Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].[N+:11]([O-])([OH:13])=[O:12]>>[N+:11]([C:7]1[CH:8]=[CH:9][C:4]2[NH:3][C:2](=[O:10])[O:1][C:5]=2[CH:6]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: O=c1[nH]c2ccccc2o1
Product: O=c1[nH]c2ccc([N+](=O)[O-])cc2o1
Temperature: 0 °C

Procedure:
A solution of 3H-Benzooxazol-2-one (10.0 g) in concentrated HNO3 (100 ml) was stirred at 40° C. A precipitate formed and the reaction temperature rose. It was cooled below 50 ° C. in an ice bath. The mixture was diluted with ice water, and the precipitate was isolated by filtration. The product was washed with water to give a white solid. (8.4 g). M.P. 239-241.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:18])/[CH2:11][CH2:12][C:13](=[O:17])[C:14]([CH3:16])=[CH2:15])=[CH:3]\[C:4]([NH2:6])=[O:5].S[CH2:20][CH2:21][OH:22].C(N(CC)CC)C>CO>[OH:22][CH2:21][CH2:20][CH2:15][CH:14]([CH3:16])[C:13](=[O:17])[CH2:12][CH2:11]/[C:10](/[CH3:18])=[CH:9]/[CH2:8][CH2:7]/[C:2](/[CH3:1])=[CH:3]/[C:4]([NH2:6])=[O:5]
Reactant: C=C(C)C(=O)CC/C(C)=C/CC/C(C)=C/C(N)=O
Reactant: OCCS
Solvent: CCN(CC)CC
Solvent: CO
Product: C/C(=C\C(N)=O)CC/C=C(\C)CCC(=O)C(C)CCCO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4.1 g (0.016 mol) of (E,E)-3,7,11-trimethyl-10-oxo-2,6,11-dodecatrienamide in 125 ml of methanol is treated with 3.5 ml of 2-mercaptoethanol and 7 ml of triethylamine. The solution is stirred at room temperature for 18 hours. After removing the solvent the residue is taken up three times in toluene and freed from solvent on a rotary evaporator. The residue is chromatographed on silica gel with ether-methanol 10:1. There is obtained (2E,6E)-12-(2-hydroxyethyl)-3,7,11-trimethyl-10-oxo-2,6-dodecadienamide which exhibits the following absorption bands in the IR spectrum: 3340 cm-1, 3201 cm-1, 2924 cm-1, 1707 cm-1, 1669 cm-1, 1608 cm-1, 1409 cm-1, 1369 cm-1, 1305 cm-1, 1046 cm-1, 1012 cm-1.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][CH3:14]>CO>[CH2:13]([C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[C:3]([OH:15])=[O:2])[CH3:14]
Reactant: CCc1ccc([N+](=O)[O-])cc1C(=O)OC
Solvent: CO
Product: CCc1ccc([N+](=O)[O-])cc1C(=O)O
Yield: 48.2 %

Procedure:
Ethyl-5-nitrobenzoic acid methyl ester (1.0 g) in methanol/2N sodium hydroxide (60 ml, 1:1) was stirred for 1 h at 60° C. Half the solvent was removed at reduced pressure, the residue diluted with water (20 ml), washed with dichloromethane and the aqueous phase acidified with 2N HCl. The acidic phase was extracted with dichloromethane, the combined extracts dried (MgSO4) and solvent removed at reduced pressure to give the title compound (0.45 g) as a colourless solid. 1H NMR (CDCl3) δ: 1.32 (3H, t, J=7.6 Hz), 3.19 (2H, q, J=7.6 Hz), 7.52 (1H, d, J=8.4 Hz), 8.33 (1H, dd, J=2.5, 8.4 Hz), 8.90 (1H, d, J=2.5 Hz).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[N:8]([CH3:17])[C:7]2[CH:18]=[CH:19][CH:20]=[N:21][C:6]1=2)=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[CH2:28]1[O:43][C:42]2[CH:41]=[CH:40][C:32]([CH2:33][N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[CH:31][C:30]=2[O:29]1>C(O)C>[CH3:17][N:8]1[C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:5]([C:3](=[O:4])[CH2:2][N:37]2[CH2:38][CH2:39][N:34]([CH2:33][C:32]3[CH:40]=[CH:41][C:42]4[O:43][CH2:28][O:29][C:30]=4[CH:31]=3)[CH2:35][CH2:36]2)[C:6]2[N:21]=[CH:20][CH:19]=[CH:18][C:7]1=2
Reactant: CN1C(=O)c2ccccc2N(C(=O)CCl)c2ncccc21
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CN1C(=O)c2ccccc2N(C(=O)CN2CCN(Cc3ccc4c(c3)OCO4)CC2)c2ncccc21

