Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[CH2:15]([O:22][C:23](OC1CC(=O)NC1=O)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[C:23]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7])([O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:24]
Reactant: O=C1CC(OC(=O)OCc2ccccc2)C(=O)N1
Reactant: NCCOCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCOCCO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
To 2-(2-aminoethoxyl)ethanol (20 g) dissolved in dichloromethane (200 ml) was added stepwise triethylamine (26.5 ml) and benzyloxy(carbonyloxy)succinimide (47.47 g). The reaction mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in deionized water (500 ml). The insoluble layer was separated, and the aqueous layer was mixed with 50 g of NaCl and the pH adjusted to 5.0 with 5% H3PO4. The product was extracted with dichloromethane (100 ml, 50 ml, and 50 ml) and the extract was dried with MgSO4, filtered, and evaporated to dryness under reduced pressure. The residue was dried under vacuum overnight, then combined with the previously separated insoluble layer and dissolved in dichloromethane (300 ml). The solution was washed with 5-% aqueous NaCl solution (3×50 ml) and dried with MgSO4. The solvent was distilled under reduced pressure, and the residue was dried overnight under vacuum, giving 40 g of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][CH3:11].[C:12](O)(=O)CC(O)=O.N1CCCCC1.O>CN(C=O)C>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:12])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: O=C(O)CC(=O)O
Reactant: COc1cc(C=O)ccc1O
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Solvent: O
Product: C=Cc1ccc(O)c(OC)c1
Yield: 51 %

Procedure:
A mixture of 4-hydroxy-3-methoxybenzaldehyde (3.42 mmol), malonic acid (13.68 mmol), piperidine (15.58 mmol) in DMF (20 ml) were taken in a 100 ml round bottom flask fitted with a condenser. The flask was shaken well and placed inside the monomode microwave oven and irradiated (250 W, 160° C.) for 15 minutes in parts. After completion, the reaction mixture was poured in ice cooled water and extracted with ethyl acetate. The organic layer was washed with dil. HCl, brine and water and dried over sodium sulphate. The solvent was evaporated under reduced pressure to obtain liquid which was purified on silica gel by column chromatography using a mixture of hexane and ethyl acetate (9:1 to 6:4), provided 4-hydroxy-3-methoxystyrene, a sweet and pleasant smelling liquid, in 51% yield; 1H NMR (CDCl3) 7.36 (21-1, d), 6.94 (2H, m), 6.83 (5H, m), 5.59 (1H, s), 3.86 (3H, s), 3.75 (3H, s); 13C NMR (CDCl3) 159.0, 146.7, 145.2, 130.3, 127.4, 126.6, 126.1, 120.1, 114.5, 114.1, 108.0, 55.9 and 55.3.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:30])[CH:14]([NH:19][C:20]([O:22]CC1C=CC=CC=1)=O)[C:15]([CH3:18])([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:31][C:32]1[CH:40]=[CH:39][C:35](C(O)=O)=[CH:34][C:33]=1[Cl:41].CCN(C(C)C)C(C)C.C(Cl)CCl>CO.CCOC(C)=O.C(Cl)Cl.CN(C=O)C.[Pd]>[C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:30])[CH:14]([NH:19][C:20](=[O:22])[C:35]1[CH:39]=[CH:40][C:32]([NH2:31])=[C:33]([Cl:41])[CH:34]=1)[C:15]([CH3:17])([CH3:18])[CH3:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1CCCN1C(=O)C(NC(=O)OCc1ccccc1)C(C)(C)C
Reactant: Nc1ccc(C(=O)O)cc1Cl
Agent: [Pd]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1CCCN1C(=O)C(NC(=O)c1ccc(N)c(Cl)c1)C(C)(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 96.8 %

