Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]2[O:32][C:31]([CH2:33][OH:34])=[CH:30][C:29]=2[CH:35]=1.C([O-])([O-])=O.[K+].[K+].[CH2:42](OC(Cl)=O)[C:43]1C=CC=CC=1>C1COCC1.O>[CH2:42]([O:34][CH2:33][C:31]1[O:32][C:28]2[CH:27]=[CH:26][C:25]([O:24][CH2:23][C:3]3[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]5[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=5)[C:6]=4[C:2]=3[CH3:1])=[CH:35][C:29]=2[CH:30]=1)[CH3:43]
Reactant: Cc1c(COc2ccc3oc(CO)cc3c2)oc2cccc(OCCCNCc3cccnc3)c12
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOCc1cc2cc(OCc3oc4cccc(OCCCNCc5cccnc5)c4c3C)ccc2o1
Reaction time: 3 h

Procedure:
To a solution of the compound in Example 40 (15 mg, 0.03 mmol) in anhydrous THF/H2O were added K2CO3 and benzyloxycarbonyl chloride (3 eq), the mixture was stirred for 3 hours. The crude mixture was purified over SiO2 column. The product was dissolved in anhydrous DMF (2 ml), NaH (5 mg) was added. The mixture was stirred for 10 minutes. Ethyl bromide (excess) was added to the reaction flask. The mixture was stirred for one hour. The crude product was hydrogenated over 10% Pd/C in MeOH to give the desired product as a colorless oil. ESI-MS: m/z 501 (MH+); 1H-NMR (CDCl3): δ 1.36 (3H, t, J=6.9 Hz), 2.16 (2H, m), 2.43 (3H, s), 2.98 (2H, t, J=6.9 Hz), 3.72 (2H, q, J=6.9 Hz), 3.94 (2H, s), 4.25 (2H, t, J=5.9 Hz), 4.68 (2H, s), 5.20 (2H, s), 5.40 (2H, s), 6.69 (1H, d, J=7.9 Hz), 6.73 (1H, s), 7.08 (1H, dd, J=9 Hz, 2.5 Hz), 7.18 (1H, d, J=18 Hz), 7.25-7.32 (3H, m), 7.46 (1H, d, J=9 Hz), 7.75 (1H, d, J=7.9 Hz), 8.59 (1H, dd, J=5 Hz, 1.5 Hz), 8.66 (1H, d, J=1.5 Hz).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2=[C:7]([CH:40]=1)[O:8][CH2:9][C:10]1[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:11]=1/[C:12]/2=[CH:13]\[C:14]1[CH:34]=[CH:33][C:17]2[N:18]([C@H:24]([CH3:32])[CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)/[C:19](=[N:21]/[C:22]#[N:23])/[NH:20][C:16]=2[CH:15]=1.[O:41]1CCOCC1>>[F:2][C:3]1[CH:4]=[CH:5][C:6]2=[C:7]([CH:40]=1)[O:8][CH2:9][C:10]1[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:11]=1/[C:12]/2=[CH:13]\[C:14]1[CH:34]=[CH:33][C:17]2[N:18]([C@H:24]([CH3:32])[CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)/[C:19](=[N:21]/[C:22]([NH2:23])=[O:41])/[NH:20][C:16]=2[CH:15]=1
Reactant: C1COCCO1
Reactant: C[C@H](CN1CCOCC1)n1/c(=N/C#N)[nH]c2cc(/C=C3/c4ccc(F)cc4OCc4c(F)cccc43)ccc21
Agent: Cl
Product: C[C@H](CN1CCOCC1)n1/c(=N/C(N)=O)[nH]c2cc(/C=C3/c4ccc(F)cc4OCc4c(F)cccc43)ccc21
Reaction time: 48 h
Yield: 38 %

Procedure:
Prepare a solution of 4 M hydrogen chloride in dioxane by diluting 12 M hydrochloric acid (10 mL) with dioxane (20 mL). Slowly add this solution to (E)-N—((R)-5-((E)-3,7-difluoro-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-1-(1-methyl-2-morpholin-4-yl-ethyl)-1,3-dihydro-benzoimidazol-2-ylidene)-cyanamide (0.005 mol, 3.0 g) at room temperature and stir for 48 hours. Quench the reaction mixture with aqueous 4 N potassium hydroxide solution, extract with dichloromethane and wash with saturated sodium bicarbonate solution. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduce pressure. Purify on silica gel column using 1% methanol in dichloromethane to obtain the title compound (1.2 g, 38%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) mixture of (E,Z)-N isomers. Major isomer: δ 1.44 (d, 3H), 2.23-2.26 (m, 2H), 2.32-2.33 (m 1H), 2.63 (dd, 1H), 2.77-2.82 (m 1H), 3.29-3.46 (m, 5H), 4.77-4.82 (m, 1H), 5.35-5.44 (br d, 2H), 6.65 (dd, 1H), 6.89 (dt, 3H), 7.13 (s 1H), 7.1 (s, 1H), 7.21-7.28 (m, 2H), 7.31-7.42 (m 1H), 7.55-7.62 (m, 1H), 9.95 (s, 1H). Minor isomer: δ 1.39 (d, 3H, E,Z-isomer), 2.23-2.26 (m, 2H), 2.32-2.33 (m 2H), 2.88-3.0 (m 1H), 3.29-3.46 (m, 5H), 4.80-4.99 (m, 1H), 5.35-5.44 (br d, 2H), 6.65 (dd, 1H), 6.89 (dt, 3H), 7.13 (s 1H), 7.1 (s, 1H), 7.21-7.28 (m, 2H), 7.31-7.42 (m 1H), 7.55-7.62 (m, 1H), 9.95 (s, 1H).
Reaction SMILES: S(O[CH2:12][C@H:13]1[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)(C1C=CC(C)=CC=1)(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+].[Na+].[I-]>CN(C=O)C>[N:26]([CH2:12][C@H:13]1[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)=[N+:27]=[N-:28]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@H](CN=[N+]=[N-])C1
Temperature: 70 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
(S)-tert-butyl 2-((tosyloxy)methyl)morpholine-4-carboxylate (63.7 g, 171.52 mmol) was dissolved in DMF (550 ml), and then NaN3 (44.59 g, 686.08 mmol) and NaI (2.5 g, 17.15 mmol) were added, followed by stirring at 70° C. overnight. After the completion of the reaction, the reaction mixture was extracted with H2O and EA, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (EA:Hex=1:5), to give (S)-tert-butyl 2-(azidomethyl)morpholine-4-carboxylate as a white solid (31.1 g, 75%).
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([O:22]CC)=[O:21].[OH-].[Li+]>C(O)C.O>[O:1]=[C:2]1[C:6]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Temperature: 80 °C

Procedure:
The product from Example 21B (0.92 g, 2.84 mmol) was dissolved in ethanol (20 mL). A solution of lithium hydroxide (0.57 g, 23.8 mmol) in water (5 mL) was added, and the reaction was heated to 80° C. for 2 hours. The reaction mixture was cooled to room temperature, concentrated, neutralized with 2 N HCl, and then diluted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and then concentrated to give the title compound. MS (DCI+) m/z 296.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)=[O:19].[OH-].[Ba+2].[OH-].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.O>[CH3:16][O:17][C:18]([C:20]1[CH:25]=[C:24]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[CH:23]=[CH:22][CH:21]=1)=[O:19]
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: Brc1cccc(OCc2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cccc(-c2cccc(OCc3ccccc3)c2)c1
Yield: 55.3 %

Procedure:
A degassed mixture of 3-benzyloxy-phenyl bromide (28) (0.176 g, 0.67 mmol), 3-methoxycarbonylphenylboronic acid (0.18 g, 1 mmol), barium hydroxide (0.25 g, 1.47 mmol), Pd(PPh3)4 (0.077 g, 0.067 mmol), DME (5 mL) and H2O (3 mL) was microwaved with vigorous stirring using a CEM-discover system (ram time: 2 min, hold time: 5 min, temperature: 120° C., pressure: 200 psi, power: 250 W). The crude reaction mixture filtered through a plug of celite and concentrated in vacuo. The residue obtained was purified by flash column chromatography (25% diethyl ether-hexane) to give the title compound (29) (0.118 g, 60% yield) as a viscous liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH3:22])[N:11]2[C:16]=1[C:15]([N:17]1[CH:21]=NC=N1)=[N:14][CH:13]=[N:12]2.[CH:23]1([C:26]2[N:27]=[CH:28][C:29]3[CH2:35]NC[CH2:32][C:30]=3[N:31]=2)[CH2:25][CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH:23]1([C:26]2[N:27]=[CH:28][C:29]3[CH2:35][N:17]([C:15]4[C:16]5=[C:8]([C:3]6[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=6[F:1])[N:9]=[C:10]([CH3:22])[N:11]5[N:12]=[CH:13][N:14]=4)[CH2:21][CH2:32][C:30]=3[N:31]=2)[CH2:25][CH2:24]1
Reactant: c1nc(C2CC2)nc2c1CNCC2
Reactant: Cc1nc(-c2ccccc2F)c2c(-n3cncn3)ncnn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccc2F)c2c(N3CCc4nc(C5CC5)ncc4C3)ncnn12
Reaction time: 18 h

Procedure:
A mixture of C6 (6.40 g, 21.7 mmol), 2-cyclopropyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (3.84 g, 21.9 mmol) and cesium carbonate (7.06 g, 21.7 mmol) was stirred in N,N-dimethylformamide (45 mL) for 2 hours at room temperature. The reaction mixture was concentrated in vacuo, then stirred with water (45 mL) for 18 hours. Filtration provided the product as an off-white powder. Yield: 6.68 g, 16.6 mmol, 76%. This material was combined with product from two similar runs (total weight: 20.37 g) and triturated with a mixture of heptane (100 mL) and ethyl acetate (100 mL) for 3 days at room temperature. Filtration provided the product as an off-white powder (19.6 g). LCMS m/z 402.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 7.97 (s, 1H), 7.92 (br s, 1H), 7.63 (ddd, J=7.6, 7.4, 1.8 Hz, 1H), 7.36-7.41 (m, 1H), 7.27 (ddd, J=7.6, 7.6, 1.1 Hz, 1H), 7.07 (br ddd, J=9, 9, 1 Hz, 1H), 4.51 (s, 2H), 3.86-3.90 (m, 2H), 2.73 (s, 3H), 2.71-2.76 (m, 2H), 2.12-2.18 (m, 1H), 1.00-1.08 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:7]([OH:9])=[O:8])([O-])=O.[H][H]>[Ni].CO>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:7]([OH:9])=[O:8]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(=O)O)cc1N

Procedure:
0.447 mol of 3-nitro-4-methylsulfonylbenzoic acid was reduced with hydrogen by employing 100 g of Raney nickel in 2.5 l of methanol. The mixture was then heated to reflux and filtered off hot with suction. The filtrate was concentrated.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[Cl:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](Cl)=[O:38]>C(#N)C>[Cl:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([NH:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24])=[O:38]
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2Cc3c(CNC(=O)c4cccc(Cl)c4)cccc3C2=O)C(=O)N1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
1,8 Diazabicyclo[5,4,0]-undec-7-ene (0.8 g, 5.3 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride in acetonitrile (100 mL). The mixture was stirred for 30 minutes. 3-Chlorobenzoyl chloride (0.6 g, 3.2 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was stirred with CH2Cl2 (60 mL) and 2N HCl (30 mL). The mixture was filtered and the solid was slurried with ethanol (20 mL) to give 3-chloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-benzamide (0.8 g, 96%) as a white solid: mp 266-268° C.; 1H NMR (DMSO-d6) δ 2.01-2.06 (m, 1H), 2.37-2.66 (m, 2H), 2.86-2.99 (m, 1H), 4.48 (d, J=17.3 Hz, 1H), 4.53 (d, J=21.1 Hz, 1H), 4.55 (s, 2H), 5.12-5.20 (dd, J=5.0 and 13.2 Hz, 1H, CH), 7.48-7.66 (m, 5H, Ar), 7.87 (d, J=7.7 Hz, 1H, Ar), 7.93 (d, J=1.3 Hz, 1H, Ar), 9.23 (t, J=5.6 Hz, 1H, NH), 11.03 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.60, 31.20, 39.66, 46.28, 51.60, 121.76, 126.07, 127.08, 128.38, 130.40, 130.77, 131.22, 131.65, 133.23, 134.37, 136.01, 140.21, 164.94, 168.07, 171.04, 172.88; Anal. calcd. for C21H18N3O4Cl: C, 61.24; H, 4.41; N, 10.20; Cl, 8.61. Found: C, 60.92; H, 4.21; N, 10.01; Cl, 8.92.
Reaction SMILES: [NH2:1][C:2](=[O:21])[CH2:3][NH:4][C:5]1[C:10]([NH:11][C:12](=O)[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:9][CH:8]=[CH:7][N:6]=1>C(O)CO.CO>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:4]([CH2:3][C:2]([NH2:1])=[O:21])[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:10]3[N:11]=2)=[CH:14][CH:15]=1
Reactant: NC(=O)CNc1ncccc1NC(=O)c1ccc(Cl)cc1
Solvent: OCCO
Solvent: CO
Product: NC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 190 °C
Yield: 24.8 %

Procedure:
A mixture of N-[2-[(2-amino-2-oxoethyl)amino]-3-pyridinyl]-4-chlorobenzamide (6.0 g, 0.02 mole) in 150 ml of ethylene glycol was heated at 190° C. for 40 minutes. The precipitate, which formed, was filtered off and washed with water. The filtrate was diluted with water to produce a second crop. The first crop was heated to boiling in 300 ml of methanol, filtered through a Celite pad, seeded, and refrigerated overnight. The crystalline precipitate was filtered, washed with cold methanol, and dried under high vacuum at 60° C. overnight to give 1.42 g (25%) of title compound, mp 270°-1° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.C1C(=O)N([Br:18])C(=O)C1>C(Cl)Cl>[Br:18][C:10]1[C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[Br:1])[NH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Brc1ccnc2[nH]ccc12
Solvent: ClCCl
Product: Brc1ccnc2[nH]cc(Br)c12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 72.3 %

Procedure:
A mixture of 4-bromo-1H-pyrrolo[2,3-b]pyridine (1.00 g, 5.08 mmol) and NBS (0.918 g, 5.16 mmol) in DCM (20.0 mL) was stirred at 0° C. for 1.5 hour. The resulting suspension was filtered, washed with DCM, residue collected, dried in a 50° C. oven overnight to afford the title compound (1.014 g). LCMS (A): m/z (M+H)+ 277, C7H4Br2N2 requires 276 (basic).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH2:29][O:30][CH3:31])[O:5][C:6]1[CH:7]=[C:8]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][N:20]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([NH2:17])=O)=[CH:11]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>O1CCCC1>[CH3:1][O:2][CH2:3][CH:4]([CH2:29][O:30][CH3:31])[O:5][C:6]1[CH:7]=[C:8]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][N:20]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15](=[S:41])[NH2:17])=[CH:11]2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C(N)=O)[nH]c12
Solvent: C1CCOC1
Product: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C(N)=S)[nH]c12
Temperature: 50 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
To a solution of 7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxamide (1.66 g) in tetrahydrofuran (40 mL) was added Lawesson's reagent (1.5 g), and the mixture was stirred at 50° C. for 2 h. Lawesson's reagent (0.5 g) was added to the mixture again. After stirring at 50° C. for 1 h, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the mixture was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by basic silica gel column chromatography (methanol/ethyl acetate/hexane=0/10/90 to 10/90/0, volume ratio) to give the title compound (1.69 g, 98%) as a yellow amorphous solid. MS 466 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.[O:19]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][CH2:21][CH2:20]1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>ClCCl>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[C:6]([C:7]([N:22]2[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:19][CH2:20][CH2:21]2)=[O:9])=[CH:10][CH:11]=[CH:12][N:13]=1
Reactant: c1ccc2c(c1)NCCO2
Reactant: O=C(O)c1cccnc1Oc1cc(Cl)ccc1Cl
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCOc2ccccc21
Temperature: 25 °C
Yield: 18.3 %

Procedure:
To a solution of 2-(2,5-dichloro-phenoxy)-nicotinic acid (42.6 mg, 0.15 mmol, 1.0 equiv; Example 31, Step 1) in dichloromethane (1.5 mL) was added 3,4-dihydro-2H-benzo[1,4]oxazine (22.9 mg, 0.17 mmol, 1.1 equiv; [CAS RN 5735-53-5]), triethylamine (30.4 mg, 42 μL, 0.3 mmol, 2.0 equiv; [CAS RN 121-44-8]) and 2-chloro-1-methylpyridinium iodide (42.2 mg, 0.17 mmol, 1.1 equiv; [CAS RN 14338-32-0]). The reaction mixture was stirred at rt over night. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 11 mg (18%) of the title compound. MS (ISP): 401.0 [M+H]+.
Reaction SMILES: [C:1]([SiH:5]([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:15]([O:18][CH2:19][C:20]1[O:25][CH2:24][N:23]([C:26]([CH3:38])([CH3:37])[C:27]([O:29]CC2C=CC=CC=2)=[O:28])[C:22](=[O:39])[C:21]=1[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=[O:17])[CH3:16]>ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:15]([O:18][CH2:19][C:20]1[O:25][CH2:24][N:23]([C:26]([CH3:38])([CH3:37])[C:27]([O:29][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6])=[O:28])[C:22](=[O:39])[C:21]=1[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OCC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)OCc2ccccc2)CO1
Reactant: C[SiH](C)C(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)O[Si](C)(C)C(C)(C)C)CO1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of palladium (II) acetate (25 mg), tert butyl-dimethylsilane (1.25 ml) and triethylamine (0.05 ml) in dichloromethane was stirred at room temperature under an inert atmosphere for 0.25 hour. A solution of benzyl 2-(6-acetoxymethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoate (1.0 g) was added and stirring continued for 18 hours. The mixture was filtered (hyflo) and evaporated to give tert butyldimethylsilyl 2-(6-acetoxymethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoate (0.92 g) as a yellow oil, NMR (CDCl3)δ 0.25(s,9H), 1.5(s,6H), 2.0(s,3H), 4.5(s,2H), 5.2(s,2H), 7.0-7.3(m,5H).
Reaction SMILES: Cl[C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[CH2:35][CH2:34][CH2:33][C:32](=[O:36])[CH:31]=1)CCC>CN(C=O)C.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:11][C:10]1[C:2]([C:30]2[CH2:35][CH2:34][CH2:33][C:32](=[O:36])[CH:31]=2)=[N:3][C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[C:5]([CH:9]=1)[C:6]([NH2:8])=[O:7]
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CC(=O)CCC1
Reactant: NC(=O)c1cc(F)c(Cl)nc1Nc1ccc(N2CCOCC2)cc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)c1cc(F)c(C2=CC(=O)CCC2)nc1Nc1ccc(N2CCOCC2)cc1
Yield: 23.5 %

Procedure:
A solution of 6-chloro-5-fluoro-2-(4-morpholinophenylamino)nicotinamide (80 mg, 0.228 mmol), 3-(tributylstannyl)cyclohex-2-enone (105 mg, 0.274 mmol) (synthesized according to literature procedure: Tet. Lett., 31:1837-1840 (1990)), and dichloro bis(triphenylphosphine)palladium (II) (16.05 mg, 0.023 mmol) in DMF (2 mL) was microwaved at 160° C. for 1 h. The reaction mixture was diluted with methylene chloride, washed with satd. NaHCO3, water, and concentrated. The residue was purified prep-HPLC. The product containing fractions were collected, basified with 1N NaOH, and extracted with methylene chloride twice. The combined organic fractions were washed with water, concentrated, and further purified by MPLC (ISCO, 5% ammonia/methanol/methylene chloride, 40 g silica gel column) to give 22 mg brown solid. LC-MS: (M+H)+=411.25. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.76-10.84 (1H, m), 8.28-8.39 (1H, m), 8.13-8.21 (1H, m), 7.83-7.91 (1H, m), 7.45-7.53 (2H, m), 6.88-6.96 (2H, m), 6.52-6.57 (1H, m), 3.67-3.77 (4H, m), 3.04 (4H, d, J=4.95 Hz), 2.76-2.85 (2H, m), 2.39-2.46 (2H, m), 2.01-2.09 (2H, m).
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([CH:12]3[CH2:14][CH2:13]3)[O:11][C:7]=2[C:6]([F:15])=[C:5]([NH:16]C(=O)OC(C)(C)C)[C:4]=1[CH3:24])#[N:2].FC(F)(F)C(O)=O>ClCCl>[NH2:16][C:5]1[C:6]([F:15])=[C:7]2[O:11][C:10]([CH:12]3[CH2:13][CH2:14]3)=[N:9][C:8]2=[C:3]([C:1]#[N:2])[C:4]=1[CH3:24]
Reactant: Cc1c(NC(=O)OC(C)(C)C)c(F)c2oc(C3CC3)nc2c1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(N)c(F)c2oc(C3CC3)nc2c1C#N
Reaction time: 6 h
Yield: 97.3 %

Procedure:
tert-Butyl (4-cyano-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazol-6-yl)carbamate (I-319) (40 mg, 0.12 mmol) was dissolved in dichloromethane (1 ml), then at room temperature, trifluoroacetic acid (1 ml) was added. The solution was stirred at the same temperature for 6 hours, then the solvent was evaporated away under reduced pressure, and the residue was fractionated with dichloromethane and an aqueous saturated sodium hydrogencarbonate solution. The aqueous layer was further extracted twice with dichloromethane. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, then the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, n-hexane:ethyl acetate=2:1, v/v) to obtain the entitled compound (27 mg, 97%) as a pale brown solid.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[NH:11][NH2:12]>C1CCCCC1>[CH3:1][C:2](=[N:12][NH:11][C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)=O
Reactant: CC(C)(C)OC(=O)NN
Solvent: C1CCCCC1
Product: CCCCCCC(C)=NNC(=O)OC(C)(C)C

Procedure:
40 g (312 mmol) of 2-octanone and 41.23 g (312 mmol) of tert-butyl carbazate are refluxed for 2 hours in 350 ml of cyclohexane. The solvent and water are removed in vacuo. This gives 74.10 g (98%) of a waxy solid.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[O:6][CH2:7][CH:8]([CH2:19][OH:20])[C:9]3[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1.[CH3:23]I>ClCCl.[Ag]=O>[Br:1][C:2]1[CH:22]=[CH:21][C:5]2[O:6][CH2:7][CH:8]([CH2:19][O:20][CH3:23])[C:9]3[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1
Reactant: CI
Reactant: CCOC(=O)c1nc2c(s1)C(CO)COc1ccc(Br)cc1-2
Agent: O=[Ag]
Solvent: ClCCl
Product: CCOC(=O)c1nc2c(s1)C(COC)COc1ccc(Br)cc1-2
Temperature: 50 °C
Reaction time: 6 h
Yield: 53.1 %

Procedure:
A suspension of ethyl 9-bromo-4-(hydroxymethyl)-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate (200 mg, 0.52 mmol, 1.00 equiv), MeI (750 mg, 5.28 mmol, 10.00 equiv) and silver oxide (480 mg, 2.07 mmol, 4.00 equiv) in dichloromethane (15 mL) was stirred for 6 h at 50° C. The solids were filtered out and the filtrate was concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1:10) to give 110 mg (53%) of the titled compound as an off-white solid; LC-MS (ES, m/z) 398,400 [M+H]+.