Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[Cl:12].Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1.ClC1N=CC2C(=CC=CC=2)N=1>O.CS(C)=O>[Cl:12][C:6]1[CH:7]=[C:8]([O:11][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH:9]=[CH:10][C:5]=1[NH2:4]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1ccc(O)cc1Cl
Agent: Cl
Agent: Clc1ncc2ccccc2n1
Agent: [H-]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
Sodium hydride (60 wt %, 5.80 g) was added to dimethyl sulfoxide (40 ml). The mixture was stirred at 60° C. for 30 min and was then cooled to room temperature. Next, 4-amino-3-chlorophenol hydrochloride (13.05 g) was added thereto. The mixture was stirred at room temperature for 10 min. 4-Chloro-6,7-dimethoxyquinazoline (8.14 g), which is a chloroquinazoline derivative synthesized by a conventional method as described, for example, in J. Am. Chem. Soc., 68, 1299 (1946) or J. Am. Chem. Soc., 68, 1305 (1946), was then added thereto. The mixture was stirred at 110° C. for 30 min. Water was then added to the reaction solution, followed by extraction with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and methanol was added to the residue to prepare a suspension. The precipitated crystal was collected by suction filtration to give 9.13 g (yield 76%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]([C:10]([OH:12])=O)[C:8]=1[C:16]([OH:18])=O.Cl.[NH2:23][CH:24]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]1=[O:26]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]2[C:8]=1[C:16](=[O:18])[N:23]([CH:24]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]1=[O:26])[C:10]2=[O:12]
Reactant: NC1CCC(=O)NC1=O
Reactant: O=C(O)c1cccc(OCc2cccc(Br)c2)c1C(=O)O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(OCc4cccc(Br)c4)c3C2=O)C(=O)N1
Yield: 60.6 %

Procedure:
A mixture of 3-(3-bromo-benzyloxy)-phthalic acid (2.4 g, 6.7 mmol), alpha-amino-glutarimide hydrochloride (1.2 g, 7.1 mmol) in pyridine was refluxed overnight. The mixture was evaporated and the residue was purified by flash column chromatography (methanol/methylene chloride) to give 4-(3-bromo-benzyloxy)-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione as a white solid (1.8 g, 62% yield); HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 60/40 CH3CN/0.1% H3PO4, 3.55 min (99.9%); mp, 246-248° C.; 1H NMR (DMSO-d6) δ 2.03-2.08 (m, 1H, CHH), 2.54-2.62 (m, 2H, CH2), 2.83-2.95 (m, 1H, CHH), 5.12 (dd, J=6, 12 Hz, 1H, CH), 5.39 (s, 2H, CH2), 7.37-7.88 (m, 7H, Ar), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.96, 30.92, 48.77, 69.00, 115.72, 116.69, 120.10, 121.76, 126.05, 129.75, 130.69, 130.74, 133.26, 137.07, 138.99, 155.19, 165.31, 166.74, 169.89, 172.74. Anal Calcd For C20H15N2O5Br: C, 54.19; H, 3.41; N, 6.32; Br, 18.03. Found: C, 54.02; H, 3.22; N, 6.27; Br, 17.81.
Reaction SMILES: N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:25]I.[CH2:27]([N:29]1[CH2:34][N:33]([CH3:35])[CH2:32][N:31]([C:36]2[S:37][C:38]3[C:44]([CH2:45]O)=[CH:43][C:42]([C:47]4[CH:48]=[N:49][C:50]([N:53]5[CH2:58][CH2:57][C:56]([CH3:64])([C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:55][CH2:54]5)=[N:51][CH:52]=4)=[CH:41][C:39]=3[N:40]=2)[C:30]1=[O:65])[CH3:28]>C(Cl)Cl>[CH2:27]([N:29]1[CH2:34][N:33]([CH3:35])[CH2:32][N:31]([C:36]2[S:37][C:38]3[C:44]([CH2:45][I:25])=[CH:43][C:42]([C:47]4[CH:48]=[N:49][C:50]([N:53]5[CH2:58][CH2:57][C:56]([CH3:64])([C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:55][CH2:54]5)=[N:51][CH:52]=4)=[CH:41][C:39]=3[N:40]=2)[C:30]1=[O:65])[CH3:28]
Reactant: II
Reactant: CCOC(=O)C1(C)CCN(c2ncc(-c3cc(CO)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C1(C)CCN(c2ncc(-c3cc(CI)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55.3 %

