Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([CH:10]([C:12]2[CH:25]=[C:24]3[C:15]([O:16][CH2:17][CH2:18][N:19]4[C:23]3=[N:22][C:21]([C:26]3[N:30]([CH:31]([CH3:33])[CH3:32])[N:29]=[CH:28][N:27]=3)=[CH:20]4)=[CH:14][CH:13]=2)[CH3:11])[CH2:7]1)(=O)=O.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>O1CCOCC1>[CH:31]([N:30]1[C:26]([C:21]2[N:22]=[C:23]3[C:24]4[CH:25]=[C:12]([CH:10]([N:8]5[CH2:9][CH:6]([N:34]6[CH2:39][CH2:38][O:37][CH2:36][CH2:35]6)[CH2:7]5)[CH3:11])[CH:13]=[CH:14][C:15]=4[O:16][CH2:17][CH2:18][N:19]3[CH:20]=2)=[N:27][CH:28]=[N:29]1)([CH3:32])[CH3:33]
Reactant: C1COCCN1
Reactant: CC(c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2)N1CC(OS(C)(=O)=O)C1
Solvent: C1COCCO1
Product: CC(c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2)N1CC(N2CCOCC2)C1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(1-{4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-13-yl}ethyl)azetidin-3-yl methanesulfonate (70 mg, 0.15 mmol) and morpholine (20 mg, 1.5 mmol) in 1,4-dioxane (4 mL) was stirred at 80° C. for 16 h under nitrogen atmosphere. After concentration, the residue was purified by reverse phase Combiflash eluting with a 0-50% gradient of CH3CN in 0.3% NH4HCO3 to give 163. The enantiomers were separated by chiral HPLC (OD column, 10% EtOH (0.1% DEA) in n-hexane isocratic) to give: 24 mg of one enantiomer and 25 mg of the other (71% total yield)
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]([NH2:23])=[O:22].C(=O)([O-])[O-].[Na+].[Na+].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.O.C(O)C>[NH:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:1]([OH:3])=[O:2])[CH:5]=1)[C:21]([NH2:23])=[O:22]
Reactant: NC(=O)Nc1ccccc1Br
Reactant: O=C(O)c1cccc(B(O)O)c1
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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: NC(=O)Nc1ccccc1-c1cccc(C(=O)O)c1
Temperature: 100 °C
Yield: 96.7 %

Procedure:
3-Carboxyphenyl boronic acid (100 mg, 0.60 mmol), 2-bromophenyl urea (130 mg, 0.60 mmol), tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.030 mmol), sodium carbonate (192 mg, 1.81 mmol), toluene (5 mL), water (3 mL), and ethanol (3 mL) were mixed at 25° C. under nitrogen then heated in a microwave reactor for 30 minutes at 100° C. Water (5 mL) was added followed by removal of the EtOH in vacuo. The aqueous layer was washed with diethyl ether (2×) and the pH was adjusted to 3 with 1N HCl. The aqueous layer was extracted with ethyl acetate (2×) and the combined were dried over sodium sulfate and then concentrated in vacuo to give 2′-ureidobiphenyl-3-carboxylic acid (150 mg, 0.58 mmol, 97% yield) as a tan glass. MS found: (M+H)+=257.29
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:27]([O:31][C:32](=[O:42])[NH:33][CH2:34][CH:35]([NH2:41])[C:36]1[CH:40]=[CH:39][S:38][CH:37]=1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:42])[NH:33][CH2:34][CH:35]([NH:41][C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)[C:36]1[CH:40]=[CH:39][S:38][CH:37]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CN1CCN(c2nccn3c(-c4ccnc(S(C)(=O)=O)n4)cnc23)CC1
Reactant: CC(C)(C)OC(=O)NCC(N)c1ccsc1
Product: CN1CCN(c2nccn3c(-c4ccnc(NC(CNC(=O)OC(C)(C)C)c5ccsc5)n4)cnc23)CC1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
The mixture of 3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine (from Example 46 supra) (200 mg, 0.536 mmol) and (2-amino-2-thiophen-3-yl-ethyl)-carbamic acid tert-butyl ester (from Example 74 supra) (520 mg, 2.14 mmol) was heated at 140° C., with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 10:1 to 4:1) to afford crude (2-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-2-thiophen-3-yl-ethyl)-carbamic acid tert-butyl ester. (yield 150 mg). LC-MS: [M+H]+ 536.
Reaction SMILES: Br[C:2]([F:27])([F:26])[C:3]([F:25])([F:24])[O:4][C:5]1[C:10](Cl)=[CH:9][C:8]([N:12]2C(=O)C3=CC=CC=C3C2=O)=[CH:7][C:6]=1[Cl:23].O.NN>C(O)C>[NH2:12][C:8]1[CH:7]=[C:6]([Cl:23])[C:5]2[O:4][C:3]([F:25])([F:24])[C:2]([F:27])([F:26])[C:10]=2[CH:9]=1
Reactant: O=C1c2ccccc2C(=O)N1c1cc(Cl)c(OC(F)(F)C(F)(F)Br)c(Cl)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1cc(Cl)c2c(c1)C(F)(F)C(F)(F)O2

