Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[C:3]([NH:6][NH:7][C:8](=[O:10])[CH3:9])(=[O:5])[CH3:4].[CH2:11]([O:14][CH2:15][CH2:16]Cl)[CH2:12]Cl>CS(C)=O>[C:3]([N:6]1[N:7]([C:8](=[O:10])[CH3:9])[CH:16]=[CH:15][O:14][CH:11]=[CH:12]1)(=[O:5])[CH3:4]
Reactant: CC(=O)NNC(C)=O
Reactant: ClCCOCCCl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(=O)n1ccoccn1C(C)=O
Temperature: 82.5 °C
Yield: 78.1 %

Procedure:
10.6 g of finely pulverised 85% potassium hydroxide are introduced into a solution of 9.3 g of N,N′-diacetylhydrazine and 141 g of dimethyl sulfoxide in such a manner that a temperature of 33° C. is not exceeded. After heating to 80 to 85° C., 23 g of 2,2′-dichlorodiethyl ether are added dropwise to the reaction mixture over the course of 50 minutes. The resulting highly fluid suspension is maintained at 80 to 85° C. for 3 hours, then cooled to 20 to 25° C. and filtered, and the filtration residue is washed with dimethyl sulfoxide. 11.4 g (76.0%) of 4,5-diacetyl-[1,4,5]-oxadiazepine are obtained from the combined filtrates by concentration by evaporation.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]2C(=O)C3=CC=CC=C3C2=O)=[CH:3][CH:2]=1.O.NN>C(O)C>[NH3:14].[C:1]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:2]=[CH:3][C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCOc1ccc(-c2ccccc2)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: N
Product: NCCCCCCOc1ccc(-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A mixture of N-[6-(4-biphenyloxy)hexyl]phthalimide (17 g), ethanol (500 ml) and hydrazine hydrate (10 ml) was heated at reflux for 16 hours, cooled to room temperature, filtered, and evaporated to dryness. The remaining material was stirred with dichloromethane (500 ml), filtered and evaporated to dryness. The crude product was chromatographed on silica gel, eluting with 95:5 dichloromethane:methanolic ammonia, yielding 6-(4-biphenyloxy)-1-aminohexane as an oil, which was converted to the hydrochloride salt, (m.p. 201°-202° C.), according to the method of Example 3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([CH2:19]Cl)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([CH2:19][O:31][C:28]3[CH:27]=[CH:26][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:30][CH:29]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(CCl)cs2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(COc3ccc(S(C)(=O)=O)cc3)cs2)CC1

Procedure:
A mixture of 4-(4-Chloromethyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 1, 463 mg, 1.46 mmol), 4-methanesulfonyl-phenol (252 mg, 1.46 mmol) and K2CO3 (404 mg, 2.92 mmol) in acetone (25 mL) was heated under reflux overnight. After cooling, the solid was filtered through a pad of celite. The filtrate was concentrated in vacuo. The residue was purified on silica gel (EtOAc-hexanes, 1:1) to afford the desired product. 1H NMR (CDCl3): δ 7.88 (2H, d, J=8.8 Hz), 7.23 (1H, s), 7.12 (2H, d, J=8.8 Hz), 5.24 (2H, s), 4.21 (2H, br), 3.17 (1H, m), 3.04 (3H, s), 2.88 (2H, m), 2.11 (2H, m), 1.73 (2H, m), 1.47 (9H, s).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:5]([OH:11])=[N:6][C:7]([OH:10])=[N:8][CH:9]=1.[C:12]([O:15]C(=O)C)(=[O:14])[CH3:13].N1C=CC=CC=1>O>[CH3:13][C:12]([O-:15])=[O:14].[C:12]([O:1][CH2:2][CH2:3][C:4]1[C:5]([OH:11])=[N:6][C:7]([OH:10])=[N:8][CH:9]=1)(=[O:14])[CH3:13]
Reactant: OCCc1cnc(O)nc1O
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCCc1cnc(O)nc1O
Product: CC(=O)[O-]
Yield: 74 %

