Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[C:10]1[O:14][N:13]=[C:12]([CH3:15])[CH:11]=1)[NH2:6].[C:16](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:17]>ClCCl>[N:6]([C:5]1[CH:7]=[CH:8][C:9]([C:10]2[O:14][N:13]=[C:12]([CH3:15])[CH:11]=2)=[C:3]([O:2][CH3:1])[CH:4]=1)=[C:16]=[S:17]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: COc1cc(N)ccc1-c1cc(C)no1
Solvent: ClCCl
Product: COc1cc(N=C=S)ccc1-c1cc(C)no1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.6 %

Procedure:
Step H (3): Dichloromethane (20 mL) was added to a flask charged with 3-methoxy-4-(3-methylisoxazol-5-yl)aniline (500 mg, 2.448 mmol) and 1,1′-thiocarbonyldipyridin-2(1H)-one (569 mg, 2.448 mmol). The resulting mixture was stirred for 24 h at rt. The crude reaction mixture was concentrated and the crude products were purified using silica gel chromatography (20-50% EtOAc/hexane) linear gradient to afford 5-(4-isothiocyanato-2-methoxyphenyl)-3-methylisoxazole (0.510 g, 84% yield). LC-MS (M+H)+ 247.2. 1H NMR (400 MHz, methanol-d4) δ ppm 7.86 (d, J=8.56 Hz, 1 H) 7.06 (d, J=2.01 Hz, 1 H) 6.99 (dd, J=8.44, 1.89 Hz, 1 H) 6.73 (s, 1 H) 3.97 (s, 3 H) 2.31 (s, 3 H).
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[N:14]([O:16][O-])=[O:15]>P([O-])([O-])([O-])=O>[N+:14]([NH:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)([O-:16])=[O:15]
Reactant: O=NO[O-]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: O=P([O-])([O-])[O-]
Product: O=C(O)[C@H](Cc1ccc(O)cc1)N[N+](=O)[O-]

Procedure:
Nitration of L-tyrosine: Peroxynitrite (0.44 μmol) was reacted with 0.16 μmol of L-tyrosine in 2 mL phosphate buffer solution, pH 7.4 at T=24° C. for 5 min. The concentration of such formed nitrotyrosine was estimated by recording the 438 nm absorbance (ε=4200 M−1cm−1) of basified solutions (via the addition of 0.2 ml of 7.8 M NaOH). The same experiments were repeated in the presence of either 0.1 μmol 1-Fe or 1-Mn.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:11]([O:22][CH3:23])(=[O:21])[C:12]1[CH:20]=[CH:19][C:17]([OH:18])=[C:14]([O:15][CH3:16])[CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[CH3:23][O:22][C:11](=[O:21])[C:12]1[CH:20]=[CH:19][C:17]([O:18][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=2[CH:7]=[O:8])=[C:14]([O:15][CH3:16])[CH:13]=1
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(Oc2ccc(Br)cc2C=O)c(OC)c1
Yield: 42.4 %

