Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>C(#N)C>[F:13][C:9]1[CH:8]=[C:7]([CH:2]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:3]([O:5][CH3:6])=[O:4])[CH:12]=[CH:11][CH:10]=1
Reactant: C1CCNCC1
Reactant: COC(=O)C(Br)c1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)C(c1cccc(F)c1)N1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.3 %

Procedure:
Methyl 2-bromo-2-(3-fluorophenyl)acetate (310 mg, 1.25 mmol), piperidine (0.15 ml, 1.51 mmol), and DIPEA (0.26 ml, 1.51 mmol) were dissolved in acetonitrile (15 ml) and stirred at room temperature for 16 hours. The solvent was evaporated and the crude was purified by flash chromatography (petroleum ether/EtOAc=9/1) to afford methyl 2-(3-fluorophenyl)-2-(piperidin-1-yl)acetate (224 mg, 71% yield) as a colorless oil.
Reaction SMILES: O[CH:2]([C:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=2)[NH:15][C:14]=1[C:24]1[CH:25]=[N:26][CH:27]=[N:28][CH:29]=1)[C:3]1[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl.C(OCC)(=O)C>[CH3:23][O:22][C:18]1[CH:17]=[C:16]2[C:21]([C:13]([CH2:2][C:3]3[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=3)=[C:14]([C:24]3[CH:25]=[N:26][CH:27]=[N:28][CH:29]=3)[NH:15]2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1cccc(C(O)c2c(-c3cncnc3)[nH]c3cc(OC)ccc23)n1
Agent: CC[SiH](CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc(Cc2c(-c3cncnc3)[nH]c3cc(OC)ccc23)n1
Reaction time: 1 h
Yield: 58.9 %

Procedure:
To a suspension of methyl 6-[hydroxyl(6-methoxy-2-pyrimidin-5-yl-1H-indol-3-yl)methyl]pyridine-2-carboxylate (828 mg) in dichloromethane (21.2 mL) was added triethylsilane (1.35 mL) under ice-cooling. Then trifluoroacetic acid (0.649 mL) was added dropwise thereto, and the mixture was stirred under ice-cooling for 30 minutes and then at room temperature for 1 hour. Triethylsilane (1.35 mL) and trifluoroacetic acid (0.649 mL) were added thereto, and the mixture was stirred at room temperature for additional 5 hours. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: methanol-ethyl acetate) to obtain the title compound (468 mg). 1H-NMR (CDCl3) δ ppm: 3.86 (3H, s), 4.03 (3H, s), 4.48 (2H, s), 6.80 (1H, dd, J=2.3, 8.8 Hz), 6.92 (1H, d, J=2.3 Hz), 7.23-7.28 (1H, m), 7.37 (1H, d, J=8.8 Hz), 7.64-7.71 (1H, m), 7.94-8.00 (1H, m), 8.16 (1H, br s), 9.04 (2H, s), 9.17 (1H, s). ESI-MS (m/z): 375 (M+H)+
Reaction SMILES: I[C:2]([F:11])([F:10])[C:3]([F:9])([F:8])[C:4]([F:7])([F:6])I.I[C:13]1[CH:14]=[C:15]([C:21]#[N:22])[C:16](=[CH:19][CH:20]=1)[C:17]#[N:18].CS(C)=O>[Cu].O>[C:21]([C:15]1[CH:14]=[C:13]([C:2]([F:11])([F:10])[C:3]([F:9])([F:8])[C:4]([F:7])([F:6])[C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]#[N:22])[CH:14]=2)[CH:20]=[CH:19][C:16]=1[C:17]#[N:18])#[N:22]
Reactant: FC(F)(I)C(F)(F)C(F)(F)I
Reactant: N#Cc1ccc(I)cc1C#N
Agent: [Cu]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(C(F)(F)C(F)(F)C(F)(F)c2ccc(C#N)c(C#N)c2)cc1C#N
Yield: 54.4 %

