Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH2:15]([C:17]1[CH:40]=[CH:39][C:20]2[CH:21]([C:31]3[C:32](=[O:38])[NH:33][C:34](=[O:37])[NH:35][CH:36]=3)[C:22]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:23]=3[CH:24]=[CH:25][C:19]=2[CH:18]=1)[CH3:16]>>[CH2:15]([C:17]1[CH:40]=[CH:39][C:20]2[CH:21]([C:31]3[C:32](=[O:38])[NH:33][C:34](=[O:37])[N:35]([C:2]4[N:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=4)[CH:36]=3)[C:22]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:23]=3[CH:24]=[CH:25][C:19]=2[CH:18]=1)[CH3:16]
Reactant: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1c[nH]c(=O)[nH]c1=O
Reactant: CC(C)(C)OC(=O)c1ccnc(Cl)n1
Product: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2nccc(C(=O)OC(C)(C)C)n2)c(=O)[nH]c1=O

Procedure:
The subtitle compound was prepared from the product of step (iii) and the product of example 15 step (vii) by the method of example 19 step (ii).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C([Li])(C)(C)C.[Br:26]Br>C1COCC1.CCCCC>[Br:26][C:8]1[C:7]([O:9][CH3:10])=[CH:6][N:5]=[C:4]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(C#Cc2ncc(OC)cc2OC)cc1
Reactant: BrBr
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1ccc(C#Cc2ncc(OC)c(Br)c2OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29 %

Procedure:
To a solution of 3,5-dimethoxy-2-(4-methoxyphenylethynyl)pyridine M (120 mg, 0.446 mmol) in dry THF (2.5 ml) at −78° C. was added t-butyllithium (0.49 mmol, 0.30 ml of a 1.6M solution in pentane) and the reaction stirred for 10 minutes. After this time bromine (25 μL, 0.50 mmol) was added neat and the reaction was allowed to warm to room temperature and quenched by the addition of water (10 ml) and ethyl acetate (10 ml). The organic layer was washed with brine (10 ml), dried over MgSO4 and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica-gel, eluted with hexanes:EtOAc, 3:1) to afford the product as a white solid (45 mg, 29%). 1HNMR (300 MHz, CDCl3) δ 7.99 (s, 1H), 7.52 (d, J=8.7 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H), 4.05 (s, 3H), 4.01 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: [NH2:1]/[C:2](/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH:3]\[C:4]#[N:5].[SH2:12]>CCO.C1COCC1>[C:6]1([C:2]2[CH:3]=[C:4]([NH2:5])[S:12][N:1]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#C/C=C(\N)c1ccccc1
Reactant: S
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cc(-c2ccccc2)ns1
Reaction time: 20 h

