Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2]>C1COCC1>[C:4]1([CH:1]([OH:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Solvent: C1CCOC1
Product: CC(O)c1ccccc1
Yield: 79 %

Procedure:
NaAlH[(S)-BINOL](OMe) gave surprisingly and unexpectedly high conversion (chemical yield) and enantioselectivity values relative to LiAlH[(S)-BINOL](OMe), when admixed with acetophenone (AP). In a comparative experiment, NaAlH[(S)-BINOL](OMe) was admixed with AP in THF at -70° C. to afford 79% 1-phenylethanol (PET) with the (S)-enantiomer in 97% enantiomeric excess, whereas under similar conditions, LiAlH((R)-BINOL)(OMe) afforded only 60% PET with the (R)-enantiomer in only 87% enantiomeric excess (J. Am. Chem. Soc., 1984, 106, 6709). Thus, NaAlH[(S)-BINOL](OMe) is surprisingly and unexpectedly a more efficient and enantioselective reducing agent than its lithium analog.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH:7]([CH2:11][N:12]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:6]2)[O:4][CH2:3][CH2:2]1.NN>C(O)C>[O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH:7]([CH2:11][NH2:12])[CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1CC1CC2(CCN1)OCCO2
Agent: NN
Solvent: CCO
Product: NCC1CC2(CCN1)OCCO2
Temperature: 80 °C
Reaction time: 6 h
Yield: 63.3 %

Procedure:
To a suspension of the above 2-(1,4-dioxa-8-aza-spiro[4.5]dec-7-ylmethyl)isoindole-1,3-dione (3.85 mmol) in absolute ethanol (25 ml) was added hydrazine (0.36 ml, 11.55 mmol). The reaction was stirred at 80° C. (oil bath) for 6 hours, then cooled to ambient temperature and stirred for an additional 12 hours. The thick precipitate was filtered off and washed with ethanol. The filtrate was concentrated in vacuo and reconstituted in dichloromethane (20 ml), forming a small amount of a second precipitate, which was filtered off. The filtrate was evaporated in vacuo and the resulting oil was dissolved in water (10 ml) and basified with 1 N sodium hydroxide until pH=10. The aqueous layer was extracted with 20% isopropyl alcohol/chloroform (12×40 ml). The combined organic extracts were dried (K2CO3), filtered and the solvent evaporated in vacuo affording 0.42 g (63%) of (1,4-dioxa-8-aza-spiro[4.5]dec-7-yl)methylamine as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:6][C:7]1[CH:14]=[C:12]([I:13])[C:11]([O:15][C:16]2[CH:23]=[C:21]([I:22])[C:20]([OH:24])=[C:18]([I:19])[CH:17]=2)=[C:9]([I:10])[CH:8]=1)[NH2:5].[C:26]([NH:36][CH2:37][C:38]([NH:40][CH2:41][C:42](O)=[O:43])=[O:39])([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].C1(N=C=NCCN2CCOCC2)CCCCC1.O>CC(N(C)C)=O>[CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:6][C:7]1[CH:8]=[C:9]([I:10])[C:11]([O:15][C:16]2[CH:17]=[C:18]([I:19])[C:20]([OH:24])=[C:21]([I:22])[CH:23]=2)=[C:12]([I:13])[CH:14]=1)[NH:5][C:42](=[O:43])[CH2:41][NH:40][C:38](=[O:39])[CH2:37][NH:36][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]
Reactant: O=C(O)CNC(=O)CNC(=O)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Agent: C(=NCCN1CCOCC1)=NC1CCCCC1
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)[C@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC(=O)CNC(=O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Thyroxine methyl ester (5 g), as prepared above, N-carbobenzoxyglycylglycine (1.67 g) and cyclohexylmorpholinoethylcarbodiimide (5.3 g) were combined in 40 ml of dimethylacetamide. The mixture was stirred at room temperature for 24 hours, poured into deionized water, and the resulting residue collected and washed with water. The residue was recrystallized from methanol and water, yielding the product, N-carbobenzoxyglycylglycylthyroxine methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9](O)[CH2:10][C:4]=2[CH:3]=1.[Cl-:18].[Ca+2].[Cl-].Cl>C1C=CC=CC=1>[Cl:18][CH:9]1[C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[S:6][C:5]2[CH:16]=[CH:17][C:2]([F:1])=[CH:3][C:4]=2[CH2:10]1
Reactant: [Cl-]
Reactant: OC1Cc2cc(F)ccc2Sc2ccccc21
Agent: Cl
Agent: [Ca+2]
Solvent: c1ccccc1
Product: Fc1ccc2c(c1)CC(Cl)c1ccccc1S2