Procedure:
10.5 gm of 11-chloroacetyl-5,11-dihydro-5-methyl-6H-pyrido[2,3-b]-[1,4]benzodiazepine-6-one, 3.8 gm of sodium carbonate and 8 gm of 1-[(3,4-methylenedioxy)benzyl]-piperazine were reacted in 200 ml of absolute ethanol and worked up in analogy to Example 1.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[CH:3]=1.[H-].[Na+].[F:21][C:22]([F:29])([F:28])[CH2:23][CH2:24][C:25](Cl)=[O:26].C(=O)([O-])O.[Na+]>CN(C=O)C.O>[C:12]1([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][N:7]=3)[C:2]([O:1][C:25](=[O:26])[CH2:24][CH2:23][C:22]([F:29])([F:28])[F:21])=[CH:3][C:4]2=[O:18])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)CCC(F)(F)F
Reactant: O=c1cc(O)c2cccnc2n1-c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCC(F)(F)F)Oc1cc(=O)n(-c2ccccc2)c2ncccc12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
In accordance with a process described in JP-61-246183A, 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one was synthesized. To a suspension of the synthesized compound (953 mg, 4.0 mmol) in DMF (32 mL) was added sodium hydride (purity of about 60%, 176 mg, 4.4 mmol, 1.1 eq.), and the mixture was stirred at a room temperature for 40 minutes. Then, 4,4,4-trifluorobutyryl chloride (4.4 mmol, 1.1 eq.) was added thereto with cooling in an ice bath, and the mixture was stirred at a room temperature for 2 hours. Thereafter, a sodium hydrogencarbonate aqueous solution and water were added to the reaction solution, and the precipitate was separated by filtration and dried to give 1-phenyl-4-(4,4,4-trifluorobutyryloxy)-1,8-naphthyridin-2(1H)-one as a form of crystal (955 mg, yield 66%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=O)[CH:3]=1.C(N(CC)C(C)C)(C)C.Cl.[NH2:29][OH:30]>CO>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8]/[C:9](/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:29]/[OH:30])[CH:3]=1
Reactant: COc1ccc(C(=O)Cc2cc(Br)ccn2)cc1
Reactant: NO
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1ccc(/C(Cc2cc(Br)ccn2)=N\O)cc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 67.8 %

Procedure:
To a stirred solution of 2-(4-bromopyridin-2-yl)-1-(4-methoxyphenyl)ethanone (3.8 g, 12.4 mmol) and N,N-diisopropylethylamine (5.4 mL, 31 mmol) in methanol (60 mL) at room temperature was added hydroxylamine hydrochloride (1.7 g, 24.8 mmol). The mixture was stirred at 60° C. for 2 days. After cooling to room temperature, the precipitate formed was filtered and dried under vacuum to afford white needles (2.7 g, 68%). The material was used as is in the next step. LCMS m/z 321.0; 323.0 (M+H)+, ret. time=2.37 min.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9](=[N:15][OH:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH2:17]([Cl:20])[C:18]#[CH:19]>O>[Cl:20][CH2:17][C:18]1[O:16][N:15]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:19]=1
Reactant: CCOC(=O)C(Cl)=NO
Reactant: C#CCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(CCl)on1
Reaction time: 1 h

