Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:23][C:24]1([F:38])[CH2:27][N:26]([C:28](=[O:37])[CH2:29][O:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:25]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:38][C:24]1([F:23])[CH2:27][N:26]([C:28](=[O:37])[CH2:29][O:30][CH:31]2[CH2:36][CH2:35][N:34]([C:4]([C:3]3[CH:7]=[C:8]([CH:9]=[CH:10][C:2]=3[F:1])[CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[NH:14][N:13]=3)=[O:6])[CH2:33][CH2:32]2)[CH2:25]1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: O=C(COC1CCNCC1)N1CC(F)(F)C1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1)N1CC(F)(F)C1
Reaction time: 1 h
Yield: 17.7 %

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.2 g, 0.67 mmol), 1-(3,3-difluoroazetidin-1-yl)-2-(piperidin-4-yloxy)ethanone (88) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (0.215 g, 0.67 mmol) were dissolved in DMF (10 mL), to this was added DIPEA (0.117 mL, 0.67 mmol) and the reaction was stirred for 1 hour. The solvent was evaporated to dryness and the gum was dissolved in acetonitrile (4 mL). The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compounds were evaporated to dryness to afford 4-(3-(4-(2-(3,3-difluoroazetidin-1-yl)-2-oxoethoxy)piperidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (89) as a white solid (0.061 g, 17.7% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.67-1.48 (2H, m), 1.86-1.75 (1H, m), 2.01-1.89 (1H, m), 3.19-3.06 (1H, m), 3.56-3.39 (2H, m), 3.66-3.57 (1H, m), 4.17-3.95 (3H, m), 4.28 (2H, s), 4.39-4.33 (2H, m), 4.62-4.57 (2H, m), 7.02 (1H, t), 7.31-7.26 (2H, m), 7.79-7.70 (3H, m), 8.48-8.46 (1H, m), 10.53 (1H, s) m/z (LC-MS, ESI+), RT=1.83 (M+H 515). and 2-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperidin-4-yloxy)acetic acid (90) as a white solid (0.016 g, 5.50%); 1H NMR (400.132 MHz, CDCl3) δ 1.68-1.60 (1H, m), 1.84-1.71 (2H, m), 2.05-1.96 (1H, m), 3.16-3.04 (1H, m), 3.53-3.45 (2H, m), 3.78-3.68 (1H, m), 4.23-4.04 (3H, m), 4.32-4.28 (2H, m), 7.07-7.02 (1H, m), 7.30-7.24 (2H, m), 7.86-7.74 (3H, m), 8.47-8.42 (1H, m), 11.12 (1H, s) COOH missing; m/z (LC-MS, ESI+), RT=0.91 (M+H 440).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([N:28](S(C4C=CC=CC=4[N+]([O-])=O)(=O)=O)[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:62])[CH2:34][CH2:35][NH:36][C:37](=[O:61])[CH2:38][CH2:39][NH:40][C:41](=[O:60])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]4[CH:53]=[CH:52][C:51]([N+:54]([O-:56])=[O:55])=[CH:50][C:49]=4[N+:57]([O-:59])=[O:58])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C([O-])([O-])=O.[K+].[K+].C1(S)C=CC=CC=1>CN(C=O)C.C1COCC1>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([NH:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:62])[CH2:34][CH2:35][NH:36][C:37](=[O:61])[CH2:38][CH2:39][NH:40][C:41](=[O:60])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]4[CH:53]=[CH:52][C:51]([N+:54]([O-:56])=[O:55])=[CH:50][C:49]=4[N+:57]([O-:59])=[O:58])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](N(CCCNC(=O)CCNC(=O)CCNC(=O)CCCCCNc5ccc([N+](=O)[O-])cc5[N+](=O)[O-])S(=O)(=O)c5ccccc5[N+](=O)[O-])CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](NCCCNC(=O)CCNC(=O)CCNC(=O)CCCCCNc5ccc([N+](=O)[O-])cc5[N+](=O)[O-])CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 18 h
Yield: 73.1 %