Procedure:
1, 3-Diiodoperfluoropropane (2.0 g, 5 mmol), 1.8 g (30 meq) of activated copper, 2.5 g (10 mmol) of 4 - iodophthalonitrile and 6 ml of dry dimethyl sulfoxide were purged for 15 minutes with argon and the mixture was then heated at 115°-120° C. for 4 hours. After cooling, the content was poured into 100 ml of water and extracted with four 50 ml portions of ether. The combined ethereal extract was washed with water, charcoaled, dried over anhydrous sodium sulfate and concentrated at reduced pressure to afford 1.1 g (52%) of product, m.p. 133°-135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:11](=[O:33])(=[O:32])[N:12]([CH3:31])[C:13]3[CH:20]=[CH:19][C:18]([C:21]#[C:22][CH2:23][O:24]C4CCCCO4)=[CH:17][C:14]=3[C:15]=2[OH:16])=[O:9])=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:11](=[O:33])(=[O:32])[N:12]([CH3:31])[C:13]3[CH:20]=[CH:19][C:18]([C:21]#[C:22][CH2:23][OH:24])=[CH:17][C:14]=3[C:15]=2[OH:16])=[O:9])=[CH:34][CH:35]=1
Reactant: CN1c2ccc(C#CCOC3CCCCO3)cc2C(O)=C(C(=O)NCc2ccc(Cl)cc2)S1(=O)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CN1c2ccc(C#CCO)cc2C(O)=C(C(=O)NCc2ccc(Cl)cc2)S1(=O)=O
Temperature: 55 °C
Yield: 63.7 %

Procedure:
To a solution of N-(4-chlorobenzyl)-4-hydroxy-1-methyl-6-(3-(tetrahydro-2H-pyran-2-yloxy)-1-propynyl)-1H-2,1-benzothiazine-3-carboxamide 2,2-dioxide (Preparation 53, 0.30 g) in CH3OH (30 mL) is added p-TsOH.H2O (30 mg). The reaction mixture is heated to 55° C. for 2 h. The solvent is evaporated in vacuo and the residue is diluted with Et2O (20 mL) and sonicated. The resulting precipitate is filtered and washed with Et2O to afford 0.16 g (61%) of the title compound as a white solid. Physical characteristics: m.p. 167-168° C.; 1H NMR (300 MHz, CDCl3) δ15.82, 8.21, 7.93, 7.69, 7.36, 7.17, 4.60, 4.53, 3.49, 2.21; IR (diffuse reflectance) 3344, 1615, 1579, 1554, 1540, 1490, 1392, 1385, 1325, 1310, 1293, 1279, 1160, 1093, 1031 cm−1; MS (ESI+) m/z 433 (MH+); HRMS (FAB) m/z 433.0614 (C20H17ClN2O5S+H). Anal. Found: C, 54.57; H, 4.16; N, 6.10.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=O)[C:15]12[O:26]CCCO1)(=[O:11])=[O:10].Cl[CH2:28][C:29]1([C:33]#[N:34])[CH2:32][CH2:31][CH2:30]1>>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:20]=[CH:19][C:18]2[N:17]3[CH2:28][C:29]4([CH2:32][CH2:31][CH2:30]4)[CH2:33][N:34]=[C:16]3[C:15](=[O:26])[C:14]=2[CH:13]=1)(=[O:10])=[O:11]
Reactant: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C1(OCCCO1)C(=O)N2
Reactant: N#CC1(CCl)CCC1
Product: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C(=O)C1=NCC3(CCC3)CN12

Procedure:
The title compound was prepared as a yellow solid from 5′-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]sulfonyl}spiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one and 1-chloromethyl-cyclobutanecarbonitrile (Syn. Comm. 20(12) 1757, 1990) using a procedure similar to that of steps 3-5 of Example 12. NMR (400 Mz, DMSO-d6): consistent. MS: (ES−) m/z 402 [M−H]. m.p.: 146.8.8-147.4° C.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([OH:14])[CH:10]=[C:11](O)[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C[C:16]1[CH:17]=[CH:18][C:19](S(O)(=O)=O)=[CH:20][CH:21]=1.O.CO[C:29](=[O:40])[C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]=1[NH2:39]>C(O)CCCCC>[CH2:18]([O:36][C:34]([C:33]1[CH:37]=[CH:38][C:30]2[C:29](=[O:40])[C:10]3[C:11]([NH:39][C:31]=2[CH:32]=1)=[CH:12][C:7]([N:1]1[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1)=[CH:8][C:9]=3[OH:14])=[O:35])[CH2:17][CH2:16][CH2:21][CH2:20][CH3:19]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(=O)c1ccc(C(=O)O)cc1N
Reactant: Oc1cc(O)cc(N2CCOCC2)c1
Solvent: O
Solvent: CCCCCCO
Product: CCCCCCOC(=O)c1ccc2c(=O)c3c(O)cc(N4CCOCC4)cc3[nH]c2c1
Temperature: 25 °C

