Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([C:14]([OH:16])=O)=[C:10]([F:13])[CH:11]=[CH:12][C:7]=3[N:6]=[C:5]2[C@@H:17]([NH:19][C:20]2[N:28]=[CH:27][N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][N:24]3C2CCCCO2)[CH3:18])[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:59]1[CH2:64][CH2:63][O:62][CH2:61][CH2:60]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:1]1([N:4]2[C:8]3[C:9]([C:14]([N:59]4[CH2:64][CH2:63][O:62][CH2:61][CH2:60]4)=[O:16])=[C:10]([F:13])[CH:11]=[CH:12][C:7]=3[N:6]=[C:5]2[C@@H:17]([NH:19][C:20]2[N:28]=[CH:27][N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][NH:24]3)[CH3:18])[CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(C(=O)O)c2n1C1CC1
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: ClCCl
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(C(=O)N3CCOCC3)c2n1C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
A mixture of 3-cyclopropyl-5-fluoro-2-{(S)-1-[9-(tetrahydropyran-2-yl)-9H-purin-6-ylamino]ethyl}-3H-benzoimidazole-4-carboxylic acid (64 mg, 0.14 mmol), HATU (63 mg, 0.17 mmol), morpholine (18 μL, 0.216 mmol) and DIPEA (47 μL, 0.28 mmol) in DCM (2 mL) was stirred at RT for 1 h. The crude mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford 389 (46 mg, 75%) as a white solid. LCMS (Method K): RT 2.49 and 2.53 min [M+H]+ 451.05. 1H NMR (DMSO-d6, 400 MHz): δ 8.24-7.83 (3H, m), 7.69-7.60 (1H, m), 7.10 (1H, t, J=9.53 Hz), 6.07-5.84 (1H, m), 3.90-3.83 (1H, m), 3.80-3.72 (1H, m), 3.69-3.59 (2H, m), 3.59-3.50 (2H, m), 3.41-3.35 (2H, m), 3.28-3.20 (1H, m), 1.72-1.63 (3H, m), 1.26-0.85 (4H, m)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH:5]([O:7][P:8]([CH2:17][C:18]([CH3:41])=[CH:19][CH2:20][C:21]1[C:22]([O:34]CC[Si](C)(C)C)=[C:23]2[C:27](=[C:28]([CH3:32])[C:29]=1[O:30][CH3:31])[CH2:26][O:25][C:24]2=[O:33])([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[CH3:6])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:42])[CH:5]([O:7][P:8]([CH2:17][C:18]([CH3:41])=[CH:19][CH2:20][C:21]1[C:22]([OH:34])=[C:23]2[C:27](=[C:28]([CH3:32])[C:29]=1[O:30][CH3:31])[CH2:26][O:25][C:24]2=[O:33])([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)OP(=O)(CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)Oc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)OP(=O)(CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
To a solution of 2-({4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phenoxy-phosphinoyloxy)-propionic acid ethyl ester (24 mg, 0.039 mmol) in DCM (1 mL) was added TFA (0.5 mL) and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was dried under reduced pressure and the residue was purified by RP-HPLC to provide 18 mg (90%) of the desired product as a clear oil. 1H NMR (300 MHz, CDCl3) δ 1.18-1.34 (m, 3H), 1.36-1.48 (dd,3H), 2.02 (m, 3H), 2.17 (s, 3H), 2.78-2.98 (dd, 2H), 3.45 (m, 2H), 3.79 (s, 3H), 4.05-4.25 (m, 2H), 4.97 (m, 1H), 5.21 (s, 2H), 5.48 (t, J=7.2 Hz, 1H), 7.05-7.18 (m, 5H) ppm; 31P (121.4 MHz, CDCl3) δ 24.59, 26.13 ppm; MS (m/z) 517 [M−H]−, 519 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=2)[O:25][C:26]=1[CH3:27]>>[CH2:17]([O:16][CH:5]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:21][C:22]1[N:23]=[C:24]([C:28]3[CH:29]=[C:30]([O:38][CH3:39])[C:31]([O:36][CH3:37])=[C:32]([O:34][CH3:35])[CH:33]=3)[O:25][C:26]=1[CH3:27])[CH:11]=[CH:10]2)[C:4]([OH:3])=[O:19])[CH3:18]
Reactant: COc1cc(-c2nc(CCl)c(C)o2)cc(OC)c1OC
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3cc(OC)c(OC)c(OC)c3)oc2C)c1)C(=O)O
Yield: 3 %

