Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:12][Si](C)(C)C)[CH2:9]OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([C@H:23]2[CH2:27][O:26][C:25](=[O:28])[N:24]2[C:29](=[O:38])/[CH:30]=[CH:31]/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.ClCCl>[CH2:1]([N:8]1[CH2:12][C@H:31]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C@@H:30]([C:29]([N:24]2[C@@H:23]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:27][O:26][C:25]2=[O:28])=[O:38])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C(/C=C/c1ccccc1)N1C(=O)OC[C@@H]1c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1OC[C@H](c2ccccc2)N1C(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccccc1
Reaction time: 0.33 h
Yield: 64.7 %

Procedure:
N-Benzyl-N-(methoxymethyl)trimethylsilylmethylamine (10.03 g, 40.5 mmol) was added to (S)-4-phenyl-3-[(E)-(3-phenyl-acryloyl)]-oxazolidin-2-one (10.3 g, 35.1 mmol) in toluene (150 mL) at 0° C. and stirred for 20 minutes. Trifluoroacetic acid (9.7 mL) in dichloromethane (125 mL) was added dropwise to the reaction mixture keeping the internal temperature at 0° C. The reaction was stirred at room temperature overnight. The reaction mixture was poured into saturated sodium bicarbonate (200 mL) and extracted with dichloromethane (2×75 mL). The combined organic phases were washed with brine and dried over sodium sulfate. The organic phases were concentrated to give a waxy solid, which was purified by flash silica gel chromatography eluting with ethyl acetate:hexanes (1:9) to give 9.68 g (61%) of (S)-3-((3R,4S)-1-benzyl-4-phenyl-pyrrolidine-3-carbonyl)-4-phenyl-oxazolidin-2-one.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC1(C)C(C)(C)OB([C:54]2[CH:55]=[CH:56][C:57]([NH2:60])=[N:58][CH:59]=2)O1>ClCCCl>[NH2:60][C:57]1[N:58]=[CH:59][C:54]([C:2]2[N:3]=[C:4]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:5]3[S:10][C:9]([CH2:11][N:25]4[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][OH:19])[CH2:23][CH2:24]4)=[CH:8][C:6]=3[N:7]=2)=[CH:55][CH:56]=1
Reactant: OCCN1CCNCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Nc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCN(CCO)CC4)cc3n2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde (1.3 g, 4.6 mmol) in 1,2-dichloroethane (45 mL) was added 1-(2-hydroxyethyl)piperazine (0.8 mL, 6.4 mmol) and AcOH (260 μL, 4.6 mmol). After stirring 10 min at room temperature, Na(OAc)3BH (1.2 g, 5.5 mmol) was added and the resulting mixture stirred overnight. The reaction was quenched by the addition of saturated aqueous NaHCO3 and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 and the combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. A portion (0.4 mmol) of the crude intermediate was coupled using General Procedure A with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine to provide 157 after reverse phase HPLC purification (21 mg). MS (Q1) 456 (M)+.
Reaction SMILES: [C:1]12([NH:11][C:12]3[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([CH2:22]Cl)=[CH:14][N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CN(C)C=O.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]12([NH:11][C:12]3[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([CH2:22][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:14][N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: FC(F)(F)c1nc(NC23CC4CC(CC(C4)C2)C3)ncc1CCl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1nc(NC23CC4CC(CC(C4)C2)C3)ncc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of N-adamantan-1-yl-5-(chloromethyl)-4-(trifluoromethyl)pyrimidin-2-amine (170 mg) and N,N-dimethyl formamide (4 mL) were added morpholine (0.21 mL) and potassium carbonate (136 mg) under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain N-adamantan-1-yl-5-(morpholin-4-ylmethyl)-4-(trifluoromethyl)pyrimidin-2-amine (160 mg) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[H][H].[Cl:19][C:20]1[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=1>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(Cl)cc1
Reactant: [H][H]
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(OC2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C

