Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=12.[CH3:18][N:19]([CH2:21][C:22](Cl)=[O:23])[CH3:20].CCN(C(C)C)C(C)C>CN(C=O)C.C([O-])(O)=O.[Na+]>[NH2:11][C:7]1[C:6]2[N:5]([C:4]([CH:12]3[CH2:17][CH2:16][N:15]([C:22](=[O:23])[CH2:21][N:19]([CH3:20])[CH3:18])[CH2:14][CH2:13]3)=[N:3][C:2]=2[I:1])[CH:10]=[CH:9][N:8]=1
Reactant: Nc1nccn2c(C3CCNCC3)nc(I)c12
Reactant: CN(C)CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1CCC(c2nc(I)c3c(N)nccn23)CC1
Temperature: 25 °C

Procedure:
To a stirred mixture of 1-iodo-3-piperidin-4-yl-imidazo[1,5-a]pyrazin-8-ylamine (1.000 g, 2.91 mmol) and dimethylamino-acetyl chloride (0.38967 g, 3.20 mmol) in DMF (10.00 mL) was added DIEA (2.58 mL, 14.57 mmol) at 0° C. The resulting mixture was stirred at rt. overnight. The mixture was diluted with sat. aq. NaHCO3 and extracted with DCM (50 ml×3). The extracts were combined, dried (Na2SO4). Solvent was then removed under reduced pressure and the resulting residue was used for next step without further purifications. MS (ES+): m/z 428.74 [MH+].
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH3:6])[CH2:3][NH2:4].C(N(CC)CC)C.Cl[C:15](Cl)([O:17]C(=O)OC(Cl)(Cl)Cl)Cl.[NH:26]1[CH2:30][CH2:29][CH2:28][C@H:27]1[C:31]([O:33][CH2:34][CH2:35][CH2:36][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)=[O:32]>C(Cl)Cl>[CH3:1][CH:2]([CH2:5][CH3:6])[CH2:3][NH:4][C:15]([N:26]1[CH2:30][CH2:29][CH2:28][C@H:27]1[C:31]([O:33][CH2:34][CH2:35][CH2:36][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)=[O:32])=[O:17]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: O=C(OCCCc1cccnc1)[C@@H]1CCCN1
Reactant: CCC(C)CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)CNC(=O)N1CCC[C@H]1C(=O)OCCCc1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 167.3 %

Procedure:
A solution of 2-methylbutylamine (113 mg; 1.3 mmol) and triethylamine (132 mg; 1.3 mmol) in methylene chloride (5 mL) was added to a solution of triphosgene (128 mg; 0.43 mmol) in methylene chloride (5 mL). The resulting mixture was refluxed for 1 hour and then cooled to room temperature. 3-(3-Pyridyl)-1-propyl (2S)-pyrrolidine-2-carboxylate (300 mg; 1.3 mmol) in 5 mL of methylene chloride was added and the resulting mixture was stirred for 1 hour and then partitioned between water and a 1:1 mixture of ethyl acetate and hexane. The organic phase was dried, concentrated and purified by column chromatography (50% ethyl acetate/hexane) to obtain 250 mg (55%) of the compound of Example 1 (1, Table I) as an oil, 1H NMR (CDCl3, 300 MHz): δ 0.89-0.93 (m, 6H); 1.10-1.20 (m, 1H); 1.27 (s, 1H); 1.36-1.60 (m, 2H); 1.72 (s, 2H); 1.97-2.28 (m, 6H); 2.70-2.75 (m, 2H); 2.92-3.54 (m, 4H); 4.16-4.20 (dt, 2H); 4.45-4.47 (m, 2H); 7.21-7.29 (m, 1H); 7.53-7.56 (dd, 1H); 8.46-8.48 (s, 2H). Anal. Calcd. for C19H29N3O3—0.5 H2O: C, 64.02; H, 8.48; N, 11.79. Found: C, 63.72; H, 8.42; N, 11.83.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=O.[NH2:16][C:17]1[NH:21][N:20]=[C:19]([C:22]([OH:24])=[O:23])[CH:18]=1>C(O)(=O)C>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:5]1[CH:4]=[C:3]([C:2]([F:15])([F:14])[F:1])[N:21]2[N:20]=[C:19]([C:22]([OH:24])=[O:23])[CH:18]=[C:17]2[N:16]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccn1
Reactant: Nc1cc(C(=O)O)n[nH]1
Solvent: CC(=O)O
Product: O=C(O)c1cc2nc(-c3ccccn3)cc(C(F)(F)F)n2n1
Yield: 71.5 %

