Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10](=[O:15])[N:11]2[CH3:14])=[CH:6][N:5]=1)[CH3:2].N1C=CC=CC=1.C1([Se][Br:29])C=CC=CC=1>C(Cl)Cl>[Br:29][C:9]1[C:10](=[O:15])[N:11]([CH3:14])[C:12]2[C:7]([CH:8]=1)=[CH:6][N:5]=[C:4]([NH:3][CH2:1][CH3:2])[CH:13]=2
Reactant: CCNc1cc2c(ccc(=O)n2C)cn1
Reactant: Br[Se]c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCNc1cc2c(cn1)cc(Br)c(=O)n2C
Temperature: 39 °C

Procedure:
To a solution of 7-(ethylamino)-1-methyl-1,6-naphthyridin-2(1H)-one (20 mg, 0.1 mmol) and pyridine (27 μL, 0.3 mmol) in DCM (2 mL) was added phenylselenium bromide (72 mg, 0.3 mmol). The mixture was heated at 39° C. for 6 h, and then the solvent was removed under vacuum. The residue was chromatographed on silica gel (30% ethyl acetate in hexanes eluant) to provide the title compound. MS (m/z) 282.0 (M+1).
Reaction SMILES: C(O)C.[CH3:4][S:5]([C:7](SC)=[CH:8][N+:9]([O-:11])=[O:10])=O.Cl.[Cl:15][CH2:16][CH2:17][NH2:18]>C(N(CC)CC)C>[Cl:15][CH2:16][CH2:17][NH:18][C:7]([S:5][CH3:4])=[CH:8][N+:9]([O-:11])=[O:10]
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Reactant: NCCCl
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CSC(=C[N+](=O)[O-])NCCCl
Temperature: 25 °C
Yield: 57.6 %

Procedure:
With 10 ml of ethanol was mixed 1.6 g of 1-methylsulfinyl-1-methylthio-2-nitroethene, and 1.2 g of 2-chloroethylamine hydrochloride was then added thereto, after which 1.0 g of triethylamine was added dropwise at -20° C. in a nitrogen atmosphere. After they were subjected to reaction at the same temperature for 2 hours and then gradually heated to room temperature. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and 20 ml of ethyl acetate was added to the resulting residue, after which the resulting mixture was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure to obtain 1.0 g (yield 54.8%) of 1-(2-chloroethyl)amino-1-methylthio-2-nitroethene having a melting point of 115°-117° C.
Reaction SMILES: [CH:1]([N:4](CC)[CH:5](C)C)(C)C.[F:10][C:11]1[CH:24]=[C:23]([C:25]2[CH:26]=[N:27][C:28]3[N:29]([C:31]([C:34]4([C:37]5[CH:38]=[C:39]6[C:44](=[CH:45][CH:46]=5)[N:43]=[CH:42][CH:41]=[CH:40]6)[CH2:36][CH2:35]4)=[CH:32][N:33]=3)[CH:30]=2)[CH:22]=[CH:21][C:12]=1[C:13]([NH:15][CH:16]([CH3:20])[C:17]([OH:19])=O)=[O:14].CNC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:1][N:4]([CH3:5])[C:17](=[O:19])[CH:16]([NH:15][C:13](=[O:14])[C:12]1[CH:21]=[CH:22][C:23]([C:25]2[CH:26]=[N:27][C:28]3[N:29]([C:31]([C:34]4([C:37]5[CH:38]=[C:39]6[C:44](=[CH:45][CH:46]=5)[N:43]=[CH:42][CH:41]=[CH:40]6)[CH2:35][CH2:36]4)=[CH:32][N:33]=3)[CH:30]=2)=[CH:24][C:11]=1[F:10])[CH3:20]
Reactant: CC(NC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1F)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(NC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1F)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N-Diisopropylethylamine (31 μL, 0.18 mmol) was added to a mixture of 2-(2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoylamino)propanoic acid (29.7 mg, 0.06 mmol), dimethylamine (4.0 mg, 0.09 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (40 mg, 0.09 mmol) in N,N-dimethylformamide (0.5 mL). The reaction mixture was stirred overnight at RT and purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=523.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]2[C:14]([CH:19]=[O:20])=[N:15][C:16]([Cl:18])=[CH:17][C:12]=2[N:11]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[BH4-].[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:13]2[C:14]([CH2:19][OH:20])=[N:15][C:16]([Cl:18])=[CH:17][C:12]=2[N:11]([C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([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)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1nc(Cl)cc2c1c(OCc1ccccc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: OCc1nc(Cl)cc2c1c(OCc1ccccc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-(benzyloxy)-6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbaldehyde (2.8884 g, 5.45 mmol) in DCM (10 ml) was charged with MeOH (20 ml) and then sodium borohydride (0.309 g, 8.17 mmol). Stirred at RT for 2 hr. Quenched with water and extracted into DCM. Dried organics over MgSO4, filtered, concentrated in vacuo and used as-is. MS: [M+H]+ m/z 532.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]1[CH:23]=[CH:22][C:21]([SH:24])=[CH:20][CH:19]=1>[N+](C1C=CC=CC=1)([O-])=O.[Cu]>[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccccc1I
Reactant: Fc1ccc(S)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)c1ccccc1Sc1ccc(F)cc1
Temperature: 160 °C
Reaction time: 0.67 h

