Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(B1O[C:9]([CH3:11])([CH3:10])[C:6]([CH3:8])([CH3:7])O1)(C)=C.ClC1C=[C:22]2[C:17]([C:18]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=3[F:36])=[CH:19][C:20]([C:24]([O:26][CH3:27])=[O:25])=[N:21]2)=[CH:16]C=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].O>[F:36][C:29]1[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:28]=1[C:18]1[C:17]2[C:22](=[CH:11][C:9]([C:6]([CH3:7])=[CH2:8])=[CH:10][CH:16]=2)[N:21]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH:19]=1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2F)c2ccc(Cl)cc2n1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C=C(C)c1ccc2c(-c3ccc(OC)cc3F)cc(C(=O)OC)nc2c1
Temperature: 25 °C
Yield: 64.9 %

Procedure:
Isopropenylboronic acid pinacol ester (2.67 g, 15.91 mmol), methyl 7-chloro-4-(2-fluoro-4-methoxyphenyl)quinoline-2-carboxylate (5 g, 14.46 mmol), potassium phosphate tribasic (9.21 g, 43.4 mmol) and dioxane (43.8 ml)/water (4.38 ml) were combined and then degassed with nitrogen for 5 minutes. Added palladium(II) acetate (0.243 g, 1.085 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene (0.515 g, 1.085 mmol) and then heated to 85° C. for 4 hours. Reaction was complete and was allowed to cool to ambient temperature. The mixture was diluted with EtOAc and then washed with H2O, brine, dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel, eluting with hexanes to EtOAc to afford methyl 4-(2-fluoro-4-methoxyphenyl)-7-(prop-1-en-2-yl)quinoline-2-carboxylate (3.3 g, 9.39 mmol, 64.9% yield) as a yellow solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][S:8]([CH3:10])=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([OH:29])[CH2:19][N:20]2[C:24]([CH3:25])=[CH:23][CH:22]=[C:21]2[C:26]([OH:28])=[O:27])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:18](=[O:29])[CH2:19][N:20]2[C:24]([CH3:25])=[CH:23][CH:22]=[C:21]2[C:26]([O:28][CH2:7][S:8][CH3:10])=[O:27])=[CH:16][CH:17]=1
Reactant: Cc1ccc(C(=O)O)n1CC(O)c1ccc(F)cc1
Reactant: CS(C)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSCOC(=O)c1ccc(C)n1CC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
A solution of oxalyl chloride (0.3 mL, 3.5 mmol) in CH2Cl2 (0.5 mL) was added dropwise to a solution of DMSO (0.34 mL, 4.8 mmol) in CH2Cl2 (1.5 mL) at −65° C. and stirred for 10 min. The resultant solution was added to a suspension of 1-[2-(4-fluorophenyl)-2-hydroxyethyl]-5-methyl-1H-pyrrole-2-carboxylic acid (211 mg, 0.8 mmol) in CH2Cl2 (10 mL) at −65° C. The resultant suspension was stirred at −65° C. for 15 min, then triethylamine (1.12 mL, 8.0 mmol) was added drop-wise. Once the addition was complete the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction was then quenched by the addition of CH2Cl2 (50 mL) and water (10 mL), the organic layer was separated and the aqueous extracted with further CH2Cl2 (10 mL). The organic layers were combined and washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give a brown solid. The solid was purified by flash column chromatography (Biotage SP4, 40 g cartridge, hexane 1 CV, 0-50% EtOAc/hexanes 10 CV) to give (methylsulfanyl)methyl 1-[2-(4-fluorophenyl)-2-oxoethyl]-5-methyl-1H-pyrrole-2-carboxylate as a off-white solid (162 mg, 62%). 1H NMR (400 MHz, CDCl3): δ 2.19 (s, 3H), 2.22 (s, 3H), 5.19 (s, 2H), 5.76 (s, 2H), 6.06 (dd, 1H, J 3.9, 0.7 Hz), 7.06 (d, 1H, J 3.9 Hz), 7.13-7.24 (m, 2H), 8.06 (dd, 2H, J 9.0, 5.3 Hz). ESI-MI m/z [M+H]+ 321.80.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](Cl)=[O:18]>O1CCCC1>[Cl:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:17]([C:13]2[O:12][CH:16]=[CH:15][CH:14]=2)=[O:18])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(Cl)c1ccco1
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a suspension of 5-amino-2-chlorobenzoic acid (13.7 g, 79.85 mmol, 1.00 equiv) in tetrahydrofuran (100 mL) was added furan-2-carbonyl chloride (11.5 g, 88.10 mmol, 1.10 equiv) in a bath of ice and stirred overnight at room temperature. The resulting mixture was concentrated under vacuum and diluted with DCM. The solid was collected by filtration to give 17 g (80%) of 2-chloro-5-(furan-2-amido)benzoic acid as a gray solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:20](=[O:21])[C:19]3[S:18][C:17]4[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=4[C:11]=3[CH:10]=[N:9]2)[C:3]=1[CH:22]=[O:23].[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:46]=[N:45][CH:44]=[CH:43][N:42]=2)[C:26]1=[O:47].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.O.O.C([O-])(=O)C.[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[CH3:24][N:25]1[C:26](=[O:47])[C:27]([NH:40][C:41]2[CH:46]=[N:45][CH:44]=[CH:43][N:42]=2)=[CH:28][C:29]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([N:8]3[C:20](=[O:21])[C:19]4[S:18][C:17]5[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=5[C:11]=4[CH:10]=[N:9]3)[C:3]=2[CH:22]=[O:23])=[CH:30]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2cnccn2)c1=O
Reactant: O=Cc1c(Cl)ccnc1-n1ncc2c3c(sc2c1=O)CCCC3
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: Cn1cc(-c2ccnc(-n3ncc4c5c(sc4c3=O)CCCC5)c2C=O)cc(Nc2cnccn2)c1=O
Temperature: 100 °C
Yield: 48.9 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a reflux condenser was charged with 4-chloro-2-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-trien-5-yl}pyridine-3-carbaldehyde 124a (345 mg, 1.0 mmol), 194a (659 mg, 2.0 mmol), Pd(dppf)Cl2 (50 mg, 0.050 mmol), K3PO4 (450 mg, 2.0 mmol), sodium acetate trihydrate (300 mg, 2.0 mmol), water (6 drops) and, acetonitrile (40 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 25:1 dichloromethane/methanol to afford 194b (250 mg, 49%) as a yellow brown solid. MS-ESI: [M+H]+ 512.3.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:32][C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:13][CH:10]2[CH2:9][CH2:8][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: OC1CCN(Cc2ccc(F)cc2)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)OC2CCN(Cc3ccc(F)cc3)CC2)cc1
Yield: 45.4 %