Procedure:
Imidazole (75 mg, 1.09 mmol), triphenylphosphine (276 mg, 1.05 mmol) and iodine (267 mg, 1.05 mmol) were dissolved in CH2Cl2 (15 mL) and stirred at rt for 5 mins. A solution of ethyl 1-[5-[2-(3-ethyl-5-methyl-2-oxo-1,3,5-triazinan-1-yl)-7-(hydroxymethyl)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (485 mg, 0.88 mmol) in CH2Cl2 (10 mL) was then added and the mixture stirred at rt for 2 h. The mixture was pre-adsorbed onto silica gel and purified by flash column chromatography (80 g GraceResolv silica cartridge—dry loaded) eluting with 25-100% EtOAc/heptane to afford the desired compound (323 mg, 56%) as a pale yellow foam. MS: 664.02 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][C@H:13]([CH2:16]OS(C4C=CC(Br)=CC=4)(=O)=O)[O:12][C:8]3=2)[N:3]=1.[F:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([CH2:38][CH:39]3[CH2:44][CH2:43][CH2:42][NH:41][CH2:40]3)=[CH:34][NH:35]2)=[CH:31][CH:30]=1>>[F:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([CH2:38][CH:39]3[CH2:44][CH2:43][CH2:42][N:41]([CH2:16][CH:13]4[O:12][C:8]5=[C:9]6[C:4](=[CH:5][CH:6]=[C:7]5[O:15][CH2:14]4)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]6)[CH2:40]3)=[CH:34][NH:35]2)=[CH:31][CH:30]=1
Reactant: Fc1ccc2c(CC3CCCNC3)c[nH]c2c1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Product: Cc1ccc2c3c(ccc2n1)OCC(CN1CCCC(Cc2c[nH]c4cc(F)ccc24)C1)O3

Procedure:
This compound was prepared as described for Example 2, using (2R)-4-bromobenzenesulfonic acid 8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.22 g, 4.9 mmol), 6-fluoro-3-piperidin-3-ylmethyl-1H-indole (0.13 g, 5.9 mmol), to afford 0.11 g (50%) of the (S)-enantiomer of the title compound as a light brown oil. The hydrogen chloride salt was prepared in ethyl acetate and collected as 0.12 g of a yellow solid, m.p. 50° C. (dec).
Reaction SMILES: OC1C(=O)N(C)C2C([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=CC=CC=2.[CH:19]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:31])[C:23]1=[O:32])([CH3:21])[CH3:20]>>[OH:31][C:24]1[C:23](=[O:32])[N:22]([CH:19]([CH3:20])[CH3:21])[C:30]2[C:25]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:26][CH:27]=[CH:28][CH:29]=2
Reactant: CCOC(=O)c1c(O)c(=O)n(C)c2ccccc12
Reactant: CC(C)N1C(=O)C(=O)c2ccccc21
Product: CCOC(=O)c1c(O)c(=O)n(C(C)C)c2ccccc12

Procedure:
Intermediate 19 was prepared as a white powder following the procedure described for Intermediate 16 by replacing indoline-2,3-dione with 1-isopropylindoline-2,3-dione. 1H NMR (400 MHz, chloroform-d) δ ppm 8.10 (1 H, br. s.), 7.77 (1 H, d, J=7.8 Hz), 7.60 (1 H, d, J=8.3 Hz), 7.42 (1 H, t, J=7.7 Hz), 7.27 (1 H, t, J=7.5 Hz), 4.53 (2 H, q, J=7.1 Hz), 1.45 (3 H, t, J=7.1 Hz). LC-MS (ESI) m/z 276.0 (M+H), RT=1.93 min (Method B)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:39]#[N:40])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:38])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:39]#[N:40])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][C:34]([CH3:36])([CH3:37])[CH3:35])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:38])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC(C)(C)C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CC(C)(C)C)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Reaction time: 0.58 h