Procedure:
To a solution of (Z)-3-amino-3-phenylacrylonitrile (95 mg, 0.660 mmol) in EtOH (1.0 mL) and THF (1.0 mL) in a sealed tube, H2S gas was bubbled through for 5 min. It was then stirred at 90 C for 20 h. The mixture was concentrated in vacuo. The residue was dissolved in MeOH (2.0 mL), aq. H2O2 (30%, 0.5 mL) was added. After being stirred at room temperature for 2 min, the reaction was completed. The mixture was concentrated in vacuo. The residue was purified by HPLC to give 3-phenylisothiazol-5-amine (22 mg).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[C:20]([O:21][CH3:22])=[CH:19][C:12]2[CH2:13][C:14](=[O:18])[NH:15][CH:16]=[CH:17][C:11]=2[CH:10]=1.[CH2:23]([N:30]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]([CH2:37]Br)[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CS(C)=O.C(OCC)(=O)C>[CH2:23]([N:30]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]([CH2:37][N:15]2[C:14](=[O:18])[CH2:13][C:12]3[CH:19]=[C:20]([O:21][CH3:22])[C:9]([O:8][CH3:7])=[CH:10][C:11]=3[CH:17]=[CH:16]2)[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1cc2c(cc1OC)CC(=O)NC=C2
Reactant: BrCC1CCCCN(Cc2ccccc2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1cc2c(cc1OC)CC(=O)N(CC1CCCCN(Cc3ccccc3)C1)C=C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.3 g (0.02 mol) of potassium tert.butoxide are added to a solution of 4.4 g (0.02 mol) of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one in 100ml of absolute dimethylsulphoxide. After stirring for 30 minutes at ambient temperature, 5.6 g (0.020 mol) of 1-benzyl-3-bromomethyl-hexahydro-azepine are added and the resulting mixture is stirred for 2 hours at ambient temperature. The reaction mixture is dissolved in ethyl acetate and extracted several times with water. The organic phase is dried over magnesium sulphate and evaporated down in vacuo. The residue is purified by column chromatography over aluminium oxide N (activity II, eluant: methylene chloride, methylene chloride+0.3% ethanol). Yield: 4.2 g (50% of theory), IR spectrum (methylene chloride): 1655 cm-1 (CO).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.[Cl:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([Cl:20])[C:14]=1[O:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]I)=[CH:27][CH:26]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][CH2:23][CH2:22][O:21][C:14]3[C:15]([Cl:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[Cl:12])=[CH:26][CH:27]=2)[C:9]#[N:10])=[C:4]([F:11])[CH:3]=1
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CI)cc2)c(Cl)c1
Reactant: N#CCc1ccc(Br)cc1F
Product: Cc1cc(Cl)c(OCCOc2ccc(CC(C#N)c3ccc(Br)cc3F)cc2)c(Cl)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 1, step 4 using commercially available (4-bromo-2-fluorophenyl)acetonitrile and 1,3-dichloro-2-{2-[4-(iodomethyl)phenoxy]ethoxy}-5-methylbenzene (II.1) as starting materials. Purification by column chromatography on silica gel, eluting with Hex/Tol 50%, afforded the desired compound as a colorless oil.
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4][CH3:5])[CH3:2].C[Al](C)C.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[N:24]=[C:23]2[O:25][C:26]([C:35](OCC)=[O:36])=[C:27]([NH:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[C:22]2=[CH:21][C:20]=1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[N:24]=[C:23]2[O:25][C:26]([C:35]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:36])=[C:27]([NH:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[C:22]2=[CH:21][C:20]=1[C:40]1[CH:41]=[CH:42][C:43]([Cl:46])=[CH:44][CH:45]=1
Reactant: CCOC(=O)c1oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc2c1NC(=O)C(F)(F)F
Reactant: CCN(CC)CC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCN(CC)C(=O)c1oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc2c1NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a magnetically stirred solution of 0.119 mL (1.15 mmol) of triethylamine in 5 mL toluene was added 0.575 mL (1.15 mmol) of a 2.0 M solution of trimethylaluminum in toluene at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred for 30 min. A solution of 0.300 g (0.57 mmol) of the product of Example 181 in 1 mL CH2Cl2 was added to the reaction mixture and when the addition was complete the reaction mixture was heated at 60° C. for 2 h. The reaction mixture was allowed to cool again to room temperature and was partitioned between EtOAc and 10% aq. NaHSO4. The organic extracts were combined, washed with water and brine, dried (Na2SO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 0–30% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded the titled compound. HPLC/MS: 550.0 (M+1), 551.8 (M+3); Rt=4.74 min.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)([CH3:3])[CH3:2].[Li]CCCC.[C:15](Cl)(=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[NH4+].[Cl-]>C1COCC1>[C:15]([N:5]1[C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][O:7][C:6]1=[O:9])(=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: CCCCCCC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Temperature: -78 °C
Yield: 82.1 %