Procedure:
To a solution of 3 (19.0 g, 45.4 mmol) in MeOH (200 mL) was added 10% activated Pd on C (2.0 g) in EtOAc (50 mL) and the reaction stirred under H2 for 18 hours. The solution was filtered through Celite and the solvent evaporated to yield a viscous, colorless oil. The free amine was dissolved in dry CH2Cl2/DMF (2:1, 120 mL), the solution cooled to 0° C. and 4-amino-3-chlorobenzoic acid (7.79 g, 45.4 mmol) and DIPEA (7.90 mL, 45.4 mmol) were added. The reaction was stirred for 10 minutes, then EDC (11.32 g, 59.1 mmol) was added. The mixture was stirred at 0° C. for 30 minutes then at room temperature for 18 hours. The solution was diluted with EtOAc (300 mL), washed with 0.5N NaHSO4 (2×250 mL), 10% NaHCO3 (2×250 mL), saturated NaCl (150 mL), dried over MgSO4, and evaporated to dryness. Flash column chromatography on silica gel using CH2Cl2/MeOH, (99/1 to 98/2%) yielded the title compound as a white solid (19.25 g, 97% yield): 1H-NMR (500 MHz, CDCl3) δ 1.12 (s, 9H), 1.48 (s, 9H), 1.85–1.99 (m, 2H), 2.01–2.13 (m, 1H), 2.18–2.29 (m, 1H), 3.63–3.73 (m, 1H), 3.84–3.93 (m, 1H), 4.30–4.41 (m, 1H), 4.86 (d, 1H), 6.73 (d, 1H), 7.51 (d, 1H), 7.73 (s, 1H). Analytical HPLC (cyano column): 12.59 min. LC-MS (ES+) m/e=438.5 (M+H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:37]2[C:42](=[O:43])[C:41]3[S:44][C:45]4[CH2:50][CH2:49][CH2:48][CH2:47][C:46]=4[C:40]=3[CH:39]=[N:38]2)[C:5]([CH2:32][O:33]C(=O)C)=[C:6]([C:8]2[CH:9]=[C:10]([NH:16][C:17]3[N:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:31])[CH:29]=[CH2:30])[CH3:26])[CH:20]=[CH:19][CH:18]=3)[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.O[Li].O>C1COCC1.CC(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([N:37]2[C:42](=[O:43])[C:41]3[S:44][C:45]4[CH2:50][CH2:49][CH2:48][CH2:47][C:46]=4[C:40]=3[CH:39]=[N:38]2)[C:5]([CH2:32][OH:33])=[C:6]([C:8]2[CH:9]=[C:10]([NH:16][C:17]3[N:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:31])[CH:29]=[CH2:30])[CH3:26])[CH:20]=[CH:19][CH:18]=3)[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1
Reactant: C=CC(=O)N[C@@H](C)COc1cccc(Nc2cc(-c3cc(F)cc(-n4ncc5c6c(sc5c4=O)CCCC6)c3COC(C)=O)cn(C)c2=O)n1
Agent: [Li]O
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: C=CC(=O)N[C@@H](C)COc1cccc(Nc2cc(-c3cc(F)cc(-n4ncc5c6c(sc5c4=O)CCCC6)c3CO)cn(C)c2=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.5 %

Procedure:
To a mixture of 108d (70 mg, 0.1 mmol) in THF (6 mL), i-PrOH (2 mL) and H2O (2 mL) was added LiOH.H2O (42 mg, 1 mmol). The reaction mixture was stirred at rt for 16 h and concentrated. The residue was purified by prep-HPLC to give 108 (20 mg, 8% for two steps) as yellow solid. 1H NMR (500 MHz, DMSO-d6): δ 8.61 (d, J=10 Hz, 2H), 8.49 (s, 1H), 8.04-8.03 (m, 1H), 7.52-7.50 (m, 2H), 7.40-7.35 (m, 2H), 6.87 (d, J=8 Hz, 1H), 6.21-6.15 (m, 2H), 6.05-6.02 (m, 1H), 5.54 (d, J=10 Hz, 1H), 4.73 (bs, 1H), 4.30 (bs, 2H), 4.15 (bs, 2H), 4.02 (bs, 1H), 3.61 (s, 3H), 2.93 (bs, 2H), 2.84 (bs, 2H), 1.86 (bs, 4H), 0.97 (bs, 3H). ESI-LCMS: m/z=657.3 [C34H33FN6O5S+H]+
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:18]1[CH:19]=[CH:20][CH:21]=[N:22][C:17]=1[N:4]1[CH2:3][CH2:2][N:1]([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)[CH2:6][CH2:5]1
Reactant: c1ccn(CCCCN2CCNCC2)c1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cnc(N2CCN(CCCCn3cccc3)CC2)nc1