Procedure:
0.5 g (0.00239 mol) of 1-(4-fluoro-benzyl)-piperidin-4-ol and 0.67 ml (0.00478 mol) of triethylamine were dissolved in 15 ml of toluene, treated with 0.632 ml (0.00478 mol) of p-toluoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.355 g (59%) of 1-(4-fluoro-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as a yellow oil. MS: me/e=328 (C2H23FNO2+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N:25]4[CH2:29][CH2:28][CH2:27][CH:26]4[CH3:30])[N:20]=3)[C:12]3[N:13]([CH:15]=[CH:16][N:17]=3)[N:14]=2)[CH:6]=[CH:7][CH:8]=1.O=[C:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCl>[CH3:30][CH:26]1[CH2:27][CH2:28][CH2:29][N:25]1[C:21]1[N:20]=[C:19]([NH:18][C:11]2[C:12]3[N:13]([CH:15]=[CH:16][N:17]=3)[N:14]=[C:9]([C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=3)[CH2:2][NH:1][CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)[CH:10]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(CN)c3)nn3ccnc23)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC1CCCN1c1cccc(Nc2cc(-c3cccc(CNC4CCN(C(=O)OC(C)(C)C)CC4)c3)nn3ccnc23)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.9 %

Procedure:
To a solution of 6-(3-(aminomethyl)phenyl)-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (50 mg, 1.52 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (38 mg, 0.188 mmol) and NaBH(OAc)3 (80 mg, 0.375 mmol) in dichloromethane (5 mL) was added HOAc (12 mg). The mixture was stirred at room temperature for 3 h. The solvent was concentrated in vacuo. The residue was purified by chromatography (silica, EtOAc) to give tert-butyl 4-(3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzylamino)piperidine-1-carboxylate (35 mg, 48%) as a yellow oil. LC/MS: 583.3 [M+H]+, tR=1.52 min.
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6][CH:7]=[CH2:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([NH:26][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:19][CH:18]([C:20](=[O:25])N(OC)C)[CH2:17]2)=[CH:12][CH:11]=1>C1COCC1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2([NH:26][C:27](=[O:34])[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:17][CH:18]([C:20](=[O:25])[CH2:8][CH2:7][CH:6]=[CH2:5])[CH2:19]2)=[CH:14][CH:15]=1
Reactant: C=CCCBr
Reactant: CON(C)C(=O)C1CC(NC(=O)c2ccccc2)(c2ccc(Cl)cc2)C1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCCC(=O)C1CC(NC(=O)c2ccccc2)(c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 0.2 h