Procedure:
To a solution of oxazolidone (2) (30.2 g, 0.234 mol) in 400 mL THF at −78° C. was added n-BuLi (2.5 M in hexanes, 96.0 mL, 0.240 mol) dropwise over a period of 30 min. The solution was stirred at −78° C. for an hour. Heptanoyl chloride (37.15 g, 0.250 mol) was gradually added by syringe and the resulting solution stirred at −78° C. for 1 h and then warmed to 0° C. A saturated aqueous solution of NH4Cl (100 mL) was added and the mixture gradually warmed to room temperature. The mixture was extracted with ethyl acetate (3×20 mL) and the combined organic layers were washed with brine and dried over anhydrous MgSO4. The solvent was removed by a rotary evaporation and the yellowish residue chromatographed on a silica gel column using Hexane/EtOAc (8:1) as the eluant to give 4 as a colorless oil (46.272 g, 0.192 mol, 82%). 1H NMR (400 MHz, CDCl3) δ 0.87 (t, J=7.2 Hz, 3H), 0.88 (d, J=16.9 Hz, 3H), 0.90 (d, J=16.9 Hz, 3H), 1.24-1.39 (m, 6H), 1.59-1.69 (m, 2H)2.31-2.43 (m, 1H), 2.81-3.02 (m, 2H), 4.19-4.29 (m, 2H), 4.41-4.45 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 13.9, 14.5, 17.9, 22.4, 24.3, 28.3, 28.7, 31.4, 35.4, 58.3, 63.2, 154.0, 173.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][CH2:16][OH:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][CH2:16][O:17][S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCC2CCCCN2C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Yield: 77 %

Procedure:
The title compound from Step B above (2 g, 8.22 mmoles) was dissolved in anhydrous pyridine (10 mL) and the solution was cooled with stirring to 0° C. 4-Toluenesulfonyl chloride (1.88 g, 9.86 mmoles) was added and the mixture was stirred at 0° C. for 2 h. The mixture was evaporated to dryness and the residue was taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate, water, dried (MgSO4), filtered and evaporated to dryness. The product was chromatographed on silica gel using 0.25% methanol in dichloromethane as the eluant to give the title compound (2.53 g, 77%): ESMS: m/z 398.1 (MH+).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[C:18]1[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].I[CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:36].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:32][CH2:33][CH2:34][C:35](=[O:36])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:10][CH2:11]2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:4][N:3]1[C:18]1[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=1[C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21]
Reactant: O=C(CCCI)c1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccccc1N1CN(c2ccccc2)C2(CCNCC2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccccc1N1CN(c2ccccc2)C2(CCN(CCCC(=O)c3ccccc3)CC2)C1=O
Temperature: 68 °C
Reaction time: 16 h
Yield: 81.5 %

Procedure:
A mixture of tert-butyl 2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)benzoate (370 mg, 0.909 mmol, 1 equiv), 4-iodo-1-phenylbutan-1-one (250 mg, 0.909 mmol, 1 equiv) and potassium carbonate (251 mg, 1.82 mmol, 2 equiv) in N,N-dimethylformamide was stirred at 68° C. for 16 h. After cooling the reaction mixture, the crude mixture was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered, concentrated, and the crude residue was purified using the Biotage flash chromatography system (SNAP 50 g cartridge, Rf=0.5, gradient—1%-10% methanol in dichloromethane) to afford the title compound as a white powder (410 mg, 82%); 1H NMR (400 MHz, DMSO-d6): δ 1.49 (s, 9H); 1.74-1.83 (m, 4H); 2.37 (t, 2H, J=7.2 Hz); 2.61 (t, 2H, J=10 and 11.2 Hz); 2.726-2.73 (m, 4H); 3.05 (t, 2H, J=6.8 and 7.2 Hz); 5.06 (s, 2H); 6.79 (t, 1H, J=7.2 and 7.6 Hz); 6.87 (s, 1H); 6.89 (s, 1H); 7.20 (m, 2H); 7.46-7.69 (m, 6H); 7.76-7.78 (m, 1H); 7.95-7.99 (m, 2H); MS for C34H39N3O4 m/z 554.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[H][H]>C(O)C.[Ni]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C=Cc1ccc(F)cc1F
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(F)cc1F