Procedure:
5-Morpholin-4-yl-benzene-1,3-diol (290 mg, 1.50 mmol), TsOH.H2O (30 mg, 0.20 mmol), and 2-amino-terephthalic acid 1-methyl ester (290 mg, 1.50 mmol) were heated at 160° C. in hexanol (5 mL) for 12 hours. The reaction mixture was cooled to room temperature. A red/orange precipitate was filtered, and the solid washed with EtOAc/hexanes (3:1, 30 mL) to yield 159 mg (31%). 1H NMR (CDCl3, 400 MHz) δ: 13.90 (s, 1H), 11.9 (s, 1H), 8.22 (d, 1H), 8.07 (s, 1H), 7.68 (d, 1H), 6.27 (s, 1H), 6.19 (s, 1H), 4.33 (t, 2H), 3.74-3.64 (m, 4H), 3.33-3.22 (m, 4H), 1.76-1.73 (m, 2H), 1.54-1.20 (m, 6H), 0.89 (5, 3H). LRMS (APCI, positive): Da/e 425.2 (m+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-])=O.C(O)C.C(O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O.[Fe]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH2:10]
Reactant: COc1ccc(Br)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(Br)c(N)c1
Temperature: 100 °C

Procedure:
A mixture of 1-bromo-4-methoxy-2-nitrobenzene (10 g; 43.1 mmol), ethanol (100 ml), acetic acid (100 ml) and iron powder (9.63 g; 172 mmol) was heated at 100° C. for 2 h. The mixture was cooled to room temperature and diluted with water (300 ml). The suspension was neutralized with solid potassium carbonate. The mixture was filtered on a plug of celite and extracted with dichloromethane. The combined organic layers were dried over magnesium sulphate and concentrated under reduced pressure to afford 2-bromo-5-methoxyaniline, which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.N1C=CN=C1.[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16].O>C(Cl)Cl>[Si:19]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a stirred solution of 4-hydroxybenzaldehyde (20.0 g, 0.16 mol) in 200 mL of CH2Cl2 at 0° C., imidazole (24.5 g, 0.36 mol) and tBuSiMe2Cl (27.2 g, 0.18 mol) were added. The reaction mixture was stirred at 25° C. for 1 h. The reaction mixture was poured into H2O and extracted with CH2Cl2. The organic phase was dried over anhydrous MgSO4 and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, hexanes:ethyl acetate=50:1 (v/v)) to give colorless oil (35.1 g, 90.7%). 1H NMR (300 MHz, CDCl3, δ): 9.86 (s, 2H), 7.77 (d, J=8.8 Hz, 2H), 6.92 (d, J=8.8 Hz, 2H), 0.97 (s, 9H), 0.23 (s, 6H). 13C{1H} NMR (75 MHz, CDCl3, δ): 190.76, 161.49, 131.87, 130.50, 120.47, 25.55, 18.25, −4.37. HRMS-FAB (m/z): [M+H]+ calcd for C14H23O2Si, 251.1467; found, 251.1469.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14](N2C=CN=C2)=O)[N:2]=1.[OH:21][NH:22][C:23](=[NH:26])[CH2:24][CH3:25]>C1(C)C=CC=CC=1.CN(C=O)C>[CH2:24]([C:23]1[N:26]=[C:14]([C:3]2[N:2]=[CH:1][C:13]3[NH:12][C:11]4[C:6]([C:5]=3[CH:4]=2)=[CH:7][CH:8]=[CH:9][CH:10]=4)[O:21][N:22]=1)[CH3:25]
Reactant: O=C(c1cc2c(cn1)[nH]c1ccccc12)n1ccnc1
Reactant: CCC(=N)NO
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCc1noc(-c2cc3c(cn2)[nH]c2ccccc23)n1
Reaction time: 72 h
Yield: 56.8 %

