Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.[Cl:6][C:7]1[C:12]([CH2:13][C:14]([O:16]C)=[O:15])=[C:11]([Cl:18])[N:10]=[C:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=3)=[O:28])=[CH:22][CH:21]=2)[N:8]=1.[OH-].[Na+]>O>[Cl:18][C:11]1[C:12]([CH2:13][C:14]([OH:16])=[O:15])=[C:7]([Cl:6])[N:8]=[C:9]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:27]([C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=3)=[O:28])=[CH:24][CH:25]=2)[N:10]=1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1c(Cl)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 15 %

Procedure:
A THF (1.5 mL) solution of methyl {4,6-dichloro-2-[4-(2-naphthoylamino)benzyl]pyrimidin-5-yl}acetate (0.048 g, 0.10 mmol) at room temperature was treated with 1N NaOH (1 mL). After stirring for 16 hours at room temperature, the reaction mixture was poured into water and washed with EtOAc. The aqueous layer was acidified with 1N HCl and back extracted with EtOAc. The combined organic extracts was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The remaining residue was chromatographed over silica gel eluting with 10% THF in CH2Cl2 containing 0.5% AcOH to give {4,6-dichloro-2-[4-(2-naphthoyl-amino)benzyl]pyrimidin-5-yl}acetic acid (0.007 g, 15% yield) as a white solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH:14]1([CH2:17][NH:18][CH2:19][CH2:20][CH3:21])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.O>[CH:14]1([CH2:17][N:18]([CH2:19][CH2:20][CH3:21])[C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:16][CH2:15]1
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Reactant: CCCNCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1C=O
Temperature: 120 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
2-Fluoro-5-trifluoromethyl-benzaldehyde (1.3 g) and cyclopropylmethyl-propyl-amine (1.15 g) are dissolved in toluene (13 ml), and thereto is added potassium carbonate (2.81 g) and the mixture is stirred at 120° C. overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=1:0→97:3) to give 2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzaldehyde (1.7 g). MS (m/z): 286 [M+H]+
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:20])([S:17][S:18][CH3:19])[CH3:16])(=O)=O)=CC=1.O[C:22]1[CH:27]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:25]=[C:24]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:20][C:15]([S:17][S:18][CH3:19])([CH3:16])[CH2:14][CH2:13][CH2:12][O:11][C:22]1[CH:23]=[C:24]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:25]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:27]=1
Reactant: CSSC(C)(C)CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)c1cc(O)cc(C(=O)OCC)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCCCC(C)(C)SSC)cc(C(=O)OCC)n1
Temperature: 90 °C
Reaction time: 18 h
Yield: 52.1 %

Procedure:
To a stirred solution of 4-methyl-4-(methyldisulfanyl)pentyl 4-methylbenzenesulfonate (5c) (0.48 g, 1.435 mmol) and diethyl 4-hydroxypyridine-2,6-dicarboxylate (5a) (0.343 g, 1.435 mmol) in anhydrous dimethylformamide (6.5 mL) was added Potassium carbonate (0.297 g, 2.152 mmol). The reaction was stirred at 90° C. for 18 hours. Then allowed to cool to ambient temperature and quenched with saturated ammonium chloride. The mixture was extracted three times with ethyl acetate. The extracts were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (30% hexanes/ethyl acetate) yielded diethyl 4-(4-methyl-4-(methyldisulfanyl)pentyloxy)pyridine-2,6-dicarboxylate (5d)(300 mg, 52%); 1H NMR (400 Hz, CDCl3): δ 7.70 (s, 2H), 4.40 (q, 4H, J=7.2, 14.4 Hz), 4.07 (t, 2H, J=6. Hz), 2.35 (s, 3H), 1.86 (m, 2H), 1.70 (m, 2H), 1.38 (t, 6H, J=7.2 Hz), 1.27 (s, 6H); MS (m/z). found 424.1 (M+Na), 440.1 (M+K). See FIG. 5.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][CH2:22][C:23]([OH:25])=[O:24]>>[C:1]([NH:21][CH2:22][C:23]([OH:25])=[O:24])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCC(=O)O
Product: O=C(O)CNC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 90 %