Procedure:
A mixture of 4.14 g (20 mmol) of 1-[4-(piperazinyl)-butyl)pyrrole, 2.29 g (20 mmol) of 2-chloropyrimidine and 4.1 g (30 mmol) of potassium carbonate in 60 ml of dimethylformamide is refluxed for 5 hours. The reaction mixture is evaporated under vacuum, chloroform is added and the mixture is washed with water, dried over sodium sulphate and evaporated under vacuum and 3.3 g of 1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]-butyl}pyrrole are obtained in the form of a liquid.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH2:5]([N:12]1[CH:21]=[C:20]([CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:28]3[CH:29]=[C:30]([CH:35]=[CH:36][C:37]=3[CH3:38])[C:31](OC)=[O:32])[CH:18]=2)[C:13]1=[O:39])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C([Mg]Cl)(C)C>C1COCC1>[CH2:5]([N:12]1[CH:21]=[C:20]([CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:28]3[CH:29]=[C:30]([CH:35]=[CH:36][C:37]=3[CH3:38])[C:31]([NH:4][CH:1]3[CH2:3][CH2:2]3)=[O:32])[CH:18]=2)[C:13]1=[O:39])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(=O)n(Cc4ccccc4)cc(CCCN(C)C)c3c2)c1
Reactant: NC1CC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccccc3)cc(CCCN(C)C)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of cyclopropylamine (0.18 mL) and the product from step ii) (120 mg) in THF (5 mL) was treated with isopropylmagnesium chloride (2N/THF, 1 mL) and stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL), and extracted into ethyl acetate (2×10 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo. Purification by HPLC gave the title compound as a solid (31 mg).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[C:24]([CH:32]=O)=[CH:25][C:26]4[O:30][CH2:29][O:28][C:27]=4[CH:31]=3)[CH:8]=2)[N:3]=1.[C:34]([NH2:38])([CH3:37])([CH3:36])[CH3:35].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O1CCCC1.O>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[C:24]([CH2:32][NH:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:25][C:26]4[O:30][CH2:29][O:28][C:27]=4[CH:31]=3)[CH:8]=2)[N:3]=1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc4c(cc3C=O)OCO4)ccc2n1
Reactant: CC(C)(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)NCc1cc2c(cc1-c1ccc3nc(N)nc(C(=O)N4Cc5ccccc5C4)c3c1)OCO2
Temperature: 60 °C
Reaction time: 6 h

Procedure:
100 mg of 6-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]-benzo-1,3-dioxole-5-carbaldehyde are dissolved in 2 ml of 1,2-dichloroethane and 2 ml of tetrahydrofuran. 30 μl of tert-butylamine and 13 μl of glacial acetic acid are added, and the mixture is stirred at 60° C. for 6 h. After cooling to 25° C., 102 mg of sodium triacetoxyborohydride are added and stirred at 25° C. for a further 12 h. The mixture is poured into water, extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).
Reaction SMILES: C1(N2CCNCC2)C=CC=CC=1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][N:23](CCN2C(=O)C3C=CC=C4C=3C(=CC=C4)C2=O)[CH2:22][CH2:21]1>>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCN1CCN(c2ccccc2Cl)CC1
Agent: c1ccc(N2CCNCC2)cc1
Product: Clc1ccccc1N1CCNCC1