Procedure:
99 mg (176 μmol) of tert-butyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4-dimethylpentanoyl}amino)benzoate (racemate) and 270 μl (3.51 μmol) of TFA were reacted according to General Method 2. The crude product was purified by preparative HPLC [column: Chromatorex C18, 10 μm, 125 mm×30 mm, mobile phase: acetonitrile/water gradient (0 to 3 min 15% acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90% acetonitrile)]. Yield: 57 mg (64% of theory)
Reaction SMILES: O=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][O:3]1.[NH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CN(C1C=CN=CC=1)C>[O:3]=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:12]1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1cccnc1
Reactant: COC(=O)c1cccoc1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cccn(-c2cccnc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 141.9 %

Procedure:
To a solution of methyl 2-oxo-2H-pyran-3-carboxylate (462 mg, 3 mmol, Aldrich) in DMF (6 mL) at rt was added 3-aminopyridine (282 mg, 3 mmol). The reaction mixture was stirred overnight at rt, treated with EDCI.HCl (650 mg, 3.4 mmol) and DMAP (200 mg), stirred for an additional 24 h, and concentrated in vacuo. The residue was purified by preparative HPLC to afford the desired product (980 mg, 95%) as a beige solid. 1 H NMR (CDCl3) δ 13.00 (br s, 1H), 8.83 (br s, 1H), 8.74 (br s, 1H), 8.29 (dd, 1H, J=7.2, 1.7 Hz), 8.18 (d, 1H, J=8.3 Hz), 7.73 (dd, 1H, J=7.7, 5.0 Hz ), 7.66 (dd, 1H, J=6.6, 1.6 Hz), 6.42 (t, 1H, J=7.1 Hz), 3.87 (s, 3H).
Reaction SMILES: [CH2:1]1[CH2:19][O:18][O:17][C:4]([O:15][CH3:16])([CH:5]=[CH:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][CH:8]=2)[O:3][O:2]1.C.[H][H]>CO>[CH2:19]1[CH2:1][O:2][O:3][C:4]([O:15][CH3:16])([CH2:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([CH:13]=[O:14])=[CH:11][CH:12]=2)[O:17][O:18]1
Reactant: [H][H]
Reactant: COC1(C=Cc2ccc(C=O)cc2)OOCCOO1
Solvent: CO
Product: COC1(CCc2ccc(C=O)cc2)OOCCOO1
Yield: 88.1 %

Procedure:
A solution of methyl 4-formylcinnamate ethylenedioxy acetal (15.24 g, 0.065 mole, from example 32) in methanol (200 ml) was hydrogenated over 10% palladinised charcoal (0.5 g) until 1 equivalent of hydrogen was absorbed. The filtered solution was then evaporated to give 15.36 g (100%) of an oil, νmax (film), 1730, 1610 cm-1, δ(CDCl3) 2.54 (2H, m, ArCH2), 2.91 (2H, m, CH2CO2), 3.63 (3H, s, ester CH3), 4.00 (4H, m, OCH2CH2O), 5.72 (1H, s, OCHO), 7.25 (4H, ABq, J 10 Hz, Δν19.5 Hz).
Reaction SMILES: CN[C:3]([O:5][CH:6]([CH2:9][O:10][C:11](=[O:31])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7]O)=O.[CH2:32]([S:48][CH2:49][CH:50]([O:72][C:73](=[O:76])[NH:74][CH3:75])[CH2:51][O:52][C:53]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47].[CH2:77](SCC(OC)CN)CCCCCCCCCCCCCCC>>[NH2:74][CH2:73][C:6]1([CH2:9][O:10][C:11](=[O:31])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][CH2:77][CH2:3][O:5]1.[CH2:32]([S:48][CH2:49][CH:50]([O:72][C:73](=[O:76])[NH:74][CH3:75])[CH2:51][O:52][C:53]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)([C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CO)OC(=O)NC
Reactant: CCCCCCCCCCCCCCCCSCC(CN)OC
Agent: CCCCCCCCCCCCCCCCSCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC(=O)NC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC1(CN)CCCO1