Procedure:
Mixture of 5-(2-hydroxyethyl)pyrimidine-2,4-diol (1.0 g, 6.4 mmole), 5 ml. of acetic anhydride, and ca. 30 ml. of dry pyridine was stirred for 1 hr. under anhydrous condition. The clear solution was treated with water and evaporated under vacuum to leave a white residue that was recrystallized from water to yield the monoacetate as white powder 2-(2,4-dihydroxypyrimidin-5-yl)ethyl acetate (0.95 g. 74%). LC-MS (m/z)=199 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1.[CH2:24]([NH2:27])[CH2:25][NH2:26]>C(Cl)Cl.C(Cl)Cl.CN(C=O)C>[NH2:26][CH2:25][CH2:24][NH:27][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:5]2[C:4]3[C:9](=[C:10]([Cl:12])[CH:11]=[C:2]([Cl:1])[CH:3]=3)[CH2:8][N:7]([CH3:13])[CH2:6]2)[CH:15]=1)(=[O:22])=[O:21]
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)Cl)c2)C1
Reactant: NCCN
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCN)c2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.5 %

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzene-1-sulfonyl chloride (intermediate 1.6) (100 mg, 0.26 mmol, 1.00 equiv) in DCM (5 mL). This was followed by the addition of a solution of ethane-1,2-diamine (307 mg, 5.11 mmol, 19.96 equiv) in DCM/DMF (10/1 mL). The resulting solution was stirred for 5 h at room temperature. The mixture was concentrated under vacuum. The resulting solution was diluted with 50 mL of ethyl acetate and washed with 2×10 mL of water and then 1×10 mL of Brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to afford 90 mg (76%) of N-(2-aminoethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide as yellow oil.
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[CH:14](=O)[CH2:15][CH3:16]>[Zn].C(OC(=O)C)(=O)C>[CH3:2][C:3]1[NH:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[C:7]=1[CH2:14][CH2:15][CH3:16]
Reactant: CCC=O
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)OC(C)=O
Product: CCCc1c(C)[nH]c(C(=O)OCC)c1C

Procedure:
Acetic anhydride (20 ml) was added to stirred and cooled concentrated hydrochloric acid (5 ml), and 2,4-dimethyl-5-carbethoxy-pyrrole (0.668 g) was dissolved in this. Propionaldehyde (0.6 ml) and amalgamated zinc (10 g, 20 mesh) was added, the mixture stirred 15 min, at 20°-25° then decanted into ice water (100 ml). The solid was distilled (80°-95°, 1 × 10-4 mm) and crystallized from aqueous ethanol as colourless irregular prisms (48%), m.p. 99°-99.5° (lit19) 98°). Anal. Calc. for C12H19NO2 : C, 68.86; H, 9.15; N, 6.69. Found: C, 68.75; H, 9.19; N, 6.89.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])([CH3:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:11]1([CH3:14])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC1(c2ccccc2Cl)CCN(Cc2ccccc2)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: CC1(c2ccccc2Cl)CCNCC1
Reaction time: 12 h
Yield: 73.4 %