Procedure:
Starting from rac-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester and 4-chloromethyl-5-methyl-2-(3,4,5-trimethoxy-phenyl)-oxazole, the title compound was obtained in 3% yield as a white solid. MS: (M+H)+ 495.2.
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[CH:12]=[C:11](OC)[C:10](OC)=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:4](C)[N:3]=1.[OH-].[K+].CC1(C)C(C)(C)OB(C2C=CC(N3CCN(C(OC(C)(C)C)=O)CC3)=CC=2)O1.O>O1CCOCC1>[CH:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[NH:4][N:3]=1
Reactant: COc1cc2ncc3c(c(Br)nn3C)c2cc1OC
Agent: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: c1ccc2c(c1)ncc1[nH]ncc12
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 59.1 %

Procedure:
1-Bromo-7,8-dimethoxy-3-methyl-3H-pyrazolo[3,4-c]quinoline (30 mg, 93 μmol) is dissolved in dioxane (1.0 ml) under argon. KOH (5.2 mg, 93 μmol), tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate (83 mg, 214 μmol), trans-bis(tricyclohexylphosphine)palladium(II) dichloride (10.4 mg, 14 μmol) and water (50 μl) are subsequently added. The reaction suspension is subsequently heated at 110° C. (microwave) for 90 min. The mixture is subsequently poured into water, stirred for 15 min, and the precipitate obtained is filtered off with suction. The filter residue is then treated in formic acid (2.5 ml) at room temperature for 18 h, subsequently diluted with water and extracted twice with ethyl acetate. The combined organic phases are washed with water, dried over Na2SO4, filtered with suction and evaporated to dryness in vacuo. The residue is purified by chromatography (pHPLC, solvent gradient water/1-30% by vol. of acetonitrile, 0.1% by vol. of formic acid), and the product fractions are freeze-dried, giving 7,8-dimethoxy-3-methyl-1-(4-piperazin-1-yl)phenyl)-3H-pyrazolo[3,4-c]quinoline (22 mg, 55 μmol) as a solid. MS: 404.1 (M+H+). TLC (HPTLC): Rf=0.19 (methanol/Hünig's base 99:1, parts by volume).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[CH2:30]([CH2:32][NH2:33])[OH:31].C([BH3-])#N.[Na+].Cl>CO.O1CCOCC1.CCOCC.CO>[ClH:1].[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:33][CH2:32][CH2:30][OH:31])[CH2:25][CH2:24]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:9][CH:10]3[CH2:11][CH:12]([CH2:13][CH:14]([CH2:16]3)[CH2:15]1)[CH2:17]2)=[O:5]
Reactant: O=C1CCN(Cc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Reactant: NCCO
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: C1COCCO1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CN2CCC(NCCO)CC2)ccc1Cl
Reaction time: 48 h

Procedure:
To a solution of 2-chloro-5-[(4-oxo-1-piperidinyl)methyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.150 g, Example 83a) in methanol (3ml ) at room temperature were added ethanolamine (0.11 ml) and sodium cyanoborohydride (0.068g). The pH was adjusted to 6 by adding a 4N solution of hydrogen chloride in dioxane and the reaction stirred for 48 h. The reaction was acidified with concentrated hydrochloric acid until gas evolution ceased. The precipitate was removed by filtration and the filtrate concentrated under vacuum. The residue was partitioned between ethyl acetate and water. The aqueous layer was basified with 5% aqueous sodium hydroxide and extracted with dichloromethane. The organics were washed with brine and dried over magnesium sulfate. The crude material was purified on silica gel (5% 7N ammonia in methanol/95% dichloromethane) to afford a white foam which was dissolved in ether/methanol and treated with a 4N solution of hydrogen chloride in dioxane to give the title compound (0.135 g).
Reaction SMILES: [CH2:1]([N:13]1[N:17]=[N:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[N:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Br:22]Br>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[Br:22][CH:18]([C:15]1[N:16]=[N:17][N:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:14]=1)[C:19]([OH:21])=[O:20]
Reactant: BrBr
Reactant: CCCCCCCCCCCCn1nnc(CC(=O)O)n1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCCCCCCn1nnc(C(Br)C(=O)O)n1
Temperature: 45 °C
Reaction time: 5 h
Yield: 89.4 %