Procedure:
21.2 g (210 mmol) of triethylamine were added dropwise with stirring to a mixture, cooled to 10-15° C., of 30 g (198 mmol) of ethyl 2-chloro-2-hydroxyiminoacetate and 150 ml of propargyl chloride, stirring was continued for 1 hour at room temperature, water was subsequently added, the mixture was extracted with ether, and the organic phase was dried over magnesium sulfate and evaporated in vacuo in a rotary evaporator. The residue was distilled in vacuo at 0.5 torr, the product distilling over at 116-122° C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([CH2:16][CH2:17][CH:18]4[N:24]=[C:23]([NH2:25])[CH2:22][CH2:21][CH2:20][CH2:19]4)[NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][N:27]([CH3:56])[S:28](C1C=CC(C2C=C3N=C(CCC4CCCCC(=S)N4)NC3=NC=2)=CC=1)(=[O:30])=[O:29].N>CO>[NH2:25][C:23]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]([CH2:17][CH2:16][C:14]2[NH:13][C:10]3=[N:11][CH:12]=[C:7]([C:1]4[CH:2]=[CH:3][C:4]([S:28]([N:27]([CH3:56])[CH3:26])(=[O:30])=[O:29])=[CH:5][CH:6]=4)[CH:8]=[C:9]3[N:15]=2)[N:24]=1
Reactant: NC1=NC(CCc2nc3cc(-c4ccccc4)cnc3[nH]2)CCCC1
Reactant: CN(C)S(=O)(=O)c1ccc(-c2cnc3[nH]c(CCC4CCCCC(=S)N4)nc3c2)cc1
Agent: N
Solvent: CO
Product: CN(C)S(=O)(=O)c1ccc(-c2cnc3[nH]c(CCC4CCCCC(N)=N4)nc3c2)cc1

Procedure:
The title compound is synthesized as described for 7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-4,5,6,7-tetrahydro-3H-azepin-2-ylamine (compound 1) from 50 mg of N,N-dimethyl-4-{2-[2-(7-thioxo-azepan-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-benzenesulfonamide (compound A5) and 2.53 ml of methanol containing ammonia (strength: 7.0 M) at 50° C. for 65 hours. Purification by flash chromatography on LiChroprep-NH2® (eluent: dichloromethane/0-10 vol. % methanol) and lyophilisation from dioxane/water (10:1 parts by volume) afford 32 mg of the title compound as an amorphous, colorless solid of m.p. 195° C. (decomp.). ESI-MS: 441.2 (MH+). TLC: Rf=0.44 (LiChroprep-NH2® HPTLC, methanol/water 10:1 parts by volume).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:25][C:26]1([NH2:30])[CH2:29][O:28][CH2:27]1>>[CH3:25][C:26]1([NH:30][C:21]([C:17]2[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH3:24])[CH:16]=2)=[O:22])[CH2:29][O:28][CH2:27]1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)n(C)n1
Reactant: CC1(N)COC1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NC2(C)COC2)n(C)n1
Yield: 90 %

Procedure:
As described for example 55, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.3 mmol) was converted, using 3-methyl-3-oxetanamine instead of 2-amino-2-methyl-1-propanol, to the title compound (109 mg, 90%), which was obtained as a white solid. MS: m/e=401.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[C:23]([OH:24])=[CH:22][C:21]3[C:20]([CH3:26])([CH3:25])[CH2:19][CH2:18][C:17]([CH3:28])([CH3:27])[C:16]=3[CH:15]=2)=[O:13])[CH:8]=[C:7]([F:29])[C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].I[CH2:37][CH3:38]>CC(C)=O>[F:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[C:23]([OH:24])=[CH:22][C:21]3[C:20]([CH3:25])([CH3:26])[CH2:19][CH2:18][C:17]([CH3:28])([CH3:27])[C:16]=3[CH:15]=2)=[O:13])[CH:8]=[C:7]([F:29])[C:3]=1[C:4]([O:6][CH2:37][CH3:38])=[O:5]
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)Nc3cc(F)c(C(=O)O)c(F)c3)c(O)cc21
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(F)cc(NC(=O)c2cc3c(cc2O)C(C)(C)CCC3(C)C)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2,6-difluoro-4-[(3-hydroxy-5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-carbonyl)-amino]-benzoic acid (Compound B, 56 mg, 0.13 mmol) in 4 ml of acetone was added potassium carbonate (36 mg, 0.26 mmol) and iodoethane (0.012 ml, 0.14 mmol). The reaction mixture was stirred at room temperature for 4 hours then concentrated and purified by column chromatography with ethyl acetate: hexane (1:9) to yield the title compound as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:26])[C@@H:5]([NH2:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1.[NH2:27][C:28]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:29]=1[C:30](O)=[O:31].Cl>CCOC(C)=O>[CH3:2][O:3][C:4](=[O:26])[C@@H:5]([NH:25][C:30](=[O:31])[C:29]1[CH:33]=[C:34]([Cl:37])[CH:35]=[CH:36][C:28]=1[NH2:27])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([CH3:22])([CH3:23])[CH3:24])=[CH:19][CH:20]=2)=[CH:9][CH:8]=1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2ccc(C(C)(C)C)cc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(OCc2ccc(C(C)(C)C)cc2)cc1)NC(=O)c1cc(Cl)ccc1N
Yield: 62 %