Procedure:
Magnesium powder (1.05 g, 42.0 mmol) was placed into a round-bottomed flask with a small piece of iodine. Dry THF was added to cover the magnesium and the solution was heated to a gentle reflux for 30 minutes. While refluxing, a second solution of 4-bromo-1-buten (4.72 mL, 42.0 mmol) in dry THF (5 mL) was added. After 12 min, the mixture was cooled to room temperature and added to a solution of N-(1-(4-chlorophenyl)-3-(methoxy(methyl)carbamoyl)cyclobutyl)benzamide (1.12 g, 3.0 mmol) in dry THF (30 mL). After 2 h, the reaction was quenched with saturated aqueous NH4Cl. 1M HCl was added to pH-3 and the solution was extracted with diethyl ether (×2). The combined organic layers were washed successively with 1M HCl, water and saturated aqueous sodium chloride, dried over MgSO4, filtered and concentrated to give the crude product that was used to the next step without further purification. 1H NMR (CDCl3, 600 MHz) δ 7.76 (d, J=7.2 Hz, 2H), 7.47-7.50 (m, 1H), 7.46 (d, J=8.7 Hz, 2H), 7.40-7.43 (m, 2H), 7.33 (d, J=8.7 Hz, 2H), 6.77 (s, 1H), 5.72-5.80 (m, 1H), 4.92-5.01 (m, 2H), 3.16-3.22 (m, 1H), 2.90-2.94 (m, 2H), 2.82-2.86 (m, 2H), 2.54 (t, J=7.3 Hz, 2H), 2.30-2.35 (m, 2H). ESI MS found for C22H22ClNO2 m/z [368.4/370.4 (M+1)].
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1C=O.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([O-])=O.[C]=O>N1C=CC=CC=1.[OH-].[Rh+3].[OH-].[OH-]>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=[N:13][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: O=Cc1ccc2ccccc2c1
Agent: [Rh+3]
Agent: [C]=O
Agent: [OH-]
Solvent: c1ccncc1
Product: C1=Cc2ccccc2CC1=Nc1ccccc1
Temperature: 170 °C
Yield: 75 %

Procedure:
A solution of β-naphthaldehyde (0.1 mole), nitrobenzene (0.11 mole) and rhodium hydroxide [Rh(OH)3 ] in 50 ml of pyridine were charged into a stainless steel rocking autoclave of 0.5 l capacity. The autoclave was pressurized to 140 atm with carbon monoxide and heated to 170°C for 3 hours. On completion of the reaction period, the pressure vessel was allowed to cool and the gases vented. Work-up of the reaction mixture gave 75% yield of β-naphthylideneaniline, the product being unequivocally identified by mixed melting point and spectroscopic (ir and nmr) comparison with an authentic sample.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].I.[F:35][C:36]1[CH:58]=[CH:57][C:39]([CH2:40][N:41]2[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[N:43]=[C:42]2[N:50]2[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)=[CH:38][CH:37]=1>>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:53]2[CH2:54][CH2:55][CH2:56][N:50]([C:42]3[N:41]([CH2:40][C:39]4[CH:57]=[CH:58][C:36]([F:35])=[CH:37][CH:38]=4)[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:51][CH2:52]2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8]1)=[O:6]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Reactant: Fc1ccc(Cn2c(N3CCCNCC3)nc3ccccc32)cc1
Agent: I
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCN2CCCN(c3nc4ccccc4n3Cc3ccc(F)cc3)CC2)(c2ccccc2)C1