Procedure:
4,4,4-Trifluoro-1-pyridin-2-yl-butane-1,3-dione (3.00 g, 13.8 mmol) and 5-amino-1H-pyrazole-3-carboxylic acid (1.76 g, 13.8 mmol) in acetic acid (100 ml) was heated at reflux overnight. The reaction mixture was concentrated under reduced pressure and the crude product was purified by column chromatography on silica gel to give 5-pyridin-2-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (3.04 g, 71%).
Reaction SMILES: Br[C:2]1[C:6]([CH3:8])([CH3:7])[O:5]/[C:4](=[C:9]2/[C:10](=[O:19])[NH:11][C:12]3[C:17]/2=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)/[CH:3]=1.[CH:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1COCC1>[F:18][C:14]1[CH:13]=[C:12]2[C:17](/[C:9](=[C:4]3/[CH:3]=[C:2]([C:25]4[CH:26]=[CH:27][C:22]([CH:20]=[O:21])=[CH:23][CH:24]=4)[C:6]([CH3:8])([CH3:7])[O:5]/3)/[C:10](=[O:19])[NH:11]2)=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(C=O)cc1
Temperature: 65 °C
Yield: 51 %

Procedure:
To a mixture of (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one (2.0 g, 6.17 mmol), 4-formyl phenylboronic acid (1.85 g, 12.3 mmol), aqueous potassium carbonate (1M, 31 mL, 31 mmol) in THF (120 mL) under a nitrogen atmosphere, was added palladium(0)tetrakis(triphenylphosphine) (356 mg, 0.3 mmol, 5 mol %). The mixture was heated at 65° C. overnight (20 h). The reaction was cooled to room temperature and ethyl acetate (500 mL) was added. The organic phase was washed with water (100 mL×2), dried over sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (5% CH3OH/CH2Cl2 elution). Trituration of the product obtained from the column chromatography with ethyl acetate/hexane (1/1), followed by isolation of the precipitate by filtration, provided 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzaldehyde as a red orange solid (1.1 g, yield 51%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:9]2[N:13]3[N:14]=[C:15]([N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[CH:16]=[CH:17][C:12]3=[N:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.ClC1C=CC=C(C(OO)=[O:32])C=1.[OH2:35]>C(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:4]=[C:5]([C:9]2[N:13]3[N:14]=[C:15]([N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[CH:16]=[CH:17][C:12]3=[N:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1)(=[O:32])=[O:35]
Reactant: CSc1cccc(-c2nnc3ccc(N4CCCCC4)nn23)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O
Solvent: ClCCl
Product: CS(=O)(=O)c1cccc(-c2nnc3ccc(N4CCCCC4)nn23)c1
Reaction time: 13 h