Procedure:
To a slurry of N-[3-({3-[(3-{(3β)-cholest-5-en-3-yl[(2-nitrophenyl)sulfonyl]amino}propyl)amino]-3-oxopropyl}amino)-3-oxopropyl]-6-[(2,4-dinitrophenyl)amino]hexanamide (21, 60 mg, 0.057 mmol) and K2CO3 (90 mg, 0.651 mmol) in DMF (4 mL) and THF (1 mL) was added thiophenol (80 μL, 0.874 mmol). After 18 h at 23° C., solids were removed by filtration and solvent was removed in vacuo. The crude product was purified by flash column chromatography (CH2Cl2/MeOH/TEA, 93: 4:3) to afford 2 (36 mg, 72%) mp 191-193° C.; 1H NMR (400 MHz, CDCl3) δ 9.14 (d, J=2.6 Hz, 1H), 8.56 (t, J=4.9 Hz, 1H), 8.27 (dd, J=2.6 Hz, J=9.50 Hz, 1H), 7.40 (t, J=5.2 Hz, 1H), 6.93 (d, J=9.6 Hz, 1H), 6.69 (t, J=5.5 Hz, 1H), 6.60 (t, J=5.4 Hz, 1H), 5.32 (d, J=4.4 Hz, 1H), 3.54-3.50 (m, 4H), 3.42 (dt, J=6.9 Hz, J=5.6 Hz, 2H), 3.34 (dt, J=5.6 Hz, J=5.60 Hz, 2H), 2.76 (t, J=5.6 Hz, 2H), 2.39-2.34 (m, 5H), 2.21 (t, J=7.3 Hz, 2H), 2.02-1.00 (m, 37H), 0.98 (s, 3H), 0.91 (d, J=6.5 Hz, 3H), 0.87 (d, J=1.6 Hz, 3H), 0.86 (d, J=1.6 Hz, 3H), 0.67 (s, 3H); 13C NMR (125.8 MHz, CDCl3) δ 172.5, 171.8, 171.3, 148.3, 141.2, 136.0, 130.5, 130.3, 124.3, 121.1, 113.9, 58.3, 56.8, 56.2, 50.3, 45.5, 43.3, 40.1, 39.8, 39.5, 39.3, 38.0, 37.0, 36.2 (×2), 35.8, 35.6 (×2), 35.5, 35.4, 31.9 (×2), 29.7, 29.6, 28.8, 28.4, 28.2, 28.0, 26.4, 25.0, 24.3, 23.8, 22.8, 22.5, 21.0, 19.4, 18.7, 11.8; IR (film) νmax 3295, 2927, 2849, 1633, 1546, 1340 cm−1; CI m/z 864.5959 (MH+, C48H78N7O7 requires 864.5963).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[N:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[CH:5][CH:4]=1.CC(C)=[O:30].OS(O)(=O)=O.O=[Cr](=O)=O.C(OCC)(=O)C.O>CC(C)=O>[NH2:23][S:20]([C:17]1[CH:16]=[CH:15][C:14]([N:13]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([OH:30])=[O:1])=[CH:8][CH:7]=3)=[CH:10][C:11]([C:24]([F:25])([F:26])[F:27])=[N:12]2)=[CH:19][CH:18]=1)(=[O:22])=[O:21]
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(CO)cc2)cc1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(C(=O)O)cc2)cc1