Procedure:
A mixture of 2.3 g N-[4-(2-bromo-1,1,2,2-tetrafluoroethoxy)-3,5-dichlorophenyl]phthalimide (0.0062 mole) and 0.25 g (0.0068 mole) hydrazine hydrate in 50 ml of ethanol was heated at reflux for one hour. Most of the solvent was removed by distillation under reduced pressure, and the residual liquid was poured into water. This mixture was extracted with three 150 ml portions of diethyl ether and the extracts were combined. This organic solution was washed with 200 ml of an aqueous 2N sodium hyroxide solution. The washed organic solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 5-amino-7-chloro-2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran as an oil. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[F:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13](=[O:18])[CH:14]=[C:15]([CH3:17])[CH3:16])=[CH:8][CH:7]=1>C(=S)=S>[F:5][C:6]1[CH:7]=[C:8]2[C:9](=[CH:10][CH:11]=1)[O:12][C:13](=[O:18])[CH2:14][C:15]2([CH3:16])[CH3:17]
Reactant: CC(C)=CC(=O)Oc1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC1(C)CC(=O)Oc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 77.2 %

Procedure:
To a stirred suspension of aluminum trichloride (18.0 g) in carbon disulfide (30 mL) was added dimethylacrylate 4-fluorophenyl ester (18.0 g, 92.7 mmol) dropwise over a 0.5 hour period. The reaction mixture was stirred at room temperature for 14.0 hours. The reaction was poured onto ice and extracted with ethyl acetate-hexanes (1:10, 200 mL). The organic phase was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and evaporated in vacuo. Trituration of the residue with cold hexane gave a colorless crystalline 6-fluoro-4,4-dimethylchroman-2-one (13.9 g, 77%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:22])[N:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8](=[O:15])[C:9]3[C:14]=2[C:13]=1[CH:12]=[CH:11][CH:10]=3.[OH-].[Na+].[CH2:25]([OH:29])[CH2:26][CH2:27][OH:28]>O>[OH:28][CH2:27][CH2:26][CH2:25][O:29][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:22])[N:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8](=[O:15])[C:9]3[C:14]=2[C:13]=1[CH:12]=[CH:11][CH:10]=3
Reactant: O=C1c2cccc3c(Br)ccc(c23)C(=O)N1c1ccccc1
Reactant: OCCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1c2cccc3c(OCCCO)ccc(c23)C(=O)N1c1ccccc1
Temperature: 120 °C
Reaction time: 10 h