Procedure:
In a manner similar to the method described in Example 50a, 5-bromo-2-fluorobenzaldehyde (4.1 g, 20 mmol) (Alfa) was reacted with methyl vanillate (3.64 g, 20 mmol)(Aldrich) and K2CO3 in N,N-dimethylacetamide to give 4-(4-bromo-2-formyl-phenoxy)-3-methoxy-benzoic acid methyl ester as a white solid (Yield 3.1 g, 92%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:17][CH:16]=2)=[C:11]([N+:29]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC>P(OCC)(OCC)OCC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:17][C:16]=3[NH:29]2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OCc3ccccc3)cc2[N+](=O)[O-])cc1
Agent: CCOP(OCC)OCC
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)[nH]c1cc(OCc3ccccc3)ccc12
Temperature: 145 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
A suspension of tert-butyl 4′-(benzyloxy)-2′-nitrobiphenyl-4-ylcarbamate (740 mg, 1.67 mmol) in 2 mL of triethyl phosphite was heated at 145° C. for 15 h under Ar atmosphere and cooled to rt. It was added 10 mL of hexane and let sit for 10 min. Solid was collected via filtration and washed with ether/hexane (v:v 1/1, 10 mL) and dried under high vacuum to afford tert-butyl 7-(benzyloxy)-9H-carbazol-2-ylcarbamate as a off-white solid (480 mg, 74%). 1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.83-7.78 (m, 3H), 7.46 (d, J=7.2 Hz, 2H), 7.38 (m, 2H), 7.32 (d, J=7.2 Hz, 1H), 6.94 (d, J=2.0 Hz, 1H), 6.88 (dd, J=8.8, 2.4 Hz, 1H), 6.83 (dd, J=8.4, 2.0 Hz, 1H), 6.60 (s, 1H), 5.15 (s, 2H), 1.52 (s, 9H); MS (ESI) m/z 389 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C:10]2[CH:29]=[CH:28][C:13]3[N:14]=[C:15]([N:17]4[C@@H:21]5[CH2:22][CH2:23][CH2:24][CH2:25][C@H:20]5[O:19][C:18]4([CH3:27])[CH3:26])[S:16][C:12]=3[CH:11]=2)[C:3]=1[N+:30]([O-])=O.CCOC(C)=O>CO.[Pd]>[CH3:26][C:18]1([CH3:27])[N:17]([C:15]2[S:16][C:12]3[CH:11]=[C:10]([CH2:9][NH:8][C:4]4[C:3]([NH2:30])=[CH:2][N:7]=[CH:6][N:5]=4)[CH:29]=[CH:28][C:13]=3[N:14]=2)[C@@H:21]2[CH2:22][CH2:23][CH2:24][CH2:25][C@H:20]2[O:19]1
Reactant: CC1(C)O[C@@H]2CCCC[C@H]2N1c1nc2ccc(CNc3ncnc(Cl)c3[N+](=O)[O-])cc2s1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1(C)O[C@@H]2CCCC[C@H]2N1c1nc2ccc(CNc3ncncc3N)cc2s1
Reaction time: 15 h
Yield: 125.9 %

Procedure:
To a stirred mixture of 6-chloro-N-((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methyl)-5-nitropyrimidin-4-amine (153 mg, 0.3 mmol) from Step 5 of this Example in MeOH (5 mL) and EtOAc (5 mL) was added Pd 10% wt. on carbon (20 mg, 0.02 mmol). Hydrogen gas was bubbled through the stirred mixture for 2 min, then stirring was continued for 15 h under 1 atm of H2. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford N4-((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methyl)pyrimidine-4,5-diamine as an oil (155 mg). The material was used in the next step without further purification. LCMS (ESI) m/z 411 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[OH:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([N:24]3[CH2:25][CH2:26][CH:21]([OH:20])[CH2:22][CH2:23]3)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2]
Reactant: OC1CCNCC1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)N3CCC(O)CC3)s2)c(C)[nH]c1=O
Yield: 63.6 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 4-hydroxypiperidine as described in Step 5, Example 24 to give the title compound as a solid (63.6% yield). LC/MS: RT 2.48 min; m/e 383 (M+H); 1H NMR (δ, ppm): 11.8 (1H, s), 7.6 (1H, d); 7.4 (1H, s); 7.3 (1H, d), 3.6 (1H, s), 3.2 (2H, m), 2.8 (2H, m), 2.4 (2H, q), 2.36 (3H, s), 1.8 (2H, m), 1.5 (2H, m), 1.05 (3H, t).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12](OC)=[O:13])[CH:10]=[N:11][C:5]=2[N:4]2[CH2:16][CH2:17][C@@H:3]12.[H-].[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>O1CCCC1.O.CO>[OH:13][CH2:12][C:9]1[CH:10]=[N:11][C:5]2[N:4]3[CH2:16][CH2:17][C@H:3]3[C:2](=[O:1])[NH:7][C:6]=2[CH:8]=1
Reactant: COC(=O)c1cnc2c(c1)NC(=O)[C@@H]1CCN21
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C1Nc2cc(CO)cnc2N2CC[C@@H]12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.2 %