Procedure:
Following the procedure of example 1 but substituting 5.2 g. (0.026 mole) of 1-(o-chlorophenyl)piperazine in part (c) for the N-phenylpiperazine, one obtains the hydrochloride salt of 2-[2-[4-(2-chlorophenyl)-1-piperazinyl]ethyl]-1H-benz[de]isoquinoline-1,3(2H)-dione. This salt is neutralized with aqueous sodium hydroxide and extracted with chloroform. The chloroform solution is dried (Na2SO4), concentrated to 200 ml. and allowed to stand open to the air. The product slowly crystallizes and is removed by filtration. Drying at 50° (60 mm.) overnight yields 4 g. of 2-[2-[4-(2-chlorophenyl)-1-piperazinyl]ethyl]-1H-benz[de]isoquinoline-1,3(2H)-dione; m.p. 213°-214°.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([NH2:12])[C:9]([NH2:11])=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:13].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:23]([C:25]2[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=2)=O)=O)=[CH:17][CH:16]=1>CO>[CH3:1][N:2]1[C:6]2=[CH:7][C:8]3[N:12]=[C:21]([C:18]4[CH:19]=[CH:20][C:15]([Br:14])=[CH:16][CH:17]=4)[C:23]([C:25]4[CH:26]=[CH:27][C:28]([Br:31])=[CH:29][CH:30]=4)=[N:11][C:9]=3[CH:10]=[C:5]2[N:4]=[C:3]1[CH3:13]
Reactant: Cc1nc2cc(N)c(N)cc2n1C
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Solvent: CO
Product: Cc1nc2cc3nc(-c4ccc(Br)cc4)c(-c4ccc(Br)cc4)nc3cc2n1C
Temperature: 25 °C

Procedure:
To a solution of 1,2-dimethyl-5,6-diaminobenzoimidazole in methanol was added 4,4′-dibromo-benzil. The reaction mixture was refluxed for 3 h and cooled to room temperature. The precipitate which formed was filtered and recrystallized from n-butyl alcohol to give the title quinoxaline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16][CH2:15]1)[CH:5]=O.[C:22]([C:26]1[CH:27]=[C:28]([NH2:33])[C:29]([NH2:32])=[CH:30][CH:31]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([C:26]1[CH:31]=[CH:30][C:29]2[NH:32][C:5]([C:4]3[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][CH2:13][N:14]4[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16][CH2:15]4)=[C:2]([Cl:1])[CH:3]=3)=[N:33][C:28]=2[CH:27]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CN1CCCN(CCCOc2ccc(C=O)cc2Cl)CC1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Product: CN1CCCN(CCCOc2ccc(-c3nc4cc(C(C)(C)C)ccc4[nH]3)cc2Cl)CC1
Yield: 34.1 %

Procedure:
This compound was prepared by the method described in Example 1, using 3-chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-benzaldehyde (62 mg, 0.20 mmol, 1.0 equiv), 4-tert-butyl-benzene-1,2-diamine (33 mg, 0.20 mmol, 1.0 equiv), and Na2S2O5 (50 mg, 0.26 mmol, 1.3 equiv) in General Procedure 3. Purification by Method 2 afforded 31 mg (34%) of the title compound. MS (electrospray): mass calculated for C26H35ClN4O, 454.25. m/z found, 455.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.12 (d, J=2.2 Hz, 1H), 7.98 (dd, J=8.6, 2.3 Hz, 1H), 7.6 (s, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.37 (dd, J=8.6, 1.8 Hz, 1H), 7.22 (d, J=8.7 Hz, 1H), 4.19 (t, J=6.0 Hz, 2H), 2.84-2.74 (m, 10H), 2.40 (s, 3H), 2.08-1.97 (m, 2H), 1.90-1.83 (m, 2H), 1.41 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([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:5][C:4]=1[CH2:20][NH:21][CH:22]1[CH2:27][CH2:26][CH:25]([N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:24][CH2:23]1.[Cl:37][C:38]1[C:39]2[CH:49]=[CH:48][CH:47]=[CH:46][C:40]=2[S:41][C:42]=1[C:43](Cl)=[O:44]>>[Cl:37][C:38]1[C:39]2[CH:49]=[CH:48][CH:47]=[CH:46][C:40]=2[S:41][C:42]=1[C:43]([N:21]([CH2:20][C:4]1[CH:5]=[C:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]([F:18])([F:17])[F:19])=[CH:13][CH:14]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH:22]1[CH2:27][CH2:26][CH:25]([N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:24][CH2:23]1)=[O:44]
Reactant: COc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Product: COc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 31 (220 mg, 0.43 mmol) is treated with 3-chloro-benzo[b]thiophene-2-carbonyl chloride (120 mg, 0.52 mmol) using Method D to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([OH:14])[C:6]([OH:13])=[N:7]2.O.[CH:16]([CH:18]=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>[OH-].[Na+]>[OH:14][C:5]1[C:6]([OH:13])=[N:7][C:8]2[C:3]([N:4]=1)=[C:2]1[C:11](=[CH:10][CH:9]=2)[N:12]=[CH:18][CH:16]=[N:1]1
Reactant: O=CC=O
Reactant: Nc1ccc2nc(O)c(O)nc2c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1nc2ccc3nccnc3c2nc1O
Temperature: 50 °C
Yield: 35.9 %