Procedure:
(S)-2-(2-Amino-5-chloro-benzoylamino)-3-[4-(4-tert-butyl-benzyloxy)-phenyl]-propionic acid methyl ester (175 mg) was prepared from (S)-2-amino-3-[4-(4-tert-butyl-benzyloxy)-phenyl]-propionic acid methyl ester-hydrochloride (214 mg, 0.57 mmol) and 2-amino-5-chloro-benzoic acid (101 mg) as described in Procedure A, except for an adapted work-up. After reaction completion, the reaction mixture was poured onto 5 mL of 1N HCl and 5 mL of EtOAc. The organic layer was washed with 1N HCl, saturated sodium bicarbonate, dried over sodium sulfate and evaporated. The crude material was purified over silica gel (DCM).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=2)[N:3]=1.O.[NH2:22][NH2:23]>C1COCC1>[Cl:8][C:6]1[N:7]=[C:2]([NH:22][NH2:23])[N:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=2)[N:5]=1
Reactant: Fc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1C(F)(F)F
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: NNc1nc(Cl)nc(Nc2ccc(F)c(C(F)(F)F)c2)n1
Temperature: 25 °C
Yield: 77.5 %

Procedure:
To a solution of the compound XVII (1.83 g, 6 mmol) in THF (10 mL) was added hydrazine monohydrate (0.84 mg, 17 mmol) and the mixture was stirred at room temperature over night. The mixture was concentrated to a volume of about 3 mL and diluted with ethyl acetate (50 mL) and water (10 mL). The organic phase was separated, rinsed with brine, dried over anhydrous magnesium sulfate, filtered and the solvent removed in vacuo to afford the titled compound XXII (1.5 g, 83% yield, 92% purity): ESI/MS 319 (M+H), 317(M−H); 1H NMR (DMSO-d6): δ 10.40 (bs, 1H), 9.24 (bs, 1H), 8.08 (m, 1H), 7.42 (m, 2H), 4.43 (m, 2H)
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][C:8]=1[N+:25]([O-])=O)(=[O:3])[CH3:2]>C1COCC1.O=[Pt]=O>[C:1]([O:4][CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][C:8]=1[NH2:25])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1c([N+](=O)[O-])cc(OCc2ccccc2)c2ccccc12
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: CC(=O)OCCc1c(N)cc(OCc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
A solution of 2-[4-benzyloxy-2-nitronaphthalen-1-yl]ethyl acetate (0.2 g, 0.55 mmol) in THF (30 mL) was added to a suspension of PtO2 (100 mg) in THF (10 mL) and the suspension was hydrogenated (with shaking) at 55 psi at room temperature for 1 h. The suspension was filtered over Celite and the filtrate was concentrated in reduced pressure to yield 2-[4-benzyloxy-2-aminonaphthalen-1-yl]ethyl acetate as a brown solid (0.18 g, 97.58%). Mp 76-82° C; 1H NMR (CDCl3, 500 MHz) δ 8.24 (d, 8.0, 1H), 7.80 (d, 8.5, 1H), 7.22-7.53 (m, 7H), 6.41 (s, 1H), 5.20 (s, 2H), 4.25 (t, 8.0, 2H), 3.21 (t, 8.0, 2H),2.11 (s, 3H); EIMS m/z 335 (M+); IR (neat) νmax 3378, 2927, 1731, 1624, 1600, 1516, 1454, 1410, 1366, 1239, 1158, 1133, 1028, 827, 759, 698 cm−1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([O:9][CH3:10])=[C:4]([NH2:11])[CH:3]=1.[N:12]([O-])=O.[Na+].O.O.Cl[Sn]Cl>>[Br:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([NH:11][NH2:12])=[C:5]([O:9][CH3:10])[CH:6]=1
Reactant: COc1cc(Br)c(Cl)cc1N
Reactant: O=N[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COc1cc(Br)c(Cl)cc1NN
Yield: 67.3 %