Procedure:
The 2-dodecyltetrazoleacetic acid (4.7 g, 15.8 mmol) was suspended in carbon tetrachloride (5 mL) and warmed to 45° C. The solution was diluted by dropwise addition of bromine (2.6 g, 16.3 mmol), and the mixture was further heated to reflux with stirring for 5 hours. The solution was cooled to room temperature, diluted with 50 mL of ethyl acetate, washed with brine, dried (MgSO4), and filtered. The filtrate was concentrated in vacuo to give α-bromo-2-dodecyltetrazoleacetic acid (5.3 g, 86%) as an orange colored liquid;
Reaction SMILES: [Br:1][C:2]1[C:3]([S:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:6]=2[CH:17]=1.I([O-])(=O)(=O)=[O:24].[Na+].I([O-])(=O)=O.[Na+]>CO.O>[Br:1][C:2]1[C:3]([S:18]([CH2:19][C:20]([OH:22])=[O:21])=[O:24])=[CH:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:6]=2[CH:17]=1
Reactant: O=C(O)CSc1cc2onc(-c3ccccc3F)c2cc1Br
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Agent: [O-][I+2]([O-])[O-]
Solvent: O
Solvent: CO
Product: O=C(O)CS(=O)c1cc2onc(-c3ccccc3F)c2cc1Br
Yield: 86 %

Procedure:
2.8 g (7.33 mmol) of [[5-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]thio]acetic acid was combined with 30 ml (2 eq.) of 0.5M sodium periodate solution in 300 ml of 4:1 methanol/water. The mixture was refluxed for 18 hours during which the insoluble sodium iodate precipitated. The reaction mixture was then poured into excess 3N HCl and extracted several times with ethyl acetate. The ethyl acetate extracts were combined, washed with water and a saturated salt solution, dried over magnesium sulfate, filtered and evaporated to yield a white solid. The solid was triturated with hexanes and dried under vacuum to yield 2.51 g (86%) of [[5-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]sulfinyl]acetic acid, m.p. 173°-174° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.OC1(C2C=NC(OC)=CC=2)CCC(=O)CC1.[NH2:32][CH:33]([CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45]C(C)(C)C)=O)[CH2:39][CH2:38]1)[C:34]([NH2:36])=[O:35].[F:50][C:51]1[CH:52]=[C:53]([CH:59]=[C:60]([F:63])[C:61]=1[F:62])/[CH:54]=[CH:55]/C(O)=O>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][CH:12]([NH:32][CH:33]([CH:37]3[CH2:38][CH2:39][N:40]([C:43](=[O:45])/[CH:55]=[CH:54]/[C:53]4[CH:59]=[C:60]([F:63])[C:61]([F:62])=[C:51]([F:50])[CH:52]=4)[CH2:41][CH2:42]3)[C:34]([NH2:36])=[O:35])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2CCC(=O)CC2)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)C(N)=O)CC1
Reactant: O=C(O)/C=C/c1cc(F)c(F)c(F)c1
Agent: COc1ccc(C2(O)CCC(=O)CC2)cn1
Product: COc1ccc(C2CCC(NC(C(N)=O)C3CCN(C(=O)/C=C/c4cc(F)c(F)c(F)c4)CC3)CC2)cn1