Procedure:
21.2 g of 2-fluoro-10,11-dihydro-dibenzo[b,f]thiepin-10-ol, 110 ml of benzene and 7.9 g of finely powdered calcium chloride are saturated with hydrochloric acid gas at 15° C (2 hours). The precipitate is filtered off and washed with benzene. The filtrate is evaporated under reduced pressure. There is obtained 10-chloro-2-fluoro-10,11-dihydro-dibenzo-[b,f]thiepin as pink crystals which melt at 90°-92° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].OS(O)(=O)=O.O.[CH3:17]O>>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:17])=[O:6]
Reactant: O=C(O)c1cccc(I)c1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1cccc(I)c1
Temperature: 25 °C

Procedure:
To a solution of 3-iodobenzoic acid (50.0 g, 0.202 mol) in methanol (300.0 ml) was added H2SO4 (1.0 ml). The reaction mixture was heated to reflux. After reflux 24 h, heating was stopped. The reaction mixture was cooled to room temperature. Water (400.0 ml) was added, the product was extracted with ethyl acetate (2×300.0 ml). The organic layer was washed with 20% of NaHCO3 water solution and followed with water. After removal of ethyl acetate, the crude product was purified by recrystallization from ethanol/water. Final white pure product was obtained in 51.0 g (96.5%) after dry under vacuum. 1H NMR (400 MHz, CDCl3, δ): 8.35 (t, J=1.6 Hz, 1H), 7.97 (dt, J1=8.4 Hz, J2=1.6 Hz, 1H), 7.85 (dt, J1=8.4 Hz, J2=1.6 Hz, 1H), 7.14 (t, J=8.4 Hz, 1H), 3.89 (s, 3H, OCH3). 13C NMR (100 MHz, CDCl3, δ): 165.56, 141.70, 138.42, 131.93, 130.03, 128.70, 93.76, 52.38.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:38])=[C:4]([C@:9]23[CH2:16][O:15][C@H:14]([CH2:17][O:18][C:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C@H:13]2[CH2:12][O:11][NH:10]3)[CH:5]=[CH:6][C:7]=1[F:8]>C(O)(=O)C.[Zn]>[NH2:10][C@@:9]1([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[C:3]=2[F:38])[CH2:16][O:15][C@H:14]([CH2:17][O:18][C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@H:13]1[CH2:12][OH:11]
Reactant: Fc1ccc([C@]23CO[C@H](COC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@H]2CON3)c(F)c1Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: N[C@@]1(c2ccc(F)c(Cl)c2F)CO[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
Zinc (2.75 g, 42.1 mmol) was added in one portion to a stirred suspension of (3aR,4S,6aS)-6a-(3-chloro-2,4-difluorophenyl)-4-((trityloxy)methyl)hexahydrofuro[3,4-c]isoxazole (4.5 g, 8.43 mmol) in acetic acid (15 mL) at RT. An exotherm was noted. The mixture was stirred at RT overnight. The zinc was removed by filtration through Celite® washing with methanol. The filtrate was evaporated and the residue was partitioned between DCM and saturated aqueous NaHCO3. The mixture was filtered through Celite® again—washing with DCM and water. The layers were separated and the aqueous layer was further extracted with DCM (×3). The combined extracts were dried by passing through a hydrophobic frit and evaporated to give the title compound (4.38 g). 1H NMR (400 MHz, CDCl3) δ ppm: 2.61-2.71 (m, 1 H) 3.23-3.32 (m, 2 H) 3.68 (dd, J=12.04, 5.32 Hz, 1 H) 3.91 (dd, J=12.10, 4.28 Hz, 1 H) 3.96 (dd, J=9.23, 2.63 Hz, 1 H) 4.28-4.37 (m, 2 H) 6.94-7.01 (m, 1 H) 7.20-7.34 (m, 9 H) 7.38-7.53 (m, 7 H.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[N:4][CH:3]=[N:2]1.[OH-].[Na+].[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[Cl:22])[C:16](Cl)=[O:17]>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[Cl:22])[C:16]([NH:9][CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)=[O:17]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: NCCCn1cncn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCCCn1cncn1)c1ccc(Cl)c(Cl)c1
Reaction time: 8 h