Procedure:
Prepare by the method of Example 47.3 using 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) (2.2 g, 4.67 mmol) and 4-(1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (2.82 g, 4.86 mmol) to give the title compound: Rf=0.37 (silica gel, dichloromethane/methanol/concentrated aqueous ammonia 90/10/0.1).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH:14]([CH3:16])[CH3:15])=[C:10]([CH:13]=1)[CH:11]=O>CO>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH:14]([CH3:16])[CH3:15])=[C:10]([CH:11]=[N:4][CH:1]2[CH2:3][CH2:2]2)[CH:13]=1
Reactant: CC(C)c1ccc(Cl)cc1C=O
Reactant: NC1CC1
Solvent: CO
Product: CC(C)c1ccc(Cl)cc1C=NC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
Cyclopropylamine (39.2 g, 0.69 mol) was added to a solution of 5-chloro-2-isopropylbenzaldehyde (II) (120 g, 0.65 mol, 99.6 GC-% by area) in methanol (1200 ml) and the mixture was stirred at room temperature for 2 hours. The solvent was subsequently removed under reduced pressure and N-[(5-chloro-2-isopropylphenyl)-methylene]cyclopropanamine (144 g, 99.2 GC-% by area, 98.5% of theory) was obtained as a light-yellow oil.
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[O:7].Br[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+].[I-]>O.CN(C)C=O>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[O:7]
Reactant: Brc1ccccn1
Reactant: O=c1cccc[nH]1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccccn1-c1ccccn1
Temperature: 120 °C
Reaction time: 2 h
Yield: 21.8 %

Procedure:
25 ml of a dimethylformamide solution containing 4.00 g of 2(1H)-pyridone and 8.00 g of 2-bromopyridine was incorporated with 3.80 g of potassium carbonate and 0.51 g of cupurous iodide, followed by stirring at 120° C. for 2 hours. After the mixture was returned to room temperature, water was added thereto. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with water and brine, and then dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (ethyl acetate/hexane=1:1), to give 1.58 g of the title compound as a pale yellow wax.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)(=O)[CH3:2].Cl.[NH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25]([O:27][CH3:28])=[O:26]>N1C=CC=CC=1>[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[C:1](=[N:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH3:2]
Reactant: CC(=O)c1ccc2ccccc2c1
Reactant: COC(=O)Cc1ccccc1CON
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)Cc1ccccc1CON=C(C)c1ccc2ccccc2c1
Temperature: 90 °C
Yield: 105.7 %

Procedure:
2'-acetonaphthone (1.02 g) and the title compound of Step C (1.39 g) were dissolved in 40 mL of pyridine. The solution was heated to 90° C. for 3 h, and then was cooled to room temperature overnight. The pyridine was removed in vacuo and the residue was taken up in 40 mL of 1N HCl solution and extracted with ethyl acetate (3×50 mL) The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to yield 2.2 g (about 100% yield) of the title compound of Step D as an amber oil. 1H NMR (CDCl3): δ 7.99 (d,1H), 7.86 (m,4H), 7.48 (m,3H), 7.31 (m,3H), 5.33 (s,2H), 3.85 (s,2H), 3.68 (s,3H), 2.34 (s,3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])[N:13]=[C:12]2[CH3:28])[CH:5]=1.[Cl:30]N1C(=O)CCC1=O>C(O)(C)C.ClC(Cl)C(O)=O>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]([Cl:30])=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])[N:13]=[C:12]2[CH3:28])[CH:5]=1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3F)cc2=O)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(O)C(Cl)Cl
Solvent: CC(C)O
Product: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3F)c(Cl)c2=O)c1
Temperature: 60 °C
Yield: 81.4 %

Procedure:
To a solution of 3-[4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H-pyrimidin-1-yl]-4-methyl-benzoic acid methyl ester from Example 1, Step A (260 mg, 0.65 mmol) in isopropanol (5 mL) was added N-chlorosuccinimide (95 mg, 0.71 mmol) and 3 drops of dichloroacetic acid. The solution was heated at 60° C. for three hours. The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated to provide the chlorinated product as a light yellow semi-solid (230 mg, 82%). MS (M+H): 435
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)=O>CC(C)=O>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=3[CH3:8])[S:13][CH:15]=2)=[CH:19][CH:20]=1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Reactant: Cc1ccc(C(=O)CBr)cc1
Solvent: CC(C)=O
Product: COC(=S)c1cc(-c2nc(-c3ccc(C)cc3)cs2)c(C)s1
Yield: 72.4 %

Procedure:
103 mg (0.416 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 5 mL of reagent grade acetone. 2-Bromo-4′-methyl acetophenone (0.416 mmol; 89 mg) was added and the solution was allowed to reflux for 3 h. The solution was allowed to cool and crude product was filtered and washed two times with acetone and purified on a 1 mm silica plate eluting with 20% ethyl acetate/hexane to afford 104 mg (69% yield) of methyl 4-[4-(4-methylphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
Reaction SMILES: Cl[P:2]1[N:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[P:4](Cl)[N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].[C:15]([C:19]1[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:22]=[C:21]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:20]=1[OH:33])([CH3:18])([CH3:17])[CH3:16]>C(N(CC)CC)C>[C:15]([C:19]1[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:22]=[C:21]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:20]=1[O:33][P:2]1[N:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[P:4]([O:33][C:20]2[C:21]([C:29]([CH3:30])([CH3:31])[CH3:32])=[CH:22][C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:24][C:19]=2[C:15]([CH3:18])([CH3:17])[CH3:16])[N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)N1P(Cl)N(C(C)(C)C)P1Cl
Reactant: CC(C)(C)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(C(C)(C)C)c(OP2N(C(C)(C)C)P(Oc3c(C(C)(C)C)cc(C(C)(C)C)cc3C(C)(C)C)N2C(C)(C)C)c(C(C)(C)C)c1