Procedure:
The title compound was prepared by the general procedure described above for Preparations 2a-i using 4-chloro-5-bromo-2-aminoanisole (7.68 g), NaNO2 (2.25 g), and SnCl2.2H2O (15 g). Workup gave 5.5 g (73%) of (4-bromo-5-chloro-2-methoxyphenyl)hydrazine which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH2:11].[N:12]([C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[CH:18][NH:19]2)=[C:13]=[O:14]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:13]([NH:12][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[CH:18][NH:19]2)=[O:14]
Reactant: O=C=Nc1cccc2[nH]ccc12
Reactant: NCCc1ccc(Cl)cc1Cl
Product: O=C(NCCc1ccc(Cl)cc1Cl)Nc1cccc2[nH]ccc12

Procedure:
2-(2,4-Dichlorophenyl)ethylamine (0.21 g, 1.1 mmol) and the product of Example 80A (0.16 g, 1. mmol) were treated as described in Example 80B to provide the title compound. mp 170° C.; 1H NMR (300 MHz, DMSO-d6) δ 2.90 (m, 2H), 3.31 (m, 2H), 6.47 (m, 2H), 6.93 (m, 2H), 7.23 (m, 1H), 7.40 (m, 2H), 7.60 (m, 2H), 8.15 (s, 1H), 11.02 (s, 1H). MS (DCI+) m/z 347 (M+H). Anal. Calcd. for C17H15N3Cl2O: C, 58.63; H, 4.34; N, 12.07. Found: C, 58.49; H, 4.49; N, 12.38.
Reaction SMILES: CCN=C=NCCCN(C)C.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[C:23]([C:26]([OH:28])=O)=[CH:22][CH:21]=[N:20]2)=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C.[CH3:38][O:39][C:40]1[CH:75]=[CH:74][C:43]([CH2:44][N:45]2[C:49]3=[N:50][CH:51]=[CH:52][C:53]([O:54][C:55]4[CH:60]=[CH:59][C:58]([NH2:61])=[CH:57][C:56]=4[F:62])=[C:48]3[C:47]([NH:63][CH:64]3[CH2:69][CH2:68][N:67]([CH2:70][CH2:71][O:72][CH3:73])[CH2:66][CH2:65]3)=[N:46]2)=[CH:42][CH:41]=1>C(Cl)Cl>[CH3:38][O:39][C:40]1[CH:41]=[CH:42][C:43]([CH2:44][N:45]2[C:49]3=[N:50][CH:51]=[CH:52][C:53]([O:54][C:55]4[CH:60]=[CH:59][C:58]([NH:61][C:26]([C:23]5[C:24](=[O:25])[N:19]([C:16]6[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=6)[N:20]=[CH:21][CH:22]=5)=[O:28])=[CH:57][C:56]=4[F:62])=[C:48]3[C:47]([NH:63][CH:64]3[CH2:65][CH2:66][N:67]([CH2:70][CH2:71][O:72][CH3:73])[CH2:68][CH2:69]3)=[N:46]2)=[CH:74][CH:75]=1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: COCCN1CCC(Nc2nn(Cc3ccc(OC)cc3)c3nccc(Oc4ccc(N)cc4F)c23)CC1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCN1CCC(Nc2nn(Cc3ccc(OC)cc3)c3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c23)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
EDCI (47 mg, 0.24 mmol) was added to a stirred mixture of 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (57 mg, 0.24 mmol, prepared according to the procedure for Example 19, Step C), HOBt-hydrate (38 mg, 0.24 mmol), and DIEA (0.070 mL, 0.404 mmol) in DCM (1 mL) at ambient temperature, and the reaction was stirred for 15 minutes at ambient temperature. 1-(4-Methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-N-(1-(2-methoxyethyl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (42 mg, 0.0807 mmol) was added, and the resulting solution was stirred for 2 days at ambient temperature. The crude reaction mixture was loaded directly on to a preparative TLC plate (2 mm thickness) and eluted with 10% MeOH/DCM. The product was obtained as a waxy solid (45 mg, 76%). LRMS (APCI+): 100% purity, 220 nm, m/z 737 (M+1) detected.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:30]1(O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: Oc1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Cl)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccccc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-chlorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and phenol. ESMS m/e: 490.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([F:22])=[CH:20][C:19]([O:23][CH3:24])=[CH:18][C:17]=2[F:25])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([F:22])=[CH:20][C:19]([O:23][CH3:24])=[CH:18][C:17]=1[F:25]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(F)c(-c2c(-c3ccc(Cl)cc3)c(C)n[nH]c2=O)c(F)c1