Procedure:
To a solution of 3-[3-(methylsulfanyl)phenyl]-6-piperidin-1-yl-1,2,4-triazolo[4,3-b]pyridazine (550 mg) in methylene chloride (30 ml), 3-chloroperbenzoic acid (1.25 g) was added at room temperature, and the mixture was stirred for 13 hours. The reaction solution was combined with water, and diluted with methylene chloride. The organic phase washed successively with water, 1M aqueous solution of sodium hydroxide and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (eluent:chloroform:methanol=98:2) and washed with ethanol to obtain 3-[3-(methylsulfonyl)phenyl]-6-piperidin-1-yl-1,2,4-triazolo[4,3-b]pyridazine (250 mg) as colorless crystals.
Reaction SMILES: COC[O:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]([OH:16])=O)[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.Cl.[CH3:18][NH:19][O:20][CH3:21].P(C#N)(OCC)(OCC)=O>>[OH:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]([N:19]([O:20][CH3:21])[CH3:18])=[O:16])[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CNOC
Reactant: COCOc1cccc2sc(C(=O)O)cc12
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Product: CON(C)C(=O)c1cc2c(O)cccc2s1
Yield: 89.3 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 16 using 4-(methoxymethyloxy)benzo(b)thiophene-2-carboxylic acid (4.5 g), N,O-dimethylhydroxylamine hydrochloride (2.1 g) and diethyl cyanophosphate (3.2 g), 4-hydroxy-N-methoxy-N-methylbenzo(b)thiophene-2-carboxamide (4.0 g) was obtained as a brown oil. By the reactions in the same manner as in Starting Material Synthesis Example 1 using the brown oil (2.0 g) and (S)-glycidyl nosylate (2.0 g), the title compound (1.1 g) was obtained as brown crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:17][CH3:18])[C:11]=2[CH:15]=O)[CH:6]=1)=[O:4].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][CH2:15][C:11]2[C:10]([O:17][CH3:18])=[CH:9][CH:8]=[C:7]3[C:12]=2[CH:13]=[CH:14][C:5]([C:3]([OH:2])=[O:4])=[CH:6]3)=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc2c(C=O)c(OC)ccc2c1
Reactant: NCc1ccc(F)cc1
Product: COc1ccc2cc(C(=O)O)ccc2c1CNCc1ccc(F)cc1

Procedure:
The title compound was prepared as a white solid (0.212 g, 34% for two steps) from 6-methoxy-5-formyl-2-naphthoic acid methyl ester using 4-fluorobenzyl amine and a procedure similar to steps 3-4 of Example 1, mp 268-270° C. (decomp.); 1H NMR (DMSO-d6) δ3.94 (s, 3H), 4.29 (s, 2H), 4.48 (s, 2H), 7.31 (t, J=8.9 Hz, 2H), 7.60 (d, J=9.2 Hz, 1H), 7.65 (dd, J=5.7, 8.6 Hz, 2H), 7.99 (dd, J=1.5, 8.9 Hz, 1H), 8.12 (d, J=9.0 Hz, 1H), 8.28 (d, J=9.2 Hz, 1H), 8.60 (d, J=0.92 Hz, 1H), 9.07-9.42 (bs, 2H), 12.73-13.27 (bs, 1H); IR (neat) 3470, 3390, 2880-3080, 2820, 2760, 2680, 2610, 1710, 1630, 1600, 1595, 1515, 1485, 1465, 1445, 1270, 1260, 1235, 1210, 1195, 1185, 1095, and 1000 cm−1; mass spectrum [(+) ESI], m/z 340 (M +H)+ and [(−) ESI], m/z 338 (M−H)−; Anal. Calcd. for C20H18FNO3.HCl.0.5H2O: C, 62.42; H, 4.98; N, 3.64, Found: C, 62.07; H, 5.37; N, 3.53.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9].C(OC([N:26]1[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][C@@H:27]1[C:35](O)=[O:36])=O)(C)(C)C.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NC(C)C)(C)C>C1COCC1>[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:35]([C@H:27]3[CH2:28][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:30][CH2:31][NH:26]3)=[O:36])[CH2:15][CH2:14]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCNCC1
Reactant: CC(C)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN[C@@H](C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Reaction time: 4 h
Yield: 30.2 %