Procedure:
A solution of 1-benzyl-4-(2-chloro-phenyl)-4-methyl-piperidine (0.59 g, 1.95 mmol) in 1,2-dichloroethane (10 mL) was treated with 1-chloroethyl chloroformate (0.28 mL, 2.6 mmol). This mixture was stirred for 12 hr at reflux, then evaporated in vacuo. The residue was redissolved in methanol (10 mL) and heated to reflux for 1 hr, then evaporated in vacuo. The resulting brown solid (the hydrochloride salt) was washed with ethyl acetate, then freebased with ethyl acetate/sodium hydroxide to yield 0.30 g (72%) of the title compound, ESI-MS m/z: 246 [M+1].
Reaction SMILES: C(OC([NH:8][CH:9]([P:19]([O:23][CH3:24])([O:21][CH3:22])=[O:20])[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=O)(C)(C)C.C(OC(=O)[NH:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[S:39][CH:40]=[CH:41][CH:42]=2)=[CH:34][C:33]=1[NH2:43])(C)(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:24][O:23][P:19]([CH:9]([NH2:8])[C:10]1[CH:11]=[CH:12][C:13]([C:14](=[O:16])[NH:43][C:33]2[CH:34]=[C:35]([C:38]3[S:39][CH:40]=[CH:41][CH:42]=3)[CH:36]=[CH:37][C:32]=2[NH2:31])=[CH:17][CH:18]=1)(=[O:20])[O:21][CH3:22]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Reactant: COP(=O)(OC)C(NC(=O)OC(C)(C)C)c1ccc(C(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COP(=O)(OC)C(N)c1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-[tert-Butoxycarbonylamino-(dimethoxy-phosphoryl)-methyl]-benzoic acid (76 mg, 0.212 mmol), (2-amino-4-thiophen-2-yl-phenyl)-carbamic acid tert-butyl ester (74 mg, 0.254 mmol), EDC (61 mg, 0.317 mmol), HOBT (39 mg, 0.254 mmol), and DIPEA (82 mg, 0.635 mmol) were combined and diluted with DMF (0.85 mL). The resulting mixture was stirred at ambient temperature for 18 hours. The reaction mixture was purified directly by HPLC (20-85% MeCN in water w/0.025% TFA). Pure fractions were identified, combined, then concentrated in vacuo. The residue was diluted with 10:1 DCM:TFA and stirred at ambient temperature. After 2 h the mixture was concentrated in vacuo to give the title compound: 1H NMR (DMSO-d6, 600 MHz) 9.81 (s, 1H), 9.06 (br-s, 2H), 8.05 (d, J=9.0 Hz, 2H), 7.62 (d, J=9.0 Hz, 2H), 7.44-7.46 (m, 1H), 7.34-7.36 (m, 1H), 7.29-7.32 (m, 1H), 7.22-7.24 (m, 1H), 7.03-7.05 (m, 1H), 6.82 (d, J=7.8 Hz, 2H), 5.20 (d, J=17.4 Hz, 1H), 3.73 (d, J=10.8 Hz, 3H), 3.58 (d, J=10.8 Hz, 3H). MS: cal'd 432 (MH+), exp 432 (MH+).
Reaction SMILES: [C:1]([N:3]=C(OCC)C)#[N:2].[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[O:15][C:16]([CH3:29])([CH3:28])[C@@H:17]([OH:27])[C@H:18]([NH:19][CH2:20][C:21]3C=CC=CC=3)[C:13]=2[CH:12]=1)#N.[C:32](OCC)(=O)C>>[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[O:15][C:16]([CH3:28])([CH3:29])[C@@H:17]([OH:27])[C@H:18]([NH:19][C:20](=[N:3][C:1]#[N:2])[CH3:21])[C:13]=2[CH:12]=1)#[CH:32]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](NCc2ccccc2)[C@@H]1O
Reactant: CCOC(C)=NC#N
Reactant: CCOC(C)=O
Product: C#Cc1ccc2c(c1)[C@@H](NC(C)=NC#N)[C@H](O)C(C)(C)O2
Reaction time: 2 h