Procedure:
A solution of 21.6 g of 1-benzyl-4-piperidinol in 75ml. of dimethylformamide is added slowly to a stirred suspension of 8.7 g of a 50% oil dispersion of sodium hydride in 225 ml. of dimethylformamide at 60°-70° C. After addition is complete stirring and heating are continued until no more hydrogen gas is liberated. A solution of 19.6 g of 1-chloro-4-fluorobenzene in 75 ml. of dimethylformamide is added, and the solution is permitted to stir at 65°-70° C. for 16 hours. After cooling to ambient temperature, the solution is poured into 600 ml. of water, the aqueous solution is extracted with benzene, the benzene extracts are dried, and the benzene is removed under reduced pressure, leaving a yellow oil of 1-benzyl-4-(p-chlorophenoxy)piperidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[C:10](Br)[CH3:11])=[CH:5][CH:4]=1.C([Li])CCC.Cl[P:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Cl-].[NH4+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[C:10]([P:27]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=C(C)Br)c2ccc(OC)cc2)cc1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(=C(C)P(c2ccccc2)c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: -65 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
Into a reactor were introduced 2.00 g (6.00 mmol) of the 1,1-bis(4-methoxyphenyl)-2-bromopropene and 30 mL of THF under a nitrogen atmosphere. The contents were cooled to −65° C., and 4.0 mL (6.0 mmol; 1.5 M hexane solution) of butyllithium was gradually added dropwise thereto. The resultant mixture was stirred for 30 minutes. Thereafter, 0.90 mL (5.0 mmol) of chlorodiphenylphosphine was added, and this mixture was stirred at that temperature for 1 hour and then at room temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture. The resultant mixture was extracted with ethyl acetate, and the extract was dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The concentrate was recrystallized from ethanol to obtain 1.45 g (66%) of the target compound as white crystals.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH:10]=[O:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[C:12]([O:18]CCl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].[C:21](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[O-2].[O-2].[Mn+4]>[CH2:1]([C:5]1[N:6]([O:18][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[C:7]([CH:10]=[O:11])=[C:8]([CH3:21])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(C=O)[nH]1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C([O-])[O-]
Agent: [Mn+4]
Agent: [K+]
Agent: [O-2]
Solvent: CN(C)C=O
Product: CCCCc1nc(C)c(C=O)n1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A suspension of 2-butylimidazol-5-aldehyde (16.92 g, 0.111 mmol, prepared by manganese dioxide oxidation of the alcohol, prepared in Example 1), chloromethyl pivalate (21.77 g, 0.145 mmol), and potassium carbonate (20.07 g, 0.145 mmol) in 200 ml of dimethylformamide was stirred at ambient temperature under argon for four days The solids were removed by filtration and washed with ether. The combined filtrates were partitioned between ether and water. The ether phase was washed successively with water and brine, dried over magnesium sulfate and concentrated under vacuum to give 23.6 g of 2-n-butyl-1-pivalyloxy-methylimidazole-5-aldehyde
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[CH:21]=3)[NH:16][CH:15]=2)=[N:12][N:13]=1.[CH2:29]([N:31](CC)CC)[CH3:30].CN(C1C=CC=CN=1)C.C1(S(Cl)(=O)=O)C=CC=CC=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:30][C:29]#[N:31])[C:9]1[O:10][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[CH:21]=3)[NH:16][CH:15]=2)=[N:12][N:13]=1
Reactant: CCN(CC)CC
Reactant: Cn1cc(-c2cnc3[nH]cc(-c4nnc(Nc5ccccc5Cl)o4)c3c2)cn1
Agent: CN(C)c1ccccn1
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: CN(C)C=O
Product: Cn1cc(-c2cnc3[nH]cc(-c4nnc(N(CC#N)c5ccccc5Cl)o4)c3c2)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.3 g of (2-chlorophenyl)-{5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]-pyridin-3-yl]-1,3,4-oxadiazol-2-yl}amine are dissolved in 15 ml of DMF at 60° C. When the solution has re-cooled to RT, 1.4 ml of triethylamine and 40 mg of dimethylaminopyridine are added. This solution is then cooled to 0° C., before 0.5 ml of benzenesulfonyl chloride is added dropwise. When the addition is complete, the batch is stirred at RT for a further 4 h. After undissolved constituents have been filtered off, the solution which remains is evaporated completely to dryness, and the residue is partitioned between ethyl acetate and water, with crystals precipitating out after a short time. The product is filtered off with suction and combined with the second crystal batch, giving 1.3 g of the title compound. HPLC-MS: Rt=2.567 min; [M+H+]: 532.1
Reaction SMILES: CN(C)[CH:3]=[O:4].N1C=CN=C1.[F:11][C:12]([F:48])([F:47])[C:13]1[CH:14]=[C:15]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:16][N:17]([CH3:39])[C:18](=[O:38])[C:19]1[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])=[CH:23][C:22]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[N:21][CH:20]=1>>[F:48][C:12]([F:47])([F:11])[C:13]1[CH:14]=[C:15]([CH:40]=[C:41]([C:43]([F:45])([F:46])[F:44])[CH:42]=1)[CH2:16][N:17]([CH3:39])[C:18](=[O:38])[C:19]1[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])=[CH:23][C:22]([N:32]2[CH2:33][CH2:34][N:35]([CH:3]=[O:4])[CH2:36][CH2:37]2)=[N:21][CH:20]=1
Reactant: CN(C)C=O
Reactant: Cc1ccccc1-c1cc(N2CCNCC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: c1c[nH]cn1
Product: Cc1ccccc1-c1cc(N2CCN(C=O)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C