Procedure:
2-Methylcarbamoyloxy-3-octadecylcarbamoyloxypropanol V c2 is allowed to react and worked up by the same procedure as described in (3) to give an amine IV c2 of m.p. 91°-92° C. The summary of the experimental condition and the physical data of the product are listed in the Table 5 and 6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:31])/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][C:22]([CH2:25][N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:21][CH:20]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1>[Ni].CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:31])[CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:21][CH:20]=3)=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(NC(=O)/C=C/c3ccc(CN4CCCC4)cc3)cc2)cc1
Agent: [Ni]
Solvent: CO
Product: COc1ccc(-c2ccc(NC(=O)CCc3ccc(CN4CCCC4)cc3)cc2)cc1
Reaction time: 4 h

Procedure:
A reaction mixture of 60 mg (0.14 mmol) of (E)-N-(4′-methoxybiphenyl-4-yl)-3-(4-pyrrolidin-1-ylmethylphenyl)acrylamide and 10 mg of Raney nickel in 30 mL of methanol is hydrogenated for 4 hours. The catalyst is filtered off and the filtrate is evaporated to dryness. Yield: 56 mg (93.2% of theory); melting point: 185° C.-188° C.; C27H30N2O2 (M=414.55); calc.: molecular ion peak (M+H)+: 415; found: molecular ion peak (M+H)+: 415; Rf value: 0.29 (silica gel, dichloromethane/methanol/ammonia (90:10:1)).
Reaction SMILES: CO[C:3](=O)[C:4]1[CH:9]=[C:8]([NH2:10])[N:7]=[C:6]([NH2:11])[CH:5]=1.[NH3:13]>>[NH2:13][CH2:3][C:4]1[CH:9]=[C:8]([NH2:10])[N:7]=[C:6]([NH2:11])[CH:5]=1
Reactant: COC(=O)c1cc(N)nc(N)c1
Reactant: N
Product: NCc1cc(N)nc(N)c1
Temperature: 60 °C

Procedure:
A compound of formula I-3 may be prepared as follows: A solution of 2,6-diamino-isonicotinic acid methyl ester (X) is treated for 1 hour with gaseous ammonia. The mixture is heated for 36 hours at about 60° C. in an autoclave and is then filtered through decalite. The obtained 2,6-diamino-isonicotinamide is suspended in THF and boran-dimethylsulfide-complex (or NaBH4) is added. The mixture is refluxed for 4 days. After cooling to room temperature HCl is added and the mixture is neutralized with NaOH, to give 4-aminomethyl-pyridine-2,6-diamine. A solution of this compound in pyridine is treated with a compound of formula XII together with a catalytic amount of 4-dimethylaminopyridine, and stirred for 2.5 hours at room temperature to obtain a compound of formula III. Furthermore, to the obtained solution of a compound of formula III in dioxane is added O-mesitylenesulfonylhydroxylamine and then an aldehyde of formula V. The mixture is heated to about 100° C. and after 2.5 hours KOH in methanol is added. After stirring the mixture at room temperature a compound of formula I-3 is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([NH2:28])=[N:10][CH:11]=[N:12][C:13]=2[O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[CH:5]=[CH:6][CH:7]=1.[O:29]1[CH2:34][CH2:33][N:32]([CH2:35]/[CH:36]=[CH:37]/[C:38](O)=[O:39])[CH2:31][CH2:30]1>>[NH2:28][C:9]1[C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:38](=[O:39])/[CH:37]=[CH:36]/[CH2:35][N:32]3[CH2:31][CH2:30][O:29][CH2:34][CH2:33]3)[CH:7]=[CH:6][CH:5]=2)=[C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[N:12]=[CH:11][N:10]=1
Reactant: Nc1cccc(-c2c(N)ncnc2Oc2ccc(Oc3ccccc3)cc2)c1
Reactant: O=C(O)/C=C/CN1CCOCC1
Product: Nc1ncnc(Oc2ccc(Oc3ccccc3)cc2)c1-c1cccc(NC(=O)/C=C/CN2CCOCC2)c1
Yield: 15 %