Procedure:
N-tritylglycine was prepared in 90% yield from trityl chloride and glycine according to the procedure of Zervas et al., J. Am. Chem. Soc. 78:1359 (1956).
Reaction SMILES: [OH:1][CH:2]([CH2:17][O:18][CH2:19][CH2:20][CH:21]([CH2:25][CH3:26])[CH2:22][CH2:23][CH3:24])[CH2:3][NH:4][C:5]([CH3:16])([CH3:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.OC(COC(C)C)CN[C:31](C)([CH3:41])[CH2:32][C:33]1C=CC(OC)=CC=1>>[OH:1][CH:2]([CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:33]=[CH:32][CH:31]=[CH:41][CH:26]=2)[CH:20]=1)[CH2:3][NH:4][C:5]([CH3:16])([CH3:15])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COC(C)C)cc1
Reactant: CCCC(CC)CCOCC(O)CNC(C)(C)Cc1ccc(OC)cc1
Product: COc1ccc(CC(C)(C)NCC(O)COc2cccc(-c3ccccc3)c2)cc1

Procedure:
GC/MS (me, 0.1), 284 (100), 121 (28), 285 (27), 152 (13), 70 (13), 71 (11), 153 (10).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:23])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:26][C@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[C:33]1[N:37]2[CH:38]=[C:39]([O:42][C@H:43]3[C:52]4[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=4)[C@@H:46]([NH2:53])[CH2:45][CH2:44]3)[CH:40]=[CH:41][C:36]2=[N:35][N:34]=1.CCN(C(C)C)C(C)C.CO>O1CCOCC1.C(Cl)Cl>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:53][C@@H:46]2[C:47]3[C:52](=[CH:51][CH:50]=[CH:49][CH:48]=3)[C@H:43]([O:42][C:39]3[CH:40]=[CH:41][C:36]4[N:37]([C:33]([N:28]5[CH2:29][CH2:30][CH2:31][CH2:32][C@@H:27]5[CH3:26])=[N:34][N:35]=4)[CH:38]=3)[CH2:44][CH2:45]2)=[O:23])[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:9]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)cc1

Procedure:
An orange-brown solution of (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 106 mg, 0.263 mmol), Intermediate 81d (94.4 mg, 0.250 mmol) and DIPEA (0.054 mL, 0.313 mmol) in dry dioxane (3 mL) was stirred at 70° C. for 16 h. The cooled solution was concentrated in vacuo, suspended in water (5 mL) and extracted with DCM (2×5 mL). The combined organics were passed through a hydrophobic fit and concentrated in vacuo to leave a brown gum. FCC, using 2-6% MeOH in DCM, gave a pale yellow solid (123 mg). Further purification by HPLC (XBridge C18 column, 40-90% MeCN in H2O, 0.1% NH4OH) gave the title compound as a white powder after freeze-drying (72.4 mg, 46%). LCMS (Method 5): Rt 5.04 min, m/z 633 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J 6.3), 1.27 (9H, s), 1.48-1.55 (2H, m), 1.63-1.71 (2H, m), 1.75-1.97 (4H, m), 2.00-2.16 (2H, m), 2.36 (3H, s), 2.90 (1H, ddd, J 12.1, 9.0, 3.9), 3.16 (1H, dt, J 12.1, 4.3), 3.29 (1H, m), 4.82 (1H, td, J 8.6, 5.5), 5.51 (1H, t, J 4.4), 6.32 (1H, s), 7.08 (1H, d, J 8.6), 7.19 (1H, dd, J 9.9, 2.2), 7.25-7.38 (8H, m), 7.64 (1H, dd, J 9.8, 0.8), 7.69 (1H, d, J 2.1), 8.04 (1H, s).
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9]C(C)(C)C)=[O:8])[CH2:5][N:4]([C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[C:3]1=[O:21].[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23].C(Cl)Cl>>[OH:28][C:22]([C:24]([F:27])([F:26])[F:25])=[O:23].[CH3:1][N:2]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][N:4]([C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[C:3]1=[O:21]
Reactant: Cc1cccnc1N1CC(C(=O)OC(C)(C)C)N(C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccnc1N1CC(C(=O)O)N(C)C1=O