Procedure:
To a mixture of 0.089 ml (1.1 mmol) N,N-dimethylformamide and 38 mg (0.56 mmol) imidazole 0.071 ml (0.56 mmol) trimethylchlorosilane were added dropwise at room temperature. The reaction mixture was cooled to 0° C., and 0.10 g (0.19 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-piperazin-1-yl-4-o-tolyl-nicotinamide (Example 53) were added. The ice-water bath was removed and the mixture stirred over night. The reaction was quenched with a mixture of 2 ml 1 N aqueous hydrochloric acid solution and 4 ml water, and the mixture was extracted with ethyl acetate. The combined extracts were dried with sodium sulfate and concentrated. Flash column chromatography afforded 81 mg (82%) of the, title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](B(O)O)[C:5]([Cl:11])=[CH:4][N:3]=1.Br[C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][N:14]=1>O1CCOCC1.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:1][C:2]1[CH:7]=[C:6]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][N:14]=2)[C:5]([Cl:11])=[CH:4][N:3]=1
Reactant: Cc1cnc(Br)c(C)c1
Reactant: OB(O)c1cc(Cl)ncc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1cnc(-c2cc(Cl)ncc2Cl)c(C)c1
Temperature: 25 °C
Yield: 26.3 %

Procedure:
A mixture of 2,5-dichloropyridin-4-ylboronic acid (75.6 g, 0.4 mol), 2-bromo-3,5-dimethylpyridine (56.2 g, 0.3 mol), Pd(dppf)Cl2 (13.5 g, 17 mmol) and K3PO4.3H2O (162 g, 0.6 mol) in dioxane (600 mL) and H2O (120 mL) was stirred at reflux under N2 atmosphere overnight. TLC (petroleum ether/EtOAc=10:1) showed that the reaction was complete. After cooling to room temperature, the mixture was filtered. Water (500 mL) was then added to the filtrate. The mixture was extracted with dichloromethane (500 mL×3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum ether/EtOAc=50:1 to 30:1) to give title compound (20 g, 26%) as a yellow solid. 1H NMR (400 MHz, MeOD): δ 8.54 (s, 1H), 8.31 (s, 1H), 7.68 (s, 1H), 7.50 (s, 1H), 2.41 (s, 3H), 2.15 (s, 3H); m/z for C12H10Cl2N2 253.1 (M+H)+.
Reaction SMILES: O=[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]#[N:13])[CH:8]=2)[NH:3]1.O=P(Cl)(Cl)[Cl:16]>CN(C=O)C.C(Cl)Cl>[Cl:16][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]#[N:13])[CH:8]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1ccc2[nH]c(=O)cnc2c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1ccc2nc(Cl)cnc2c1
Temperature: 100 °C

Procedure:
2-Oxo-1,2-dihydroquinoxaline-6-carbonitrile was suspended in POCl3 (25 mL) and DMF (10 drops) was added. The mixture was heated at 100° C. for 2 h, cooled and concentrated under reduced pressure to leave a black residue. The residue was dissolved in CH2Cl2 (200 mL), washed with satd aq NaHCO3 (25 mL) and brine (25 mL) and dried over Na2SO4. Removal of the solvent left an off white solid (4.50 g). A 0.50-g portion was purified by chromatography on a 40-g silica gel cartridge eluted with a 0-50% EtOAc in hexanes gradient to afford 2-chloroquinoxaline-6-carbonitrile (118 mg). LC-MS Method 1 tR=1.42 min, m/z=190.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[CH2:5][NH:6][CH2:7][CH2:8][OH:9].O1C[C@@H]1[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].[C:29]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:30]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[CH2:5][N:6]1[CH2:30][CH2:29][O:9][C@@H:8]([CH2:17][N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:28])[CH2:7]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: OCCNCc1ccc(Cl)c(Cl)c1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Temperature: 105 °C
Yield: 71.5 %

