Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH:4]([C:16]1[CH:21]=[CH:20][C:19](SC)=[C:18]([Cl:24])[CH:17]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][C:8]2([O:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH2:7]1.Cl[C:27]1C=C(C=CC=1)C(OO)=O.C(=O)(O)[O-].[Na+].[S:42](=[O:45])(O)[O-:43].[Na+]>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:25])[CH:4]([C:16]1[CH:21]=[CH:20][C:19]([S:42]([CH3:27])(=[O:45])=[O:43])=[C:18]([Cl:24])[CH:17]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][C:8]2([O:11][CH2:12][CH2:13][CH2:14][O:15]2)[CH2:7]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])O
Reactant: COC(=O)C(CC1CCC2(C1)OCCCO2)c1ccc(SC)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(CC1CCC2(C1)OCCCO2)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
A solution of 2-(3-chloro-4-methylsulfanyl-phenyl)-3-(6,10-dioxa-spiro[4.5]dec-2-yl)-propionic acid methyl ester (1.18 g, 3.07 mmol) in methylene chloride (8 mL) cooled to 0° C. was slowly treated with a mixture of 3-chloroperoxybenzoic acid (˜70%, 1.51 g based on 70%, 6.13 mmol) and sodium bicarbonate (1.03 g, 12.26 mmol) in methylene chloride (8 mL). The thick reaction mixture was diluted with methylene chloride (8 mL) and was then allowed to warm to 25° C., where it was stirred for 4 h. The reaction mixture was diluted with methylene chloride (200 mL) and water (200 mL). The organic phase was cooled down to 0° C. and then slowly treated with a saturated aqueous sodium bisulfite solution (200 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (100 mL), water (100 mL), and a saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(6,10-dioxa-spiro[4.5]dec-2-yl)-propionic acid methyl ester (1.22 g, 95%) as a colorless oil: EI-HRMS m/c calcd for C19H25ClO6S (M)+ 416.1060 found 416.1054.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[C:14]([F:17])([F:16])[F:15].[I:18]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C.O>[F:6][C:7]1[C:8]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:10]([OH:13])=[C:11]([I:18])[CH:12]=1
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Oc1cc(C(F)(F)F)c(F)cc1I
Reaction time: 1 h
Yield: 119.2 %

Procedure:
Concentrated sulfuric acid (0.78 mL. 15.0 mmol) was added to a mixture of 4-fluoro-3-(trifluoromethyl)phenol (8.00 g, 44.4 mmol) and N-iodosuccinimide (5.00 g, 22.2 mmol) in acetic acid (40 mL) at 0° C. After 1 hour, the ice bath was removed and an additional portion of N-iodosuccinimide (1.50 g. 6.67 mmol) added. After an additional 1 hour at ambient temperature, the final portion of N-iodosuccinimide (1.0 g, 4.4 mmol) was added. The reaction mixture was stirred for 1 hour then diluted with water (300 mL), treated with 20 wt % aqueous sodium thiosulfate, and extracted with ether (3×100 mL). The combined organic layers were washed with aqueous sodium thiosulfate then brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by automated silica gel flash chromatography (100% hexanes to 50% dichloromethane in hexanes gradient elution) to afford the title compound as a yellow oil (8.1 g).
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[N:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[C:51]1([NH2:54])[CH2:53][CH2:52]1>CN(C=O)C.CCOC(C)=O>[C:10]([O:9][C:7](=[O:8])[NH:1][C@H:2]([C:4](=[O:6])[NH:54][C:51]1([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][N:45]=2)[CH2:53][CH2:52]1)[CH3:3])([CH3:13])([CH3:12])[CH3:11]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NC1(c2ccccn2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1(c2ccccn2)CC1
Reaction time: 1.5 h
Yield: 74.1 %