Procedure:
To 1.54 g of ethyl N-cyanoacetimidate, 3.86 g of 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-benzylamino-2H-benzo[b]pyran-3-ol was added, and the mixture was reacted under stirring at a temperature of from 100° to 120° C. for 2 hours. The reaction mixture was cooled, then dissolved in 100 ml of ethyl acetate, washed twice with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The residual solid was purified by silica gel chromatography to obtain 1.65 g of the above identified compound in the form of crystals.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20](C=O)=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:31]([CH2:33][NH2:34])[OH:32].[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([BH3-])#N.[Na+]>O.ClCCCl>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH2:35][NH:34][CH2:33][CH2:31][OH:32])=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:29])([F:28])[F:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NCCO
Reactant: O=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: OCCNCc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
A mixture of 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (Preparation 88A, 40 mg, 0.097 mmol), Ethanolamine (0.059 mL, 0.975 mmol), 1,2-dichloroethane (3 mL) and sodium triacetoxyborohydride (62.0 mg, 0.292 mmol) was stirred at room temperature overnight. Sodium cyanoborohydride (20 mg, 0.318 mmol) was then added. The mixture was stirred at room temperature for 1 h before water (1 mL) was added. The aqueous layer was extracted with ethyl acetate (3×1 mL). The combined organic solutions were concentrated under reduced pressure. Purification using reverse phase HPLC (Phenomenex Luna AXIA 5 u c18 30×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA), concentration, neutralization with saturated aqueous sodium bicarbonate solution, and extraction with ethyl acetate gave 2-((3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methylamino)ethanol (28 mg, 0.060 mmol, 61.8% yield) as a white solid.
Reaction SMILES: [OH-:1].[K+].C([C:5]([CH2:16]CC(O)=O)([CH2:9][CH2:10][C:11]1[CH:15]=[CH:14][S:13][CH:12]=1)[C:6]([O-:8])=[O:7])C.C([OH:23])C>O>[C:16]([CH:5]([CH2:9][CH2:10][C:11]1[CH:15]=[CH:14][S:13][CH:12]=1)[C:6]([OH:8])=[O:7])([OH:23])=[O:1]
Reactant: CCC(CCC(=O)O)(CCc1ccsc1)C(=O)[O-]
Reactant: CCO
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: O=C(O)C(CCc1ccsc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1.4 g (24.96 mmol) of potassium hydroxide in 7.0 ml of 50% ethanol in water, was added the above diester (765 mg, 2.83 mmol) prepared in Example 6. The resulting reaction was allowed to stir at room temperature for two hr, followed by overnight reflux. The resulting mixture was poured into ice-10% HCl, followed by three ether extractions. The combined organic layer was dired with Na2SO4 and evaporated to afford a white solid in 90% which was recrystallized from chloroform-hexane to produce colorless needles. Mp, 118°-119° C.; nmr (DMSO/d6, δ rel TMS) 12.60br s, 2H; 7.53-6.80m, 3H; 3.20t, 1H; 2.60t, 2H; 1.99q, 2H. Ir (KBr, v, cm-1) 2900w, 1710s, 1410w, 1260w, 925w, 780s. El. Anal. Calcd. for C9H10O4S: C, 56.45; H, 5.92; S, 18.83. Found: C, 56.39; H, 5.92; S, 18.67.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[NH:11][C:10]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:9]=3[C:8]=2[CH:7]=[CH:6][C:5]=1[Cl:25].Br[CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[Cl:3][C:4]1[C:12]2[N:11]([CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:10]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:16][CH2:17][C:9]=3[C:8]=2[CH:7]=[CH:6][C:5]=1[Cl:25]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3c(Cl)c(Cl)ccc3c2CC1
Reactant: BrCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCOc3ccccc3)c3c(Cl)c(Cl)ccc23)CC1
Reaction time: 0.5 h
Yield: 55 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 51 mg, 1.3 mmol) was added to a solution of tert-butyl 7,8-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.30 g, 0.84 mmol) in DMF (5 mL). After 30 min, β-bromophenetole was added (0.31 mL). The reaction was quenched with saturated aqueous NH4Cl after 18 h and extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40S) with heptane/EtOAc (17:3) to give 0.22 g (55%) of a white solid: mp 138.4-139.7° C.; 1H NMR (300 MHz, CDCl3) δ 6.92 (m, 1H), 6.79 (m, 2H), 4.90 (m, 2H), 4.27 (m, 2H), 3.80 (m, 2H), 3.66 (m, 2H), 3.17 (m, 2H), 2.93 (m, 2H), 1.49 (s, 9H); IR (diffuse reflectance) 2979, 1687, 1467, 1443, 1416, 1365, 1253, 1239, 1223, 1172, 1165, 1156, 923, 808, 760 cm−1; MS (EI) m/z 474 (M+), 420, 418, 332, 86, 84, 57, 56, 55, 51; Anal. Calcd for C25H28Cl2N2O3: C, 63.16; H, 5.94; N, 5.89; found: C, 63.15; H, 6.00; N, 5.89.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:13]([C@@H:14]([CH2:23][O:24]S(C2C=CC(C)=CC=2)(=O)=O)[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:35]2[CH:43]=[C:41]([CH3:42])[C:39](=[O:40])[NH:38][C:36]2=[O:37])[C@@H:10]1OS(C1C=CC(C)=CC=1)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[CH2:16]([O:15][C@H:14]1[C@@H:13]2[C@@H:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:10]([C@H:11]([N:35]3[CH:43]=[C:41]([CH3:42])[C:39](=[O:40])[NH:38][C:36]3=[O:37])[O:12]2)[O:24][CH2:23]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](OCc2ccccc2)[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@H](OS(=O)(=O)c3ccc(C)cc3)[C@@H]2OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cn([C@@H]2O[C@H]3[C@@H](OCc4ccccc4)[C@@H]2OC[C@H]3OCc2ccccc2)c(=O)[nH]c1=O