Product: COc1cc(F)c(-c2c(Cl)nnc(C)c2-c2ccc(Cl)cc2)c(F)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
185 mg of 5-(4-chlorophenyl)-4-(2,6-difluoro-4-methoxyphenyl)-6-methyl-2H-pyridazin-3-one and 5 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. There action mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure. The residue was subjected to preparative thin layer chromatography (stationary phase: silica gel, developing solvent: hexane/ethyl acetate=3/1), to obtain 161 mg of 3-chloro-5-(4-chlorophenyl)-4-(2,6-difluoro-4-methoxyphenyl)-6-methylpyridazine (hereinafter, referred to as compound (v) of the present invention).
Reaction SMILES: [CH2:1]([O:6][C:7]1[C@@H:12]([C@H:13]([CH2:15][OH:16])[OH:14])[O:11][C:9](=[O:10])[C:8]=1[OH:17])[CH:2]([CH2:4][OH:5])[OH:3].C(=O)([O-])O.[Na+].[CH2:23](Br)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>CS(C)=O>[CH2:1]([O:6][C:7]1[C@@H:12]([C@H:13]([CH2:15][OH:16])[OH:14])[O:11][C:9](=[O:10])[C:8]=1[O:17][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23])[CH:2]([CH2:4][OH:5])[OH:3]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(OCC(O)CO)=C1O
Reactant: CCCCCCCCCCCCCCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCCCCCCCCCCCCOC1=C(OCC(O)CO)[C@@H]([C@@H](O)CO)OC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
Under an argon atmosphere, 3-O-glyceryl ascorbic acid (5.10 g) obtained in Example 1 was stirred in DMSO (20 mL), and further, sodium hydrogen carbonate (1.71 g) was added and the mixture was stirred at room temperature for 30 minutes. Thereafter, hexadecyl bromide (9.42 g) was added and the mixture was heated up to 100° C. and stirred for 3 hours, followed by extraction with ethyl acetate. Then, the extracted liquid was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and 13.6 g of the resultant residue was subjected to silica gel column chromatography. Elution was performed with chloroform/methanol/water(volume ratio:20/3/0.4), and concentration was performed under reduced pressure to obtain 3-O-glyceryl-2-O-hexadecyl ascorbic acid (4.09 g).
Reaction SMILES: [CH:1]1[C:6](=[O:7])[NH:5][C:4]([NH2:8])=[N:3][CH:2]=1.[Br:9]Br>C(O)(=O)C>[NH2:8][C:4]1[N:5]=[C:6]([OH:7])[C:1]([Br:9])=[CH:2][N:3]=1
Reactant: BrBr
Reactant: Nc1nccc(=O)[nH]1
Solvent: CC(=O)O
Product: Nc1ncc(Br)c(O)n1
Reaction time: 1 h
Yield: 140 %

Procedure:
To a solution of isocytosine(1.04 g, 9.36 mmol) in acetic acid(25 ml) are added dropwise bromine(0.51 ml, 9.83 mmol) at room temperature. After the addition is completed, the reaction mixture is stirred for 1 hour at this temperature, successively concentrated under reduced pressure to give the residue, which is washed with ethyl ether, dried to afford white powders(2.49 g, 98%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]#[N:10])[CH:2]=1.Cl.[NH2:12][OH:13].C([O-])([O-])=O.[K+].[K+]>C(O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9](=[N:12][OH:13])[NH2:10])[CH:2]=1
Reactant: N#CCCc1cccnc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: NC(CCc1cccnc1)=NO
Yield: 61 %

Procedure:
20.1 g (0.15 mol) of 3-(3-pyridyl)propionitrile is dissolved in a mixture of 61 ml of ethanol, and 15 ml of water and 9.5 g (0.14 mol) of hydroxylamine hydrochloride and 21 g (0.15 mol) of K2CO3 are added. After 24 hours at reflux, the solvent is removed in a vacuum, and the residue is extracted twice with ethanol. The extracts are concentrated by evaporation and recrystallized in hot ethanol. 14.1 g (56%) of product is obtained. Melting point 119-121° C.