Procedure:
N-(3,4-Dichlorophenyl)piperazine-1-carboxamide hydrochloride (251 mg) and (2R)-1-(tert-Butoxycarbonyl)-4-isopropylpiperazine-2-carboxylic acid (200 mg) were dissolved in dry THF (10 mL) followed by addition of N,N-di-isopropylethylamine (0.26 ml) and HATU (335 mg) and the reaction was stirred for 4 h. A further 0.26 ml of N,N-di-iso-propylamine was added and the reaction was stirred for 18 h at rt. The solvent was evaporated under reduced pressure then redissolved in dichloromethane (50 ml) followed by washing with sat. aqueous NaHCO3 (20 ml). The organic layer was separated on a phase separation cartridge and evaporated. Purification by chromatography (3-10% methanol:dichloromethane) afforded the crude product (180 mg) as a foam which was used without further purification. The foam was then dissolved in TFA/DCM (1:1, 10 ml) and stirred for 30 mins. The solvent was removed under reduced pressure then taken up in 1M. aqueous sodium hydroxide (30 ml) and extracted with dichloromethane (2×30 ml). The organic layer was separated on a phase separation cartridge and evaporated. Purification by chromatography (5-25% MeOH:DCM) afforded the title compound (95 mg) as a white foam
Reaction SMILES: [Br:1]/[C:2](/[CH:27]=C/C1C(C)(C)C2C(N=1)=[N+](CCCS([O-])(=O)=O)C=C(Cl)C=2)=[CH:3]\[CH:4]=[C:5]1\[N:6]([CH2:20][CH2:21][CH2:22][S:23]([O-:26])(=[O:25])=[O:24])[C:7]2[C:12]([C:13]\1([CH3:15])[CH3:14])=[CH:11][C:10](S([O-])(=O)=O)=[CH:9][CH:8]=2.[Na+:48].[Na+].[CH3:50][C:51]1([CH3:80])[C:59]2[C:58]3[CH:60]=[C:61]([S:68]([O-:71])(=[O:70])=[O:69])[CH:62]=[C:63]([S:64]([O-:67])(=[O:66])=[O:65])[C:57]=3[CH:56]=[CH:55][C:54]=2[N+:53]([CH2:72][CH2:73][CH2:74][S:75]([O-:78])(=[O:77])=[O:76])=[C:52]1[CH3:79].[Na+].[Na+]>>[Br:1]/[C:2](=[CH:3]\[CH:4]=[C:5]1\[N:6]([CH2:20][CH2:21][CH2:22][S:23]([O-:26])(=[O:24])=[O:25])[C:7]2[CH:8]=[CH:9][C:10]3[C:61]([S:68]([O-:71])(=[O:69])=[O:70])=[CH:62][C:63]([S:64]([O-:67])(=[O:66])=[O:65])=[CH:57][C:11]=3[C:12]=2[C:13]\1([CH3:15])[CH3:14])/[CH:27]=[CH:79]/[C:52]1[C:51]([CH3:80])([CH3:50])[C:59]2[C:58]3[CH:60]=[C:61]([S:68]([O-:71])(=[O:69])=[O:70])[CH:62]=[C:63]([S:64]([O-:67])(=[O:65])=[O:66])[C:57]=3[CH:56]=[CH:55][C:54]=2[N+:53]=1[CH2:72][CH2:73][CH2:74][S:75]([O-:78])(=[O:77])=[O:76].[Na+:48].[Na+:48].[Na+:48].[Na+:48].[Na+:48]
Reactant: CC1(C)C(/C=C/C(Br)=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)=Nc2c1cc(Cl)c[n+]2CCCS(=O)(=O)[O-]
Reactant: CC1=[N+](CCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2C1(C)C
Agent: [Na+]
Product: CC1(C)C(/C=C/C(Br)=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)=[N+](CCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c21