Procedure:
A mixture of about 3.78 g of 1H-1,2,4-triazole-1-propanamine and about 33 ml of approximately 1N sodium hydroxide in about 100 ml of methylene chloride was stirred. An about 6.9 g portion of 3,4-dichlorobenzoyl chloride was added, the mixture was stirred about 6 hours, then allowed to stand overnight. An about 10 ml portion of approximately 1N sodium hydroxide and about 100 ml of methylene chloride were added and the mixture was shaken, then allowed to separate. The organic layer was washed with two about 40 ml portions of water, dried, filtered and evaporated to a solid which was crystallized from ethyl acetate, giving about 5.0 g of the desired product as off-white crystals, mp 128°-130° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8])(=[O:3])[CH3:2].[N+:14]([O-])([OH:16])=[O:15]>>[C:1]([NH:4][C:5]1[CH:12]=[C:11]([Cl:13])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:6]=1[C:7]#[N:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(Cl)ccc1C#N
Reactant: O=[N+]([O-])O
Product: CC(=O)Nc1cc(Cl)c([N+](=O)[O-])cc1C#N
Temperature: 0 °C

Procedure:
25 g of 2-acetylamino-4-chlorobenzonitrile obtained in Step (3) above was added little by little to 200 ml of fuming nitric acid which had been cooled at 0° C. After the completion of the addition, the mixture was reacted for 30 minutes, and then the reaction solution was poured into 1 liter of ice water. The crystals thus-deposited were collected by filtration, washed thoroughly with water and dried. Yield: 22.2 g (72.4%).
Reaction SMILES: O.[NH2:2][C:3]1[NH:4][C:5](=[O:22])[C:6]2[S:11][C:10](=[O:12])[N:9]([C@@H:13]3[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@H:14]3[OH:15])[C:7]=2[N:8]=1.S1C2C(=O)N=CNC=2NC1=O.CCC[C@H](NC([C@H]1N(C([C@@H](NC([C@@H](NC(C2C=NC=CN=2)=O)C2CCCCC2)=O)C(C)(C)C)=O)C[C@H]2[C@@H]1CCC2)=O)C(C(NC1CC1)=O)=O>>[CH2:20]([OH:21])[C@H:18]1[O:19][C@@H:13]([N:9]2[C:10](=[O:12])[S:11][C:6]3[C:5]([N:4]=[C:3]([NH2:2])[NH:8][C:7]2=3)=[O:22])[C@H:14]([OH:15])[C@@H:16]1[OH:17]
Reactant: Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: CCC[C@H](NC(=O)[C@@H]1[C@H]2CCC[C@H]2CN1C(=O)[C@@H](NC(=O)[C@@H](NC(=O)c1cnccn1)C1CCCCC1)C(C)(C)C)C(=O)C(=O)NC1CC1
Agent: O=c1[nH]c2[nH]cnc(=O)c2s1
Solvent: O
Product: Nc1nc(=O)c2sc(=O)n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2[nH]1

Procedure:
5-Amino-3-beta-D-ribofuranosylthiazolo(4,5-d)pyrimidine-2,7(3H,6H)-dione monohydrate; Thiazolo(4,5-d)pyrimidine-2,7(3H,4H)-dione, 5-amino-3-beta-D-ribofuranosyl-, monohydrate); VX-950
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([NH:22][CH2:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:29]3[CH:34]=[CH:33][C:32]([O:35]C)=[CH:31][CH:30]=3)[S:8][C:7]=2[CH:37]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([NH:22][CH2:23][CH2:24][C:25]([F:28])([F:26])[F:27])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:29]3[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=3)[S:8][C:7]=2[CH:37]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/C(=O)NCCC(F)(F)F)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(Oc2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1)NCCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
To a 30 mL vial containing (E)-3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)-N-(3,3,3-trifluoropropyl)acrylamide (38 mg, 0.07 mmol) in DCM (1 mL) was added BBr3 (1 M in heptane, 0.072 mL, 0.07 mmol) and the reaction was stirred at room temperature for 1 h. The reaction was quenched with 4 mL MeOH and stirred for 10 min at room temperature after which time the resulting mixture was concentrated to 50% volume and the crude product was purified by reverse phase HPLC (acidic condition, 0.1% TFA in 1-100% CH3CN/H2O) to afford (E)-3-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)-N-(3,3,3-trifluoropropyl)acrylamide (31 mg, 0.06 mmol, 86% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm=7.40-7.63 (m, 5H), 7.21 (d, J=2.02 Hz, 1H), 7.15 (d, J=8.59 Hz, 1H), 6.88-6.98 (m, 2H), 6.68-6.87 (m, 3H), 6.45 (d, J=15.66 Hz, 1H), 3.54 (t, J=7.07 Hz, 2H), 2.46 (tq, J=6.82, 10.95 Hz, 2H). LC/MS (m/z, MH+): 500.4.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[C:17]([C:18](OC)=[O:19])[C:11]=3[N:10]=2)=[CH:5][CH:4]=1)#[N:2].[NH3:22]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([NH2:22])=[O:19])[C:11]=3[N:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1cccc2[nH]c(-c3ccc(C#N)cc3)nc12
Reactant: N
Product: N#Cc1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)cc1