Procedure:
A mixture of 0,5 g (2,6 mmol) 5,6-diamino-2,3-dihydroxyquinoxaline and 20 ml water was added 0,6 ml (3,9 mmol) 40% aqueous glyoxal and 0,41 g (3,9 mmol) sodium carbonate. The reaction mixture was stirred at 50° C. for 1,5 h. After cooling to 25° C., the precipitate was filtered off and washed with water to give 0,49 g. The crude product was dissolved in 2N sodium hydroxide and reprecipitated with 2N hydrochloric acid to pH 6-7 to give 0,2 g (36%) 2,3-dihydroxypyrazino(2,3-f)quinoxaline, m.p.>300° C. NMR (DMSO-d6): 8.30 (1H,d), 8.20 (1H,d), 7.27 (1H,d), 7.0 (1H,d).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8]O)[CH:5]=[N:6][CH:7]=1.S(Cl)([Cl:12])=O>C(Cl)Cl>[Cl:12][CH2:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: OCc1cncc(F)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Fc1cncc(CCl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of (5-fluoropyridin-3-yl)methanol (0.19 g, 1.50 mmol) in DCM (5 mL) was added thionyl chloride (0.19 ml, 2.6 mmol) at 0° C. The reaction was stirred at room temperature for 2 h. The reaction was concentrated and the residue was dried in vacuo to yield 3-(chloromethyl)-5-fluoropyridine (166 mg) which was used without characterization.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH2:16])=[N:13][C:12]=1[CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24](Cl)(=[O:33])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>O1CCCC1.CN(C)C1C=CN=CC=1>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][C:24](=[O:33])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:13][C:12]=1[CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc(CN2CCOCC2)c(C(=O)NCc2ccccc2)s1
Reactant: O=C(Cl)CCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCc1ccccc1)Nc1nc(CN2CCOCC2)c(C(=O)NCc2ccccc2)s1
Temperature: 25 °C
Yield: 74.1 %