Procedure:
A mixture of 6-bromo-2-phenyl-benzo[de]isoquinoline-1,3-dione (4.0 g), sodium hydroxide (0.67 g) and 1,3-propane diol (50 ml) was maintained with stirring at 120° C. for 10 hrs. The reaction mixture was cooled to room temperature. Water (100 ml) was added to the mixture and solid separated out. The solid was filtered, washed with water, and dried at 100° C. for 8 hours to provide a crude product in a yield of 1.90 g. The crude product was purified using mono chloro benzene (60 ml) and activated charcoal (0.20 g). The weight of the of the purified product obtained was 1.15 g. 1H-NMR: 3.93 δ (m, 2 protons); 4.35 δ (m, 1 proton); 2.25 δ (m, 2 protons); 3.96 δ (m, 2 protons); 4.47 δ (m, 2 proton); 7.13 δ (m, 2 protons); 5.14 δ (m, 1 proton); 7.36 δ (m, 3 protons); 7.51 δ (m, 3 protons); 7.84 δ (m, 1 proton); 8.46 δ (m, 2 protons); 8.69 δ (m, 1 proton).
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:10]2[CH:14]=[C:13]([C:15]([NH2:17])=[O:16])[C:12]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:11]2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:2].[C:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=O)[CH3:27].C(O)(=O)C.C([BH3-])#N.[Na+]>CO.CN(C=O)C>[C:1]([CH2:3][C:4]1([N:10]2[CH:14]=[C:13]([C:15]([NH2:17])=[O:16])[C:12]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)=[N:11]2)[CH2:9][CH2:8][N:7]([CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:27])[CH2:6][CH2:5]1)#[N:2]
Reactant: CC(=O)c1ccccc1
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccc(F)cc3)n2)CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CO
Product: CC(c1ccccc1)N1CCC(CC#N)(n2cc(C(N)=O)c(Nc3ccc(F)cc3)n2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-(4-(cyanomethyl)piperidin-4-yl)-3-((4-fluorophenyl)amino)-1H-pyrazole-4-carboxamide (Intermediate #38-5) (50 mg, 0.11 mmol) in MeOH (0.32 mL) and DMF (0.063 mL) was added acetophenone (41 mg, 0.34 mmol) and acetic acid (0.065 mL, 1.1 mmol). The reaction mixture was allowed to stir at room temperature for 15 minutes. Sodium cyanoborohydride (7 mg, 0.1 mmol) was added and the reaction mixture was allowed to stir for 24 hours at ambient temperature. The mixture was then purified directly by mass-triggered reverse-phase preparative HPLC (MeCN/water, with 0.1% v/v TFA modifier). Desired fractions were identified, combined, and concentrated in vacuo. The residue was dissolved in MeOH and passed through a Si-Carbonate cartridge to afford the title compound as a free base.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:10][C:5]2=[N:4][CH:3]=1.C1C(=O)N([I:28])C(=O)C1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCCl>[CH2:14]([O:13][C:11]([N:9]1[CH2:8][CH2:7][N:6]2[C:2]([CH3:1])=[C:3]([I:28])[N:4]=[C:5]2[CH2:10]1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cnc2n1CCN(C(=O)OCc1ccccc1)C2
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1c(I)nc2n1CCN(C(=O)OCc1ccccc1)C2
Temperature: 25 °C
Yield: 89.4 %

Procedure:
To a solution of benzyl 3-methyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (1.085 g, 4.00 mmol) in 1,2-dichloroethane (60 ml) was added NIS (4.50 g, 20.00 mmol) and the reaction was heated at reflux for one hour. The reaction was cooled to room temperature and poured into 100 ml of saturated 5% sodium thiosulfate solution. The layers were separated and the aqueous layer was re-extracted with 1,2-dichloroethane (40 ml). The combined organic layers were washed with water (100 ml), dried over sodium sulfate, filtered and concentrated. Product was extracted from the residue by trituration with 3×50 ml portions of ether. The extract was filtered and concentrated to yield 2-Iodo-3-methyl-5,6-dihydro-8H-imidazo[1,2-a] pyrazine-7-carboxylic acid benzyl ester (1.42 g, 89%) as a pale yellow oil. LCMS (Table 1, Method a) Rt=3.32 min, m/z 398.59 (M+H)+; 1H NMR (400 MHz, CHCl3)δ 7.35 (m, 5H), 5.13 (s, 2H), 4.56 (s,broad, 2H), 4.38 (t, 2H), 3.82 (s, broad, 2H), 2.09 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:6]2=[CH:7][CH:8]=[C:9]3[C:14]([O:13][C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[C:11]([I:21])[C:10]3=[O:22])=[C:5]2[NH:4][N:3]=1.[C:23](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[Cl:1][C:2]1[C:6]2=[CH:7][CH:8]=[C:9]3[C:14]([O:13][C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[C:11]([I:21])[C:10]3=[O:22])=[C:5]2[N:4]([CH3:23])[N:3]=1
Reactant: O=c1c(I)c(-c2ccccc2)oc2c1ccc1c(Cl)n[nH]c12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nc(Cl)c2ccc3c(=O)c(I)c(-c4ccccc4)oc3c21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.3 %