Procedure:
Following standard procedure C, methyl 2-(4′-cyanophenyl)-1-H-benzimidazole-4-carboxylate (169.5 mg, 0.612 mmol) was treated with ammonia under pressure. The crude product was recrystallised from boiling methanol to yield the title compound pure as white crystals. (116.5 mg, 73%) mp >310° C.; Found C 67.81 H 3.89 N 20.87, C15H10N4O.0.2 MeOH Requires C 67.95 H 4.05 N 20.85; vmax(cm−1) 3332.27, 3274.86, 3177.98, 2230.85, 1658.54, 1608.10; δH 7.45-7.49 (1H, t); 7.87-7.91 (1H, d), 7.91 (1H, br s), 7.98-8.02 (1H, d); 8.13-8.17 (2H, d, J=8.3), 8.50-8.54 (2H, d, J=8.3), 9.2-9.4 (1H, br s), 13.6-13.8 (1H, br 8); m/z (EI) 262 (M+), 245, 217, 102.
Reaction SMILES: CCN(C(C)C)[CH:4]([CH3:6])[CH3:5].[ClH:10].Cl.Cl.[NH2:13][CH2:14][CH:15]([C:23]1[C:27]2[CH:28]=[CH:29][C:30]([C:32]3[C:33]4[C@H:40]([CH3:41])[CH2:39][C@@H:38]([OH:42])[C:34]=4[N:35]=[CH:36][N:37]=3)=[CH:31][C:26]=2[S:25][N:24]=1)[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.CC(C)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].Cl>ClCCCl.C1COCC1.C(Cl)Cl.CCOCC>[ClH:22].[ClH:10].[ClH:22].[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH:15]([C:23]2[C:27]3[CH:28]=[CH:29][C:30]([C:32]4[C:33]5[C@H:40]([CH3:41])[CH2:39][C@@H:38]([OH:42])[C:34]=5[N:35]=[CH:36][N:37]=4)=[CH:31][C:26]=3[S:25][N:24]=2)[CH2:14][NH:13][CH:4]([CH3:6])[CH3:5])=[CH:21][CH:20]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(-c3ccc4c(C(CN)c5ccc(Cl)cc5)nsc4c3)c21
Reactant: CCN(C(C)C)C(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)NCC(c1ccc(Cl)cc1)c1nsc2cc(-c3ncnc4c3[C@H](C)C[C@H]4O)ccc12

Procedure:
DIEA (0.035 mL, 0.20 mmol) was added to a stirred suspension of (5R,7R)-4-(3-(2-amino-1-(4-chlorophenyl)ethyl)benzo[d]isothiazol-6-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol trihydrochloride (22 mg, 0.050 mmol) in DCE (1.5 mL). The suspension was shaken until dissolved. A solution of acetone (0.022 mL, 0.30 mmol) in THF (0.3 mL) was added. The reaction was allowed to stir at room temperature for 15 minutes, at which point Na(OAc)3BH (27 mg, 0.13 mmol) was added. The reaction was allowed to stir at room temperature for 1 hour. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3 solution and brine, dried and concentrated. The resulting residue was purified by column chromatography (DCM:7N ammonia in MeOH, 30:1) to give the free base, which was taken up in DCM and acidified with 2N HCl in ether. Removal of the solvents under reduced pressure gave (5R,7R)-4-(3-(1-(4-chlorophenyl)-2-(isopropylamino)ethyl)benzo[d]isothiazol-6-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol trihydrochloride. LCMS (APCI+) m/z 479, 481 [M+H]+; Rt=2.69 min.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][C:3](Cl)=[O:4].[CH:8]([N:11]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36])[C:12](=[O:28])[CH2:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:10])[CH3:9]>C1COCC1>[O:6]=[C:1]1[N:14]([CH2:13][C:12]([N:11]([CH:8]([CH3:10])[CH3:9])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])=[O:28])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:3](=[O:4])[CH2:2]1
Reactant: O=C(Cl)CC(=O)Cl
Reactant: COc1ccccc1N(C(=O)CNc1ccccc1Nc1ccccc1)C(C)C
Solvent: C1CCOC1
Product: COc1ccccc1N(C(=O)CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21)C(C)C
Reaction time: 8 h