Procedure:
The procedure of Example 1 is repeated using 2,4-dichloro-1,3-di-tert-butyl-1,3,2,4-diazadiphosphetidine, 2,4,6-tri-tert-butylphenol and triethylamine to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][CH2:11][C:12]#[C:13][C:14]2[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:16][N:15]=2)[CH:3]=1.Cl.[NH2:30][OH:31].C([O-])(=O)C.[Na+]>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:30]/[OH:31])=[C:4]([O:10][CH2:11][C:12]#[C:13][C:14]2[C:18]([C:19]([F:21])([F:20])[F:22])=[C:17]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[O:16][N:15]=2)[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1OCC#Cc1noc(-c2ccccc2)c1C(F)(F)F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O/N=C/c1ccc(Br)cc1OCC#Cc1noc(-c2ccccc2)c1C(F)(F)F
Yield: 96.4 %

Procedure:
A mixture of 4-bromo-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)prop-2-ynyloxy)benzaldehyde (Preparation 62D, 0.050 g, 0.111 mmol), hydroxylamine hydrochloride (9.26 mg, 0.133 mmol), and sodium acetate (0.018 g, 0.222 mmol) in methanol (2.0 mL) was heated at reflux for 30 min. The solvent was removed under reduce pressure, and the residue was diluted with dichloromethane, washed with water, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded (E)-4-bromo-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)prop-2-ynyloxy)benzaldehyde oxime (0.050 g, 0.107 mmol, 97% yield) as a white solid. The product had an HPLC with a ret. time=3.26 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=466.8.
Reaction SMILES: [C:1]([CH:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][N:7]=1)[CH3:5])([OH:3])=[O:2].S(Cl)(Cl)=O.[CH3:21][CH2:22]O>>[O:16]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([CH:4]([CH3:5])[C:1]([O:3][CH2:21][CH3:22])=[O:2])=[N:7][NH:8]1
Reactant: CCO
Reactant: CC(C(=O)O)c1n[nH]c(=O)c2ccccc12
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C)c1n[nH]c(=O)c2ccccc12
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(1-carboxyethyl)-1(2H)-phthalazinone (1.5 g, 6.9 mmol) in EtOH (50 mL) was added thionyl chloride (1.10 mL, 15.1 mmol). The mixture was stirred at 80° C. for 4 hours, cooled to 0° C., and quenched with 1M NaHCO3 (40 mL). The aq layer was extracted with EtOAc (2×50 mL), dried (Na2SO4), filtered, and concentrated to give the title compound: MS (ESI+) M/Z 247 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=O)=[CH:6][N:5]=[C:4]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[N:3]=1.[NH2:23][NH2:24]>C(O)C.C1COCC1>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][C:4]1[N:3]=[C:2]2[NH:23][N:24]=[C:8]([C:10]3[S:11][CH:12]=[CH:13][CH:14]=3)[C:7]2=[CH:6][N:5]=1
Reactant: O=C(c1cccs1)c1cnc(Oc2ccccc2Cl)nc1Cl
Reactant: NN
Solvent: CCO
Solvent: C1CCOC1
Product: Clc1ccccc1Oc1ncc2c(-c3cccs3)n[nH]c2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.6 %

Procedure:
[4-Chloro-2-(2-chloro-phenoxy)-pyrimidin-5-yl]-thiophen-2-yl-methanone (82 mg, 0.23 mmol) was dissolved in a mixture of 10 mL ethanol and 0.5 mL THF, and 15 mg of anhydrous hydrazine was added. The reaction mixture was stirred at room temperature for 10 minutes and then was heated to 80° C. for 20 minutes. Solvent was removed under reduced pressure, and the residue was purified by preparative scale TLC using 1.8% MeOH in methylene chloride to yield 36 mg of 6-(2-Chloro-phenoxy)-3-thiophen-2-yl-1H-pyrazolo[3,4-d]pyrimidine. Mass Spec. M+H=329. Mp=221.3-223.1° C.