Procedure:
A solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (600 mg, 3 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 2-bromo-3-methylpyridine (515 mg, 3 mmol) in 1,4-dioxane (20 ml) was treated with cesium carbonate (1464 mg, 4.5 mmol), Xantphos™ (130 mg, 0.225 mmol) and tris(dibenzylideneacetone)dipalladium(0) (68.6 mg, 0.075 mmol) and the mixture was heated under reflux under argon for 18 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with water and brine and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in isohexane to give 1,1-dimethylethyl 3-methyl-1-(3-methyl-2-pyridinyl)-2-oxo-4-imidazolidinecarboxylate (700 mg, 80%). LC/MS [M+H]+=292. (ii) A solution of 1,1-dimethylethyl 3-methyl-1-(3-methyl-2-pyridinyl)-2-oxo-4-imidazolidinecarboxylate (700 mg, 2.4 mmol) in TFA/DCM (1:2, 12 ml) was stirred at room temperature for 6 hours. The solution was evaporated and the residue was co-evaporated with toluene and dried to give 3-methyl-1-(3-methyl-2-pyridinyl)-2-oxo-4-imidazolidinecarboxylic acid TFA salt (assume ˜2.4 mmol) which was used in the next step. LC/MS [M+H]+=236.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH:10]2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]3[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:31]=3[CH:41]=2)=[CH:5][CH:4]=1.[NH:42]1[CH:46]=[CH:45][N:44]=[CH:43]1>>[N:42]1([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[O:16])[CH2:11][CH:10]3[O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]4[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:31]=4[CH:41]=3)=[CH:5][CH:4]=2)[CH:46]=[CH:45][N:44]=[CH:43]1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CCl)cc3)cc21
Reactant: c1c[nH]cn1
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(Cn4ccnc4)cc3)cc21

Procedure:
Analogously to Example 269a, 0.103 g of benzyl 4-(4-chloromethylphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 270b) and 0.013 g of imidazole are reacted. The title compound is obtained as a yellowish oil. Rf=0.47 (200:10:1 dichloromethane-methanol-25% conc. ammonia). Rt=4.34.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[N:19][OH:20])[CH2:10][O:11][C@@H:12]([CH:17]=[CH2:18])[C:13]([F:16])([F:15])[F:14].C1(C=CC(O)=CC=1)O>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]12[CH2:10][O:11][C@H:12]([C:13]([F:15])([F:16])[F:14])[CH:17]1[CH2:18][O:20][NH:19]2
Reactant: C=C[C@H](OCC(=NO)c1cccc(F)c1F)C(F)(F)F
Agent: Oc1ccc(O)cc1
Product: Fc1cccc(C23CO[C@H](C(F)(F)F)C2CON3)c1F
Temperature: 140 °C
Yield: 77.1 %

Procedure:
(S)-1-(2,3-difluorophenyl)-2-((1,1,1-trifluorobut-3-en-2-yl)oxy)ethanone oxime (4.10 g) was dissolved in xylenes (40 mL) and hydroquinone (380 mg) was added. The reaction mixture was heated to reflux (heating block temperature 140° C.) for 20 h, then cooled and evaporated. The residue was purified by silica gel column chromatography (1% to 25% EtOAc in hexanes) to obtain the title compound (3.16 g). 1H NMR (400 MHz, CDCl3) δ ppm 3.77 (br. s., 1H), 3.99-4.16 (m, 1H), 4.16-4.22 (m, 1H), 4.22-4.44 (m, 2H), 4.51 (d, J=9.9 Hz, 1H), 5.44 (s, 1H), 7.07-7.24 (m, 2H), 7.38 (br. s., 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[OH-].[Na+]>Cl>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:17][CH2:16][C:11](=[O:12])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Clc1cnc(N2CCC3(CC2)OCCO3)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1CCN(c2ncc(Cl)cn2)CC1

Procedure:
A solution of 8-(5-chloropyrimidin-2-yl)-1,4-dioxa-8-azaspiro[4.5]decane (4.2 g) in 6 M aqueous HCl (50 mL) is stirred at room temperature for 60 h. The solution is cooled in ice bath and 4 M aqueous NaOH solution (90 mL) is added in portions to make the solution strongly basic (pH˜14). The mixture is extracted with dichloromethane (2×200 mL) and the combined organic layers are dried over Na2SO4, filtered and concentrated to yield the title compound.
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[N:5]1.C([O-])(=O)C.[Na+]>>[Br:1][C:7]1[C:6]([C:10]([F:12])([F:11])[F:13])=[N:5][N:4]([CH3:3])[C:8]=1[CH3:9]
Reactant: Cc1cc(C(F)(F)F)nn1C
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Cc1c(Br)c(C(F)(F)F)nn1C
Reaction time: 96 h
Yield: 79.5 %