Procedure:
To a solution of Boc-Ala (100 mg, 0.53 mmol), HATU (261 mg, 0.69 mmol) and triethylamine (0.15 mL, 1.1 mmol) in DMF (2 mL) was added a solution of 1-pyridin-2-yl-cyclopropylamine (80 mg, 0.60 mmol) in DMF (1 mL). The mixture was stirred for 1.5 h then diluted with EtOAc (30 mL), washed with water (3×30 mL), brine (1×25 mL), dried with MgSO4, filtered, and concentrated to afford a crude solid. The crude material was purified by flash chromatography on silica gel, eluting with Hex/EtOAc (50/50 to 75/25) to afford [(S)-1-(1-pyridin-2-yl-cyclopropylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (120 mg, 74%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C@@H:3]([NH2:5])[CH3:4].C(Cl)Cl.N1([C:16](N2C=CN=C2)=[O:17])C=CN=C1.[F:23][C:24]([F:42])([F:41])[C:25]1[CH:30]=[CH:29][C:28]([C@@H:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34][CH2:33][NH:32]2)=[CH:27][CH:26]=1>C1COCC1>[F:42][C:24]([F:23])([F:41])[C:25]1[CH:26]=[CH:27][C:28]([C@@H:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34][CH2:33][N:32]2[C:16]([NH:5][C@@H:3]([CH3:4])[C:2]([F:7])([F:6])[F:1])=[O:17])=[CH:29][CH:30]=1
Reactant: C[C@H](N)C(F)(F)F
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@H](NC(=O)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1)C(F)(F)F
Reaction time: 2 h

Procedure:
To a solution of (S)-1,1,1-trifluoropropan-2-amine (90.9 μl, 884 μmol) in 4:1 CH2Cl2:THF (5 mL) is added di(1H-imidazol-1-yl)methanone (215 mg, 1326 μmol) and the flask was sealed and stirred at room temperature for 1.5 h. (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (307 mg, 1105 μmol) was added and the reaction stirred at 2 h. The reaction was directly purified by reverse phase HPLC to give (R)-1-(4-(trifluoromethyl)phenyl)-N—((S)-1,1,1-trifluoropropan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide as a white powder. MS (ESI pos. ion) m/z: 417 (M+1).
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5].[CH3:14]O>>[CH3:14][O:5][C:4](=[O:6])[CH:3]([OH:2])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)C(O)Cc1ccccc1
Reactant: CO
Agent: Cl
Product: COC(=O)C(O)Cc1ccccc1
Reaction time: 7 h
Yield: 98 %

Procedure:
Hydrochloric acid gas was bubbled into a solution of 2-hydroxy-3-phenyl-propionic acid (6.0 g, 36.10 mmol) in MeOH (250 ml) at room temperature under CaSO4 tube for 20 minutes. The resulting colorless solution was stirred for 7 hours and concentrated in vacuo to afford 2-hydroxy-3-phenyl-propionic acid methyl ester as a brown syrup (6.36 g, 98% yield): MS (ESI) m/z 181.
Reaction SMILES: [S:1]1[C:5]([C:6]([Cl:8])=[O:7])=[CH:4][N:3]=[N:2]1.[NH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[C:12]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[N:11]=1>>[ClH:8].[NH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[C:12]([N:24]2[CH2:29][CH2:28][N:27]([C:6]([C:5]3[S:1][N:2]=[N:3][CH:4]=3)=[O:7])[CH2:26][CH2:25]2)[N:11]=1
Reactant: O=C(Cl)c1cnns1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Product: COc1cc2nc(N3CCN(C(=O)c4cnns4)CC3)nc(N)c2cc1OC
Product: Cl

Procedure:
Reaction of 1,2,3-thiadiazole-5-carbonyl chloride and 4-amino-6,7-dimethoxy-2-(1-piperzinyl)quinazoline according to the procedure of Example 1 provided the title compound having a melting point of 295°-297° C. after crystallization from aqueous ethanol.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)=O)(C)(C)C.[F:13][C:14]([F:19])([F:18])[C:15]([OH:17])=[O:16]>C(Cl)Cl>[F:13][C:14]([F:19])([F:18])[C:15]([OH:17])=[O:16].[NH:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC1CNC1
Reaction time: 1.25 h