Procedure:
Compound 25 is prepared analogously to compound 9 (Example 9), except that compound 23 is used as a starting material.
Reaction SMILES: C([N:8]1[C:13](=O)[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=C(Cl)C(OCC2C=CC=CC=2)=N1)C1C=CC=CC=1.[CH2:31]([N:38]1[C:43](=[O:44])[C:42](Cl)=[C:41]([C:46]2[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=2)[C:40]([O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[N:39]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O[CH2:71][CH3:72])(=O)C>C1(C)C=CC=CC=1.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>[CH2:31]([N:38]1[C:43](=[O:44])[C:42]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[C:41]([C:72]2[CH:71]=[CH:43][N:38]=[CH:31][CH:32]=2)[C:40]([O:53][CH2:54][C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)=[N:39]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1.[CH2:31]([N:38]1[C:43](=[O:44])[C:42]([C:15]2[CH:12]=[CH:13][N:8]=[CH:19][CH:20]=2)=[C:41]([C:46]2[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=2)[C:40]([O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[N:39]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=c1c(-c2ccc(Cl)cc2)c(Cl)c(OCc2ccccc2)nn1Cc1ccccc1
Reactant: CCOC(C)=O
Reactant: O=c1c(Cl)c(-c2ccc(Cl)cc2)c(OCc2ccccc2)nn1Cc1ccccc1
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
Product: O=c1c(-c2ccc(Cl)cc2)c(-c2ccncc2)c(OCc2ccccc2)nn1Cc1ccccc1
Product: O=c1c(-c2ccncc2)c(-c2ccc(Cl)cc2)c(OCc2ccccc2)nn1Cc1ccccc1
Temperature: 100 °C
Reaction time: 0.03 h

Procedure:
To a solution the mixture of 2-benzyl-6-(benzyloxy)-5-chloro-4-(4-chlorophenyl)pyridazin-3(2H)-one and 2-benzyl-6-(benzyloxy)-4-chloro-5-(4-chlorophenyl)pyridazin-3(2H)-one (9.9 g, 22.7 mmol), prepared as described in Example 8A, in toluene (136 ml) was added Pd(PPh3)4 (2.35 g, 1.17 mmol). After 2 min, 2N sodium carbonate (45.4 ml, 90.8 mmol) solution was added, followed by 4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)pyridine (8.5 g, 41.4 mmol). The reaction was stirred at 100° C. for 42 hours. After this time, the reaction mixture was cooled to RT and diluted with ethyl acetate. The resulting solution was washed with water and saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel column chromatography using an automated system and eluting with a gradient of 20-50% Ethyl acetate-Hexane to give the title compounds 2-benzyl-6-(benzyloxy)-4-(4-chlorophenyl)-5-(pyridin-4-yl)pyridazin-3(2H)-one and 2-benzyl-6-(benzyloxy)-5-(4-chlorophenyl)-4-(pyridin-4-yl)pyridazin-3(2H)-one as a mixture, as light yellow solid (4.5 g, 29% two steps).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[N:4][N:5]2[C:10](O)=[C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:8]([CH3:17])=[N:7][C:6]=12.O=P(Cl)(Cl)[Cl:21]>>[Cl:1][C:2]1[C:3]([CH3:18])=[N:4][N:5]2[C:10]([Cl:21])=[C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:8]([CH3:17])=[N:7][C:6]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)Cc1c(C)nc2c(Cl)c(C)nn2c1O
Product: COC(=O)Cc1c(C)nc2c(Cl)c(C)nn2c1Cl
Temperature: 0 °C
Yield: 59 %