Procedure:
The title compound was prepared from 4-(6-methoxypyridin-3-yl)cyclohexanone (prepared from commercially available 4-hydroxy-4-(6-methoxypyridin-3-yl)cyclohexanone according to the general procedure shown in scheme 5), 2-amino-2-(1-tert-butoxycarbonyl-piperidin-4-yl)-acetamide (from Example 1, step G), and trans-3,4,5-trifluorocinnamic acid, by the methods of Example 1, steps H to K, giving a pale yellow solid as a mixture of cyclohexyl diastereomers.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[O:17][C:18]4[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH2:28][CH2:29][NH:30][CH2:31][C:32]5[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=5)[C:19]=4[C:20]=3[CH3:21])=[CH:10][C:8]=2[CH:9]=1)[CH3:2].C=O.[C:40](O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([O:3][CH2:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[O:17][C:18]4[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH2:28][CH2:29][N:30]([CH3:40])[CH2:31][C:32]5[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=5)[C:19]=4[C:20]=3[CH3:21])=[CH:10][C:8]=2[CH:9]=1)[CH3:2]
Reactant: CCOCc1cc2cc(OCc3oc4cccc(OCCCNCc5cccnc5)c4c3C)ccc2o1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOCc1cc2cc(OCc3oc4cccc(OCCCN(C)Cc5cccnc5)c4c3C)ccc2o1

Procedure:
A mixture of the compound of Example 42 (25.3 mg), formalin (37%, 5.7 μl), acetic acid (12 μl) and sodium cyanoborohydride (6.4 mg) was stirred in MeOH (2 ml) at room temperature for 1.5 hours. MeOH was evaporated to dryness, the residue was purified by silica gel TLC (dichloromethane-MeOH=10:1) to give the title compound as a colorless oil (23.4 mg). FAB-MS: m/z 515 (MH+); 1H-NMR (CDCl3): δ 1.26 (3H, t, J=7 Hz), 2.03 (2H, quintet, J=6.5 Hz), 2.25 (3H, s), 2.27 (3H, s), 2.61 (2H, t, J=7 Hz), 3.55 (2H, s), 3.61 (2H, q, J=7 Hz), 4.10 (2H, t, J=6 Hz), 4.57 (2H, s), 5.09 (2H, s), 6.58 (1H, d, J=8 Hz), 6.63 (1H, s), 6.97 (1H, dd, J=9 Hz, 2.5 Hz), 7.0-7.2 (4H, m), 7.37 (1H, d, J=9 Hz), 7.64 (1H, dt, 7.5 Hz, 1.5 Hz), 8.42 (1H, dd, J=5 Hz, 1.5 Hz), 8.51 (1H, d, J=1.5 Hz).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O)(=[O:3])[CH3:2].[NH:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1>C(O)(=O)CC>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:8]2[C:17]3[NH:13][C:14]([C:8]([C:7]4[CH:10]=[CH:11][CH:12]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=4)=[C:14]4[N:13]=[C:17]([C:8]([C:7]5[CH:10]=[CH:11][CH:12]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=5)=[C:14]5[NH:13][C:17](=[C:8]([C:7]6[CH:10]=[CH:11][CH:12]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=6)[C:14]6[CH:15]=[CH:16][C:17]=2[N:13]=6)[CH:16]=[CH:15]5)[CH:16]=[CH:15]4)=[CH:15][CH:16]=3)[CH:10]=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: c1cc[nH]c1
Reactant: CC(=O)Nc1cccc(C=O)c1
Solvent: CCC(=O)O
Product: CC(=O)Nc1cccc(-c2c3nc(c(-c4cccc(NC(C)=O)c4)c4ccc([nH]4)c(-c4cccc(NC(C)=O)c4)c4nc(c(-c5cccc(NC(C)=O)c5)c5ccc2[nH]5)C=C4)C=C3)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
16.32 g (0.10 mol) of 3-acetylaminobenzaldehyde (EMS-Dottikon AG) is dissolved in 300 ml of propionic acid and the solution is heated to 60° C. 6.71 g (0.10 mol) of pyrrole is instilled slowly and the dark solution is stirred for one hour at 110° C. After cooling, it is completely concentrated by evaporation in a vacuum, and the residue is recrystallized from pyridine/diethyl ether.
Reaction SMILES: [CH2:1]([N:8]([CH3:28])[C:9]1[NH:10][C:11](=[O:27])[C:12]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14][C:13]=2[N:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.[CH3:34][O+](C)C>C(Cl)Cl>[CH2:1]([N:8]([CH3:28])[C:9]1[N:10]=[C:11]([O:27][CH3:34])[C:12]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:15][CH2:14][C:13]=2[N:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)c1nc2c(c(=O)[nH]1)CCN(C(=O)OC(C)(C)C)CC2
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COc1nc(N(C)Cc2ccccc2)nc2c1CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 2 h
Yield: 41 %