Procedure:
42.4 g (0.20 mol) of ethyl 3-(2,4-difluorophenyl)-2-propenoate are dissolved in 400 ml of ethanol, 4 g of Raney nickel in ethanol are added, and the mixture is hydrogenated at 20°-25° C. using hydrogen gas. When the theoretical amount of hydrogen has been taken up, the solution is filtered and evaporated on a vacuum rotary evaporator. 41.4 g of a pale brown oil which is subjected to fractional distillation at 120° C. in vacuo (20 mbar) are obtained. 33 g (77% of theory) of a colourless oil are obtained.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[C:15]([S:16]([CH2:19][C:20]([OH:23])([CH3:22])[CH3:21])(=[O:18])=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=1)=O)(C)(C)C.Cl.O1CCOCC1>CO>[NH2:8][CH2:9][C:10]1[C:15]([S:16]([CH2:19][C:20]([OH:23])([CH3:21])[CH3:22])(=[O:18])=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CC(C)(O)CS(=O)(=O)c1cccnc1CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(O)CS(=O)(=O)c1cccnc1CN

Procedure:
A solution of 121 mg (0.35 mmol) 2-tert-butoxycarbonylaminomethyl-3-(2-hydroxy-2-methylpropanesulfonyl)pyridine, 10 mL 4M HCl/dioxane and 5 mL methanol was stirred at room temperature for 2 hours. The reaction was evaporated to dryness. The residue was treated with triethylamine and purified by chromatography on SiO2 using 0:100 to 5:95 methanol-chloroform yielding a yellow oil: 1H NMR (CDCl3): δ1.44 (s, 6H), 3.56 (s, 2H), 4.41 (s, 2H), 7.43 (dd, 1H), 8.32 (dd, 1H), 8.79 (dd, 1H).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]1[C:13](=[O:14])[C:12]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])=[CH:16][C:17](Cl)=[N:18][C:11]=2[O:10][CH2:9][CH2:8]1.[N:36]1([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:40][CH2:39][CH2:38][CH2:37]1>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]1[C:13](=[O:14])[C:12]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])=[CH:16][C:17]([N:44]3[CH2:45][CH2:46][CH:41]([N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[CH2:42][CH2:43]3)=[N:18][C:11]=2[O:10][CH2:9][CH2:8]1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Cc1ccccc1-c1cc(Cl)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCO2
Product: Cc1ccccc1-c1cc(N2CCC(N3CCCC3)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCO2
Yield: 13.6 %

Procedure:
In a similar manner to Example 1, 4-[3,5-bis(trifluoromethyl)benzyl]-8-chloro-6-(2-methylphenyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (51.5 mg) was reacted with 4-(pyrrolidine-1-yl)piperidine (46.3 mg) to obtain 4-[3,5-bis(trifluoromethyl)benzyl]-6-(2-methylphenyl)-5-oxo-8-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (8.6 mg, 14%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[C:7]([NH2:17])[N:8]=[C:9]([N:12]3[CH:16]=NC=N3)[C:10]=2[N:11]=1.N1C[CH2:22][O:21][CH2:20][CH2:19]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[C:7]([NH2:17])[N:8]=[C:9]([N:12]3[CH2:16][CH2:22][O:21][CH2:20][CH2:19]3)[C:10]=2[N:11]=1
Reactant: Nc1nc(-n2cncn2)c2nc(Cl)ccc2n1
Reactant: C1COCCN1
Solvent: ClCCl
Product: Nc1nc(N2CCOCC2)c2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 244.6 %

Procedure:
A suspension of 6-chloro-4-[1,2,4]triazol-1-yl-pyrido[3,2-d]pyrimidin-2-ylamine (0.1 g, 0.4 mmol) and morpholine (0.07 mL, 0.8 mmol) in DCM (10 mL) was stirred at room temperature for 48 hours. After the removal of solvent, the residue was purified by flash chromatography (using 5% i-PrOH/DCM as the eluent), providing the title compound (0.26 g, 99% yield) as a yellow solid which was characterised as follows: MS (m/z) 266.0 [M+H]+.
Reaction SMILES: N[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[I:12]I.N(OC(C)(C)C)=O>C(Cl)(Cl)Cl>[I:12][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1
Reactant: Nc1cncc(C(F)(F)F)n1
Reactant: II
Agent: CC(C)(C)ON=O
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1cncc(I)n1
Reaction time: 0.67 h