Procedure:
To the product from Example 11 in 2 mL of acetone was added 1.33 M Jones reagent until an orange color persisted. The reaction was poured into 20 mL of ethyl acetate and 20 m of H2O and the organic layer separated, washed with saturated sodium bisulfite and dried over MgSO4. The crude was product was filtered through silica gel/Celite to afford the title compound as a yellow solid: HRMS m/z 411.0507 (calc'd for C17H12N3O4SF3, 411.0500).
Reaction SMILES: Cl.[C:2]([C:5]1[C:6]([CH3:16])=[CH:7][C:8]([CH3:15])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])(=[NH:4])[NH2:3].Br[CH2:18][C:19]([C@@H:21]1[CH2:25][CH2:24][CH2:23][O:22]1)=O.C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH3:15][C:8]1[CH:7]=[C:6]([CH3:16])[C:5]([C:2]2[NH:3][C:19]([C@@H:21]3[CH2:25][CH2:24][CH2:23][O:22]3)=[CH:18][N:4]=2)=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: O=C(CBr)[C@@H]1CCCO1
Reactant: COC(=O)c1cc(C(=N)N)c(C)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(-c2ncc([C@@H]3CCCO3)[nH]2)c(C)cc1C
Temperature: 75 °C
Reaction time: 72 h
Yield: 24.9 %

Procedure:
To a round-bottom flask was added a solution of methyl 5-carbamimidoyl-2,4-dimethylbenzoate hydrochloride (compound 2.5, 1.30 g) in CH3CN (30 mL). (S)-2-bromo-1-(tetrahydrofuran-2-yl)ethanone (compound 257.2, 1.92 g, 9.95 mmol) and potassium carbonate (4.20 g, 30.4 mmol) were added to the reaction. The resulting solution was stirred for 3 days at 75° C. under nitrogen. After cooling to ambient temperature, the solids were removed by filtration. The filtrate was concentrated in vacuo and diluted with 30 mL of H2O. The aqueous phase was extracted with 3×50 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate, then concentrated in vacuo. The mixture was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:2) as eluent to yield 400 mg (25%) of (S)-methyl 2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoate as a light yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([C@H:15]([CH3:20])[C:16]([O:18]C)=[O:17])[C:9]2=[O:14])([O-:3])=[O:2].[I-].[Li+].C(OCC)(=O)C>>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([C@H:15]([CH3:20])[C:16]([OH:18])=[O:17])[C:9]2=[O:14])([O-:3])=[O:2]
Reactant: COC(=O)[C@@H](C)n1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: C[C@H](C(=O)O)n1ccc2c([N+](=O)[O-])cccc2c1=O

Procedure:
(R)-Methyl 2-(5-nitro-1-oxoisoquinolin-2(1H)-yl)propanoate (5.2 g, 0.019 mol) and lithium iodide (10 g, 0.08 mol) were refluxed in ethyl acetate (200 mL, 2 mol) for 64 hours. The solid was filtered, and the filtrate was concentrated and gave a brown solid.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:17]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[CH:20][CH2:21]2.O>COCCOC.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>[C:1]1([C:17]2[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]3[C:18]=2[CH:19]=[CH:20][CH2:21]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc2c(c1Br)C=CC2
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: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc2c(c1-c1ccccc1)C=CC2
Yield: 85.8 %

Procedure:
phenylboronic acid (8.3 g, 68 mmol) was dissolved in ethylene glycol dimethylether (DME, 100 mL), and aqueous solution (100 mL) of cesium carbonate (30 g), 4-bromo-5-methylindene (10 g, 48 mmol), tetrakis(triphenylphosphine)palladium (3.0 g, 2.6 mmol) were sequentially added. Solution was reacted for 55 hours while heating under reflux, then, reaction solution was added into water (200 mL), and extracted with diisopropylether. Organic layer was washed with 1N hydrochloric acid and saturated aqueous solution of sodium chloride, then was dried over sodium sulfate, and solvent was distilled off under reduced pressure to obtain the crude product. This was purified by silica-gel column chromatography (Silica-gel 60: produced by Kanto Chemical Co., Inc, hexane) to obtain 4-phenyl-5-methylindene (8.5 g, yield: 86%) as colorless liquid.
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH2:9][CH2:8]2.Cl[Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].N1C=CN=C1>CN(C=O)C>[CH3:20][C:19]([Si:16]([CH3:18])([CH3:17])[O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH2:9][CH2:8]2)([CH3:22])[CH3:21]
Reactant: O=C1CCc2cc(C#CCO)ccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCc1ccc2c(c1)CCC2=O
Reaction time: 10 h
Yield: 93.3 %