Procedure:
(E)-N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-4-morpholinobut-2-enamide was prepared from 5-(3-aminophenyl)-6-(4-phenoxyphenoxy)pyrimidin-4-amine and (E)-4-morpholinobut-2-enoic acid using Method E (15% yield). HPLC: 100%, RT=3.662 min. MS: m/z=524 [M+H]+, RT=3.66 min.
Reaction SMILES: [SH:1][C:2]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.[CH2:11]([O:15][C:16](=[O:35])[C@H:17]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[NH:18][C:19]([C:21]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])[CH2:12][CH2:13][CH3:14].ON1C2N=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.C(N(CC)CC)C>[CH2:11]([O:15][C:16](=[O:35])[C@H:17]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[NH:18][C:19]([C:21]1([NH:26][C:7]([C:2]2([SH:1])[CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:9])[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(N)CCCC1
Reactant: O=C(O)C1(S)CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(NC(=O)C2(S)CCCC2)CCCC1
Reaction time: 14 h

Procedure:
To a stirred solution of 1-mercapto-1-cyclopentanecarboxylic acid (1.74 g, 4.54 mmol) in dichloromethane (50 mL) and triethylamine (0.63 mL) is added [(1-amino-(1-cyclopentyl)carbonyl]-L-tyrosine butyl ester hydrochloride (0.66 g). To this solution is added 1-hydroxy-7-azabenzotriazole (0.68 g, 4.55 mmol) and 1,3-dicyclohexylcarbodiimide (1.03 g, 4.99 mmol). The mixture is stirred for 14 hours and then the solid precipitate is removed by filtration. The organic phase is washed with a saturated solution of sodium bicarbonate (10 mL), brine (10 mL), dried over magnesium sulfate and the solvent is removed to give a clear oil. The oil is purified by flash chromatography (SiO2, hexane/ethyl acetate, 6:4) to give a clear foam. The foam is crystallized from ethyl ether to yield N-[[1-[[(1-mercapto-1-cyclopentyl)carbonyl]amino]-1-cyclopentyl]carbonyl]-L-tyrosine butyl ester, m.p. 106°-107° C.
Reaction SMILES: S=[C:2]1[CH2:6][O:5][C:4](=[O:7])[NH:3]1.[CH2:8]([NH2:11])[C:9]#[CH:10]>C(O)C>[CH2:8]([NH:11][C:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]=1)[C:9]#[CH:10]
Reactant: C#CCN
Reactant: O=C1NC(=S)CO1
Solvent: CCO
Product: C#CCNC1=NC(=O)OC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
To a solution of 4-thioxooxazolidin-2-one (180 mg) in ethanol (3 mL) was added prop-2-yn-1-amine (85 mg) at room temperature. The reaction mixture was stirred at room temperature for 2 hr. The precipitated white solid was collected by filtration, and washed with ethyl acetate/hexane to give the title compound (168 mg).
Reaction SMILES: C[CH2:2][S:3]([N:6]([C:10]1[CH:15]=[C:14]([CH2:16]O)[CH:13]=[C:12]([CH2:18][O:19][CH2:20][C:21]([NH2:30])([CH3:29])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:11]=1)[CH2:7][CH2:8][CH3:9])(=[O:5])=[O:4].C(Br)(Br)(Br)[Br:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[NH2:30][C:21]([CH3:29])([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:20][O:19][CH2:18][C:12]1[CH:11]=[C:10]([N:6]([CH2:7][CH2:8][CH3:9])[S:3]([CH3:2])(=[O:5])=[O:4])[CH:15]=[C:14]([CH2:16][Br:32])[CH:13]=1
Reactant: CCCN(c1cc(CO)cc(COCC(C)(N)Cc2ccccc2)c1)S(=O)(=O)CC
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCN(c1cc(CBr)cc(COCC(C)(N)Cc2ccccc2)c1)S(C)(=O)=O
Reaction time: 15 h

