Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.[C:19]([S-:21])#[N:20].[K+]>C(O)C.O.Cl>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][CH2:6][N:5]2[CH:4]=[CH:3][N:20]=[C:19]2[SH:21])=[CH:10][CH:11]=1
Reactant: COc1ccc(CCCNCC(OC)OC)cc1
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(CCCn2ccnc2S)cc1

Procedure:
A solution of 3.62 g (.014 mole) of N-[3-(4-methoxyphenyl)propyl]aminoacetaldehyde dimethyl acetal and 1.4 g (.0144 mole) of KSCN in 20 ml of ethanol, 5 ml of H2O and 2 ml of concentrated HCl was refluxed for five hours. Fifty ml of H2O was added, the mixture was cooled and a solid was filtered, washed with H2O and dried. Recrystallization from ethanol gave 1-[3-(4-methoxyphenyl)propyl]-2-mercaptoimidazole, 2.4 g (69%), mp 108-109°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2B(O)O)=[CH:4][CH:3]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: OB(O)c1ccccc1-c1ccc(Cl)cc1
Product: NS(=O)(=O)c1ccc(-c2ccccc2-c2ccc(Cl)cc2)cc1
Yield: 67 %

Procedure:
Following the general procedure outlined in Synthetic Scheme IX, 1.6 g (6.9 mmol) of 2-(4-chlorophenyl)phenylboronic acid (Step 2) was reacted with 1.8 g (7.6 mmol) of 4-bromobenzenesulfonamide. Purification by silica gel chromatography (Waters LC-2000) with ethyl acetate/hexane (3:7) and subsequent recrystallization from ethyl acetate/hexane gave 1.59 g (67%) of 4-[2-(4-chlorophenyl)phenyl]benzenesulfonamide as a colorless solid: mp 206.2°-207.0° C.; NMR (CDCl3) δ 4.77 (s, 2H), 7.04 (d, J=9 Hz, 2H), 7.16-7.31 (m, 4H), 7.36-7.51 (m, 4H), 7.80(d, J=9 Hz, 2H). MS (EI): m/e (rel intensity) 343 (100), 308 (13), 262 (21), 228 (82); HRMS Calc'd for C18H14ClNO2S: 343.0434. Found: 343.0434.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[CH:9]=2)[N:5]=[C:4]([NH2:15])[N:3]=1.[F:16][C:17]([F:26])([F:25])[C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>>[Br:14][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]([NH2:15])[N:3]=[C:2]([NH:22][C:21]3[CH:23]=[CH:24][C:18]([C:17]([F:16])([F:25])[F:26])=[CH:19][CH:20]=3)[CH:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1nc(Cl)cc(-c2cccc(Br)c2)n1
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: Nc1nc(Nc2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)c2)n1
Yield: 30 %

Procedure:
Following the method described in Example 53, 4-chloro-6-(3-bromo-phenyl)-pyrimidin-2-ylamine and 4-trifluoromethylaniline provided the title compound (30% yield). 1H NMR (CD3OD) δ 6.50 (s, 1H, Ar), 7.25-7.35 (t, 1H, Ar), 7.4-7.6 (m, 4H, Ar) 7.88 (d, 1H, Ar), 7.90 (d, 1H, Ar) 7.96 (d, 2H, Ar), 8.10 (s, 1H, Ar).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:9]=[C:8]([NH:10][CH:11]=[O:12])[CH:7]=[CH:6][CH:5]=1>CN(C)C=O>[CH2:3]([N:10]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:3])[N:9]=1)[CH:11]=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: Cc1cccc(NC=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCN(C=O)c1cccc(C)n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 77 %