Procedure:
A mixture of 147 g of iodobenzoic acid, 45.5 g of potassium carbonate in 57 ml of nitrobenzene is maintained with stirring at 160° C. for 40 minutes. Thereafter, 46.5 g of additional potassium carbonate which is followed by the addition of 73.1 g of 4-fluorothiophenol, another 46.5 g of potassium carbonate and 0.35 g of copper powder. The reaction mixture is stirred in a 160° C. bath for 45 minutes. The resulting solid is collected and then cooled to 0° C. before being mixed with 100 ml of water and 220 ml of 6 N hydrochloric acid. The aqueous mixture is then diluted to 1 liter total volume before being stirred with 450 ml of chloroform. The resulting white solid is collected and washed successively with chloroform and water. The solid is dissolved in hot acetone and the acetone solution is successively filtered and cooled to provide a white crystalline product. The product is recrystallized from acetone and then converted to a salt with potassium carbonate. The salt is dissolved in water and the aqueous solution acidified with 1 N hydrochloric acid to provide 2-(4-fluorophenylthio)benzoic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:32]([OH:34])=[O:33])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][N:21]2C(=O)C3=CC=CC=C3C2=O)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:32]([OH:34])=[O:33])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][CH2:20][NH2:21])=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1)C(=O)O
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCCCN)cc1)C(=O)O
Yield: 78.7 %

Procedure:
A mixture of diphenylmethyl ester of N-tert-butoxycarbonyl-O-(3-phthalimidopropyl)-L-tyrosine (4.4 g) and hydrazine hydrate (0.52 g) in ethanol (50 ml) was heated under reflux for 2.5 hours. After cooling, the resulting precipitates were filtered off and the filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The extract was washed with water and brine, dried and evaporated to dryness to give diphenylmethyl ester of N-tert-butoxycarbonyl-O-(3-aminopropyl)-L-tyrosine (2.5 g) as oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:1][CH2:2][CH2:3][NH:4][C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:14])([F:15])[F:16])[CH:6]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(O)cc1
Reactant: N#Cc1ccc(NCCO)cc1C(F)(F)F
Product: COc1ccc(OCCNc2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Prepared as described in Example 1C from 4-[(2-hydroxyethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-methoxyphenol: 1H NMR (300 MHz, CDCl3) δ 7.58 (d, J=8.6 Hz, 1H), 6.93 (d, J=1.6 Hz, 1H), 6.85 (s, 4H), 6.76 (dd, J=8.7, 1.7 Hz, 1H), 5.66 (bs, 1H), 4.15 (t, J=4.7, 2H), 3.78 (s, 3H), 3.59 (t, J=4.9 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[F:16][C:14]([F:15])([F:17])[C:12]1[CH:11]=[C:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:20][CH:19]=2)[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:32]3[CH:33]=[CH:34][C:29]([NH2:28])=[N:30][CH:31]=3)[CH:7]=[CH:6][CH:5]=2)[CH:13]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-c3cccc(Br)c3)n2)cc1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cccc(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (example E.20) (0.525 g, 1.0 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.286 g, 1.3 mmol) according to the general procedure VI. Obtained as a white solid (0.10 g, 22%). MS (ISP) 460.2 [(M+H)+]; mp 170-172° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:8][C:7]=1[C:23]1[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>ClCCl>[C:36]([NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:8][C:7]=1[C:23]1[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=1)(=[O:38])[CH3:37]
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2ccc(OCCNC(C)=O)c(-c3ccnn3C)c2)c1
Reaction time: 0.25 h
Yield: 54.3 %