Procedure:
To a solution of tert-butyl 2-[benzyl(methyl)amino]-4-oxo-3,4,5,6,8,9-hexahydro-7H-pyrimido[4,5,d]azepine-7-carboxylate of Preparation 16, Step A (70 mg, 0.19 mmol) in DCM (2 ml) was added trimethyloxonium tetrafluoroborate (3 eq., 84.1 mg, 0.57 mmol) and the mixture was stirred for 2 h. The combined organic layers were combined, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with ethyl actate/pentane (1:3 to 1:1). The relevant fractions were combined and concentrated in vacuo to afford the title compound as a colourless oil (31 mg, 41% yield).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:20]=[CH:19][C:6]([CH:7]=[CH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[CH:5][CH:4]=1.NC(N)=[S:23].[OH-].[Na+].S(=O)(=O)(O)O>CCOCC.ClCCl.C(O)C>[SH:23][CH2:2][C:3]1[CH:20]=[CH:19][C:6]([CH:7]=[CH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[CH:5][CH:4]=1
Reactant: COc1ccc(OC)c(C=Cc2ccc(CCl)cc2)c1
Reactant: NC(N)=S
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(OC)c(C=Cc2ccc(CS)cc2)c1
Yield: 38.7 %

Procedure:
A solution of 4'-chloromethyl-2,5-dimethoxystilbene (856 mg, 2.96 mmol), thiourea (0.29 g, 3.8 mmol), and ethanol (16 ml) was heated to reflux for 3.5 h. Aqueous sodium hydroxide (2.5 M, 2.8 ml) was added and the mixture refluxed for further 2 h. The reaction mixture was allowed to cool and dichloromethane (50 ml), ether (200 ml) and sulfuric acid (10%, 10 ml) were added. The organic layer was separated, washed with water (2×200 ml), brine (100 ml), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography over silica (dichloromethane/hexane; 4:1) to give (32b) (328 mg, 39%); νmax /cm-1 2950s, 1490m, 1470s, 1430m, 1390s, 1215s, 1180s, 1050s.
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26].C(N(CCCC)CCCC)CCC>C(#N)C>[CH2:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:26])[O:27][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: O=C(O)CCCCCCCCCCCCCCO
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CC#N
Solvent: CCCCN(CCCC)CCCC
Product: O=C1CCCCCCCCCCCCCCO1
Yield: 74 %

Procedure:
To a refluxing solution of 510 mg (2.0 mmol) of 2-chloro-1-methylpyridinium iodide in 50 ml of acetonitrile, there was added a solution of 134 mg (0.5 mmol) of 15-hydroxypentadecanoic acid and 740 mg (4.0 mmol) of tri-n-butylamine in 40 ml of acetonitrile over a period of 8 hours at a continuous and uniform rate, and the reaction mixture was refluxed for an additional 30 minutes after the addition was completed. After evaporation of the solvent, the residue was separated chromatographically on a silica gel column. 1,15-pentadecanolide was obtained in 74% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:3]=1.[CH3:20][N:21]1[C:25]([CH3:26])=[C:24](B2OC(C)(C)C(C)(C)O2)[C:23]([CH3:36])=[N:22]1.C(=O)([O-])[O-].[Na+].[Na+].C(O)(C(F)(F)F)=O>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:17][C:16]([F:19])([F:18])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([C:24]3[C:23]([CH3:36])=[N:22][N:21]([CH3:20])[C:25]=3[CH3:26])[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1
Reactant: FC(F)(F)Oc1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cc1nn(C)c(C)c1-c1cc(Nc2ccc(OC(F)(F)F)cc2)ncn1
Temperature: 95 °C
Reaction time: 5 h
Yield: 105.2 %

