a colorless oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([O:29]CC2C=CC=CC=2)[C@@H:15]([NH:25][C:26](=[O:28])[CH3:27])[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C@H:10]([O:37][CH2:38][CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:29])[C@@H:15]([NH:25][C:26](=[O:28])[CH3:27])[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C@@H:10]([O:37][CH2:38][CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](OCc1ccccc1)[C@H]1CO[C@H](OCCC(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CO[C@@H](OCCC(C)(C)C)CN1C(=O)OC(C)(C)C
Yield: 99.2 %

Procedure:
Stir (2S,5R)-5-[(1S,2S)-2-Acetylamino-1-benzyloxy-3-(3,5-difluorophenyl)-propyl]-2-(3,3-dimethylbutoxy)-morpholine-4-carboxylic acid tert-butyl ester (0.18 g, 0.29 mmol) and 10% palladium on carbon (0.18 g) in ethanol (5 mL) under hydrogen at room temperature for 14 hours. Filter through Celite® and concentrate to give the title compound (0.148 g, 99.4% yield).