Procedure:
3-Hydroxy-azetidine-1-carboxylic acid tert-butyl ester 9b (0.73 g, 4.2 mmole) was dissolved in CH2Cl2 (2 ml) and trifluoroacetic acid (2 ml). CAUTION: The deprotection generated a rapid evolution of gas. The clear solution was stirred for 75 minutes and the solvent was removed, in vacuo, to a clear oil (1.4 g, >100%): 1H-NMR (DMSO-d6, 400 MHz) δ8.63 (2H, br. s), 4.55-4.48 (1H, m), 4.09-4.02 (2H, m), 3.76-3.68 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:11]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)([CH2:15][CH3:16])[CH2:12][C:13]#[N:14].CN1CCOCC1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl.O>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C:11]([N:6]2[C:7]3[C:3](=[C:2]([NH:1][S:32]([CH3:31])(=[O:34])=[O:33])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:5]2)([CH2:15][CH3:16])[CH2:12][C:13]#[N:14])=[CH:22][CH:21]=1
Reactant: CCC(CC#N)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Reactant: CS(=O)(=O)Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: CCC(CC#N)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reaction time: 2 h

Procedure:
To a solution of the product from Step D (170 mg, 0.52 mmol) and N-methylmorpholine (105 mg, 1.04 mmol) in dichloromethane (15 mL) was added methanesulfonyl chloride (89 mg, 0.79 mmol) at room temperature. The mixture was stirred for 2 h, then diluted with water (15 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by PREP-TLC eluting with PE/EA (3/1, v/v) to give the title compound as a colorless amorphous solid. LC/MS m/z=402.1 [M+H]+.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:17][C:18]1N(C)[C:21]2C=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=1>CN(C)C=O>[CH3:21][C:20]1[N:19]=[C:18]([CH2:17][N:7]([C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][N:4]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:13]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Cn1c(CCl)nc2ccccc21
Reactant: c1ccc(Nc2ccccn2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(CN(c2ccccn2)c2ccccn2)n1

Procedure:
To a flask were added 1.1 g of 2,2′-dipyridylamine and 25 ml of N,N-dimethylformamide. To this mixture were added 0.32 g of 60% sodium hydride in mineral oil in small portions, and after stirring at 10 C for ten minutes, 1.2 g of 2-(chloromethyl)-1-methyl-1H-benzimidazole in 5 ml of N,N-dimethylformamide were added. The reaction mixture was stirred at 22 C for several hours, and then quenched with 40 ml water. The product was extracted with 50 ml ethyl acetate, and then extracted with 30 ml of 1M hydrochloric acid, and basified with 3M sodium hydroxide. Following extraction with 20 ml ethyl acetate, the product was purified by silica gel chromatography using 33% ethyl acetate, 62% hexane, and 5% methanol, resulting in an oil which crystallized on standing. After drying, 0.6 g of a yellow solid remained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]([OH:8])=[O:7].[CH3:9]OC(OC)(C)C.[ClH:16]>CO>[ClH:16].[CH3:9][O:7][C:6]([CH2:5][S:4][CH2:3][CH2:2][NH2:1])=[O:8]
Reactant: NCCSCC(=O)O
Reactant: COC(C)(C)OC
Agent: Cl
Solvent: CO
Product: COC(=O)CSCCN
Reaction time: 12 h