Procedure:
To a solution of Compound 1 (1.05 g, 4 mmol) in a mixture of toluene (50 mL) and DMF (50 mL), N-hydroxypropanimidamide (0.53 g, 6 mmol) was added. The resulting mixture was heated at 140°-150° C. for 7 h, and stirring continued for 3 days at room temperture. The solvents were removed in vacuo, and the oily residue precipitated from water. The white solid (1.0 g) was dried and submitted to column chromatography on silica gel with CH2Cl2 /methanol(9:1) as eluent. This afforded the title compound (0.6 g, 56%). M.p. 146°-149° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([CH3:18])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:19]C)[CH:14]=3)[C:9]=2[OH:21])[CH:5]=[CH:6][CH:7]=1.F[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O.CCOC(C)=O>[OH:19][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:21][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=1)=[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[C:17]([CH3:18])=[CH:16]2
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Reactant: COc1ccc2c(O)c(-c3cccc(F)c3)c(C)cc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc2cc(O)ccc2c(Oc2ccc(C=O)c(C(F)(F)F)c2)c1-c1cccc(F)c1
Temperature: 110 °C
Yield: 67 %

Procedure:
Compound (283) (1.77 g, 5.43 mmol) was dissolved in HCl (4 N in 1,4-dioxane) (15 mL) and the solution was stirred at RT under N2 for 30 min. The reaction mixture was concentrated to give crude 2-(3-fluorophenyl)-3-methyl-6-(methyloxy)-1-naphthalenol (284) as a gold-yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 2.07 (s, 3H), 3.84 (s, 3H), 6.99-7.44 (m, 6H), 8.04 (d, J=9.3 Hz, 1H), 8.75 (s, 1H). Compound 284 (˜1.50 g, 5.32 mmol) was immediately treated with 4-fluoro-2-trifluoromethylbenzaldehyde (1.53 g, 7.96 mmol) and Cs2CO3 (2.59 g, 7.98 mmol) in DMF (5 mL). The mixture was heated at 110° C. for 16 h, cooled to RT and diluted with 100 mL each H2O and EtOAc. The organic layer was washed with 100 mL each water and brine, dried (Na2SO4) and concentrated to 2.92 g of an amber oil. The oil was purified by column chromatography with 10% EtOAc/hexanes to yield 1.57 g (65%) of the title compound 285 as a white foam. 1H NMR (400 MHz, DMSO-d6): δ 2.20 (s, 3H), 3.88 (s, 3H), 6.96 (dd, J1=2.3 Hz, J2=8.6 Hz, 1H), 7.01-7.14 (m, 4H), 7.17 (d, J=2.5 Hz, 1H), 7.23-7.38 (m, 1H), 7.39 (d, J=2.5 Hz, 1H), 7.93 (d, J=9.1 Hz, 1H), 7.79 (s, 1H), 7.90 (d, J=8.7 Hz, 1H), 10.02 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1.[CH:23]1([OH:27])[CH2:26][CH2:25][CH2:24]1>>[CH:23]1([O:27][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[CH:5]=[C:4]([NH:16][C:17]3[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=3)[N:3]=2)[CH2:26][CH2:25][CH2:24]1
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1OC
Reactant: OC1CCC1
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(OC3CCC3)c2cc1OC

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and cyclobutanol to give (1-cyclobutoxy-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 355(MH+).
Reaction SMILES: [N:1]1([C:7]2[CH:25]=[CH:24][C:10]([CH2:11][C:12]([CH3:23])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:26]=O>C(O)=O>[CH3:26][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][C:12]([CH3:23])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:24][CH:25]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)C(C)(Cc1ccc(N2CCNCC2)cc1)C(=O)OCC
Reactant: C=O
Solvent: O=CO
Product: CCOC(=O)C(C)(Cc1ccc(N2CCN(C)CC2)cc1)C(=O)OCC
Yield: 86.8 %

Procedure:
A mixture of diethyl 2-(4-(piperazin-1-yl)benzyl)-2-methylmalonate (500 mg, 1.43 mmol), formaldehyde (2 ml) and formic acid (2 ml) was heated at reflux for 2 h. The reaction mixture was concentrated and partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic layer was separated and washed with water, brine solution, dried over anhydrous sodium sulfate, filtered and concentrated to afford 400 mg (86.8%) of diethyl 2-(4-(4-methylpiperazin-1-yl)benzyl)-2-methylmalonate as brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]2[C:13]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22])=[O:4].C1C(=O)N([Cl:30])C(=O)C1>C(Cl)Cl.O>[CH3:1][O:2][C:3]([C:5]1[C:6]([Cl:30])=[C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]2[C:13]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22])=[O:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cc2ccncn2c1Nc1ccc(I)cc1F
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1c(Cl)c2ccncn2c1Nc1ccc(I)cc1F
Yield: 48.1 %