Procedure:
6-Chloro-N-(4-(trifluoromethoxy)phenyl)pyrimidin-4-amine intermediate (5.2 mg, 0.17 mmol), 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (40 mg, 0.17 mmol), Pd(PPh3)4 (10 mg, 0.085 mmol) and sodium carbonate (73 mg, 0.69 mmol) were dissolved in acetonitrile:water (v/v 1:1, 10 ml). The flask was stirred at 95° C. for 5 hr. The solvent was removed and directly subjected to prep-HPLC to afford 65 mg (80% Yield) of the title compound as TFA salt. 1H NMR 400 MHz (DMSO-d6) δ 10.32 (s, 1H), 8.75 (s, 1H), 8.39 (s, 2H), 7.84 (d, 2H, J=9.2 Hz), 7.45 (d, 2H, J=9.2 Hz), 3.84 (s, 3H), 2.89 (s, 3H), 2.24 (s, 3H). MS m/z 364.11 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([NH2:5])=[O:4].[C:6]1([S:12]([O:14][Na])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>CN(C=O)C>[C:6]1([S:12]([CH2:2][C:3]([NH2:5])=[O:4])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC(=O)CBr
Reactant: O=S(O[Na])c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)CS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of α-bromoacetamide IV in anhydrous DMF, is added PhSO2Na at 0° C. The reaction mixture is stirred for 1 hour at room temperature and is then poured into water. The organic layer is washed with brine, dried over Na2SO4, and evaporated. The residue is purified by silica gel column chromatography to give α-phenylsulfonylacetamide III.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:21][OH:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](N1C=CN=C1)([N:25]1C=CN=C1)=[O:24].N.O>C1COCC1>[C:23]([O:22][CH2:21][C@H:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])(=[O:24])[NH2:25]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(N[C@H](CO)Cc1cccc(F)c1)OCc1ccccc1
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)OC[C@H](Cc1cccc(F)c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
In a 100 mL flask equipped with magnetic stirrer, N-benzyloxycarbonyl-m-fluorophenylalaninol (0.007 mole, 2.12 g) was dissolved in 50 ml of THF and was added with 1,1'-carbonyldiimidazole (0.007 mol, 1.14 g) at 0° C. The reaction mixture was stirred at room temperature for 2 hours, followed by the injection of ammonia at 0° C. for 30 min. Following elevating to room temperature, water was added to terminate the reaction. The organic layer was extracted 3 times with dichloromethane, dried over magnesium sulfate and distilled in vacuo, to give a solid. This was recrystalized in a solution mixture of n-hexane and diethyl ether, to produce 2.18 g of O-carbamoyl-N-benzyloxycarbonyl-m-fluorophenylalaninol: Yield 91%.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Br[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19].C([O-])([O-])=O.[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O.CCCCCC.C(OCC)(=O)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:10]
Reactant: Clc1ccccc1CBr
Reactant: O=C1NCc2ccccc21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C1c2ccccc2CN1Cc1ccccc1Cl
Temperature: 70 °C
Reaction time: 16 h
Yield: 27.2 %

Procedure:
A mixture of 2,3-dihydro-isoindol-1-one (0.066 g, 0.5 mmol), 1-bromomethyl-2-chloro-benzene (0.123 g, 0.6 mmol), Cs2CO3 (0.408 g, 1.25 mmol), and 18-crown-6 (0.013 g, 0.05 mmol) in acetone (3 mL) was stirred at 70° C. for 16 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(2-chloro-benzyl)-2,3-dihydro-isoindol-1-one (0.035 g, 27%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.28 (s, 2H), 4.94 (s, 2H), 7.16-7.52 (m, 7H), 7.90 (d, 1H).