Procedure:
To a stirred solution of nucleoside 17 (0.63 g, 0.81 mmol) in a mixture of ethanol and H2O (40 cm3, 1:1, v/v) at room temperature was added an aqueous solution of sodium hydroxide (1M, 7 cm3). The resulting mixture was heated under reflux for 16 h and then neutralised by addition of dilute hydrochloric acid (10 cm3). The volume of the mixture was reduced to 50% and extraction was performed using dichloromethane (50 cm3×3). The combined organic phase was dried (Na 2SO4) and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol (99:1,v/v) as eluent to give nucleoside 18 as a white solid material (0.40 g, 93%) after evaporation of the solvents under reduced pressure.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:38][C:39]1[O:40][C:41]([CH2:44][CH3:45])=[CH:42][N:43]=1>CN(C=O)C>[CH2:44]([C:41]1[O:40][C:39]([CH2:38][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])=[N:43][CH:42]=1)[CH3:45]
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Reactant: CCc1cnc(CCl)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)o1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (800 mg; compound B50) in DMF (15 ml) are added potassium carbonate (520 mg) and 2-(chloromethyl)-5-ethyl-1,3-oxazole (270 mg; compound D1). After stirring for 1 h at 100° C. further 2-(chloromethyl)-5-ethyl-1,3-oxazole (200 mg; compound D1) and potassium carbonate (400 mg) are added to the reaction mixture. The mixture is stirred for additional 30 min at 100° C. Afterwards all volatile materials are removed in vacuo and the residue is purified by flash chromatography [silica gel, eluent: cyclohexane/EtOAc, 3/2 (v/v)] to give the title compound as a solid.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)[O:2][C:3]([CH3:5])=O.[Na+].[NH2:15][C@@H:16]([CH3:50])[C:17]([NH:19][C@H:20]1[CH2:26][O:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[N:22]([CH2:31][C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[C:47]#[N:48])[N:33]=2)[C:21]1=[O:49])=[O:18].C1OC(O)COC1O>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:47]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[N:34]1[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:32]([CH2:31][N:22]2[C:21](=[O:49])[C@@H:20]([NH:19][C:17](=[O:18])[C@@H:16]([NH:15][CH2:5][CH2:3][OH:2])[CH3:50])[CH2:26][O:25][C:24]3[CH:27]=[CH:28][CH:29]=[CH:30][C:23]2=3)=[N:33]1)#[N:48]
Reactant: C[C@H](N)C(=O)N[C@H]1COc2ccccc2N(Cc2nn(-c3ccccc3C#N)c3ccccc23)C1=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: OC1COC(O)CO1
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H](NCCO)C(=O)N[C@H]1COc2ccccc2N(Cc2nn(-c3ccccc3C#N)c3ccccc23)C1=O
Reaction time: 72 h
Yield: 63.7 %