Procedure:
To a stirred ice-cooled solution of 3-chloro-7-iodo-8-phenyl-1H-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-6-one (42 mg, 0.10 mmol) in DMF (2 mL), was added cesium carbonate (65 mg, 0.2 mmol). After 5 min, iodomethane (0.0185 mL, 0.3 mmol) was added. After a further 5 min, the reaction mixture was allowed to warm to RT. After a further 15 min, the resulting mixture was partitioned between EtOAc and water. The resulting biphasic mixture was separated, the organic phase was further extracted with EtOAc and the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 30 to 50% EtOAc in cyclohexane) to afford the title compound as a white solid (25 mg, 58%), LCMS (Method H): RT=4.19 min, [M+H]+=437/439.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]3[CH2:15][CH2:14][C@:13]([CH3:19])([C:16]([OH:18])=O)[C:12]3([CH3:21])[CH3:20])=[C:8]([C:22](=[O:24])[NH2:23])[CH:7]=[N:6][N:5]2[CH:25]=1.CC[N:28](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]3[CH2:15][CH2:14][C@@:13]([C:16](=[O:18])[NH2:28])([CH3:19])[C:12]3([CH3:21])[CH3:20])=[C:8]([C:22]([NH2:23])=[O:24])[CH:7]=[N:6][N:5]2[CH:25]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC1(C)[C@H](Nc2c(C(N)=O)cnn3cc(Br)cc23)CC[C@]1(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)[C@H](Nc2c(C(N)=O)cnn3cc(Br)cc23)CC[C@]1(C)C(N)=O
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 57.3 %

Procedure:
To a stirred solution of (1S,3R)-3-(6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-ylamino)-1,2,2-trimethylcyclopentanecarboxylic acid (182 mg, 0.445 mmol) in DMF (3.0 ml), were added Hunig's base (582 μl, 3.34 mmol) and HATU (254 mg, 0.667 mmol). After 15 minutes, ammonium chloride (119 mg, 2.223 mmol) was added. The reaction was heated at 75° C. for 24 hrs. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The solution was washed successively with water, (sat.) ammonium chloride and (sat.) sodium chloride. The ethyl acetate extract was dried with sodium sulfate, filtered, and concentrated under reduced pressure to yield the title compound (104 mg, 0.255 mmol, 57.3% yield) as a white solid. LC/MS found [M+H]+=409.9.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[C:11]([O:14][C:15](=O)C)(=O)[CH3:12]>C(O)C>[CH3:15][O:14][CH2:11][C:12]1[NH:10][C:8](=[O:9])[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=1
Reactant: NC(=O)c1nccnc1N
Reactant: CC(=O)OC(C)=O
Solvent: CCO
Product: COCc1nc2nccnc2c(=O)[nH]1