Procedure:
A total of 61.9 g (388 mmol) of bromine are added dropwise at 0° C. within 2.5 h to a suspension of 60 g (366 mmol) of 1,5-dimethyl-3-trifluoromethyl-1H-pyrazole and 30.0 g (366 mmol) of anhydrous sodium acetate in 600 ml of CHC13. On completion of addition, the mixture is allowed to come to 20° C. and is stirred for a further 4 d. After the end of the reaction, the mixture is washed with 30% NaHCO3 solution, the aqueous phase is further extracted twice using 200 ml of CHC13 each time and the combined organic phases are dried over MgSO4 and concentrated. Recystallization results in 70.6 g (291 mmol, 80%) of 4-bromo-1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazole as a bright yellow solid.
Reaction SMILES: C1(C[O:8][CH2:9][CH2:10][CH:11]=[CH:12][C:13]2[CH2:18][O:17][CH2:16][CH2:15][CH:14]=2)C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C>[O:17]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:12][CH2:11][CH2:10][CH2:9][OH:8])[CH2:18]1
Reactant: [H][H]
Reactant: C(=CC1=CCCOC1)CCOCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: OCCCCC1CCCOC1
Yield: 92 %

Procedure:
A solution of 5-{4-[(phenylmethyl)oxy]-1-buten-1-yl}-3,6-dihydro-2H-pyran (2.03 g) and 10% palladium on carbon (88 mg) in ethyl acetate (83 ml) was hydrogenated at atmospheric pressure and room temperature. Hydrogen uptake (˜500 ml) was complete after 15 hours. The catalyst was filtered through celite and the filtrate concentrated in vacuo to afford a colourless oil. Analysis by 1H-NMR showed that the benzyl group was present in the majority of the compound. Hydrogenation was continued under the same conditions for a further 24 hours with additional hydrogen uptake of ˜300 ml. The catalyst was filtered through celite and the filtrate concentrated in vacuo to afford the title compound as a colourless oil (1.21 g).
Reaction SMILES: I[C:2]1[C:3]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])=[N:4][CH:5]=[N:6][CH:7]=1.[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[C:33]([OH:35])[CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[F:28][C:29]1[CH:30]=[C:31]([C:2]2[C:3]([NH:8][C@H:9]([C:11]3[N:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:15](=[O:23])[C:14]4=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]4[N:12]=3)[CH3:10])=[N:4][CH:5]=[N:6][CH:7]=2)[CH:32]=[C:33]([OH:35])[CH:34]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncncc3I)n(-c3ccccc3)c(=O)c12
Reactant: OB(O)c1cc(O)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncncc3-c3cc(O)cc(F)c3)n(-c3ccccc3)c(=O)c12
Yield: 54.8 %

Procedure:
(S)-2-(1-((5-Iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (115 mg, 0.24 mmol) was treated with (3-fluoro-5-hydroxyphenyl)boronic acid (57 mg, 0.37 mmol), sodium carbonate (2M, 548 μl, 1.10 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (30 mg, 0.04 mmol) according to the method described in Example 3 to give 60 mg (54% yield) of the title compound. Purity 100%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][O:10][C@H:9]1[CH:14]=[O:15])([CH3:4])([CH3:3])[CH3:2].[Br-].[K+].Cl[O-].[Na+].C(=O)(O)[O-:23].[Na+].[OH-].[Na+].Cl>C(Cl)Cl.[Br-].C[N+](C)(C)C.O>[C:1]([O:5][C:6]([NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][O:10][C@H:9]1[C:14]([OH:23])=[O:15])=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCO[C@H]1C=O
Reactant: O=C([O-])O
Agent: C[N+](C)(C)C
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCCO[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 89.5 %