Procedure:
5-(Hydroxyprop-1-yn-1-yl)-2,3-dihydro-1H-indene-1-one (1.03 g, 5.42 mmol) was dissolved in DMF and treated with chloro-tert-butyldimethylsilane (981 mg, 6.51 mmol), imidazole (443 mg, 6.51 mmol) at 0° C. The reaction mixture was allowed to reach ambient temperature. After 10 h, the reaction mixture was extracted with ethyl acetate (100 mL×3), washed with water, brine and dried over MgSO4. The organic layer was concentrated under vacuum and purified by flash column chromatography to yield the 5-(3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-2,3-dihydro-1H-inden-1-one (1.54 g, 94% yield): 1H NMR (400 MHz, CDCl3): δ 7.63 (d, 1H), 7.59 (s, 1H), 7.42 (d, 1H), 4.45 (t, 2H), 3.10 (m, 2H), 2.78 (m, 2H), 2.64 (m, 2H), 1.82 (m, 2H), 0.95 (s, 9H), 0.06 (s, 6H).
Reaction SMILES: [C:1]([Si:5]([CH3:31])([CH3:30])[O:6][CH2:7][C@H:8]([N:10]1[C:15]2=[N:16][C:17](Cl)=[N:18][CH:19]=[C:14]2[CH2:13][N:12]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=2)[C:11]1=[O:29])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1>CC(O)C.ClCCl>[C:1]([Si:5]([CH3:31])([CH3:30])[O:6][CH2:7][C@H:8]([N:10]1[C:15]2=[N:16][C:17]([NH:37][C:36]3[CH:38]=[CH:39][C:33]([F:32])=[CH:34][CH:35]=3)=[N:18][CH:19]=[C:14]2[CH2:13][N:12]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=2)[C:11]1=[O:29])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1ccc(N2Cc3cnc(Cl)nc3N([C@H](C)CO[Si](C)(C)C(C)(C)C)C2=O)cc1
Reactant: Nc1ccc(F)cc1
Solvent: CC(C)O
Solvent: ClCCl
Product: CCc1ccc(N2Cc3cnc(Nc4ccc(F)cc4)nc3N([C@H](C)CO[Si](C)(C)C(C)(C)C)C2=O)cc1
Temperature: 160 °C

Procedure:
(R)-1-[2-(tert-Butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-7-chloro-3-(4-ethyl-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (100 mg, 0.21 mmol) (from Example 38e supra) was suspended in 2-propanol (2 mL) (Fisher). 4-Fluoroaniline (0.03 mL, 0.32 mmol) (Aldrich) was added and the mixture was heated to 160° C. in a microwave synthesizer (SmithSynthesizer™) for 30 minutes. After cooling to room temperature, the heterogeneous reaction mixture was diluted with dichloromethane. The resulting solution was washed with 1 N aqueous hydrochloric acid. The layers were separated and the organic phase was dried over anhydrous sodium sulfate, filtered and then concentrated under reduce pressure to give (R)-1-[2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-3-(4-ethyl-phenyl)-7-(4-fluoro-phenylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a pale yellow solid. (Yield 107 mg, 91%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[Cl:16][CH2:17][CH2:18][CH2:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH2:1]([NH:8][S:20]([CH2:19][CH2:18][CH2:17][Cl:16])(=[O:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(CCCCl)NCc1ccccc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 87 %

Procedure:
Benzylamine (1 eq.) was dissolved in anhydrous DCM (0.5 M) and Et3N (1.1 eq.) was added; after cooling at 0° C., 1-chloro-3-propanesulfonyl chloride was slowly added and the mixture was stirred at RT for 20 h. All volatiles were evaporated in vacuo and the residue taken up with Et2O; the precipitate was filtered off and the filtrate was concentrated; addition of PE afforded N-benzyl-3-chloropropane-1-sulfonamide as a white solid (87%). (ES+) m/z 248 (M+H+). Di-tert-butyl dicarbonate (1.5 eq.) was slowly added to an ice-cooled 0.45 M THF solution of N-benzyl-3-chloropropane-1-sulfonamide. DMAP (0.1 eq.) was then added and the reaction stirred overnight at RT. All volatiles were removed in vacuo and the crude diluted with EtOAc, washed with HCl, sat. aq. NaHCO3 and brine. After drying over Na2SO4, all volatiles were evaporated in vacuo and the residual material used in the next step without purification. (ES+) m/z 348, 350 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[N:5]=[C:4]([CH3:16])[N:3]=1.[CH3:17][CH:18]([OH:21])[C:19]#[CH:20].[H-].[Na+].O>CN(C)C=O>[CH3:16][C:4]1[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[CH:7]=[C:2]([O:21][CH:18]([CH3:17])[C:19]#[CH:20])[N:3]=1
Reactant: Cc1nc(Cl)cc(-c2cccc(F)c2F)n1
Reactant: C#CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CC(C)Oc1cc(-c2cccc(F)c2F)nc(C)n1
Temperature: 25 °C
Reaction time: 9 h
Yield: 86 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 255 mg of 4-chloro-2-methyl-6-(2,3-difluorophenyl)pyrimidine and 97 mg of 3-butyn-2-ol, to which 56 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 9 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 250 mg of 2-methyl-4-(2,3-difluorophenyl)-6-(1-methyl-2-propynyloxy)pyrimidine (the present compound (161)).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:9](=[O:31])[N:10]([CH3:30])[C:11]([N:20]3[CH2:24][CH2:23][CH2:22][CH:21]3[CH2:25][NH:26][CH:27]([CH3:29])[CH3:28])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[CH:32]1(B(O)O)[CH2:34][CH2:33]1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1>[CH:32]1([C:2]2[CH:3]=[C:4]([C:8]3[C:9](=[O:31])[N:10]([CH3:30])[C:11]([N:20]4[CH2:24][CH2:23][CH2:22][CH:21]4[CH2:25][NH:26][CH:27]([CH3:29])[CH3:28])=[N:12][C:13]=3[C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH:5]=[CH:6][CH:7]=2)[CH2:34][CH2:33]1
Reactant: OB(O)C1CC1
Reactant: CC(C)NCC1CCCN1c1nc(-c2ccncc2)c(-c2cccc(Br)c2)c(=O)n1C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)NCC1CCCN1c1nc(-c2ccncc2)c(-c2cccc(C3CC3)c2)c(=O)n1C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a 100 mL RBF, was added 5-(3-bromo-phenyl)-2-[2-(isopropylamino-methyl)-pyrrolidin-1-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (0.4 g, 0.82 mmol), 30 mL toluene, and cyclopropyl boronic cid (86 mg, 1.0 mmol). The mixture was degassed by nitrogen bubbled through for 1 h. After added Pd(PPh)4 (30 mg, 0.025 mmol) and NaOtBu (0.24 g, 2.5 mmol), the mixture was warmed up to 100° C. and stirred for 1 h under nitrogen. The mixture was cooled down to rt, and vacuumed down all volatile composites. After purified by flash chromatography, the title compound was obtained in 0.1 g as pale yellow solid. MS (ES+): 444 (M+H)+; (ES−): 4442 (M−H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:12](O)[CH2:13][OH:14].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]1[O:14][CH2:13][CH2:12][O:5]1
Reactant: COc1ccc(Br)c(C=O)c1
Reactant: OCCO
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(Br)c(C2OCCO2)c1
Temperature: 25 °C
Yield: 103.2 %