Procedure:
(S)-methyl 6-oxo-6,6a,7,8-tetrahydro-5H-azeto[1,2-a]pyrido[3,2-e]pyrazine-3-carboxylate (0.570 g, 2.444 mmol) was suspended in Tetrahydrofuran (Volume: 8.15 ml) under nitrogen atmosphere and NaH (196 mg, 4.9 mmol) was added in several portions over 2 min. The reaction mixture was stirred at room temperature for 10 min and cooled to below −50° C. lithium aluminum hydride (2.200 ml, 4.40 mmol) was added over the period of 5 min and the reaction was kept at a temperature between −30 and −20° C. for 1 h (LCMS: >95% conversion). The mixture was cooled to below −50° C. and MeOH (4 mL) was added. Water (1 mL) was added and the reaction mixture was stirred at rt for 10 min. Rochelle salt (20% solution) was added (10 mL) and the mixture was extracted with EtOAc (3×30 mL) and THF (3×100 mL). The combined organic extracts were dried (Na2SO4 and MgSO4), filtered and concentrated in vacuo. The residue was suspended in THF/Ethyl ether (1:1, 20 mL), filtered off and dried in vacuum to afford (S)-3-(hydroxymethyl)-7,8-dihydro-5H-azeto[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one (0.332 g, 1.618 mmol, 66.2% yield) as a light tan solid. [M+H] calc'd for C10H11N3O2, 205; found, 205.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[CH2:5]([O:12][CH:13]([C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[CH:17][C:16]=1[C:23]1[CH:24]=[N:25][C:26]2N[CH2:28][CH2:29][CH2:30][C:31]=2[CH:32]=1)[CH3:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH2:5]([O:12][CH:13]([C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[CH:17][C:16]=1[C:23]1[CH:32]=[C:31]2[C:26](=[N:25][CH:24]=1)[N:1]([C:2]([NH2:4])=[O:3])[CH2:28][CH2:29][CH2:30]2)[CH3:14])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: NC(N)=O
Reactant: CC(OCc1ccccc1)c1c(C#N)cncc1-c1cnc2c(c1)CCCN2
Product: CC(OCc1ccccc1)c1c(C#N)cncc1-c1cnc2c(c1)CCCN2C(N)=O

Procedure:
The titled product is synthesized according to the procedure of Urea Formation Method II using 4-(1-benzyloxy-ethyl)-5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-nicotinonitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH2:10].Cl[C:12]1[CH:22]=[C:16]2[N:17]([CH3:21])[CH2:18][CH2:19][CH2:20][N:15]2[C:14](=[O:23])[N:13]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:12]1[CH:22]=[C:16]2[N:17]([CH3:21])[CH2:18][CH2:19][CH2:20][N:15]2[C:14](=[O:23])[N:13]=1
Reactant: NCc1ccc(F)cc1F
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(NCc1ccc(F)cc1F)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E59 starting from (2,4-difluorophenyl)methanamine and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].C(O)(=O)C.[CH:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:14])=[O:15])[CH2:10][N:9]1[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:7])#[N:3]
Reactant: O=Cc1ccccc1
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)CN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)CN1Cc1ccccc1
Reaction time: 1 h