Procedure:
To a stirred suspension of sodium hydride (60%, 0.176 g, 4.41 mmol) in DMF (dimethyl-formamide) (5 mL), cooled to 0° C. with a brine/ice bath, under argon atmosphere, was added a solution of N-(6-methylpyridin-2-yl)formamide (500 mg, 3.67 mmol) in DMF (10 mL). The mixture was stirred 5 minutes at 0° C. then 1-iodo-2exaneane (0.86 g, 4.04 mmol) was added. After stirring at room temperature for 48 hrs, the reaction mixture was concentrated and diluted with ethyl acetate (20 mL) and water (50 mL). The aqueous phase was extracted with ethyl acetate (20 mL). The combined organics were dried over MgSO4, filtered and concentrated in vacuo. Purification on silica gel afforded N-hexyl-N-(6-methylpyridin-2-yl)formamide as an oil [0.700 g, yield 77%; HPLC/MS: m/z=221 (M+H); logP(HCOOH)=3.46].
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([F:10])([F:9])[F:8])=[C:4]([CH2:11][NH2:12])[CH:3]=1.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][N:24]([C:27]2[S:28][C:29]([C:33](O)=[O:34])=[C:30]([CH3:32])[N:31]=2)[C:23](=[O:36])[CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][N:24]([C:27]2[S:28][C:29]([C:33]([NH:12][CH2:11][C:4]3[CH:3]=[C:2]([CH3:1])[O:6][C:5]=3[C:7]([F:10])([F:8])[F:9])=[O:34])=[C:30]([CH3:32])[N:31]=2)[C:23](=[O:36])[CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Reactant: Cc1cc(CN)c(C(F)(F)F)o1
Product: Cc1cc(CNC(=O)c2sc(-n3ccc(OCc4ccccc4)cc3=O)nc2C)c(C(F)(F)F)o1
Yield: 28 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use (5-methyl-2-(trifluoromethyl)furan-3-yl)methanamine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 28% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.75 (t, J=5.7 Hz, 1H), 8.61 (d, J=8.1 Hz, 1H), 7.52-7.30 (m, 5H), 6.39 (dd, J=8.1, 2.7 Hz, 1H), 6.26 (s, 1H), 6.23 (d, J=2.7 Hz, 1H), 5.16 (s, 2H), 4.30 (d, J=5.7 Hz, 2H), 2.53 (m, 3H), 2.26 (m, 3H); MS (ES+) m/z 504.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]2)=[C:19]([Br:31])[CH:18]=1)[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:59][CH2:60][CH2:61][CH2:62][CH2:63][O:64][C:65]1[CH:74]=[CH:73][CH:72]=[C:71]([OH:75])[C:66]=1[C:67]([O:69][CH3:70])=[O:68].C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[S:27](=[O:28])(=[O:29])[NH:26][C:25](=[O:30])[CH2:24]2)=[C:19]([Br:31])[CH:18]=1)[C:13]([NH:59][CH2:60][CH2:61][CH2:62][CH2:63][O:64][C:65]1[CH:74]=[CH:73][CH:72]=[C:71]([OH:75])[C:66]=1[C:67]([O:69][CH3:70])=[O:68])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(c2ccc(C[C@H](NC(=O)OCc3ccccc3)C(=O)O)cc2Br)S(=O)(=O)N1
Reactant: COC(=O)c1c(O)cccc1OCCCCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1c(O)cccc1OCCCCNC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)c(Br)c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.5 %