Procedure:
A mixture of 2-[(3,4-dichlorobenzyl)amino]ethanol (400 g) and (S)-2-(oxiran-2-ylmethyl)-1H-isoindole-1,3(2H)-dione (399.6 g) in toluene (1150 ml) was stirred and heated at 103-107° C. under nitrogen. After 22.5 h the mixture was cooled to <60° C. and charged with tetrahydrofuran (2800 ml). Triphenyl phosphine (548 g) was added and the mixture was stirred until all the solid had dissolved, then cooled to 5-9° C. Diisopropylazodicarboxylate (412 ml) was then added over 70 min maintaining the temperature at <12°. The mixture was warmed to 21-25° and stirred for 1.5 h. The reaction mixture was concentrated by distillation to a final volume of 2800 ml. Methanol (2800 ml) was added and the concentration repeated to a volume of 2800 ml. More methanol (2000 ml) was added and the mixture was heated to 55°. After 0.75 h the slurry was cooled to 18° and then after a further 1 h the product was collected. The bed was washed with methanol (2×1200 ml) and then dried in vacuo at 40° to give the title compound (526.9 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](SC)=[C:6]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])[N:11]=[C:10]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][CH3:31])=[O:29])=[CH:23][CH:22]=3)[N:9]=2)[CH:7]=1.[S:34]([O-:39])(O[O-])(=O)=[O:35].[K+].[K+].OOS([O-])=O.[K+].[CH2:48]1COCC1.CO.O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:34]([CH3:48])(=[O:39])=[O:35])=[C:6]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])[N:11]=[C:10]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][CH3:31])=[O:29])=[CH:23][CH:22]=3)[N:9]=2)[CH:7]=1
Reactant: O=S(=O)([O-])O[O-]
Reactant: C1CCOC1
Reactant: CNC(=O)Nc1ccc(-c2nc(-c3cc(F)ccc3SC)nc(N3CCOC[C@@H]3C)n2)cc1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: CNC(=O)Nc1ccc(-c2nc(-c3cc(F)ccc3S(C)(=O)=O)nc(N3CCOC[C@@H]3C)n2)cc1
Yield: 46 %

Procedure:
(S)-1-(4-(4-(5-fluoro-2-(methylthio)phenyl)-6-(3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-methylurea (258 mg, 0.55 mmol) was stirred with Potassium peroxymonosulfate (Oxone) (1.01 g, 1.65 mmol) in THF:MeOH:H2O (5:3:2)(10 ml) for 1 hour at 0° C. Reaction allowed to reach room temperature and stirred overnight with more oxone (1.01 g, 1.65 mmol). The mixture is quenched with saturated sodium thiosulfate solution (10 ml). Diluted with DCM (50 mL) and washed with brine (50 mL). The organic layer was passed through a hydrophobic frit and concentrated in vacuo. The resulting solid was purified by prep HPLC at to afford the title compound as a yellow solid. (127 mg, Yield 46%)
Reaction SMILES: [NH2:1][C:2]1[C:19]([NH:20][CH:21]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C(N(C(C)C)C(C)C)C.[C:47](Cl)(Cl)=[O:48]>ClCCl.C1(C)C=CC=CC=1>[CH3:37][O:36][C:33]1[CH:32]=[CH:31][C:30]([CH:21]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[N:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:3]([O:4][C:5]4[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:6]=4[C:7]([O:9][CH3:10])=[O:8])[C:2]=3[NH:1][C:47]2=[O:48])=[CH:35][CH:34]=1
Reactant: O=C(Cl)Cl
Reactant: COC(=O)c1ccc(F)cc1Oc1cccc(NC(c2ccc(OC)cc2)c2ccc(OC)cc2)c1N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(F)cc1Oc1cccc2c1[nH]c(=O)n2C(c1ccc(OC)cc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 368C (0.58 g) and N-ethyl-N-isopropylpropan-2-amine (0.804 ml) in dichloromethane (8 mL) was cooled with an ice bath. Then, a 20 wt % solution of phosgene in toluene (0.850 mil) was added dropwise. The mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and washed with 5% aq. NaHCO3. The material was then absorbed on silica and purified on a silica gel column eluting with 50% ethyl acetate in hexane to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([Cl:13])=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:14](=[O:25])/[CH:15]=[CH:16]/[C:17]1[S:21][C:20]([CH:22]([CH3:24])[CH3:23])=[N:19][CH:18]=1.CC#N.OP(O)(O)=O>[Cl-].[Cl-].[Zn+2].CC(O)=O>[Cl:13][C:7]1[C:6]2[C:2]3[NH:1][CH:16]([C:17]4[S:21][C:20]([CH:22]([CH3:23])[CH3:24])=[N:19][CH:18]=4)[CH2:15][C:14](=[O:25])[C:3]=3[O:4][C:5]=2[CH:10]=[CH:9][C:8]=1[O:11][CH3:12]
Reactant: COc1ccc2oc(C(=O)/C=C/c3cnc(C(C)C)s3)c(N)c2c1Cl
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1ccc2oc3c(c2c1Cl)NC(c1cnc(C(C)C)s1)CC3=O
Temperature: 25 °C
Yield: 68.6 %