Procedure:
Obtained using the procedure described in Example 1, starting with 11.7 g (0.085 mole) of 3-amino-2-pyrazinecarboxamide, 73.0 g (0.38 mole) of triethyl orthomethoxyacetate [prepared according to E. T. Stiller, U.S. Pat. No. 2,422,598; C.A. 1947, 41, 5904a] and 75 ml of acetic anhydride. Yld: 12.3 g (75%), m.p. 187°-189° C. (ethanol).
Reaction SMILES: C([NH:4][C:5]1[N:6]=[C:7](C2N=CNN=2)[C:8]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1)(=O)C.[H-].[Na+].[CH:29]1([CH2:32][OH:33])[CH2:31][CH2:30]1>O1CCOCC1>[NH2:4][C:5]1[N:6]=[C:7]([O:33][CH2:32][CH:29]2[CH2:31][CH2:30]2)[C:8]2[N:14]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: CC(=O)Nc1nc(-c2nc[nH]n2)c2nc(-c3ccc(F)cc3)ccc2n1
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1nc(OCC2CC2)c2nc(-c3ccc(F)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
To a solution of 2-acetamido-4-(1,2,4-triazolyl)-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine (52 mg, 0.15 mmol) in cyclopropylmethanol (1 ml) and dioxane (3 ml) was added NaH (60% dispersion in mineral oil, 0.25 mmol, 15 mg). The reaction mixture was stirred overnight at room temperature. The solvents were evaporated in vacuo, and the residue was purified by preparative TLC, the mobile phase being a methanol/dichloromethane mixture in a ratio of 10:90, yielding the pure title compound (22 mg, yield: 47%) which was characterised as follows: MS (m/z): 311 ([M+H]+, 100).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[N:12]O)[CH3:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(NC(C)C)(C)C>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:11][NH:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(=NO)c1ccc2c(c1)OCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: c1cc2c(cc1C1CN1)OCO2
Temperature: 60 °C
Yield: 88.7 %

Procedure:
A solution of oxime 12 (2.7 g, 15 mmol, 1.0 equiv) in tetrahydrofuran (60 mL) at 25° C. was transferred via cannula to a stirred suspension of lithium aluminum hydride (3.5 g, 61 mmol, 4.0 equiv) and di-iso-propyl amine (8.5 mL, 61 mmol, 4.0 equiv) in tetrahydrofuran (70 mL) at 25° C. The emptied reaction vessel was rinsed with tetrahydrofuran (22 mL) and the resulting solution was also transferred via cannula. The reaction vessel was equipped with a reflux condenser under nitrogen atmosphere and heated to 60° C. via oil bath for 4 h. The mixture was cooled to 25° C., diluted with ice water (400 mL), and the product was extracted with dichloromethane (5×200 mL). The combined organic layers were dried (sodium sulfate), gravity filtered, and concentrated by rotary evaporation. The residue was purified by silica gel column chromatography (5% triethylamine in ethyl acetate) to afford 15 (2.17 g, 88% yield) as a pale yellow oil. Rf=0.40 (5% triethylamine in ethyl acetate); 1H NMR (500 MHz, CDCl3) δ 6.75 (br s, 2H, ArH), 6.70 (br s, 1H, ArH), 5.93 (s, 2H, OCH2O), 2.97 (br s, 1H, ArCH), 2.17 (br s, 1H, CH2), 1.67 (br s, 1H, CH2).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:26][C@H:25]2[C@@H:15]([CH2:16][C:17]3[C:27]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]2=4)[NH:19][CH:18]=3)[N:14](C#N)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C(O)(=O)C.[Zn]>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:26][C@H:25]2[C@@H:15]([CH2:16][C:17]3[C:27]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]2=4)[NH:19][CH:18]=3)[NH:14][CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CN1C[C@@H](NC(=O)OCc2ccccc2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: O=C(N[C@@H]1CN[C@@H]2Cc3c[nH]c4cccc(c34)[C@H]2C1)OCc1ccccc1

Procedure:
18 g (46.5 mM) of 8α-benzyloxycarbonylamino-6-cyanoergoline obtained from step (b) in 100 ml acetic acid are added to a suspension of 40 g zinc in 100 ml acetic acid. 40 ml water are added and the mixture is heated at 100° for 10 hours. To work up, the mixture is filtered through a filtering aid such as Hyflo and concentrated in a rotary evaporator. The residue is partitioned between potassium bicarbonate aqueous solution and methylene chloride/isopropanol (b 9:1). The organic phase is dried over sodium sulphate, filtered and concentrated to give the heading compound in crude form.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:2].[S:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[S:14].N1CCCCC1>C(O)C>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[C:18]2/[C:16](=[O:17])[NH:15][C:13](=[S:14])[S:12]/2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: O=C1CSC(=S)N1
Reactant: CCOc1ccc(C=O)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOc1ccc(/C=C2\SC(=S)NC2=O)cc1
Temperature: 75 °C
Reaction time: 24 h