Procedure:
To a solution of 7-(2-fluoro-4-iodo-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid methyl ester (576 mg, 1.40 mmol) in DCM (10 mL) was added NCS (206 mg, 1.54 mmol) and the reaction heated at reflux for 3 hours. More NCS (37 mg, 0.28 mmol) was added and the reaction heated at reflux for 2 hours. The reaction mixture was diluted with water and the product extracted with DCM (3×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-40% ethylacetate in cyclohexane) to yield the title compound as an off-white solid (300 mg, 48%). LCMS (Method B): RT=4.11 min, M+H+=446.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2([CH2:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])[C:4]1=[O:18].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:23]Cl.Cl>CN(C=O)C.O>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:23][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2([CH2:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])[C:4]1=[O:18]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: O=C1CC2(C(=O)N1)C(=O)Nc1ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CC2(C(=O)N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Temperature: 90 °C
Yield: 16.5 %

Procedure:
Sodium hydride (1.1 g.; 23 mM; 50% w/w oil dispersion) was added to a stirred solution of spiro[pyrrolidine-3,3'-indoline]-2,2',5-trione (2.1 g.; 9.7 mM) in DMF (40 ml.), under an atmosphere of nitrogen. The mixture was stirred until effervescence had ceased and then heated to approximately 90° C. 3,4-Dichlorobenzyl chloride (2.2 g., 11.2 mM) was added dropwise. The reaction mixture was then allowed to cool to ambient temperature, stirred for 16 hours, and poured into water. The aqueous mixture was acidified (concentrated hydrochloric acid) and extracted with ethyl acetate (2×150 ml.). The combined extracts were washed with water (3×150 ml.), brine (150 ml.), dried MgSO4) and evaporated. The residual oil was purified by chromatography on silica gel (150 g.) using an increasing gradient of ethyl acetate in toluene as eluant. Fractions were monitored by TLC (SiO2 : 50% v/v EtOAc/toluene) and those containing the major component (relative flow value: 0.5) were evaporated to give 1'-(3,4-dichlorobenzyl)-spiro[pyrrolidine-3,3'-indoline]-2,2',5-trione (0.6 g.), m.p. 205°-207° C. (recrystallised twice from MeOH).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]C)=O)#[N:2].[CH2:8]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[C:12]([F:18])[CH:11]=1)[CH3:9]>C(O)C.CN(C1C=CN=CC=1)C>[C:1]([CH2:3][C:4]([NH:15][CH2:14][C:13]1[CH:16]=[CH:17][C:10]([CH2:8][CH3:9])=[CH:11][C:12]=1[F:18])=[O:6])#[N:2]
Reactant: COC(=O)CC#N
Reactant: CCc1ccc(CN)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: CCO
Product: CCc1ccc(CNC(=O)CC#N)c(F)c1
Temperature: 60 °C
Yield: 39.5 %