Procedure:
Malonyl dichloride (0.50 mL) in THF (22 mL) is added dropwise over 35 min to a 0° C. solution of N-Isopropyl-N-(2-methoxy-phenyl)-2-(2-phenylamino-phenylamino) acetamide, prepared as in Part C, (1.90 g, 4.87 mmol) in THF (45 mL) and the resultant mixture allowed to attain RT overnight. The solvents were removed in vacuo and the residue purified by silica gel flash column chromatography using 2% methanol in methylene chlorideas eluent to afford 2-(-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(2-methoxy-phenyl) acetamide (770 mg) as a cream foam, which exists as 3:2 mixture of rotamers (major rotamer recorded): 1H NMR (300 MHz, CDCl3) δ7.60-6.90 (m, 13H), 5.05 (m, 1H, J=6.9), 4.60-3.40 (m, 7H), 1.12 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].Cl[CH2:23][C:24]1[O:28][N:27]=[C:26]([CH2:29][CH3:30])[CH:25]=1>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:23][C:24]3[O:28][N:27]=[C:26]([CH2:29][CH3:30])[CH:25]=3)[CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Reactant: CCc1cc(CCl)on1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCc1cc(CN2C[C@@H]3COCCN3c3nc(Cl)ncc32)on1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x5 using (R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 100 mg, 0.441 mmol) in DMSO (5 mL), sodium tert-butoxide (50.9 mg, 0.529 mmol) and 5-(chloromethyl)-3-ethylisoxazole (70.7 mg, 0.485 mmol) (120 mg, 81%). ESI-MS m/z [M+H]+ calc'd for C15H18ClN5O2, 336.12; found 336.3.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[F:11].[C-:12]#[N:13].[Na+]>C(O)C.O>[F:11][C:4]1[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][C:12]#[N:13]
Reactant: COc1cccc(CCl)c1F
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cccc(CC#N)c1F
Temperature: 70 °C
Yield: 82.3 %

Procedure:
To a solution of 1-(chloromethyl)-2-fluoro-3-methoxybenzene (8.6 g, 49.3 mmol) in ethanol (60 mL) and water (10 mL), sodium cyanide (4.8 g, 98.5 mmol) was added. The resulting solution was heated at 70° C. for 16 h. After cooling to room temperature, the solution was poured into water (200 mL) and extracted with ethyl acetate (2×200 mL). The combined organic layers were washed (brine), dried (Na2SO4), and concentrated in vacuo to give the title compound (6.7 g). 1H NMR (CDCl3): δ 7.13-7.07 (m, 1H), 7.02-6.92 (m, 2H), 3.89 (s, 3H), 3.81 (s, 2H).
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH2:9][CH:10]([CH3:22])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:3][C:4]([OH:6])=[O:5].CS(Cl)(=O)=O.CC1(C)[O:33][CH:32]([CH2:34]O)[CH2:31][O:30]1.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(#N)C.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:1][C:2]([CH2:7][CH2:8][CH2:9][CH:10]([CH3:22])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:3][C:4]([O:6][CH2:34][CH:32]([CH2:31][OH:30])[OH:33])=[O:5]
Reactant: CC(=CC(=O)O)CCCC(C)CCCC(C)CCCC(C)C
Reactant: CC1(C)OCC(CO)O1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=CC(=O)OCC(O)CO)CCCC(C)CCCC(C)CCCC(C)C
Temperature: -50 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
A solution of 5.0 g of 3,7,11,15-tetramethyl-2-hexadecenoic acid and 4.3 g of 4-(N,N-dimethylamino)pyridine dissolved in 50 ml of methylene chloride was cooled to -50° C. Thereinto was dropped 1.8 g of methanesulfonyl chloride. After the completion of the dropping, the resulting mixture was stirred at the same temperature for 1 hour. Thereinto was dropped 3.2 g of 2,2-dimethyl-1,3-dioxolane-4-methanol at the same temperature. After the completion of the dropping, the temperature of the reaction mixture was elevated to room temperature in 6 hours. After the completion of the reaction, the reaction mixture was washed with 1N hydrochloric acid, 3% aqueous sodium hydrogencarbonate solution and water in this order, and the solvent was removed by distillation under reduced pressure. The residue obtained was dissolved in 50 ml of acetonitrile. To the resulting solution was added 5 ml of 2N hydrochloric acid. The resulting mixture was stirred for 5 hours at room temperature. The reaction mixture was neutralized with triethylamine, and then concentrated under reduced pressure. The residue obtained was dissolved in 20 ml of ethyl acetate. The resulting solution was washed with 1N hydrochloric acid, 3% asqueous sodium hydrogencarbonate solution and water in this order and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The redsidue obtianed was purified by a column chromatography (eluant: benzene) to obtain 6.0 g (yield: 96.7%) of oily glyceryl 3,7,11,15-tetramethyl-2-hexadecenoate.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[O-]CC.[Na+].[CH3:9][O:10][CH:11]([O:19][CH3:20])[C:12](=O)[CH:13]=[CH:14]N(C)C>C(O)C>[CH3:9][O:10][CH:11]([O:19][CH3:20])[C:12]1[CH:13]=[CH:14][N:4]=[C:2]([SH:3])[N:1]=1
Reactant: COC(OC)C(=O)C=CN(C)C
Reactant: NC(N)=S
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COC(OC)c1ccnc(S)n1
Temperature: 80 °C