Procedure:
To a solution of (2S)-2-[(benzyloxy)carbonyl]amino-3-[3-bromo-4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]propanoic acid (350 mg, 0.68 mmol) in N,N-dimethylformamide (6.54 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (318 mg, 0.719 mmol) at 0° C. under an atmosphere of nitrogen. After stirring for 15 min, methyl 2-(4-aminobutoxy)-6-hydroxybenzoate (196 mg, 0.821 mmol) and N,N-diisopropylethylamine (358 μL, 2.05 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction was diluted with ethyl acetate and quenched with sat. sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate once. The combined organic solutions were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative LCMS to afford product as a white solid (361 mg, 72% two steps). 1H NMR (500 MHz, CD3OD): δ 7.63 (d, J=15.6 Hz, 1H), 7.44 (m, 1H), 7.31 (m, 7H), 6.48 (t, J=8.0 Hz, 2H), 5.56 (m, 1H), 5.03 (d, J=13.9 Hz, 2H), 4.31 (m, 1H), 3.97 (t, J=5.6 Hz, 2H), 3.86 (s, 3H), 3.44 (m, 1H), 3.25 (m, 3H), 2.95 (m, 1H), 1.66 (m, 4H). LCMS found for C32H35BrN3O10S (M+H)+: m/z=732, 734.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:15][C@@H:14]3[C@@H:11]([CH2:12][N:13]3C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[N:6][C:7]=1[Cl:8].[C:23]1([S:29]([OH:32])(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)CC>[C:23]1([S:29]([OH:32])(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:15][C@@H:14]3[C@@H:11]([CH2:12][NH:13]3)[CH2:10]2)[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN(c3cnc(Cl)c(Cl)c3)C[C@H]21
Agent: O=S(=O)(O)c1ccccc1
Solvent: CCCO
Product: Clc1cc(N2C[C@@H]3CN[C@@H]3C2)cnc1Cl
Temperature: 75 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
Tert-butyl (1R,5S)-3-(5,6-dichloropyridin-3-yl)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate (642 mg) in 1-propanol (8 mL) was treated with benzenesulfonic acid (516 mg) and heated at 75° C. with stirring for 2 hours. The reaction mixture was cooled to room temperature, filtered, and the wetcake was dried in a vacuum oven at 50° C. to provide 292 mg of the title compound. 1H NMR (DMSO, 400 MHZ) δ 2.99 (dd, J=10, 6 Hz, 1H), 3.09 (dd, J=12.5 Hz, 1H), 3.39 (m, 1H), 3.56 (m, 1H), 3.89 (d, J=11 Hz, 1H), 4.05-4.11 (m, 1H), 4.94 (m, 1H), 7.29 (m, 3H), 7.55 (d, J=3 Hz, 1H), 7.58 (m, 2H), 7.97 (d, J=3 Hz, 1H), 8.80 (br, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([Cl:16])[CH:11]=3)[C:2]1=2.C(OB(OC(C)C)OC(C)C)(C)C.C([N-]C(C)C)(C)C.[Li+].[Cl:38][C:39]1[N:44]=[C:43](Cl)[CH:42]=[CH:41][N:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(Cl)(Cl)Cl.C(O)(C)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:38][C:39]1[N:44]=[C:43]([C:5]2[S:1][C:2]3[C:9]([C:10]4[CH:15]=[CH:14][N:13]=[C:12]([Cl:16])[CH:11]=4)=[CH:8][CH:7]=[CH:6][C:3]=3[CH:4]=2)[CH:42]=[CH:41][N:40]=1
Reactant: Clc1cc(-c2cccc3ccsc23)ccn1
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)OB(OC(C)C)OC(C)C
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: Clc1cc(-c2cccc3cc(-c4ccnc(Cl)n4)sc23)ccn1
Temperature: 25 °C
Yield: 68.3 %

Procedure:
In a 500 mL round bottom flask, cool a solution of 4-benzo[b]thiophen-7-yl-2-chloro-pyridine (13 g, 53.1 mmol) and triisopropylborate (20 g, 106 mmol) in THF (150 mL) to −70° C. under nitrogen. To the cooled solution, add lithium diisopropylamide (2 M in THF, 53 mL, 106 mmol) gradually over a period of 30 min. Stir the mixture continually for an additional hour in the cooling bath. Gradually transfer the mixture into a refluxing solution of 2,4-dichloro-pyrimidine (12 g, 106 mmol), Pd(dppf)Cl2 (2.2 g, 53 mmol) and sodium carbonate (35 mL, 3 M, 106 mmol) in THF (150 mL) over a period of 30 min. Reflux for an additional 1 h. Cool the mixture to RT and dilute with 500 mL of chloroform/IPA (3/1) and 200 mL of water. Collect the resulting solid by filtration and reserve the chloroform/IPA/water mixture. Wash the solid with DCM and dry it under vacuum. Separate the layers of the chloroform/IPA/water mixture. Wash the organic phase with water and aqueous saturated sodium chloride, dry over sodium sulfate and concentrate in vacuo to give a brown residue. Purify the residue by FCC (10% methanol in DCM) to afford additional product. Combine the two portions to give the title compound (13 g, 68%). MS (ES) m/z 358 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:7](=[O:8])[CH2:6][C:5](=[O:9])[C:4]([CH3:11])([CH3:10])[S:3]1.C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:40][CH3:41])=[C:37]([Pb+3])[CH:38]=1>C(Cl)(Cl)Cl.ClCCl.Cl>[Br:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:40][CH3:41])=[C:35]([CH:6]2[C:7](=[O:8])[C:2]([CH3:12])([CH3:1])[S:3][C:4]([CH3:11])([CH3:10])[C:5]2=[O:9])[CH:34]=1
Reactant: CC1(C)SC(C)(C)C(=O)CC1=O
Reactant: CCc1ccc(Br)cc1[Pb+3]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1ccc(Br)cc1C1C(=O)C(C)(C)SC(C)(C)C1=O
Temperature: 25 °C

Procedure:
To a solution of 2,2,6,6-tetramethylthiopyran-3,5-dione (prepared according to the procedure of E. Er and P. Margaretha, Helvetica Chimica Acta (1992), 75(7), 2265-69) (1.8 g, 9.9 mmol) and N,N-dimethylaminopyridine (5.3 g, 4.34 mmol) in chloroform (60 ml), is added toluene (18 ml) then 5-bromo-2-ethylphenyllead triacetate (6.2 g, 1.09 mmol) in one portion. The resulting mixture is heated at reflux for 2 hours, then allowed to cool to ambient temperature, diluted with dichloromethane and 1M aqueous hydrochloric acid, and the organic phase is separated. The organic phase is concentrated under reduced pressure, and the residue is purified by flash chromatography on silica gel (hexane/ethyl acetate 95:5 to 7:3 ratio), giving 4-(5-bromo-2-ethylphenyl)-2,2,6,6-tetramethylthiopyran-3,5-dione (2.42 g) as an orange solid.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:32]([N:34]([CH2:36][C:37]([NH:39][C@H:40]([C:62]([NH:64][CH2:65][C:66]([OH:68])=[O:67])=[O:63])[CH2:41][CH2:42][CH2:43][NH:44][C:45](=[NH:61])[NH:46][S:47]([C:50]1[C:59]([CH3:60])=[C:57]([CH3:58])[C:54]([O:55][CH3:56])=[CH:53][C:51]=1[CH3:52])(=[O:49])=[O:48])=[O:38])[CH3:35])=[O:33])[CH2:11][S:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[NH:69]1[C:73](=[O:74])[CH2:72][CH2:71][C@H:70]1[C:75](O)=[O:76]>>[NH:69]1[C:73](=[O:74])[CH2:72][CH2:71][C@H:70]1[C:75]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:32]([N:34]([CH2:36][C:37]([NH:39][C@H:40]([C:62]([NH:64][CH2:65][C:66]([OH:68])=[O:67])=[O:63])[CH2:41][CH2:42][CH2:43][NH:44][C:45](=[NH:61])[NH:46][S:47]([C:50]1[C:59]([CH3:60])=[C:57]([CH3:58])[C:54]([O:55][CH3:56])=[CH:53][C:51]=1[CH3:52])(=[O:49])=[O:48])=[O:38])[CH3:35])=[O:33])[CH2:11][S:12][C:13]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:76]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: COc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)CN(C)C(=O)[C@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)[C@@H](N)CC(N)=O)C(=O)NCC(=O)O)c(C)c1C
Product: COc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)CN(C)C(=O)[C@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H]2CCC(=O)N2)C(=O)NCC(=O)O)c(C)c1C

Procedure:
The coupling and Nα -deprotection processes were repeated in the same manner to prepare H-Asn-Cys(Trt)-Sar-Arg(Mtr)-Gly-resin, followed by another coupling process using pGlu-OH to obtain pGlu-Asn-Cys(Trt)-Sar-Arg(Mtr)-Gly-resin. After drying, the resin was stirred in TFA-anisole-thiophenol (10-1-1 ml) for 4 hours, filtered and washed with TFA.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.[CH3:24][NH:25][CH3:26]>C1COCC1>[NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([N:25]([CH3:26])[CH3:24])[CH:12]=3)[CH:7]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(Cl)cc21
Reactant: CNC
Solvent: C1CCOC1
Product: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(N(C)C)cc21
Temperature: 80 °C
Yield: 82 %

Procedure:
A solution of Example A3 (0.25 g, 0.710 mmol) in THF (6 mL) was treated with dimethylamine (2M in THF, 2.84 mL, 5.68 mmol) and heated at 80° C. overnight. Additional dimethylamine (2M in THF, 5.68 mL, 11.36 mmol) was added over 3 days and the reaction mixture was heated at 80° C. The mixture was partitioned between DCM and satd. NaHCO3 and extracted with DCM (3×). The combined organic extracts were dried (MgSO4) and evaporated. The crude product was purified by silica gel chromatography (EtOAc/Hex) to give 3-(5-amino-2-chloro-4-fluorophenyl)-7-(dimethylamino)-1-ethyl-1,6-naphthyridin-2(1H)-one (0.21 g, 82% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.45 (s, 1H), 7.69 (s, 1H), 7.18 (d, 1H), 6.73 (d, 1H), 6.29 (s, 1H), 5.31 (br s, 2H), 4.21 (q, 2H), 3.14 (s, 6H), 1.18 (t, 3H); MS (ESI) m/z: 361.1 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].[OH:16][CH2:17]/[CH:18]=[CH:19]/[C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1>CC(C)=O>[C:6]([O:5][C:3](=[O:4])[CH2:2][O:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20](/[CH:19]=[CH:18]/[CH2:17][OH:16])[CH:21]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OC/C=C/c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COc1cccc(/C=C/CO)c1
Reaction time: 20 h
Yield: 97.2 %

Procedure:
A solution of tert-butyl bromoacetate (0.60 mL, 4.03 mmol) and potassium carbonate (1.12 g, 8.06 mmol) was added to a solution of trans-3-(3-hydroxypropenyl)phenol (0.58 g, 3.84 mmol) in acetone (15 mL) at room temperature under a nitrogen atmosphere and stirred for about 20 hours. The mixture was filtered, and the filtrate was concentrated to dryness. Purification by flash chromatography, eluting with hexane/ethyl acetate, gave pure trans-[3-(3-hydroxypropenyl)phenoxy]acetic acid tert-butyl ester as a clear oil (0.987 g, 97%).
Reaction SMILES: C(OC([N:8]1[CH2:19][CH2:18][CH2:17][C@H:9]1[C:10]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=O)(C)(C)C.[ClH:20]>O1CCOCC1>[ClH:20].[C:13]([NH:12][C:10](=[O:11])[C@@H:9]1[CH2:17][CH2:18][CH2:19][NH:8]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)[C@@H]1CCCN1