Procedure:
13.5 g of S-(β-aminoethyl)mercaptoacetic acid and 10.8 g of 2,2-dimethoxy propane are added, successively, to a solution of 7.3 g of gaseous hydrochloric acid in 20 cc of methanol. The solution is permitted to stand for 12 hours at ambient temperature. The flakes formed (17.5 g) are filtered and washed with ethyl acetate. Fusion point = 100° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][C:13]([O:15][CH3:16])=[O:14].[H-].[Na+].[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.O>CN(C=O)C>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[C:6]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:7]2)=[O:25])=[CH:22][CH:21]=1
Reactant: COC(=O)Cc1c[nH]c2ccc(OC)cc12
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cn(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-(5-methoxy-1H-indol-3-yl)acetate (60 mg, 0.27 mmol) and NaH (8 mg, 0.33 mmol) were stirred in anhydrous DMF (1 mL) at 0° C. under argon for 30 min, at which time 4-chlorobenzoyl chloride (57 mg, 0.33 mmol) was added. The reaction mixture was stirred overnight at room temperature and was then poured into cold water (2 mL). The organic compound was immediately extracted with dichloromethane (2×2 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified on silica (ethyl acetate/hexane gradient) and recrystallized from hexane. Yield: 18 mg (18%). C19H16ClNO4, Mr=357.79; 1H NMR (400 MHz, DMSO-d6) d: 3.61 (s, 3H), 3.78 (s, 2H), 3.81 (s, 3H), 7.00 (dd, J=2.4/9.0 Hz, 1H), 7.12 (d, J=2.4 Hz, 1H), 7.35 (s, 1H), 7.65-7.77 (m, 4H), 8.17 (d, J=8.8 Hz, 1H); LCMS (ESI) tR: 2.81 min (>99%, ELSD), m/z: 358.0 [M+1]+.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH:5]([O:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[Cl:14])C.[C:18]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27]O)=[CH:20][CH:19]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(C)C=CC=CC=1.[OH-].[Na+]>>[C:18]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][CH2:27][O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:15][CH3:16])[C:4]([OH:3])=[O:17])=[C:8]([Cl:14])[CH:9]=2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1Cl)OC
Reactant: OCCCOc1ccc(-c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COC(Cc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)cc1Cl)C(=O)O

Procedure:
A mixture solution of 3-(2-Chloro-4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester from Step F and 3-(Biphenyl-4-yloxy)-propan-1-ol were allowed to react under the Standard Mitsounobu coupling conditions B (DIAD/toluene) to give the corresponding coupled product which by the Standard hydrolysis procedure C (NaOH) yield the title compound. MS (ES) for C25H25ClO5 [M+NH4]+: 458.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][NH:6][C:7]([C:9]1[C:10](=[O:21])[O:11][C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][CH:15]=[C:14]([CH3:20])[CH:13]=2)=[O:8])C.[OH-].[Na+]>O1CCCC1.CO.O>[OH:19][C:18]1[C:17]2[C:12](=[CH:13][C:14]([CH3:20])=[CH:15][CH:16]=2)[O:11][C:10](=[O:21])[C:9]=1[C:7]([NH:6][CH2:5][C:4]([OH:22])=[O:3])=[O:8]
Reactant: CCOC(=O)CNC(=O)c1c(O)c2ccc(C)cc2oc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc2c(O)c(C(=O)NCC(=O)O)c(=O)oc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
A mixture of [(4-hydroxy-7-methyl-2-oxo-2H-chromene-3-carbonyl)-amino]-acetic acid ethyl ester (106 mg, 0.347 mmol) and NaOH solution (0.70 mL, 1.38 mmol) in tetrahydrofuran (3 mL), methanol (3 mL) and water (3 mL) was stirred at rt overnight; the solvents were evaporated and the resulting residue was dissolved in water, acidified with 2 M HCl solution, the precipitates were then dried to give the desired product (80 mg). ESI (m/z): 278 (M+H)+.
Reaction SMILES: [H-].[Na+].[O:3]([CH2:10][C:11]1[S:12][C:13]2[C:14](=[O:21])[NH:15][CH2:16][CH2:17][CH2:18][C:19]=2[N:20]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.O>[O:3]([CH2:10][C:11]1[S:12][C:13]2[C:14](=[O:21])[N:15]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:16][CH2:17][CH2:18][C:19]=2[N:20]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCc1ccccc1
Reactant: O=C1NCCCc2nc(COc3ccccc3)sc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2sc(COc3ccccc3)nc2CCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A 60% dispersion of sodium hydride in mineral oils (0.014 g, 0.36 mmol) was added to a stirred solution of 5,6,7,8-tetrahydro-2-(phenoxymethyl)-4H-thiazolo[5,4-c]azepin-4-one (0.066 g, 0.24 mmol) in DMF anhydrous (1 mL) at 0° C. and the mixture was stirred at room temperature for 1 hour. Then, benzyl bromide (0.043 mL, 0.36 mmol) was added and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with H2O and extracted with DCM. The organic layer was separated, washed with brine, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in heptane 0/100 to 100/0). The desired fractions were collected and the solvents evaporated in vacuo to yield 5,6,7,8-tetrahydro-2-(phenoxymethyl)-5-(phenylmethyl)-4H-thiazolo[5,4-c]azepin-4-one (0.084 g, 96% yield) as a colourless oil. C21H20N2O2S LCMS: Rt 3.02, m/z 365 [M+H]+ (using method, LC-MS Method 6).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18].ClCCl.CO>C1(C)C=CC=CC=1>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17](=[NH:18])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: COc1cccc(C#N)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: COc1cccc(C(=N)Nc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
To a 500 mL 3-neck round bottom flask was added aniline (5.38 g, 57.8 mmol) and 150 mL toluene. The solution was cooled in an ice bath under nitrogen. Next trimethylaluminum solution in toluene was added dropwise via dropping funnel (2.0 M, 40.4 mL, 81 mmol) and the reaction mixture was stirred at room temperature for 2 h. Next 3-methoxybenzonitrile (10 g, 75 mmol) in 50 mL toluene was added and the reaction mixture was heated to 70° C. overnight under nitrogen. The reaction mixture was cooled in an ice bath and then poured onto a stirring slurry of silica gel in 2:1 dichloromethane/methanol. The silica gel was filtered off and washed with dichloromethane and methanol. The filtrate was evaporated leaving a solid which was triturated with hexane, filtered, and washed with more hexane and dried to give desired product (7.81 g, 60%).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][C:7]([CH3:12])([CH3:11])[C:6]=2[CH:5]=[C:4]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH:3]=1.[Li]CCCC.C([O:25][B:26](OC(C)C)[O:27]C(C)C)(C)C.Cl>C1COCC1.C(OCC)(=O)C>[CH2:13]([C:4]1[CH:3]=[C:2]([B:26]([OH:27])[OH:25])[C:10]2[O:9][CH2:8][C:7]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)Cc1cc(Br)c2c(c1)C(C)(C)CO2
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Cc1cc(B(O)O)c2c(c1)C(C)(C)CO2
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 49.6 %

Procedure:
To a mixture of 7-bromo-5-isobutyl-3,3-dimethyl-2,3-dihydro-benzofuran (9.9 g, 34.96 mmol) in THF (50 mL) cooled to −78° C. under an atmosphere of argon was added n-BuLi (25.17 mL, 2.5 M, 62.93 mmol) dropwise. The reaction mixture was stirred for 5 minutes and triisopropylborate (24.2 mL, 104.87 mmol) was added dropwise. The mixture was stirred at −50° C. for 2 hours then warmed up to room temperature and stirred overnight at room temperature. 1.0 N HCl (100 mL) was slowly added to the reaction mixture. After 1 hour the mixture was diluted with ethyl acetate and the layers separated. The organic layer was further washed with water, brine, dried (Mg2SO4), filtered and evaporated. The residue was chromatographed on silica gel (0 to 20% ethyl acetate in hexane) to give 4.3 g of 5-isobutyl-3,3-dimethyl-2,3-dihydro-benzofuran-7-boronic acid (46%). 1H NMR (300 MHz; CDCL3): 0.90 (d, J=6.6 Hz, 6 H), 1.33 (s, 6 H), 1.81 (m, 1 H), 2.43 (d, J=7.5 Hz, 2 H), 4.28 (s, 2 H), 5.86 (br s, 2 H), 6.98 (d, J=2.1 Hz, 1 H), 7.33 (d, J=2.1 Hz, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:12][C@@H:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[C@@H:10]2[C@@H:8]([N:9]2[P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=1)=[O:5])[CH3:2].[CH3:26][CH2:27][CH:28]([OH:31])[CH2:29][CH3:30].B(F)(F)F.CCOCC>CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH2:12][C@@H:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[C@@H:10]([NH:9][P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])[C@H:8]([O:31][CH:28]([CH2:29][CH3:30])[CH2:27][CH3:26])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C[C@H]2[C@@H]([C@H](OS(C)(=O)=O)C1)N2P(=O)(OCC)OCC
Reactant: CCC(O)CC
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NP(=O)(OCC)OCC)[C@H](OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1.94 g of 16 and 3-pentanol (20 mL) cooled to 0-5° C. in a 50 mL round-bottom flask equipped with a magnetic stirrer and an argon gas supply was added 736 μl boron trifluoride ethyl etherate. The reaction mixture was stirred for 16 h at RT and the reaction mixture was then diluted with 50 mL of EtOAc and twice extracted with 70 mL of water. The organic phase was separated, dried (Na2SO4, 25 g) filtered and concentrated in a rotary evaporator at 40° C./70-10 mbar to afford 2.18 g of the crude product as a yellow oil. The crude product was purified by SiO2 column chromatography eluting with tert-butyl methyl ether. The combined fractions were evaporated and dried on a rotary evaporator at 40° C./250-10 mbar to afford 1.47 g of 18 as a light yellow solid.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[C:6]1([N:12]=[C:13]=[S:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:15]I>CN(C=O)C>[CH3:15][S:14][C:13]([NH:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[C:2]([C:1]#[N:5])[C:3]#[N:4]
Reactant: S=C=Nc1ccccc1
Reactant: CI
Reactant: N#CCC#N
Solvent: CN(C)C=O
Product: CSC(Nc1ccccc1)=C(C#N)C#N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99 %