Procedure:
To a stirring solution of [(2R,3R)-2-formyl-tetrahydro-pyran-3-yl]-carbamic acid tert-butyl ester (57.7 mg, 0.251 mmol)in methylene chloride (2 mL) was added tetramethyl-ammonium bromide (4.1 mg, 0.012 mmol) and 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical (1 mg, 0.003 mmmol), followed by a solution of potassium bromide (3 mg, 0.03 mmol) in water (1 mL). Upon cooling the mixture to 0° C., aqueous sodium hypochlorite (3.6 mL, 0.35 M) made pH 8.6 with sodium bicarbonate (50 mg/mL of 0.35 M NaOCl) was added, and the resulting yellow/orange mixture was stirred vigorously for 5 min. The reaction was poured into 1N aqueous sodium hydroxide (50 mL), acidified with 1N aqueous hydrogen chloride (55 mL), and washed with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate, concentrated in vacuo, and the resulting residue was purified by flash chromatography (SiO2, 30-50% ethyl acetate in hexanes then 70% ethyl acetate in hexanes containing 5% acetic acid and 1% methanol) to give the desired product (55.5 mg, 89.5%) as a foamy solid. MS (ESI), m+/z: (M+H)+=244.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][C:10](=[O:20])[C:11]=2[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[N:7]=1.[NH4+:21].[Cl-].[NH4+].[OH-]>O>[NH2:21][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][C:10](=[O:20])[C:11]=2[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[N:7]=1
Reactant: O=c1ccn2nc(Cl)ccc2c1-c1c(F)cccc1F
Reactant: [NH4+]
Agent: [Cl-]
Agent: [OH-]
Solvent: O
Product: Nc1ccc2c(-c3c(F)cccc3F)c(=O)ccn2n1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To 2-chloro-5-(2,6-difluorophenyl)-6H-pyrido[1,2-b]pyridazin-6-one (1.1 g, 3.77 mmol) was added NH4Cl (100 mL) and NH4OH (100 mL). The resulting solution was heated to 90° C. and stirred for 16 hrs until complete. The reaction was cooled to ambient temperature and diluted with H2O (500 mL) until a precipitate formed. The solid precipitate was collected and dried to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([O:6][CH2:19][CH3:20])=[O:5]
Reactant: CCO
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc([N+](=O)[O-])ccc1F
Temperature: 65 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
2-Fluoro-5-nitrobenzoic acid (1.85 g) was dissolved in ethanol (30 ml). Concentrated sulfuric acid (1.0 ml) was added to the solution, and the mixture was stirred at 65° C. overnight. The solvent was removed from the reaction solution by distillation under the reduced pressure, and the residue was adjusted to pH 7 by the addition of a saturated aqueous sodium hydrogencarbonate solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under the reduced pressure to give 1.79 g (84.3%) of ethyl 2-fluoro-5-nitrobenzoate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: BrCc1ccccc1
Product: COC(=O)c1cc(O)cc(OCc2ccccc2)c1

Procedure:
The subtitle compound was prepared from methyl 3,5-dihydroxybenzoate (5 g) and benzyl bromide (3.6 ml) by the method of example 11 step (i). Purification was by chromatography eluting with 30% ethyl acetate in isohexane. Yield 2.31 g.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:20])=[C:6]([CH:19]=1)[CH2:7][N:8]([CH:16]1[CH2:18][CH2:17]1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[F-].[Cs+].[CH2:23]([Sn](CCCC)(CCCC)CCCC)[CH:24]=[CH2:25]>C1COCC1>[CH2:25]([C:2]1[CH:3]=[CH:4][C:5]([Cl:20])=[C:6]([CH:19]=1)[CH2:7][N:8]([CH:16]1[CH2:18][CH2:17]1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:24]=[CH2:23]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N(Cc1cc(Br)ccc1Cl)C1CC1
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCc1ccc(Cl)c(CN(C(=O)OC(C)(C)C)C2CC2)c1

Procedure:
A THF solution (0.13 M) of tert-butyl (5-bromo-2-chlorobenzyl)cyclopropylcarbamate from the previous step (1 eq.), Pd(PCy3)2 (0.05 eq.) and cesium fluoride (2.0 eq.) was added allyl tributylstannane (1.2 eq.). The resulting brown solution was heated at reflux for 8 h and then filtered through a pad of SiO2. The insolubles were rinsed further with ether and the filtrate was concentrated in vacuo to afford a brown semisolid. Purification of the crude product thus obtained by way of column chromatography (SiO2, Hex→90:10 (v/v) Hex:Et2O) afforded the title compound as a colorless oil.
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.C([N:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH2:36][C:37]([OH:39])=[O:38])=[CH:32][CH:31]=2)[CH2:24][CH2:23]1)C1C=CC=CC=1>C(O)C.Cl.[Pd]>[N:25]1([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH2:36][C:37]([OH:39])=[O:38])=[CH:32][CH:31]=2)[CH2:26][CH2:27][NH:22][CH2:23][CH2:24]1
Reactant: O=C(O)Cc1ccc(CCN2CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCO
Product: O=C(O)Cc1ccc(CCN2CCNCC2)cc1

Procedure:
140 g. (0.34 mole) of the dihydrochloride of 4-[2-(1-benzylpiperazin-4-yl)-ethyl]-phenylacetic acid is dissolved in a mixture of ethanol and 6N hydrochloric acid and 10% palladium-charcoal is added thereto, followed by hydrogenation in a shaker bomb. If the reaction proceeds too slowly, the catalyst is replaced by fresh catalyst. The reaction mixture is then suction filtered and the filtrate is evaporated and brought to crystallisation with some ethyl acetate. Yield 90 g. (82% of theory) of the dihydrochloride of 4-[2-(piperazin-1-yl)-ethyl]-phenylacetic acid; m.p. 238°-239° C. (recrystallised from acetone/water).