Procedure:
To a suspension of (2S,4R)-4-benzenesulfonyl-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride (0.13 mmole) prepared in analogy to experiment K1 in THF (1 ml) was added acetic acid (15 ul) followed by the addition of benzaldehyde (0.14 mmole) and stirring was continued at 22° C. for 1 h. Sodium triacetoxyborohydride (0.38 mmole) was added in one portion and stirring was continued at 22° C. for 3 h. The mixture was quenched with aqueous HCL and MeOH and the solution was purified by prep. HPLC (RP-18) using a mixture of acetonitrile and water to give (2S,4R)-4-benzenesulfonyl-1-benzyl-pyrrolidine-2-carboxylic acid cyanomethyl-amide as a colourless oil. MS: 384.1 [M+H]+.
Reaction SMILES: O[C:2]1[N:3]=[CH:4][N:5]=[C:6]2[C:13]=1[C:12]1[C@H:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=1[S:7]2.P(Cl)(Cl)([Cl:22])=O>O1CCOCC1>[Cl:22][C:2]1[N:3]=[CH:4][N:5]=[C:6]2[C:13]=1[C:12]1[C@H:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=1[S:7]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)C[C@@H]1CCc2sc3ncnc(O)c3c21
Solvent: C1COCCO1
Product: CCOC(=O)C[C@@H]1CCc2sc3ncnc(Cl)c3c21
Temperature: 110 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
To a 50-mL round-bottom flask was added ethyl 2-[(3S)-12-hydroxy-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]acetate (16.2, 560 mg, 2.01 mmol, 1.00 equiv), dioxane (10 mL) and phosphoroyl trichloride (3.5 mL). The reaction was stirred for 4 h at 110° C. under nitrogen. After concentration under reduced pressure, the resulting solution was poured dropwise into saturated aqueous NaHCO3 and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine and dried over sodium sulfate. After evaporation in vacuo, the residue was purified by column chromatography on silica gel with ethyl acetate/petroleum ether (1:7) to afford ethyl 2-[(3S)-12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]acetate (16.3, 550 mg, 92%) as a yellow oil.
Reaction SMILES: N[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[C:3]=1[CH3:11].Cl.N([O-])=O.[Na+].[C:17]([C:21]1[CH:25]=[C:24]([C:26]([NH:28][CH2:29][CH2:30][C:31]2[O:32][CH:33]=[CH:34][CH:35]=2)=[O:27])[NH:23][N:22]=1)([CH3:20])([CH3:19])[CH3:18]>O.CC(C)=O.O.O.O.O.[Fe](Cl)Cl>[C:17]([C:21]1[CH:25]=[C:24]([C:26]([NH:28][CH2:29][CH2:30][C:31]2[O:32][C:33]([C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[C:3]=3[CH3:11])=[CH:34][CH:35]=2)=[O:27])[NH:23][N:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1cc(C(=O)NCCc2ccco2)[nH]n1
Reactant: Cc1c(N)ccc(C#N)c1Cl
Agent: Cl[Fe]Cl
Agent: Cl
Agent: O=N[O-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1c(-c2ccc(CCNC(=O)c3cc(C(C)(C)C)n[nH]3)o2)ccc(C#N)c1Cl
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 2.6 %

Procedure:
4-amino-2-chloro-3-methylbenzonitrile (0.200 g, 1.20 mmol) was added to a solution of water (2 ml) and conc. HCl (2 ml) and the mixture was stirred vigorously, heated to 80° C. for 15 min and then cooled to −10° C. Sodium nitrite (0.091 g, 1.32 mmol) was dissolved in 0.5 ml of water and added drop wise to the cooled reaction mixture. After 40 min, the mixture was filtered and 3-tert-butyl-N-(2-(furan-2-yl)-ethyl)-1H-pyrazole-5-carboxamide (0.345 g, 1.32 mmol) dissolved in acetone (3 ml) was added to the filtrate. Then, a solution of iron (II) chloride tetrahydrate in water (3 ml) was added portion wise and the mixture was stirred for 15 h at RT. Water (25 ml) was added to the reaction mixture and extracted three times with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3 and water and dried with Na2SO4, filtered and evaporated to dryness. CombiFlash purification afforded 0.013 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.34 (s, 9H), 3.03 (t, 2H), 3.77 (m, 2H), 6.28 (d, 1H), 6.62 (m, 2H), 7.12 (m, 1H), 7.50 (d, 1H), 7.65 (d, 1H).
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[C:18]([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])(=[O:22])[C@@H:19]([CH3:21])[OH:20].[CH:28]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH2:29]>C(OCC)(=O)C>[CH2:31]([O:30][CH:28]([O:20][C@H:19]([CH3:21])[C:18]([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:29])[CH2:32][CH2:33][CH3:34]
Reactant: C=COCCCC
Reactant: CC(C)COC(=O)[C@@H](C)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Product: CCCCOC(C)O[C@H](C)C(=O)OCC(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
A catalytic amount of pyridinium para-toluenesulfonate was added to 29.2 g (0.2 mole) of isobutyl (R)-(+)-lactate and 22.0 g (0.22 mole) of n-butyl vinyl ether. The resulting mixture was stirred at room temperature for 4 hours to give rise to a reaction. Thereto was added 100 ml of ethyl acetate, followed by washing with 100 ml of a saturated aqueous sodium hydrogen carbonate solution, 40 ml of water and 40 ml of a saturated aqueous sodium chloride solution in this order. The washed material was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to remove the solvent, whereby was obtained 46.8 g (yield: 94.9%) of an oily title compound (diastereomixture).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[C:8](Cl)=[N:9][C:10]([Cl:14])=[N:11][C:12]=1[Cl:13])[CH3:2].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C(N(CC)CC)C>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[C:12]([Cl:13])=[N:11][C:10]([Cl:14])=[N:9][C:8]=1[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)COc1c(Cl)nc(Cl)nc1Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1c(Cl)nc(Cl)nc1N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
A mixture of (2,4,6-trichloro-pyrimidin-5-yloxy)-acetic acid ethyl ester (2.67 g, 9.35 mmol), morpholine (815 μL, 9.35 mmol) and triethylamine (2.6 mL, 18.7 mmol) in IMS (50 mL) was stirred at RT for 2 hours before the reaction was concentrated in vacuo. The resultant residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with further ethyl acetate and the combined organic extracts dried (Na2SO4) and concentrated in vacuo affording (2,4-Dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-acetic acid ethyl ester (2.97 g, 95%). LCMS: RT=3.35 min, [M+H]+=336/338/340.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]3[S:13][C:14]([C:17]([O:19]CC)=[O:18])=[CH:15][N:16]=3)[CH2:8][CH2:7]2)[N:5]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:4][NH:3]1.[OH-].[Li+].Cl>O1CCOCC1>[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]3[S:13][C:14]([C:17]([OH:19])=[O:18])=[CH:15][N:16]=3)[CH2:8][CH2:7]2)[N:5]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:4][NH:3]1
Reactant: CCOC(=O)c1cnc(N2CCC3(CC2)C(=O)NCN3c2ccccc2)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1cnc(N2CCC3(CC2)C(=O)NCN3c2ccccc2)s1