Procedure:
To a solution of methyl 2-(3-chloro-7-hydroxy-2,5-di-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (0.160 g, 0.6 mmol) was added POCl3 (1 mL). The reaction mixture was heated at reflux for 1 h. After cooling, the reaction mixture was added drop-wise to ice-water. A brown solid precipitated. The solid were filtered and washed with water, then dissolved in ethyl acetate. The organic solution was washed with saturated NaHCO3 and dried over sodium sulfate. The solvent was evaporated to give the title compound (0.1 g, 59%). NMR (500 MHz, DMSO-d6) δ ppm 2.44 (s, 3H), 2.57 (s, 3H), 3.68 (s, 3H), 4.00 (s, 2H). Used as is in the next step.
Reaction SMILES: [CH:1]([C:4]1[O:8][N:7]=[C:6]([CH:9]=[O:10])[CH:5]=1)([CH3:3])[CH3:2].[CH3:11][Mg]Br.O>O1CCOCC1.O1CCCC1>[CH:1]([C:4]1[O:8][N:7]=[C:6]([CH:9]([OH:10])[CH3:11])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: C[Mg]Br
Reactant: CC(C)c1cc(C=O)no1
Solvent: O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC(C)c1cc(C(C)O)no1
Reaction time: 1 h

Procedure:
5.70 g of 5-i-propylisoxazole-3-carbaldehyde was dissolved in 82 ml of 1,4-dioxane, and 48 ml of a 0.93 M solution of methylmagnesium bromide in tetrahydrofuran was then added under ice-cooling. The mixture was stirred for 1 hour under ice-cooling. After water was added, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 5.66 g of 1-(5-i-propyl-isoxazol-3-yl)ethanol.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].[CH3:6][O:7][C:8]1([C:17]2[O:27][C:20]3=[C:21]([O:25][CH3:26])[N:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)[CH2:13][CH2:12][N:11]([C:14](O)=[O:15])[CH2:10][CH2:9]1.[H-].[Na+].IC>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:14]([N:11]1[CH2:10][CH2:9][C:8]([O:7][CH3:6])([C:17]2[O:27][C:20]3=[C:21]([O:25][CH3:26])[N:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)[CH2:13][CH2:12]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)O
Reactant: COc1nccc2cc(C3(OC)CCN(C(=O)O)CC3)oc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1nccc2cc(C3(OC)CCN(C(=O)OC(C)(C)C)CC3)oc12
Reaction time: 0.5 h
Yield: 124.5 %

Procedure:
A solution of 4-methoxy-4-(7-methoxyfuro[2,3-c]pyridin-2-yl)piperidine carboxylic acid tert-butyl alcohol (8.59 g) in dry N,N-dimethylformamide (100 ml) was stirred at room temperature under an atmosphere of dry nitrogen. Sodium hydride (60% in oil, 1.18 g) was added portionwise and stirring continued for 30 minutes. Iodomethane (3.07 ml) was added and stirring continued for 80 minutes. The mixture was diluted with ethyl acetate (300 ml) and washed with water (4×100 ml) and brine (1×100 ml). The organic extract was dried over magnesium sulphate, filtered and the solvent removed in vacuo to give the title compound (10.19 g) as a pale yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([CH2:11][N:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14]([O:22][C:23]4[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=4)[C:13]3=[O:31])[C:5]2=[CH:4][CH:3]=1.O1CCOCC1>CO.C(Cl)Cl.Cl>[Cl-:29].[Cl:29][C:27]1[CH:28]=[C:23]([CH:24]=[C:25]([Cl:30])[CH:26]=1)[O:22][C:14]1[C:13](=[O:31])[N:12]([CH2:11][C:10]2[C:5]3[C:6](=[N:7][C:2]([NH3+:1])=[CH:3][CH:4]=3)[NH:8][N:9]=2)[CH:17]=[CH:16][C:15]=1[C:18]([F:19])([F:20])[F:21]
Reactant: Nc1ccc2c(Cn3ccc(C(F)(F)F)c(Oc4cc(Cl)cc(Cl)c4)c3=O)n[nH]c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: [Cl-]
Product: [NH3+]c1ccc2c(Cn3ccc(C(F)(F)F)c(Oc4cc(Cl)cc(Cl)c4)c3=O)n[nH]c2n1
Reaction time: 0.25 h