Procedure:
The N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide hydrochloride (30.0 mg, 74.5 μmol) and triethylamine (31.1 μL, 3.0 eq) were taken up in 2 mL of dichloromethane and stirred for 15 mins. To this was added acetyl chloride (6.35 μL, 1.2 eq) and the reaction was stirred at room temperature for 18 hrs. The solvents were evaporated under a stream of nitrogen and it was purified by HPLC. The proper fractions were collected and lyophilized to afford the title compound as a white solid in 54.3% yield. LCMS m/z (%)=409 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ ppm 1.97 (s, 3H), 3.49-3.56 (m, 2 H), 3.85 (s, 3 H), 3.88 (s, 3 H), 4.09 (t, J=5.05 Hz, 2 H), 6.36 (t, J=6.32 Hz, 1 H), 6.39 (d, J=2.02 Hz, 1 H), 7.02 (d, J=8.59 Hz, 1 H), 7.09-7.13 (m, 1 H), 7.36-7.45 (m, 2 H), 7.61 (dd, J=9.09, 2.53 Hz, 1H), 7.69 (d, J=1.52 Hz, 1 H), 7.75 (d, J=2.02 Hz, 2 H), 7.85 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:9](Cl)=[N:8][C:6]=2[N:7]=1.[CH3:21][NH2:22]>CO>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]([NH:22][CH3:21])=[N:8][C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[CH:4][C:5]=3[CH:11]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(-c2cc3cnc(N)nc3nc2Cl)cc1
Reactant: CN
Solvent: CO
Product: CNc1nc2nc(N)ncc2cc1-c1ccc(OC)cc1

Procedure:
A mixture of 3.4 g of 2-amino-7-chloro-6-(4-methoxyphenyl)-pyrido[2,3-d]pyrimidine from Example 12, 40 mL of anhydrous methylamine, and 10 mL of methanol were heated in a bomb on a steam bath for 4 hours. After cooling, the suspension was washed out of the bomb with 50 mL of methanol/water (50:50) and the solvents were evaporated in vacuo. The solid residue was slurried with 50 mL of water, filtered, and crystallized from ethanol to afford 2.2 g of the title compound 6-(4-methoxyphenyl)-N7 -methyl-pyrido[2,3-d]pyrimidine-2,7-diamine, mp 270°-275° C. dec.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[CH:11][CH:10]=1.O>N1C=CC=CC=1>[C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(CCc2ccco2)cc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(CCc2ccco2)cc1