Procedure:
Ethyl 2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl)-1,3-thiazole-5-carboxylate (0.75 g, 1.9 mmol) was made 0.25 M in 1,4-dioxane and to this stirring solution was added 3 equivalents 3M Lithium hydroxide (1.9 mL, 5.8 mmol). The resulting mixture was microwaved at 75° C. for 1 hour. The reaction mixture was then neutralized to pH=6 with 1N aqueous HCl and a white precipitate came out of solution. The precipitate was filtered off and dried in vacuo to give 2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl)-1,3-thiazole-5-carboxylic acid. The material was carried on without further purification: MS (ESI+): cal'd [M+H]+ 359.1, obs'd 359.1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([OH:17])[CH:8]=2)[CH2:3][CH2:2]1.[O:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)(O)[C:31]#[CH:32])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>C1(C)C=CC=CC=1>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3[CH:32]=[CH:31][C:30]([C:27]4[CH:28]=[CH:29][C:24]([N:21]5[CH2:20][CH2:19][O:18][CH2:23][CH2:22]5)=[CH:25][CH:26]=4)([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[O:17][C:9]=3[CH:8]=2)[CH2:5][CH2:6]1
Reactant: Oc1cc(N2CCOCC2)c2ccccc2c1
Reactant: C#CC(O)(c1ccccc1)c1ccc(N2CCOCC2)cc1
Solvent: Cc1ccccc1
Product: C1=CC(c2ccccc2)(c2ccc(N3CCOCC3)cc2)Oc2cc(N3CCOCC3)c3ccccc3c21
Yield: 73.2 %

Procedure:
A solution of 4-morpholino-2-naphthol (1.5 g, 6.5 mmol) and 1(4-morpholinophenyl)-1-phenylprop-2-yn-1-ol (1.92 g, 6.5 mmol) in toluene (65 cm3) containing acidic alumina (Brockmann 1), (4.0 g) was refluxed for 60 minutes. The cooled solution was filtered and the alumina was washed well with EtOAc (200 cm3). Removal of the solvent from the filtrate gave an oil which solidified on standing at room temperature. Recrystallisation from EtOAc/hexane gave 6-morpholino-3(4-morpholinophenyl)-3-phenyl-3H-naphtho[2,1-b]pyran (yield=2.4 g, theoretical yield=3.3 g 73%, m.p.=187-188° C. (uncorrected), λmax in toluene=469 nm, i.e. red-orange).
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:10][C:11]=2[C:12](OCC)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][OH:24].O>CO.C1COCC1>[OH:24][NH:23][C:12]([C:11]1[CH:10]=[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:13]
Reactant: CCOC(=O)c1cc(-c2ccccc2)sc1-c1ccccc1
Reactant: NO
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NO)c1cc(-c2ccccc2)sc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 21 %