Procedure:
A solution of thiourea (1.32 g, 17.3 mmol) and sodium ethoxide (21% wt in EtOH, 6.5 mL, 17.3 mmol) in ethanol (45 mL) was stirred at room temperature for 15 min, and then was added to a solution of 1,1-dimethoxy-4-dimethylaminobut-3-en-one (3.0 g, 17.3 mmol) in ethanol (20 mL). The reaction was heated to 80° C. for 16 h, and concentrated to dryness to yield 4-dimethoxymethyl-pyrimidine-2-thiol that was used crude in the methylation step. Methylation: To a solution of 4-dimethoxymethyl-pyrimidine-2-thol (4.3 g, 23.1 mmol) in DMF (55 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 1.4 g, 35.0 mmol). The reaction was stirred for 15 min at 0° C. and iodomethane (1.44 mL, 23.1 mmol) was added. After stirring for 16 h, the reaction was partitioned between ethyl acetate and water and extracted with ethyl acetate (2×). The combined organic extracts were dried with MgSO4, concentrated and purified by column chromatography (15% ethyl acetate/hexane) to yield pure acetal 46 (1.94g, 9.7 mmol, 42% for 2 steps). 1H NMR (chloroform-d1): δ=8.56 (d, 1H, J=5 Hz,), 7.19 (d, 1H, J=5 Hz,), 5.19 (s, 1H), 3.42 (s, 6H), 2.58 (s, 3H). Calculated mass=200.2, [M+H]+=201. HPLC (method C) rt=6.1 min (95.2% @ 210-370 nm).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[CH:17][N:18]([CH2:19][C:20]([N:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)=[O:21])[C:12]2=[N:11][C:10]=1[C:35]1[S:36][C:37]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)=[CH:38][N:39]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>CO.Cl>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[CH:17][N:18]([CH2:19][C:20](=[O:21])[N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:12]2=[N:11][C:10]=1[C:35]1[S:36][C:37]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=2)=[CH:38][N:39]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cn2ccn3c(=O)c(OCc4ccccc4)c(-c4ncc(Cc5ccc(F)cc5)s4)nc23)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C(Cn1ccn2c(=O)c(OCc3ccccc3)c(-c3ncc(Cc4ccc(F)cc4)s3)nc12)N1CCNCC1
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of the product of example 111 (4.32 g, 8.23 mmol) in MeOH (50 ml), 6N HCl (25 ml) was added drop-wise at room temperature. The mixture was stirred for 2 hours, after which saturated sodium bicarbonate was added to adjust the pH 9˜10, and then extracted with CH2Cl2. The extracts were combined, washed with brine, and then dried over sodium sulfate. The solvent was removed under pressure to give the titled product as yellow slide (3.0 g, 82% yield).