Procedure:
Acetic anhydride (0.28 ml) was added dropwise to a solution of 2-[2-(4-aminophenyl)ethyl]furan (0.50 g) in pyridine (5 ml) at ambient temperature with stirring. After being stirred for 1 hour, the mixture was poured into water (50 ml) and the resulting precipitate was collected by filtration to give 2-[2-(4-acetamidophenyl)ethyl]furan (0.58 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][CH:31]=1)[O:7][CH2:8][CH2:9][N:10]1[CH2:28][CH2:27][C:13]2([O:18][CH2:17][CH2:16][N:15]([C:19]([C:21]3[N:22]=[C:23]([CH3:26])[S:24][CH:25]=3)=[O:20])[CH2:14]2)[CH2:12][CH2:11]1.FC(F)(F)C(O)=O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:26][C:23]1[S:24][CH:25]=[C:21]([C:19]([N:15]2[CH2:14][C:13]3([CH2:27][CH2:28][N:10]([CH2:9][CH2:8][O:7][C:6]4[CH:5]=[C:4]([CH2:3][CH:2]=[O:1])[CH:31]=[CH:30][CH:29]=4)[CH2:11][CH2:12]3)[O:18][CH2:17][CH2:16]2)=[O:20])[N:22]=1
Reactant: Cc1nc(C(=O)N2CCOC3(CCN(CCOc4cccc(CCO)c4)CC3)C2)cs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(C(=O)N2CCOC3(CCN(CCOc4cccc(CC=O)c4)CC3)C2)cs1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of (9-(2-(3-(2-hydroxyethyl)phenoxy)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-methylthiazol-4-yl)methanone (example 24, step c) (0.152 g) in DCM (5 mL) was cooled in ice-water and treated with trifluoroacetic acid (0.039 mL) and stirred for 5 minutes. Dess-Martin periodinane (0.221 g) was added and the mixture was removed from the cooling bath and stirred at room temperature for 25 minutes. The reaction was quenched by the addition of saturated sodium thiosulphate solution (5 mL), saturated sodium bicarbonate solution (5 mL) and ethyl acetate (5 mL), and the resulting two-phase mixture was stirred for 10 minutes. The mixture was then extracted twice with ethyl acetate, and the combined organic extracts washed with brine. Acetic acid (0.1 mL) was added, and then the acidified extracts were dried over anhydrous magnesium sulphate and concentrated in vacuo to afford the subtitled compound as a brown gum. Yield 0.118 g.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH2:15][CH2:16][C@@H:17]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29]([Cl:35])[CH:28]=1)[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].[CH3:36][C:37]([CH3:41])([CH3:40])[CH:38]=O>C(Cl)Cl>[Cl:35][C:29]1[CH:28]=[C:27]([NH:26][C@H:17]([CH2:16][NH:15][CH2:36][C:37]([CH3:41])([CH3:40])[CH3:38])[CH2:18][C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH:32]=[CH:31][C:30]=1[C:33]#[N:34]
Reactant: CC(C)(C)OC(=O)C[C@@H](CN)Nc1ccc(C#N)c(Cl)c1
Reactant: CC(C)(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)CNC[C@H](CC(=O)OC(C)(C)C)Nc1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
NaBH(OAc)3 (0.5 g, 2.32 mmol) was added to a solution of 1,1-dimethylethyl (3S)-4-amino-3-[(3-chloro-4-cyanophenyl)amino]butanoate (0.48 g, 1.55 mol), and trimethylacetaldehyde (0.14 g, 1.60 mmol) in CH2Cl2 (35 mL). After stirring at room temperature for 2 h, the reaction was diluted with CH2Cl2 (35 mL), washed with saturated NaHCO3, dried over Na2SO4, filtered, and concentrated to yield the titled product (0.575 g, 98%) as an oil. LC-MS (ES) m/e 380.6 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:26]=[CH:25][C:17]([C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][C:15]=1[F:27].[CH2:28]1[O:30][CH2:29]1>C1COCC1>[Br:13][C:14]1[CH:26]=[CH:25][C:17]([C:18]([NH:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])=[C:16]([CH2:28][CH2:29][OH:30])[C:15]=1[F:27]
Reactant: C1CO1
Reactant: CC(C)(C)NC(=O)c1ccc(Br)c(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)NC(=O)c1ccc(Br)c(F)c1CCO
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (6.2 mL, 44 mmol) in THF (200 mL) was treated with n-butyllithium (17.4 mL, 44.0 mmol) at 0° C. The solution was stirred for 30 min before being cooled to −78° C. Next, a solution of 4-bromo-N-tert-butyl-3-fluorobenzamide (4.8 g, 17 mmol) in THF (100 mL) was added. The solution was then warmed to −40° C. and maintained there for 1 h. Next, ethylene oxide (10 mL, 200 mmol) was added and the solution warmed to 0° C. After 1 h, the ice bath was removed and the solution was allowed to warm to rt. LC/MS indicated desired product present. The solution was quenched with MeOH, diluted with brine (200 mL), and extracted with EtOAc (300 mL). The organic layer was removed, dried over MgSO4, filtered and concentrated. The crude product was purified using a 340 g Biotage SNAP (0-60% Hexanes: EtOAc) cartridge to yield the title compound: LC-MS: m/z 319.98 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][C@H:2]1[CH2:7][OH:8].[Cl:9][CH2:10][CH:11]1[CH2:13]O1>>[Cl:9][CH2:10][CH:11]1[O:8][CH2:7][CH:2]2[CH2:3][O:4][CH2:5][CH2:6][N:1]2[CH2:13]1
Reactant: ClCC1CO1
Reactant: OC[C@@H]1COCCN1
Product: ClCC1CN2CCOCC2CO1
Temperature: 170 °C
Yield: 35.4 %

Procedure:
A solution of (3R)-morpholin-3-ylmethanol (4.21 g, 36.0 mmol) in 2-(chloromethyl)oxirane (28.2 mL, 0.360 mol) was heated to 40° C. for 3 h and then the solution was concentrated in vacuo. The intermediate was cooled in an ice bath and treated with 30.0 mL of concentrated sulfuric acid. The mixture was heated to 170° C. for 2 h and then allowed to cool to room temperature. The mixture was poured into ice-water and solid sodium bicarbonate was carefully added until the solution was basic. 10% methanol in ethyl acetate was added and the biphasic mixture was filtered. The layers were separated and the aqueous layer was extracted (3×100 mL 10% methanol in ethyl acetate). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (SiO2, 2:5 hexanes:ethyl acetate) provided 3-(chloromethyl)hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazine 2.44 g (35%) as two separated diastereomers. (3R,9aS)-3-(chloromethyl)hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazine: (0.886 g, 13% yield): 1H NMR (400 MHz, CDCl3): 3.91 (m, 3H), 3.82 (m, 1H), 3.68 (dt, 1H), 3.61 (dd, 1H), 3.47 (dd, 1H), 3.35 (t, 1H), 3.19 (t, 1H), 2.80 (d, 1H), 2.54 (m, 2H), 2.40 (m, 2H); MS (EI) for C8H14NO2Cl: 192 (MH+). (3S,9aS)-3-(chloromethyl)hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazine: (1.55 g, 22% yield): 1H NMR (400 MHz, CDCl3): 3.85 (m, 2H), 3.73 (m, 3H), 3.50 (m, 2H), 3.29 (t, 1H), 3.18 (t, 1H), 2.85 (dd, 1H), 2.64 (dd, 1H), 2.40 (m, 2H), 2.17 (t, 1H); MS (EI) for C8H14NO2Cl: 192 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]([CH2:15][C:16]([F:19])([F:18])[F:17])[C:6](=O)[O:7]C1C=CC=CC=1.[NH2:20][NH2:21].O>C(O)C>[NH2:20][N:21]1[CH2:2][CH2:3][CH2:4][N:5]([CH2:15][C:16]([F:19])([F:18])[F:17])[C:6]1=[O:7]
Reactant: O=C(Oc1ccccc1)N(CCCCl)CC(F)(F)F
Reactant: NN
Solvent: CCO
Solvent: O
Product: NN1CCCN(CC(F)(F)F)C1=O
Temperature: 90 °C
Reaction time: 5 h