Procedure:
Methyl cyanoacetate (1.16 mL, 13 mmol) and 4-ethyl-2-fluoro-benzylamine (1.15 g, 7.5 mmol) were combined in ethanol (20 mL). 4-(N,N-dimethylamino)pyridine (catalytic) was added and the reaction was heated in a 60° C. oil bath. After 16 hours heating, the reaction was concentrated under reduced pressure to afford crude product which was purified by flash chromatography eluting with a gradient from hexane to 60% ethyl acetate/hexane to afford 2-cyano-N-(4-ethyl-2-fluoro-benzyl)-acetamide (652 mg, 40% yield). 1H-NMR (400 MHz, CDCl3): δ 7.26-7.20 (1H, m), 6.98-6.90 (2H, m), 6.39 (1h, br s), 4.49 (2H, d, J=5.8 Hz), 3.38 (2H, s), 2.64 (2H, q, J=7.6 Hz), 1.23 (3H, t, J=7.6 Hz).
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[C:6]1([CH2:12][C@H:13]2[CH2:17][O:16][C:15](=[O:18])[NH:14]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:19]1[CH2:23][O:22][CH2:21][CH2:20]1>>[O:22]=[C:21]([N:14]1[C@@H:13]([CH2:12][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:17][O:16][C:15]1=[O:18])[CH2:20][CH2:19][CH2:23][CH2:5][C:4]1[CH:2]=[CH:3][C:4]([CH3:5])=[CH:2][CH:3]=1
Reactant: C1CCOC1
Reactant: [Li]CCCC
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Product: Cc1ccc(CCCCC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
BuLi (1.6M solution in hexanes, 4.4 mmol, 2.75 ml, 1.2 equiv.) was added dropwise to a solution of (S)-4-(phenylmethyl)-2-oxazolidinone (3.64 mmol, 0.64 g) in THF (15 ml) at -78° C., under N2 atmosphere. The orange solution was stirred for 30 mins at -78° C. and then a solution of p-toylvalerylchloride (4.06 mmol, 0.86 g) in THF (5 ml) was added dropwise. The reaction mixture was stirred at -78° C. for 2 hrs before quenching at -78° C. with a mixture of brine and 10% aqueous HCl (1:1, 20 ml). On warming to ambient temperature the reaction mixture was partitioned between EtOAc and water. The aqueous layer was separated and extracted twice with EtOAc. The combined organic layers were washed once with brine, once with sodium bicarbonate solution and dried over MgSO4. The solvent was removed under vacuum to give a brown oil which was purified on silica gel (Merck 9385) eluting with 20% EtOAc/hexane to give the compound as a slightly yellow oil (0.65 g, 51%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:7]=1.Br[CH2:20][CH2:21][O:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>CCOC(C)=O>[CH3:23][O:22][CH2:21][CH2:20][O:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: COCCBr
Reactant: COC(=O)c1cc(O)cc(-c2ccc(C)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COCCOc1cc(C(=O)OC)cc(-c2ccc(C)cc2)c1
Temperature: 135 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 5-hydroxy-4′-methylbiphenyl-3-carboxylate (400 mg, 1.65 mmol), 1-bromo-2-methoxyethane (436 mg, 3.14 mmol), potassium carbonate (434 mg, 3.14 mmol), and dimethyl sulfoxide (5 mL) was stirred at 135° C. overnight. After cooling, the mixture was diluted with EtOAc and washed with aq. NaHCO3 (sat.), dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (0-100% EtOAc/hexane) to afford the title compound.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[C:11](Br)=[N:10][C:9]([Br:13])=[CH:8][N:7]=1)=[O:4].Cl.[O:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][NH2:23])[CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C>>[Br:13][C:9]1[N:10]=[C:11]2[N:23]([CH2:22][CH2:21][CH:18]3[CH2:19][CH2:20][O:15][CH2:16][CH2:17]3)[CH2:2][C:3](=[O:4])[NH:5][C:6]2=[N:7][CH:8]=1
Reactant: O=C(CBr)Nc1ncc(Br)nc1Br
Reactant: NCCC1CCOCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(CCC2CCOCC2)c2nc(Br)cnc2N1
Temperature: 85 °C
Yield: 50.7 %

Procedure:
2-Bromo-N-(3,5-dibromopyrazin-2-yl)acetamide (3.30 g, 8.83 mmol) and 2-(tetrahydro-2H-pyran-4-yl)ethanamine hydrochloride (1.46, 8.83 mmol) and diisopropyl ethylamine (6.67 mL, 35.3 mmol) were combined and heated at 85° C. Upon complete consumption of starting material (by TLC), the reaction solution was condensed and purified via Biotage chromatography (0-100% ethyl acetate in hexanes) to afford the title compound (1.53 g, 4.48 mmol, 50% yield). MS (ESI) m/z 341.4 [M]+, 343.1 [M+2]+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>ClCCl>[CH3:1][C:2]1[N:3]=[C:4]([Cl:9])[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: C1COCCN1
Reactant: Cc1nc(Cl)cc(Cl)n1
Solvent: ClCCl
Product: Cc1nc(Cl)cc(N2CCOCC2)n1
Temperature: -78 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
The crude 2-methyl-4,6-dichloropyrimidine (41.8 g; 256 mmol) was dissolved in dichloromethane (200 mL) and chilled to −78° C. in an inert atmosphere. Morpholine (48 g; 550 mol) dissolved in dichloromethane (100 mL) was added slowly. The reaction was allowed to warm to room temperature while stirring overnight. The organic layer was washed with saturated ammonium chloride (2×100 mL), dried with sodium sulfate, and evaporated to give 2-methyl-4-chloro-6-morpholino-pyrimidine (48.5 g; 227 mmol).