Procedure:
Na(OAc)3BH (14.2 mg, 67.0 μmol, Eq: 1.4) was added to a solution of (S)-2-amino-N-((S)-5-((1-(2-cyanophenyl)-1H-indazol-3-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)propanamide (23 mg, 47.9 μmol, Eq: 1.00) and glycolaldehyde dimer (3.16 mg, 26.3 μmol, Eq: 0.55) in DCM (1.5 mL). After 72 h. at RT, the mixture was diluted with NaHCO3 and extracted with DCMThecombined extracts were concentrated. The residue was purified by preparative TLC to give the title compound (16 mg, 95%) as a solid. MS m/z 525 (MH+)
Reaction SMILES: [CH3:1][NH:2][CH3:3].S(=O)(=O)(O)O.[C-:9]#[N:10].[Na+].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1>O>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]([N:2]([CH3:3])[CH3:1])[C:9]#[N:10])=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CNC
Reactant: [C-]#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CN(C)C(C#N)c1ccc(F)cc1
Reaction time: 4 h
Yield: 98.4 %

Procedure:
Into a 1 l four-necked flask equipped with a thermometer, a stirrer and a dropping funnel, 144.5 g (1.6 mol) of a 50.7% dimethylamine aqueous solution and 118.5 g of water were charged, and 159.4 g (0.38 mol) of a 25% of sulfuric acid aqueous solution was dropwise added over a period of 15 minutes at a temperature of not higher than 20° C. with stirring. Then, 67.4 g (1.38 mol) of sodium cyanide was introduced. Then, 155.1 g (1.25 mol) of 4-fluorobenzaldehyde was dropwise added over a period of 20 minutes at from 20 to 30° C. Thereafter, the reaction was carried out at 50° C. for 4 hours. After completion of the reaction, the reaction mixture was subjected to liquid separation. The organic layer was separated and washed with 500 ml of water of 50° C. to obtain 222.8 g (yield: 98.4%) of the desired compound having a purity of 98.4% (by GC analysis).
Reaction SMILES: [C:1]([N:11]([CH2:13][C:14](O)=[O:15])[CH3:12])(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:17]([O:19][CH3:20])=[O:18].[H-].[Na+]>CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+]>[C:1]([N:11]([CH3:12])[C:13](=[CH:14][OH:15])[C:17]([O:19][CH3:20])=[O:18])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(CC(=O)O)C(=O)/C=C/c1ccccc1
Reactant: COC=O
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=CO)N(C)C(=O)C=Cc1ccccc1
Reaction time: 0.25 h
Yield: 49 %

Procedure:
A solution of the methyl ester of E-N-cinnamoylsarcosine (2.03 g) and methyl formate (ca. 11 ml) in dry DMF (15 ml) was added to a stirred suspension of sodium hydride (0.42 g) in dry DMF (20 ml). Only gentle effervescence was observed at first, but after 40 minutes brisk effervescence began [further methyl formate (3 ml) added], subsiding after about 15 minutes and continuing gently until the mixture was carefully diluted with aqueous sodium carbonate after 7.5 hours. The mixture was extracted with ether, and the extracts were washed with aqueous sodium carbonate then water, dried and concentrated under reduced pressure to give recovered E-N-cinnamoylsarcosine methyl ester (0.975 g). The original basic aqueous layer was acidified with concentrated hydrochloric acid and extracted with ether. The extracts were washed with water, dried and concentrated under reduced pressure to give methyl N-cinnamoyl-N-methyl-2-amino-3-hydroxypropenoate (1.108 g, 49% yield, or 94% based on recovered starting material) as a pale red glass, used without further purification for the next step. The proton n.m.r. spectrum recorded using deuteriochloroform as solvent showed duplication of some signals (presumably due to restricted rotation about the amide bond). However, with deuterated dimethylsulphoxide as solvent, the following single set of signals was seen: