Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13][C:14]1[CH:19]=[C:18]([C:20]2[NH:29][C:28](=[O:30])[C:27]3[C:22](=[CH:23][C:24](F)=[CH:25][C:26]=3[O:31][CH3:32])[N:21]=2)[CH:17]=[C:16]([CH3:34])[N:15]=1.O>CS(C)=O>[CH3:13][C:14]1[CH:19]=[C:18]([C:20]2[NH:29][C:28](=[O:30])[C:27]3[C:22](=[CH:23][C:24]([O:10][CH2:9][CH2:8][O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:25][C:26]=3[O:31][CH3:32])[N:21]=2)[CH:17]=[C:16]([CH3:34])[N:15]=1
Reactant: COc1cc(F)cc2nc(-c3cc(C)nc(C)c3)[nH]c(=O)c12
Reactant: OCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(OCCOc2ccccc2)cc2nc(-c3cc(C)nc(C)c3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-phenoxy-ethanol (0.90 g, 6.50 mmol) in DMSO (5 mL) was added sodium hydride (60% in mineral oil, 0.16 g, 4.00 mmol) in small portions. The reaction mixture was stirred at room temperature under nitrogen for 1 hour. 2-(2,6-Dimethyl-pyridin-4-yl)-7-fluoro-5-methoxy-3H-quinazolin-4-one (0.20 g, 0.67 mmol) was added and stirring continued at 90° C. for 17 hours. The reaction was then cooled to room temperature, water (100 mL) was added, and was extracted with ethyl acetate (200 mL). The organic phase was washed with brine and dried over anhydrous Na2SO4. Solvent was removed and the crude compound was purified by column chromatography (silica gel 230-400 mesh; 5% methanol in CH2Cl2 as eluent) to give the title compound as a white solid. Yield: 70 mg (25%). MP 223-224° C. 1H NMR (400 MHz, CDCl3): δ 11.35 (s, 1H), 7.75 (s, 2H), 7.32 (t, J=8.0 Hz, 2H), 7.02-6.97 (m, 3H), 6.91 (d, J=2.0 Hz, 1H), 6.60 (d, J=1.6 Hz, 1H), 4.49-4.47 (m, 2H), 4.41-4.39 (m, 2H), 3.97 (s, 3H), 2.67 (s, 6H). MS (ES+) m/z: 418.08 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)(=[O:3])[CH3:2].[C:14]([O:17][C:18](=O)[CH3:19])(=O)C.[C:21](OC)(OC)([O:23]C)[CH3:22]>C(Cl)Cl.CO>[C:21]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:12][CH:11]=2)[C:7](=[C:18]([O:17][CH3:14])[CH3:19])[C:8]1=[O:13])(=[O:23])[CH3:22]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2
Reactant: COC(C)(OC)OC
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CO
Product: COC(C)=C1C(=O)N(C(C)=O)c2ccc(C(C)=O)cc21

Procedure:
Prepared from 5-acetyl-2-indolinone, acetic anhydride and trimethyl orthoacetate Rf=0.40 (silica gel, methylene chloride/methanol 50:1)
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:13][NH2:14]>C(O)C>[CH3:13][NH:14][CH2:2][C:3]1[CH:12]=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CN
Reactant: BrCc1cnc2ccccc2n1
Solvent: CCO
Product: CNCc1cnc2ccccc2n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
The 2-(bromomethyl)quinoxaline (3.0 g, 13.4 mmol) was added portionwise to a stirring solution of methylamine (30%) in ethanol (100 mL) at 0° C. The reaction was stirred at 0° C. for 2 hours, concentrated, and partitioned between 10% aqueous potassium carbonate/ethyl acetate. The organic phase was dried (MgSO4), decolorized (charcoal) and concentrated. Purification was accomplished by eluting the sample through a short silica plug to yield 1.80 g (78%) of a brown oil.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])(=O)=O.[Cl:17]C1C=C2C(=CC=1)NC=C2C(C)(C)CN.[NH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([CH2:41][C:42]([NH2:45])([CH3:44])[CH3:43])=[CH:33]1>>[ClH:17].[NH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([CH2:41][C:42]([NH:45][CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])([CH3:43])[CH3:44])=[CH:33]1
Reactant: COc1ccccc1OCCOS(C)(=O)=O
Reactant: CC(C)(CN)c1c[nH]c2ccc(Cl)cc12
Reactant: CC(C)(N)Cc1c[nH]c2ccccc12
Product: COc1ccccc1OCCNC(C)(C)Cc1c[nH]c2ccccc12
Product: Cl

Procedure:
Proceeding as in Example 3, but replacing 2-[2-(cyclopropylmethyloxy)phenoxy]ethyl methanesulfonate with 2-(2-methyloxyphenoxy)ethyl methanesulfonate and [1-(5-chloro-1H-indol-3-yl)-1,1-dimethylethyl]amine with [2-(1H-indol-3-yl)-1,1-dimethylethyl]amine, gave [2-(1H-indol-3-yl)-1,1-dimethylethyl][2- (2-methyloxyphenoxy)ethyl]amine hydrochloride, m.p. 156°-158° C.
Reaction SMILES: [CH2:1]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][C@@H:21]([CH2:33][N:34]([CH3:36])[CH3:35])[CH2:22][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])(=[O:19])=[O:18])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:37][I:38]>>[I-:38].[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C@@H:21]([NH:20][S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:12][CH:13]=1)(=[O:19])=[O:18])[CH2:33][N+:34]([CH3:37])([CH3:36])[CH3:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCCCCCCCCCc1ccc(S(=O)(=O)N[C@H](CC(=O)OCc2ccccc2)CN(C)C)cc1
Reactant: CI
Product: CCCCCCCCCCc1ccc(S(=O)(=O)N[C@H](CC(=O)OCc2ccccc2)C[N+](C)(C)C)cc1
Product: [I-]

Procedure:
According to the method described in example S75b, (R)-benzyl 3-(4-decylphenylsulfonamido)-4-(dimethylamino)butanoate was reacted with methyl iodide to give the title compound as a white solid (quantitative). MS ESI 531.4 [M+H]+, calcd for [C30H46N2O4S+H]+ 531.3
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][S:7][CH2:6][CH2:5][NH:4][C:3]1=[O:9].Cl[C:11](OC1C=CC([N+]([O-])=O)=CC=1)=[O:12].C(N(C(C)C)CC)(C)C.[Cl:32][C:33]1[CH:42]=[C:41]2[C:36]([C:37]([N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[CH:38][C:39]([NH2:43])=[N:40]2)=[CH:35][CH:34]=1>>[NH2:43][C:39]1[CH:38]=[C:37]([N:44]2[CH2:49][CH2:48][N:47]([C:11]([NH:1][C@H:2]3[CH2:8][S:7][CH2:6][CH2:5][NH:4][C:3]3=[O:9])=[O:12])[CH2:46][CH2:45]2)[C:36]2[C:41](=[CH:42][C:33]([Cl:32])=[CH:34][CH:35]=2)[N:40]=1
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: N[C@@H]1CSCCNC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(N2CCN(C(=O)N[C@H]3CSCCNC3=O)CC2)c2ccc(Cl)cc2n1

Procedure:
As described for example 78, (6S)-6-aminotetrahydro-1,4-thiazepin-5(2H)-one, p-nitrophenyl chloroformate, diisopropylethyl amine, and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product. LC-MS: 434 (M++1). 1H NMR (CDCl3) δ 2.55–2.95 (m, 4), 3.0–3.25 (m, 4H), 3.6–3.9 (m, 6H), 4.8–5.0 (m, 3H), 6.1–6.2 (s, 1H), 6.2–6.4 (m, 2H), 7.1–7.24 (m, 1H), 7.6 (s, 1H), 7.7–7.8 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[F:13][C:14]1[CH:23]=[CH:22][C:17]([CH2:18][NH:19][O:20][CH3:21])=[CH:16][C:15]=1[CH3:24]>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:19]([CH2:18][C:17]2[CH:22]=[CH:23][C:14]([F:13])=[C:15]([CH3:24])[CH:16]=2)[O:20][CH3:21])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CONCc1ccc(F)c(C)c1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CON(Cc1ccc(F)c(C)c1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 95 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(4-fluoro-3-methyl-benzyl)-O-methyl-hydroxylamine as described in the preparation of compound 1-A gave the title amide as white crystals (95% yield): mp 107-108° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 (6H, s, CH3), 2.26 (3H, broad s, CH3), 3.69 (3H, s, OCH3), 4.75 (2H, s, NCH2), 6.39 (1H, s, CH), 6.95 (1H, m, aromatic), 7.13-7.19 (2H, m, aromatics). Anal. calcd for C16H18FNO5: C, 59.43; H, 5.61; N, 4.33. Found: C, 59.24; H, 5.47; N 4.29.
Reaction SMILES: F[C@@H:2]1[CH2:6][N:5]([C:7](OC(C)(C)C)=O)[C@H:4]([C:14](=[O:24])[NH:15][C@@H:16]2[C@@H:23]3[C@@H:19]([CH2:20][NH:21][CH2:22]3)[CH2:18][CH2:17]2)[CH2:3]1.Cl[C:26]1[N:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1.Br[C:37]1C=C(C(F)(F)F)C=CN=1>>[CH3:7][NH:5][C@H:4]([C:14]([NH:15][C@@H:16]1[C@@H:23]2[C@@H:19]([CH2:20][N:21]([C:26]3[N:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=3)[CH2:22]2)[CH2:18][CH2:17]1)=[O:24])[CH2:3][CH:2]([CH3:6])[CH3:37]
Reactant: FC(F)(F)c1ccnc(Br)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21
Reactant: FC(F)(F)c1ccc(Cl)nn1
Product: CN[C@@H](CC(C)C)C(=O)N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)nn3)C[C@@H]21

Procedure:
The title compound was prepared by substituting tert-butyl methyl((S)-4-methyl-1-((3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-ylamino)-1-oxopentan-2-yl)carbamate from Example 619 Step 1 for (2S,4S)-tert-butyl 4-fluoro-2-((3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-ylcarbamoyl)pyrrolidine-1-carboxylate and 3-chloro-6-(trifluoromethyl)pyridazine for 2-bromo-4-(trifluoromethyl)pyridine in the procedure described in Example 637: 1H NMR (400 MHz, pyridine-d5) δ ppm 7.76 (s, 1H), 7.46 (d, J=9.4, 1H), 6.66 (d, J=9.4, 1H), 4.34-4.25 (m, 1H), 3.82 (d, J=3.9, 2H), 3.75-3.64 (m, 2H), 3.44 (dd, J=11.3, 4.7, 1H), 3.16 (dd, J=7.9, 5.8, 1H), 2.88-2.68 (m, 2H), 2.40 (s, 3H), 2.20-2.09 (m, 1H), 1.98 (dtd, J=13.1, 8.0, 5.0, 1H), 1.91-1.80 (m, 1H), 1.74-1.62 (m, 2H), 1.48 (dddd, J=15.8, 13.4, 7.9, 6.0, 2H), 0.94 (d, J=6.6, 3H), 0.90 (d, J=6.6, 3H); MS (ESI+) m/z 400 (M+H)+.
Reaction SMILES: O.NN.[C:4]([C:8]1[CH:35]=[CH:34][C:11]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=4)=[CH:19][CH:20]=3)[C:15]([C:29](=O)[C:30]([OH:32])=[O:31])=[CH:14]2)=[CH:10][CH:9]=1)([CH3:7])([CH3:6])[CH3:5].C[O-].[Na+]>COCCO>[C:4]([C:8]1[CH:35]=[CH:34][C:11]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=4)=[CH:19][CH:20]=3)[C:15]([CH2:29][C:30]([OH:32])=[O:31])=[CH:14]2)=[CH:10][CH:9]=1)([CH3:7])([CH3:5])[CH3:6]
Reactant: Cc1cccc(-c2ccc3c(c2)c(C(=O)C(=O)O)cn3Cc2ccc(C(C)(C)C)cc2)c1
Agent: C[O-]
Agent: NN
Agent: [Na+]
Solvent: COCCO
Solvent: O
Product: Cc1cccc(-c2ccc3c(c2)c(CC(=O)O)cn3Cc2ccc(C(C)(C)C)cc2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 46.7 %

Procedure:
Hydrazine monohydrate (0.56 mL, 11.75 mmol) was added to a stirring solution of 2-[1-[4-(tert-Butyl)benzyl]-5-(3-methylphenyl)-1H-indol-3-yl]-2-oxoacetic acid (WAY-201417, 1.0 g, 2.35 mmol) in 2-methoxyethanol (10 mL). After the mixture was heated to 60° C. Sodium methoxide (1.34 g, 23.5 mmol) was added portionwise to the mixture. The reaction mixture was then slowly heated to 150° C., and concentrated. The mixture was kept stirring at 150° C. for 1 hour. The reaction mixture was cooled and poured onto ice water (100 mL). The aquoues mixture was extracted with methylene chloride and acidified with concentrated hydrocloric acid at 0° C. The organic extracts were washed with water and brine. Evaporation of the solvent and purification by flash column chromatography (5% methanol in methylene chloride) afforded an orange solid (0.452 g), m.p. 91-92° C. Mass spectrum [+ESI, (M+H)+] m/z 412. 1H NMR (400 MHz, DMSO-d6) δ 12.00 (br s, 1H), 7.75 (s, 1H), 7.51 (d, 1H, J=8.55 Hz), 7.45 (s, 1H), 7.42-7.37 (m, 3H), 7.32-7.29 (m, 3H), 7.15 (d, 2H, J=8.25 Hz), 7.19 (d, 1H, J=7.48 Hz), 5.34 (s, 2H), 3.70 (s, 2H), 2.37 (s, 3H), and 1.22 ppm (s, 9H). Elemental Analysis for C28H27NO3 0.1 H2O Calculated: C, 81.36; H, 7.12; N, 3.39. Found: C, 81.15; H, 6.76; N, 3.52.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]1([CH3:19])[O:18][C:16](=[O:17])[CH2:15][C:13](=[O:14])[O:12]1.N1CCCC1C(O)=O.[CH3:28][S:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:39]=1[NH:38][CH:37]=[CH:36]2>C(#N)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([C:36]2[C:35]3[C:39](=[C:31]([CH2:30][S:29][CH3:28])[CH:32]=[CH:33][CH:34]=3)[NH:38][CH:37]=2)[CH:15]2[C:16](=[O:17])[O:18][C:11]([CH3:19])([CH3:10])[O:12][C:13]2=[O:14])=[CH:4][CH:3]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CSCc1cccc2cc[nH]c12
Agent: O=C(O)C1CCCN1
Solvent: CC#N
Product: CSCc1cccc2c(C(c3ccc(Cl)cc3)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
350 mg (2.49 mmol) of 4-chlorobenzaldehyde, 359 mg (2.49 mmol) of Meldrum's acid and 13.6 mg (0.12 mmol) of D,L-proline were added to a solution of 420 mg (2.40 mmol) of the compound from Example 8A in 20 ml of acetonitrile. The reaction mixture was stirred at RT overnight. It was concentrated, and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 650 mg (62% of theory) of the title compound.