Procedure:
To a solution of methyl N-[3-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-5-(hydroxymethyl)phenyl]-N-propylmethanesulfonamide (140 mg, 0.269 mmol) in dichloromethane (2.5 mL) were added carbon tetrabromide (116 mg, 0.350 mmol) and triphenylphosphine (85.0 mg, 0.323 mmol). After 15 h, the reaction mixture was concentrated in vacuo and purified by flash chromatography (silica, 0-35% EtOAc/hexanes) to provide N-[3-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-5-(bromomethyl)phenyl]-N-propylmethanesulfonamide as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.34 (s, 1H), 7.31 (s, 1H),), 7.30-7.20 (m, 4H), 7.18-7.14 (m, 2H), 4.60-4.50 (m, 3H), 4.49 (s, 2H), 3.64 (t, J=7.2 Hz, 2H), 3.55 (A of AB, d, J=8.7 Hz, 1H), 3.45 (B of AB, d, J=8.7 Hz, 1H), 3.14 (A of AB, d, J=13.3 Hz, 1H), 2.94 (B of AB, d, J=13.3 Hz, 1H), 2.88 (s, 3H), 1.56-1.47 (m, 2H), 1.46 (s, 9H), 1.27 (s, 3H), 0.91 (t, J=7.4 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:8]2)=[CH:4][CH:3]=1.[F:17][C:18]1[CH:19]=[C:20]([N:25]=[C:26]=[O:27])[CH:21]=[CH:22][C:23]=1[F:24]>ClCCl>[F:17][C:18]1[CH:19]=[C:20]([NH:25][C:26]([NH:14][CH2:13][CH2:12][CH2:11][N:9]2[CH2:10][CH:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:16][CH:15]=3)[CH2:8]2)=[O:27])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: NCCCN1CC(Oc2ccc(F)cc2)C1
Reactant: O=C=Nc1ccc(F)c(F)c1
Solvent: ClCCl
Product: O=C(NCCCN1CC(Oc2ccc(F)cc2)C1)Nc1ccc(F)c(F)c1

Procedure:
A solution of 3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propylamine (0.04 g, 0.178 mmol) and 3,4-difluorophenylisocyanate (0.020 ml, 0.178 mmol) in dichloromethane (1 ml) is stirred at room temperature for 5 hours. The solvent is evaporated and the crude product purified by flash silica chromatography (elution gradient a 3:97 to 5:95 methanol/dichloromethane) to afford 1-(3,4-difluoro-phenyl)-3-{3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propyl}-urea. [MH]+ 379.9.
Reaction SMILES: [CH2:1]([CH:3]1[C:9](=[O:10])[N:8]2[CH:4]1[S:5][C:6]([S:24]C(=O)C)=[C:7]2[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])[CH3:2].N1C=CN=C1>O1CCOCC1.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:1]([CH:3]1[C:9](=[O:10])[N:8]2[CH:4]1[S:5][C:6](=[S:24])[CH:7]2[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])[CH3:2]
Reactant: CCC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC(C)=O)SC12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1COCCO1
Product: CCC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=S)SC12
Reaction time: 0.17 h

Procedure:
To a stirred solution of 0.25 g of 4-nitrobenzyl 6-ethyl-7-oxo-3-acetylthio-4-thia-1-azabicyclo[3,2,0]hept-2-ene 2-carboxylate in 4 ml of dioxan and 0.5 ml of water was added, in one batch, 0.046 g of imidazole. After 10 minutes, the solution was diluted with 10 ml of 1M citric acid and extracted twice with dichloromethane. The combined organic extracts were washed with water, dried over magnesium sulphate, and evaporated in vacuo to give the title compound in a quantitative yield.