Procedure:
To a solution of 2-amino-4-morpholin-4-ylmethylthiazole-5-carboxylic acid benzylamide (0.030 g, 0.09 mmol) in tetrahydrofuran (5 mL) at 0° C. was added hydrocinnamoyl chloride (0.1 mL, 0.67 mmol), 4-dimethylaminopyridine (catalytical amount) and triethylamine (0.2 mL, 1.4 mmol). The reaction mixture was allowed to warm to ambient temperature over 18 h then concentrated in vacuo. The crude product was purified by flash column chromatography eluting with ethyl acetate/hexanes (5/95 to 100/0) to afford the title compound (0.031 g); 1H NMR (DMSO-d6, 400 MHz) δ 7.40-7.15 (m, 10H), 4.46 (d, J=5.1 Hz, 2H), 3.62 (s, 2H), 3.19 (bs, 4H), 2.91 (t, J=7.6 Hz, 2H), 2.74 (t, J=8.1 Hz, 2H), 2.24 (br, s, 4H); MS (ES+) m/z 465 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]([C:19]1[C:27]2[C:22](=[C:23]([CH2:28][S:29][CH3:30])[CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)[CH2:13][C:14](OCC)=[O:15].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.ClCCl>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]([C:19]1[C:27]2[C:22](=[C:23]([CH2:28][S:29][CH3:30])[CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)[CH2:13][CH2:14][OH:15]
Reactant: CCOC(=O)CC(c1ccc(C(F)(F)F)cc1F)c1c[nH]c2c(CSC)cccc12
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CSCc1cccc2c(C(CCO)c3ccc(C(F)(F)F)cc3F)c[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2.74 g (6.13 mmol) of the compound from Example 44A in 20 ml of tetrahydrofuran was added dropwise to 21.5 ml (21.5 mmol) of a 1N solution of lithium aluminum hydride in tetrahydrofuran in 50 ml of tetrahydrofuran at RT under argon. Stirring at RT for 15 min was followed by addition of 1N hydrochloric acid, extraction with dichloromethane, drying of the organic phase over magnesium sulfate, filtration and concentration. 2.47 g (99% of theory) of the title compound were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.[CH3:13][C:14]1(C)[O:21][C:19](=O)[CH2:18][C:16](=O)[O:15]1.C1CCC(N=C=NC2CCCCC2)CC1.C(O)C=C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](=[O:12])[CH2:13][C:14]([O:15][CH2:16][CH:18]=[CH2:19])=[O:21]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(O)Cc1ccc(F)cc1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C=CCO
Product: C=CCOC(=O)CC(=O)Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a CH2Cl2 (40 mL) solution of 2,4-difluorophenyl acetic acid (6.89 g, 40.03 mmol) at 0° C. was added DMAP (4.89 g, 40.03 mmol), and Meldrum's Acid (5.77 g, 40.03 mmol) followed by DCC (8.26 g, 40.03 mmol). The reaction mixture was warmed to ambient temperature and stirred for 4 h. The reaction was filtered to remove the DCU and the filtrate washed with 1N HCl, H2O, and brine. The organics were dried (Na2SO4), filtered and concentrated to a yellow oil. The residue was redissolved in THF (40 mL) and allyl alcohol (8 mL, 117.63 mmol). The reaction mixture was refluxed for 3 h and then concentrated to deliver 9.67 g (95% yield) of the title compound as a pale yellow oil and used without further purification. 1H NMR (CDCl3, 400 MHz) δ 7.16–7.10 (m, 1H), 6.82 (dd, J=16.6, 8.2 Hz, 2H), 5.91–5.82 (m, 1H), 5.31 (dd, J=17.3, 1.4 Hz, 1H), 5.25 (dd, J=10.3, 1.0 Hz, 1H), 4.61 (d, J=5.8 Hz, 2H), 3.82 (s, 2H), 3.52 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][NH2:8].[C:12]([O:16][C:17]([NH:19][CH2:20][CH2:21][C:22](O)=[O:23])=[O:18])([CH3:15])([CH3:14])[CH3:13].OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C(N=C=NCCCN(C)C)C>O.C(OCC)(=O)C.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][NH:8][C:22](=[O:23])[CH2:21][CH2:20][NH:19][C:17](=[O:18])[O:16][C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: COc1cccc(CCN)c1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(CCNC(=O)CCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
3-methoxyphenethylamine (Aldrich, 100 mg, 0.66 mmol), 3-((tert-butoxycarbonyl)amino)-propanoic acid (125 mg, 0.66 mmol), hydroxybenzotriazole (8.9 mg, 0.066 mmol), triethylamine (102 μL, 0.73 mmol) and dimethyformamide (6.6 mL) were combined, then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (139 mg, 0.73 mmol) was added. The solution was allowed to stir at room temperature overnight. Upon completion, ethyl acetate and water were added and the layers were separated. The aqueous phase was extracted with ethyl acetate then the combined organic layers were washed with brine and dried over Na2SO4. Solvent was removed under reduced pressure to give crude product which was purified by flash chromatography using 0-80% ethyl acetate/hexane as the eluent to give the product as a pure white solid (140 mg, 66%).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=[C:6]([F:12])[C:3]=1[C:4]#[N:5].C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:9]([CH:10]2[CH2:11][O:21]2)=[CH:8][CH:7]=[C:6]([F:12])[C:3]=1[C:4]#[N:5]
Reactant: C=Cc1ccc(F)c(C#N)c1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: N#Cc1c(F)ccc(C2CO2)c1Cl

Procedure:
2-chloro-6-fluoro-3-vinylbenzonitrile dissolved in CHCl3 (300 mL) then added mCPBA (29.4 g, 171 mmol) and stirred at RT for 16 h. When TLC showed starting materials were consumed, the mixture was washed with Na2S2O3 (1×), 1N NaOH (1×), brine (2×), then dried over Na2SO4. Filtered and concentrated then purified by MPLC chromatography using 330 g ISCO Redi-sep column and eluted with 20% ethyl acetate/hexane solvent system to yield 2-chloro-6-fluoro-3-(oxiran-2-yl)benzonitrile.