Reaction SMILES: CS(O)(=O)=O.[Cl:6][C:7]1[C:20]([Cl:21])=[CH:19][C:10]2[N:11]([CH2:15][CH2:16][CH2:17]O)[C:12](=[O:14])[NH:13][C:9]=2[CH:8]=1.[C:22]1([N:28]2[C:32]3([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[C:31](=[O:38])[NH:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[Cl:6][C:7]1[C:20]([Cl:21])=[CH:19][C:10]2[N:11]([CH2:15][CH2:16][CH2:17][N:35]3[CH2:34][CH2:33][C:32]4([N:28]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:29][NH:30][C:31]4=[O:38])[CH2:37][CH2:36]3)[C:12](=[O:14])[NH:13][C:9]=2[CH:8]=1
Reactant: O=c1[nH]c2cc(Cl)c(Cl)cc2n1CCCO
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Agent: CS(=O)(=O)O
Solvent: CN(C)C=O
Product: O=C1NCN(c2ccccc2)C12CCN(CCCn1c(=O)[nH]c3cc(Cl)c(Cl)cc31)CC2
Temperature: 60 °C

Procedure:
A mixture of 8 parts of 5,6-dichloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate, 9.2 parts of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one and 90 parts of N,N-dimethylformamide is stirred and heated at 60° C for one hour. The reaction mixture is evaporated and water is added to the residue. The whole is alkalized with ammonium hydroxide and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The solid residue is triturated in 4-methyl-2-pentanone. The product is filtered off and dried, yielding 2 parts of 8-[3-(5,6-dichloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one; mp. 275.2° C.
Reaction SMILES: N[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].N([O-])=[O:11].[Na+]>OS(O)(=O)=O.O>[OH:11][C@H:2]([CH2:3][CH2:4][S:5][CH3:6])[C:7]([OH:9])=[O:8]
Reactant: CSCC[C@@H](N)C(=O)O
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CSCC[C@@H](O)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 10 %

Procedure:
D-Methionine (100 g, 0.67 mol) was dissolved in 600 ml of 10% H2SO4 and cooled to 0°-5° C. A solution of NaNO2 (58 g, 0.84 mol) in 100 ml of H2O, also chilled to 0°-5° C., was added dropwise over 1.5 hours, maintaining the temperature of the reaction mixture at 0° C. or less by means of an ice water bath. After stirring for 18 hours at room temperature, the mixture was extracted 9×200 ml ethyl acetate. The organic extracts were combined, dried over MgSO4, and stripped to yield 10.1 g of title product as oil; tlc Rf 0.15 (ethyl acetate), 0.08 (1:1 hexane:ethyl acetate).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][C:17]([N:19]([CH2:28][CH:29](OC)[O:30]C)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[O:18])=[N:13][C:12]=1[CH3:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.FC(F)(F)C(O)=O>O1CCCC1>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:29]([OH:30])[CH2:28][N:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:17]2=[O:18])=[N:13][C:12]=1[CH3:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(CN(Cc1ccc(F)cc1)C(=O)Nc1nc(C)c(C(=O)NCc2ccccc2)s1)OC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)CC2O)sc1C(=O)NCc1ccccc1
Yield: 76 %

Procedure:
To a solution of N-benzyl-2-(3-(2,2-dimethoxyethyl)-3-(4-fluorobenzyl)ureido)-4-methylthiazole-5-carboxamide (0.47 g, 0.96 mmol) in tetrahydrofuran (10 mL) was added water (5 mL) and trifluoroacetic acid (5 mL) at ambient temperature. The resulting reaction mixture was heated to reflux for 5 hours. The solvent was removed in vacuo and the residue was purified by column chromatography to afford the title compound in 76% yield (0.32 g): mp 133-134° C.: 1H NMR (300 MHz, CDCl3) δ 7.35-6.97 (m, 9H), 6.10 (t, J=5.7 Hz, 1H), 5.99 (d, J=5.9 Hz, 1H), 5.03 (s, 1H), 4.53 (d, J=5.7 Hz, 2H), 4.41 (s, 2H), 3.60-3.54 (m, 1H), 3.27-3.23 (m, 1H), 2.52 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.4, 162.1, 160.8, 157.0, 153.5, 152.4, 137.9, 131.1, 129.9, 128.7, 127.8, 117.9, 115.9, 115.7, 49.3, 46.6, 44.0, 17.0; MS (ES+) m/z 441.3 (M+1).