Procedure:
A three liter flask was charged with a solution of 2-amino-6-trifluoromethylpyrazine (obtained by the method of J. L. Miesel, U.S. Pat. No. 4,293,552, 95% pure by HPLC analysis, 32.6 g, 0.20 mol) in chloroform (1000 mL). Freshly ground iodine (101 g. 0.40 mol) was added to give a dark purple solution. After 40 min, a solution of t-butyl nitrite (22.9 g, 0.20 mol) in chloroform (300 mL) was added dropwise over 1 h. During the addition, slow gas evolution was observed together with a mild exotherm (<10° C.) which was moderated with a cold water bath. After an additional 1 h at room temperature the reaction mixture was washed with saturated aqueous sodium sulfite (3×500 mL) to remove the excess iodine. The chloroform solution was dried over magnesium sulphate, filtered and concentrated on a Buchi to give 23 g of an orange oil. The crude product was purified by distillation from copper (40-80 mesh, 200 mg) to give 19.5 g of the title compound as a yellow oil; b.p. 50°-56° C./0.6 mmHg; δ (360 MHz, CDCl3) 9.06 (1H, s, pyrazine-H), 8.86 (1H, s, pyrazine-H); m/e 274 (M+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][C:3]=1[Cl:14].[Li]CCCC.CN([CH:23]=[O:24])C>C1COCC1.CCCCCC>[Cl:14][C:3]1[CH:4]=[C:5]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][C:2]=1[CH:23]=[O:24]
Reactant: CN(C)C=O
Reactant: Clc1cc(CN2CCCC2)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1ccc(CN2CCCC2)cc1Cl
Reaction time: 0.5 h

Procedure:
Reaction under N2 atmosphere. A solution of 1-[(4-bromo-3-chlorophenyl)methyl]-pyrrolidine (25.8 g, 93.96 mmol) in THF (200 ml) was stirred at −78° C. for 15 min A 2.5 M n-BuLi solution in hexane was added to the mixture over a period of 15 min. After 30 min, a solution of DMF (7.3 ml, 93.96 mmol) in THF (50 ml) was added dropwise to the mixture. The reaction temperature was allowed to rise to r.t. slowly, and the mixture was stirred overnight. The reaction was quenched by the addition of water at 0° C. The mixture was extracted with EtOAc (3×150 ml). The combined organic layer was washed with brine, dried (MgSO4), filtered and the solvent was evaporated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]([CH3:34])[C@@H:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][CH:18]=3)[CH2:13][C@H:12]2[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)=[O:9])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:41][N:42](C=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([CH3:34])[C@@H:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[CH:21][C:20]([C:23]([NH:42][CH3:41])=[O:25])=[CH:19][CH:18]=3)[CH2:13][C@H:12]2[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)=[O:9])=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCN(c2ccc(C(=O)O)cn2)C[C@H]1c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(N2CC[C@@H](N(C)C(=O)c3ccc(Cl)cc3)[C@H](c3ccc(Cl)c(Cl)c3)C2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
To a solution of the compound (0.150 g) obtained in Example 500 in THF (5 mL) were added oxalyl chloride (38 μL) and DMF (3 μL), and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated, and to a solution of the residue in THF (2 mL) was added a solution of methylamine (0.0269 g) in THF (5 mL), and the mixture was stirred for 10 min. To the reaction mixture was added water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure to give the title compound (0.039 g, 25%) as a white powder.
Reaction SMILES: [CH2:1]([C:3](=[CH:17][CH3:18])[CH:4]=[CH:5][CH2:6][NH:7][C:8]([C:10]1[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=1)=[O:9])[CH3:2].[CH3:19][S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1>[CH2:17]([C:3](=[CH:1][CH3:2])[CH:4]=[CH:5][CH2:6][NH:7][C:8]([C:10]1[CH:11]=[N:12][C:13]([NH:16][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:14][CH:15]=1)=[O:9])[CH3:18]
Reactant: CS(=O)(=O)Cl
Reactant: CC=C(C=CCNC(=O)c1ccc(N)nc1)CC
Solvent: c1ccncc1
Product: CC=C(C=CCNC(=O)c1ccc(NS(C)(=O)=O)nc1)CC