Procedure:
Into a 100-mL round-bottom flask, was placed phenyl N-(3-chloropropyl)-N-(2,2,2-trifluoroethyl)carbamate (1.4 g, 4.73 mmol, 1.00 equiv), NH2NH2.H2O (6 mL), ethanol (40 mL). The resulting solution was stirred for 5 h at 90° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 50 mL of H2O. The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×30 mL of brine. The mixture was dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum. This resulted in 200 mg (crude) of 1-amino-3-(2,2,2-trifluoroethyl)-1,3-diazinan-2-one as a light yellow solid.
Reaction SMILES: [BH4-].[Na+].CO.[C:5]([C:9]1[S:13][C:12]([N:14]2[C:18](=[O:19])[C:17]([CH3:20])=[C:16]([CH3:21])[C:15]2=[O:22])=[N:11][N:10]=1)([CH3:8])([CH3:7])[CH3:6]>C(O)(=O)C>[C:5]([C:9]1[S:13][C:12]([N:14]2[C:15](=[O:22])[C:16]([CH3:21])=[C:17]([CH3:20])[CH:18]2[OH:19])=[N:11][N:10]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC1=C(C)C(=O)N(c2nnc(C(C)(C)C)s2)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC1=C(C)C(O)N(c2nnc(C(C)(C)C)s2)C1=O
Reaction time: 3 h
Yield: 77.3 %

Procedure:
Sodium borohydride (0.07 g) was added at room temperature to a methanol solution (100 ml) of N-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-2,3-dimethylmaleinimide (0.95 g), and the mixture was stirred for 3 hours. After the reaction, glacial acetic acid (0.5 ml) was added and the solvent was evaporated under reduced pressure. Water (30 ml) was added to the residue, and potassium carbonate was added to make the mixture alkaline. It was extracted with dichloromethane (50 ml×2). The extractants were dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting crude crystals were washed with a small amount of diethyl ether to give the desired N-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-3,4-dimethyl-2-hydroxy-5-oxo-2,5-dihydropyrrole (0.74 g). mp. 179°-182° C.
Reaction SMILES: [NH2:1][C:2]1[N:32]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:14]=[CH:15][C:16]=3[CH3:17])=[CH:9][N:4]2[N:3]=1.C([O:36][CH2:37][C:38](Cl)=[O:39])(=O)C.C(=O)([O-])[O-].[K+].[K+].O>N1C=CC=CC=1>[C:29]([C:26]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:13]1[CH:14]=[CH:15][C:16]([CH3:17])=[C:11]([O:10][C:8]2[CH:7]=[CH:6][C:5]3[N:4]([N:3]=[C:2]([NH:1][C:37](=[O:36])[CH2:38][OH:39])[N:32]=3)[CH:9]=2)[CH:12]=1)=[O:31])([CH3:28])[CH3:27])#[N:30]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)nn2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)CO)nn2c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 78.8 %

Procedure:
To a solution of N-{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (203 mg, 0.477 mmol) in pyridine (10 mL) was added 2-chloro-2-oxoethyl acetate (103 μL, 0.954 mmol), and the mixture was stirred at room temperature for 17 hr. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in methanol (10 mL). Potassium carbonate (132 mg, 0.954 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hr. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL, 2×10 mL). The combined organic layer was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Ethyl acetate and diisopropyl ether were added to the obtained residue. The obtained precipitate was collected by filtration and dried to give the title compound (182 mg, 79%) as a colorless powder.