Procedure:
11.1 g (41.1 mmol) of 1-t-butoxycarbonyl-N-t-butyl-L-prolinamide were treated with a 4N solution of hydrogen chloride in dioxane in order to remove the t-butoxycarbonyl group and give N-t-butyl-L-prolinamide hydrochloride.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[O:24][CH:25]=[C:26]([C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:29])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH:19]1[CH2:20][N:21]([C:23]2[O:24][CH:25]=[C:26]([C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:29])[N:27]=2)[CH2:22]1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(C(=O)N3CCOCC3)co2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(c1coc(N2CC(O)C2)n1)N1CCOCC1
Reaction time: 1.5 h
Yield: 100.6 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-morpholinocarbonyl-1,3-oxazol-2-yl)azetidine (730 mg, 1.48 mmol) (obtained as described in Reference Example 72(1)) in anhydrous tetrahydrofuran (37 ml) was added a solution of 1.0 M tetra-n-butylammonium fluoride in tetrahydrofuran (1.78 ml, 1.78 mmol) in an ice bath and the mixture was stirred in an ice bath for 1.5 hours. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (95:5→9:1) as the eluant to afford 3-hydroxy-1-(4-morpholinocarbonyl-1,3-oxazol-2-yl)azetidine (377 mg, yield 100%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([I:30])[CH:27]=[CH:26][C:3]=1[NH:4][C:5]1[C:6]([C:21]([O:23]CC)=[O:22])=[CH:7][N:8]([CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[C:9](=[O:11])[CH:10]=1.[OH-].[Na+]>CCO>[F:1][C:2]1[CH:29]=[C:28]([I:30])[CH:27]=[CH:26][C:3]=1[NH:4][C:5]1[C:6]([C:21]([OH:23])=[O:22])=[CH:7][N:8]([CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[C:9](=[O:11])[CH:10]=1
Reactant: CCOC(=O)c1cn(CCOC2CCCCO2)c(=O)cc1Nc1ccc(I)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cn(CCOC2CCCCO2)c(=O)cc1Nc1ccc(I)cc1F
Yield: 88 %

Procedure:
Ethyl 4-(2-fluoro-4-iodoanilino)-6-oxo-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1,6-dihydro-3-pyridinecarboxylate was dissolved in EtOH and treated with 1 M NaOH, as for example 1, step C, to hydrolyse the ester to give 4-(2-fluoro-4-iodoanilino)-6-oxo-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1,6-dihydro-3-pyridinecarboxylic acid as a pale yellow solid (88%), used directly in the next step. 1H NMR [(CD3)2SO, 400 MHz] δ 13.33 (v br s, 1H), 9.67 (br s, 1H), 8.46 (s, 1H), 7.77 (dd, J=10.0, 1.8 Hz, 1H), 7.60 (dd, J=8.3, 0.9 Hz, 1H), 7.32 (t, J=8.5 Hz, 1H), 5.50 (s, 1H), 4.60-4.56 (m, 1H), 4.12-4.06 (m, 2H), 3.79-3.71 (m, 1H), 3.60-3.35 (m, 3H), 1.75-1.27 (m, 6H). LCMS (APCI−) calcd for C19H19FIN2O5 501 (MH+), found 501.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F-].[Cs+].[C:10]1([CH2:16][N:17]2[CH2:21][CH:20]=[C:19](B3OC(C)(C)C(C)(C)O3)[CH2:18]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=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>[C:10]1([CH2:16][N:17]2[CH2:21][CH:20]=[C:19]([C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:18]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC1(C)OB(C2=CCN(Cc3ccccc3)C2)OC1(C)C
Reactant: Brc1ncccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Product: C1=C(c2ncccn2)CN(Cc2ccccc2)C1
Temperature: 80 °C
Reaction time: 6 h
Yield: 22.8 %

Procedure:
To a solution of 2-bromopyrimidine (0.88 g) in dry tetrahydrofuran (30 mL) 1-(phenylmethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole (P13, 1.21 g), tetrakis(triphenylphosphine)palladium(0) (0.25 g) and cesium fluoride (2.59 g) were added at room temperature. The resulting mixture was stirred at 80° C. for 6 hours. After cooling the solvent was evaporated under reduced pressure, the residue partitioned between ether and water and the organic phase was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (eluting with DCM/MeOH from 100% to 96%) to give 0.23 g of the title compound.