Procedure:
1-[(6-amino-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl]-3-(3,5-dichlorophenoxy)-4-(trifluoromethyl)pyridin-2(1H)-one (0.495 g, 1.05 mmol) was dissolved in a mixture of 20% methanol in CH2Cl2 (25 mL) and 4M HCl in dioxane (0.077 g, 2.10 mmol) was added. After 15 minutes, the reaction mixture was concentrated under reduced pressure and placed under vacuum for 4 hours to afford the title compound as a solid. 1H NMR (DMSO-d6 with NH4OH) δ 7.93 (d, J=7.1 Hz, 1H), 7.58 (d, J=8.7 Hz, 1H), 7.13-7.11 (m, 1H), 7.06-7.04 (m, 2H), 6.59 (d, J=7.2 Hz, 1H), 6.37-6.34 (m, 2H), 6.31 (d, J=8.7 Hz, 1H), 5.34 (s, 2H). HRMS (M+1)=470.0392.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([NH:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[O:10])[CH:2]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([NH2:30])[CH:24]=1.FC(F)(F)C(O)=O>O1CCCC1>[NH2:30][C:25]1[CH:24]=[C:23]([F:22])[CH:28]=[CH:27][C:26]=1[NH:29][C:17](=[O:19])[C:16]1[CH:15]=[CH:14][C:13]([CH2:12][NH:11][C:9](=[O:10])[CH:8]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:21][CH:20]=1
Reactant: O=C(C=Cc1cccnc1)NCc1ccc(C(=O)O)cc1
Reactant: Nc1ccc(F)cc1N
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Nc1cc(F)ccc1NC(=O)c1ccc(CNC(=O)C=Cc2cccnc2)cc1
Temperature: 45 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
To a suspension of 0.29 g (1.78 mmol) of N,N′-carbonyldiimidazole in tetrahydrofuran (15 ml) is added 0.50 g (1.78 mmol) of 4-[(Pyridin-3-ylacryloyl)aminomethyl]benzoic acid, followed by stirring at 45° C. for 1 hour. After cooling, the reaction mixture is added to a separately prepared tetrahydrofuran (10 ml) solution including 0.28 g (2.22 mmol) of 4-fluoro-1,2-phenylenediamine and 0.20 g (1.78 mmol) of trifluoroacetic acid at room temperature. After reaction at room temperature for 24 hours, the deposited white solid is collected by filtration, washed with tetrahydro ran, and then dried to give the title compound (0.40 g, 57%). 1H NMR (300 MHz, DMSO-d6): δ ppm: 4.49 (2H, d), 4.84 (2H, br.s), 6.60 (1H, t), 6.80 (2H, m), 6.96 (1H, t), 7.18 (1H, d), 7.42 (2H, d), 7.52 (1H, d), 7.95 (2H, d), 8.02 (1H, d), 8.56 (1H, d), 8.72 (1H, br.t), 8.78 (1H, s), 9.60 (1H, br.s), IR (KBr) cm−1: 3310, 1655, 1631, 1524, 1305, 750. HRMS calcd for C22H19N4O2F: 390.4170. Found: 390.4172. MA calcd for C22H19N4O2F: C, 67.88%; H, 4.40%; N, 14.35%. Found: C, 67.52%; H, 4.38%; N, 14.42%.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.C([O-])(=O)C.[Na+]>O>[C:5]([NH:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)(=[O:7])[CH3:6]
Reactant: Nc1cccc2c1CCCC2
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1cccc2c1CCCC2
Reaction time: 0.25 h

Procedure:
Acetic acid anhydride (20 ml) was added to a mixture of 1-amino-5,6,7,8-tetrahydronaphthalene (10 g, 68 mmol), sodium acetate (20 g, 245 mmol) and water (100 ml) at 5° C. The mixture was stirred at room-temperature for 15 minutes. The mixture was cooled on ice for 1 hour followed by filtration. The crystals were washed with water. Yield 13.0 g (100%).