Procedure:
A solution of N-(4-ethyl-2,4-hexadien-1-yl)-6-amino-3-pyridinecarboxamide (3.0 g) and methanesulfonyl chloride (1.54 g) in pyridine (25 ml) was stirred at 50° C. for 3 hours. The reaction mixture was evaporated in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with 0.5N hydrochloric acid and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (3% methanol-chloroform) to give N-(4-ethyl-2,4-hexadien-1-yl)-6-methansulfonamido-3-pyridinecarboxamide.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([C:8]2[C:17]([CH:18]=O)=[CH:16][C:11]3[C:12]([CH3:15])=[N:13][O:14][C:10]=3[C:9]=2[F:20])[CH2:5][C@H:4]([CH3:21])[O:3]1.[NH:22]1[C:27](=[O:28])[CH2:26][C:25](=[O:29])[NH:24][C:23]1=[O:30]>C(O)(C)C.CO>[F:20][C:9]1[C:10]2[O:14][N:13]=[C:12]([CH3:15])[C:11]=2[CH:16]=[C:17]2[C:8]=1[N:6]1[CH2:5][C@@H:4]([CH3:21])[O:3][C@@H:2]([CH3:1])[C@@H:7]1[C:26]1([C:25](=[O:29])[NH:24][C:23](=[O:30])[NH:22][C:27]1=[O:28])[CH2:18]2
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: Cc1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(C=O)cc12
Solvent: CC(C)O
Solvent: CO
Product: Cc1noc2c(F)c3c(cc12)CC1(C(=O)NC(=O)NC1=O)[C@H]1[C@H](C)O[C@H](C)CN31
Temperature: 80 °C
Reaction time: 16 h
Yield: 70.5 %

Procedure:
To a stirred solution of 6-((2R,6S)-2,6-dimethylmorpholino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carbaldehyde (Intermediate 34, 543 mg, 1.86 mmol) in isopropanol (50 ml) was added pyrimidine-2,4,6(1H,3H,5H)-trione (238 mg, 1.86 mmol), and the reaction mixture was stirred for 16 hours at 80° C. Solvent was removed and the residue was triturated with isopropanol. The solid was filtered, washed with isopropanol, and dried in vacuo. The filtrate was concentrated and purified on silica gel (30-50% EtOAc in hexanes). The product thus obtained was combined with the filtered solid in methanol and concentrated to give the title compound (528 mg, 71%) as a racemic mixture.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:17]([O:19][CH3:20])=[O:18])(=O)=O.C(N(CC)CC)C.[C:30]1([PH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:37]1([P:36]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[C:17]([O:19][CH3:20])=[O:18])[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12

Procedure:
A stirred solution of methyl 2-trifluoromethanesulfonyloxy-1-naphthoate (52.7 g, 158 mmol, 1 eq), triethylamine (26.5 ml, 190 mmol, 1.2 eq) and palladium acetate (0.15 g, 0.7 mmol, 0.004 eq) in acetonitrile (600 ml) was sparged with nitrogen for 30 minutes. Diphenylphosphine (29.4 g, 158 mmol, 1 eq) was added instantly giving a red coloration. The solution was heated at reflux under nitrogen for 17 hours. The blood-red solution was allowed to cool and concentrated under reduced pressure to approximately half its original volume. Methanol (50 ml) was added and the mixture concentrated a little more under reduced pressure. The product crystallised from this mixture and was collected by filtration and washed with ice-cold methanol (200 ml) and dried under vacuum at ambient temperature; 31p NMR (162 mHz; CDCl3): δ−7.8. Yield 54.1 g, 92%