Procedure:
4-Ethoxybenzaldehyde (2.78 mL, 20.00 mmol) and rhodanine 7 (3.75 g, 32.0 mmol) were dissolved in 80 mL of anhydrous ethanol at room temperature, and piperidine (0.60 mL, 6.0 mmol) was added to the reaction flask. The reaction mixture was stirred at 75° C. for 1 day and then allowed to cool down to room temperature until a yellow crystalline precipitate formed, and the solid was collected by filtration, washed with water and ethyl acetate, and dried to afford compound 8 in 80.0% (2.99 g) yield as a yellow solid.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:9]([CH2:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[O:12])[N:8]=[C:7]([C:26]([F:29])([F:28])[F:27])[C:6]=1[Cl:30])=[N+]=[N-]>CO>[NH2:1][CH2:4][C:5]1[N:9]([CH2:10][C:11]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[CH2:17][CH2:18]2)=[O:12])[N:8]=[C:7]([C:26]([F:28])([F:27])[F:29])[C:6]=1[Cl:30]
Reactant: [N-]=[N+]=NCc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Solvent: CO
Product: NCc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Reaction time: 2 h

Procedure:
2.85 g (6.2 mmol) of 2-(5-Azidomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chlorophenyl)-piperazin-1-yl]-ethanone was dissolved in 80 mL methanol, and 3.61 g (16.0 mmol) of SnCl2 hydrate was added. After two hours, the reaction was concentrated in vacuo to remove the methanol. The residue was partitioned between 0.5M NaOH and ethyl acetate, and the phases were separated. The aqueous phase was back-extracted once with ethyl acetate. The combined ethyl acetate phases were extracted twice with 1M HCl. The acidic aqueous phase was basified with 1M NaOH, and was extracted once with ethyl acetate. The final ethyl acetate phase was washed once with brine, dried over Na2SO4, filtered, and concentrated to an oil. The oil was dissolved in methanol, acidified with 2M HCl in ether, and the product was isolated by filtration after precipitation: 1H NMR (DMSO-d6, 400 MHz) 8.58 (s, 3H), 7.27 (d, 2H), 7.03 (d, 2H), 5.71 (s, 2H), 4.10 (d, 2H), 3.64 (m, 4H), 3.32 (m, 2H), 3.19 (m, 2H) ppm; MS (ES) M+H expected=436.1, found=436.0.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][CH:2]1[C:6]1[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:15][CH:14]=2)=[N:8][CH:9]=[CH:10][CH:11]=1>[Pd].C(O)C>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:15][CH:14]=2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: C1=COC(c2cccnc2Oc2ccc(Nc3ccccn3)cc2)C1
Agent: [Pd]
Solvent: CCO
Product: c1ccc(Nc2ccc(Oc3ncccc3C3CCCO3)cc2)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 150 mL round bottom flask was added N-(4-(3-(2,3-dihydrofuran-2-yl)pyridin-2-yloxy)phenyl)pyridin-2-amine (660 mg, 1.992 mmol) and ethanol (7967 μL) before adding palladium, 10% wt. on activated carbon (70 mg, 0.658 mmol) portionwise. The flask was evacuated and backfilled with hydrogen under atmospheric pressure before allowing to stir at room temperature under hydrogen. The reaction was complete after 3 h. After dilution with ethyl acetate, the black suspension was filtered through a pad of Celite while rinsing with ethyl acetate (3×25 mL) before concentrating to a pale yellow residue. The residue was taken up in 5 mL DCM and applied directly to silica for purification (0 to 50% ethyl acetate/hexanes over 35 minutes). The target compound was isolated as a white solid. MS (ESI, pos. ion) m/z: 334.2 (M+1). IC50 (uM) 0.225.