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[O:15][CH2:14][N:13]([C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12](=[O:24])[CH:11]=1>C(O)(=O)C>[I:1][C:11]1[C:12](=[O:24])[N:13]([C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14][O:15][C:10]=1[CH3:9]
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)C(C)(C)N1COC(C)=CC1=O
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(C)N1COC(C)=C(I)C1=O
Temperature: 42.5 °C
Reaction time: 5 h
Yield: 21.5 %

Procedure:
N-Iodosuccinimide (238 g) was added to a stirred solution of ethyl 2-(2,3-dihydro-6-methyl-4-oxo-4H-1,3-oxazin-3-yl)-2-methylpropanoate (200 g) in acetic acid. The mixture was stirred at 40-45° C. for 5 hours then at ambient temperature overnight and evaporated. The residue was diluted with ether, washed with water, sodium carbonate solution (2M) and brine, dried (MgSO4) and evaporated. A solution of the residue in ethanol was cooled to -40° C. to give ethyl 2-(2,3-dihydro-5-iodo-6-methyl-4-oxo-4H-1,3-oxazin-3-yl)-2-methylpropanoate (66.9 g), m.p. 85-87° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][CH:3]=1.[Br:10]N1C(=O)CCC1=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][Br:10])[N:7]=1
Reactant: OCc1cccc(Br)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: BrCc1cccc(Br)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of (6-bromopyridin-2-yl)methanol (25 g, 133 mmol) in dichloromethane (200 ml) was charged with triphenylphosphene (41.8 g, 160 mmol). The reaction was cooled to 0° C. and N-bromosuccinimide (26 g, 146 mmol) was added over one minute. After 1 hour, the reaction was concentrated in vacuo and directly purified via silica gel chromatography to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Br.Br[CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15].C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCN(CC)CCBr
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCN(CC)CCNc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-Chloro-aniline (0.5 g, 3.9 mmol) was added to a solution of 2-bromo-N,N-diethylethylamine hydrobromide (1.12 g, 4.3 mmol) and N,N-diisopropylethylamine (2 mL, 11.7 mmol) in toluene (7.8 mL). The mixture was stirred at room temperature for 5 hours. The mixture was then diluted with EtOAc (30 mL) and saturated NaHCO3 (20 mL). The organic layer was washed with H2O (1×20 mL), dried (Na2SO4), filtered and concentrated to give 4-chloro-N-(2-(diethylamino)ethyl)benzenamine as an oil which was used without purification. MS (APCI+) [M+H]+ 227.3.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:11][C@H:12]([CH3:15])[CH2:13]I)[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[CH2:18]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21]>CC#N>[CH2:18]([CH:22]1[CH2:27][CH2:26][N:25]([CH2:13][C@@H:12]([CH3:15])[CH2:11][N:6]2[C:5]3[CH:16]=[CH:17][C:2]([F:1])=[CH:3][C:4]=3[O:9][CH2:8][C:7]2=[O:10])[CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21]
Reactant: C[C@H](CI)CN1C(=O)COc2cc(F)ccc21
Reactant: CCCCC1CCNCC1
Solvent: CC#N
Product: CCCCC1CCN(C[C@@H](C)CN2C(=O)COc3cc(F)ccc32)CC1
Yield: 63.7 %

Procedure:
A microwave vial was charged with (S)-7-fluoro-4-(3-Iodo-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one (111MF20) (0.274 g, 0.78 mmol) and 4-butylpiperidine (0.226 g, 1.60 mmol) in MeCN (4 mL) and sealed. After microwave irradiation, 100° C., 60 min, the reaction mixture was purified by cation exchange CC followed by flash CC (SiO2; CH2Cl2/MeOH 50:1) to give the title compound (112KK04) (0.180 g, 63%). 1H NMR (CD3OD) d 7.24-7.21 (m, 1H), 6.81-6.76 (m, 2H), 4.60 (ABq, J=17.4 Hz, J=15.1 Hz, CH2), 3.98 (dd, J=14.3 Hz, J=5.9 Hz, 1H), 3.87 (dd, J=14.3 Hz, J=7.6 Hz, 1H), 2.86 (d, J=11.0 Hz, 1H), 2.73 (d, J=9.8 Hz, 1H), 2.28-2.23 (m, 1H), 2.16-2.08 (m, 2H), 1.93-1.81 (m, 2H), 1.79-1.62 (m 2H), 1.32-1.13 (m, 9H), 0.93-0.88 (m, 2 CH3); 13C NMR (CD3OD) d 166.1, 160.3 (d, J=242.3 Hz), 148.1 (d, J=11.9 Hz), 126.4 (d, J=2.9 Hz), 117.8 (d, J=9.4 Hz), 109.9 (d, J=22.9 Hz), 105.7 (d, J=26.1 Hz), 68.6, 65.1, 56.3, 55.4, 46.6, 37.5, 37.0, 33.6, 33.4, 30.1, 29.9, 24.0, 17.2, 14.4.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]2([C:31]([F:34])([F:33])[F:32])[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([C:27]([F:30])([F:29])[F:28])[CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:70][N:71]1[CH2:76][CH2:75][CH2:74][N:73]([CH2:77][C:78]([F:81])([F:80])[F:79])[C:72]1=[O:82]>O.CN(C)C=O>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([C:13]2([C:31]([F:32])([F:33])[F:34])[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:70][N:71]4[CH2:76][CH2:75][CH2:74][N:73]([CH2:77][C:78]([F:79])([F:81])[F:80])[C:72]4=[O:82])=[O:23])=[C:20]([C:27]([F:28])([F:29])[F:30])[CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: NN1CCCN(CC(F)(F)F)C1=O
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NN1CCCN(CC(F)(F)F)C1=O)c1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 25-mL round-bottom flask, was placed 4-[5-[3,5-bis(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)benzoic acid (100 mg, 0.19 mmol, 1.00 equiv), N,N-dimethylformamide (5 mL), HATU (141 mg, 0.37 mmol, 2.00 equiv), DIEA (96 mg, 0.74 mmol, 4.00 equiv), 1-amino-3-(2,2,2-trifluoroethyl)-1,3-diazinan-2-one (40 mg, 0.20 mmol, 1.10 equiv). The resulting solution was stirred for 3 h at room temperature. The resulting solution was diluted with 20 mL of water. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×20 mL of brine. The mixture was dried over anhydrous sodium sulfate. The residue was purified by preparative TLC (EtOAc/ether=1:2). This resulted in 34.3 mg (26%) of 4-[5-[3,5-bis(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-N-[2-oxo-3-(2,2,2-trifluoroethyl)-1,3-diazinan-1-yl]-2-(trifluoromethyl)benzamide as a white solid; (ES, m/z): [M+H]+ 719.00, 1H NMR (300 MHz, DMSO): δ 10.72 (s, 1H), 8.37 (s, 1H), 8.23 (s, 2H), 8.16-8.14 (d, J=6 Hz, 1H), 8.08 (s, 1H), 7.74-7.72 (d, 1H), 4.70-4.49 (dd, J=21 Hz, J=45 Hz, 2H), 4.17-4.11 (q, J=9 Hz, 2H), 3.58-3.54 (t, J=6 Hz, 2H), 3.48-3.45 (t, J=5.1 Hz), 2.07-2.05 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[C:26]([CH3:27])=[C:25]([CH3:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[N:17]=1>>[N:19]1[CH:20]=[CH:21][N:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:12]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:13]2[C:26]([CH3:27])=[C:25]([CH3:28])[S:24][C:14]=2[N:15]=1
Reactant: Cc1sc2nc(-c3cnccn3)nc(Cl)c2c1C
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Cc1sc2nc(-c3cnccn3)nc(NCc3ccc(Cl)c(Cl)c3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyrazin-2-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-dichlorobenzylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.