Procedure:
To a solution of malononitrile (1.0 g, 15.14 mmol) in DMF 20 mL was added TEA (2.099 mL, 15.14 mmol). After the mixture was stirred at room temperature for 5 min, phenylisothiocynate (2.047 g, 15.14 mmol) was added dropwise to the mixture. The reaction mixture was stirred at room temperature for 30 min. After the reaction was complete as determined by TLC, methyl iodide (2.149 g, 15.14 mmol) was added and the reaction mixture was stirred at room temperature for 1 hr, at which time the reaction was complete as determined by TLC. The reaction mixture was poured into 100 mL ice water. The resulting precipitate was filtered and dried in an oven overnight to give compound 6 (3.226 g, 98.2% yield, 97.4% purity) as a light yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C@H:9]2[CH2:15][N:14]([C:16]3[N:17]([CH3:29])[C:18](=[O:28])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][N:25]=[CH:24][N:23]=4)[N:21]=3)[CH2:13][CH2:12][CH2:11][O:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].NO.[C:32]1(C)C=CC=CC=1.C[O:40][CH:41](OC)[N:42](C)C>C(O)C>[CH3:29][N:17]1[C:18](=[O:28])[CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][N:23]=2)[N:21]=[C:16]1[N:14]1[CH2:13][CH2:12][CH2:11][O:10][C@@H:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]3[N:42]=[C:41]([CH3:32])[O:40][N:2]=3)[CH:4]=2)[CH2:15]1
Reactant: Cn1c(N2CCCO[C@@H](c3cccc(C#N)c3)C2)nc(-c2ccncn2)cc1=O
Reactant: COC(OC)N(C)C
Reactant: Cc1ccccc1
Agent: NO
Solvent: CCO
Product: Cc1nc(-c2cccc([C@H]3CN(c4nc(-c5ccncn5)cc(=O)n4C)CCCO3)c2)no1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-[2-(3-cyano-phenyl)-[1,4]oxazepan-4-yl]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (A039) (250 mg, 0.644 mmol) in ethanol (1.29 ml) was added 50 wt. %—hydroxylamine aqueous solution (128 mg, 1.93 mmol) at room temperature. The mixture was stirred at 80° C. for 2 hours and concentrated. The residue was partitioned between water and chloroform. The organic layer was dried over sodium sulfate and concentrated in vacuo. To the residue was added toluene (1.29 ml) and N,N-dimethylformamide dimethylacetal (190 mg, 1.29 mmol) at room temperature. After the mixture was refluxed for 2 hours, the solvent was evaporated. The residue was purified by silica gel column chromatography (eluant: chloroform/methanol=98/2) to afford (S)-1-Methyl-2-{2-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]-[1,4]oxazepan-4-yl}-1H-[4,4′]bipyrimidinyl-6-one (A030) as white solid (254 mg, 89%).