Procedure:
To a solution of Compound 19 (50.0 g, 0.23 mol) in toluene (650 mL) were added ethylene glycol (14.2 mL, 0.26 mol) and camphorsulfonic acid (10.7 g, 46 mmol). The reaction solution was heated under reflux with a Dean-Stark trap for 6 h and then cooled to room temperature and diluted with ethyl acetate (300 mL). The resulting solution was washed with aqueous saturated sodium bicarbonate and brine, dried over sodium sulfate and concentrated in vacuo to give Compound 20 (61.5 g, quantitative) as a yellow oil: 1H NMR (CDCl3, 500 MHz) δ 7.44 (d, J=8.5 Hz, 1H), 7.15 (d, J=3.5 Hz, 1H), 6.79 (dd, J=8.5, 3.0 Hz, 1H), 6.04 (s, 1H), 4.18-4.06 (m, 4H), 3.81 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:17])[CH:4]=[CH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH:13]=[O:14])=[CH:8][C:7]=1[CH2:15][CH3:16]>CO.[OH-].[Na+]>[CH2:15]([C:7]1[CH:8]=[C:9]([CH:13]=[O:14])[CH:10]=[C:11]([CH3:12])[C:6]=1[CH:5]=[CH:4][C:3]([OH:17])=[O:2])[CH3:16]
Reactant: CCc1cc(C=O)cc(C)c1C=CC(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1cc(C=O)cc(C)c1C=CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
A suspension of 3-(2-ethyl-4-formyl-6-methyl-phenyl)-acrylic acid methyl ester (5.93 g, 25.53 mmol) in MeOH (140 mL) and 2 N aq. NaOH (45 mL) was stirred at rt for 1 h. The MeOH was evaporated and the aq. solution was extracted twice with DCM. The aq. layer was acidified with 37% aq. HCl. The precipitate that formed was collected, washed with water and dried. The product was further purified by recrystallisation from EA (100 mL) to give 3-(2-ethyl-4-formyl-6-methyl-phenyl)-acrylic acid as yellow crystals (4.2 g). LC-MS: tR=0.87 min.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[NH:21]1[CH2:25][CH2:24][CH:23]([NH:26][C:27](=[O:29])[CH3:28])[CH2:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:21]3[CH2:25][CH2:24][CH:23]([NH:26][C:27](=[O:29])[CH3:28])[CH2:22]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: CC(=O)NC1CCNC1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC1CCN(C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)C1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with N-(pyrrolidin-3-yl)acetamide (79286-74-1) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=395.5 [MH+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:21])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C([Li])CCC.[C:27](=[O:29])=[O:28].Cl>C1COCC1.O>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[C:4]([CH3:21])=[CH:3][C:2]([C:27]([OH:29])=[O:28])=[CH:7][N:6]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1cc(Br)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)O)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
Under an argon atmosphere, a solution of tert-butyl 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylate (400 mg) in THF (8 ml) was cooled to −78° C., and 1.63 M n-butyl lithium (0.9 ml) was added dropwise thereto, followed by stirring at the same temperature for 1 hour. Crushed dry ice was put into another flask, and THF (30 ml) was poured thereinto. The mixture to which n-BuLi had been added dropwise immediately before was added thereto, followed by stirring as it was for 1 hour. To the reaction mixture was added water and 1 M hydrochloric acid, and the pH of the aqueous layer was adjusted to around 5.0. The aqueous layer was extracted with EtOAc, the organic layer was separated, and then the aqueous layer was extracted with CHCl3 again. These organic layers were combined and dried over Na2SO4, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 6-[4-(tert-butoxycarbonyl)piperazine-1-yl]-5-methylnicotinic acid (169 mg).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[Cl:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16]>>[Cl:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[Cl:13])[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Reactant: Nc1ccccc1Cl
Product: CSc1nc(Cl)c(C=O)c(Nc2ccccc2Cl)n1

Procedure:
Prepared as described above in Example 1 starting from 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 2-chloroaniline to give the title compound 4-chloro-6-(2-chloro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 2.55 (s, 3H), 7.17 (m, 1H), 7.29 (m, 2H), 7.44 (m, 1H), 10.37 (s, 1H), 11.49 (br s, 1H). LC MS (m/e)=315 (MH+).