Procedure:
9A (3.5 g, 9.28 mmol) was added to MeCN (50 mL) and stirred at room temperature. To the mixture was added ZnCl2 (1.91 g, 13.93 mmol, 1.5 eq), followed by AcOH (50 mL) and H3PO4 (50 mL) The reaction mixture was heated to 80° C. and stirred overnight. After reaction completed, the mixture was cooled and poured into crushed ice under stirring, neutralized to pH=7˜8, extracted with ethyl acetate, dried and concentrated to give 2.4 g of product (9B).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].S(Cl)(Cl)=O.[S-:15][C:16]#[N:17].[NH4+].[CH3:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1>CC(C)=O.CN(C=O)C>[CH3:19][N:20]([C:16]1[S:15][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:5])[N:17]=1)[C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: CNc1ccc(OC(F)(F)F)cc1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CN(c1ccc(OC(F)(F)F)cc1)c1nc(=O)c2cccnc2s1
Yield: 80.6 %

Procedure:
The reaction procedure of Example 57 was followed except that 824 mg (5.23 mmol) of 2-chloronicotinoyl chloride, 10 ml of thionyl chloride, two droplets off DMF, 400 mg of ammonium thiocyanate, 10 ml of acetone, 1.0 g of N-methyl-4-trifluoromethoxyaniline and 10 ml of acetone were used. The resulting crude product was then recrystallized from ethanol to obtain 1.49 g of 2-[N-methyl-N-(4-trifluoromethoxylphenyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[C:12]1[S:13][C:14]([CH:17](OCC)[O:18]CC)=[CH:15][CH:16]=1.FC(F)(F)C(O)=O.O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[C:12]1[S:13][C:14]([CH:17]=[O:18])=[CH:15][CH:16]=1
Reactant: CCOC(OCC)c1ccc(-c2ncnc3ccc(Br)cc23)s1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1ccc(-c2ncnc3ccc(Br)cc23)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
2.6 g of 6-bromo-4-(5-diethoxymethylthiophen-2-yl)quinazoline (compound in Production Example 380) was dissolved in 10 mL dichloromethane, then 5 mL trifluoroacetic acid was added thereto, and the mixture was stirred at room temperature for 3 hours, neutralized by adding water and a sodium bicarbonate solution, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated, whereby 2.07 g of the title compound was obtained as pale yellow crystals.
Reaction SMILES: [C:1]([NH:4][N:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]>CN(C=O)C>[C:1]([N:4]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[N:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NN=Cc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCN(N=Cc1ccc(OCc2ccccc2)cc1)C(C)=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A solution of 5×10-3 moles of 4-(benzyloxy)benzaldehyde acetylhydrazone (1.34 g) in 5 ml of anhydrous DMF is added to 5×10-3 moles of sodium hydride (0.12 g) in suspension in 10 ml of anhydrous DMF. The reaction mixture is heated slowly on a water bath at 80° C. for 30 minutes. After cooling, a solution containing 0.85 g (5.1×10-3 moles) of methyl 3-bromopropionate in 5 ml of DMF is slowly added to the mixture. The latter is stirred for one hour at room temperature, then it is poured into 100 ml of ice-cold water. A product precipitates. After standing for 30 minutes, it is filtered, subjected to draining, at the end of which it is chromatographed on a MACHEREY-NAGEL silica gel 60 (0.04-0.063 ml) using a mixture of ethyl acetate and dichloromethane (1/9) as eluent. The oil obtained precipitates. The compound (I-a5) is slowly recrystallized from ether. Its melting point is 170° C. The reaction yield is 11%.