Procedure:
To a stirring solution of ethyl 2,5-diphenylthiophene-3-carboxylate 70 (0.440 g, 1.427 mmol) in methanol (7 mL) and THF (7 mL) was added 50% hydroxylamine in water (1.4 mL, 23.31 mmol) and the resulting mixture was stirred at room temperature for 45 minutes then concentrated to one third volume. The solution was neutralized with 3N HCl to pH 7 and the desired product was filtered then purified by Gilson (55 to 95% MeOH in H2O) to afford the title compound 71 (87 mg, 21% yield) as a white solid. 1H NMR: (DMSO-d6) d(ppm) 1H, 10.96 (s, 1H), 9.14 (s, 1H), 7.71-7.69 (m, 2H), 7.57-7.55 (m, 3H), 7.48-7.34 (m, 6H) LRMS (ESI): (calc) 295.36 (found) 296.22 (MH)+
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:40]([NH:43][N:44]([C:46](=[O:73])[C@H:47]([N:55]([CH3:72])[C:56](=[O:71])[C@H:57]([NH:69][CH3:70])[CH2:58][C:59]1[CH:68]=[CH:67][C:66]2[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=2)[CH:60]=1)[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH3:45])(=[O:42])[CH3:41].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:69]([C@@H:57]([C:56](=[O:71])[N:55]([C@H:47]([CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[C:46]([N:44]([CH3:45])[NH:43][C:40](=[O:42])[CH3:41])=[O:73])[CH3:72])[CH2:58][C:59]1[CH:68]=[CH:67][C:66]2[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=2)[CH:60]=1)[CH3:70])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N(C)NC(C)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NN(C)C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
To a solution of (2E)-5-(tert-butyloxycarbonylamino)-5-methylhex-2-enoic acid (0.066 g, 0.27 mmol) in methylene chloride (5 ml) was added 1-hydroxy-7-azabenzotriazole (0.037 g, 0.27 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.052 g, 0.27 mmol) and the mixture was cooled to 0° C. Then (2R)-N-[(1R)-2-(N'-acetyl-N-methylhydrazino)-1-benzyl-2-oxoethyl]-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide (0.10 g, 0.22 mmol) and diisopropylethylamine (0.049 ml, 0.29 mmol) were added and the mixture was stirred at room temperature overnight. Then methylene chloride (50 ml) was added and the mixture was washed with water (10 ml), saturated sodium bicarbonate (10 ml), brine (10 ml), dried (MgSO4), filtered and concentrated in vacuo. The product was chromatographed on silica gel (40 g) with heptane:ethyl acetate (1:1) to give 0.10 g (66%) of ((3E)-4-[N-((1R)-1-(N-[(1R)-2-(N'-acetyl-N-methylhydrazino)-1-benzyl-2-oxoethyl]-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl]-1,1-dimethylbut-3-enyl)carbamic acid tert-butyl ester as a colourless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]#[N:14])=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-]>O.CO.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C:13]#[N:14])=[CH:8][CH:9]=1
Reactant: N#CCCCc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: N#CCCCc1ccc(N)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A mixture of compound 82 (2.67 g, 14 mmol), NH4Cl (11.2 g, 210 mmol) and Iron Powder (7.8 g, 140 mmol) in water (90 mL) and CH3OH (90 mL) was stirred at 90° C. for 1 h. After cooling, the reaction mixture was filtered and the solid was washed by DCM. The filtrates were separated, and the organic layer was washed with brine, dried over Na2SO4 and concentrated to dryness to give compound 83 (1.85 g, 83%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.90 (d, 2H, J=8.1 Hz), 6.58 (d, 2H, J=8.1 Hz), 3.30 (br s, 2H), 2.59 (t, 2H, J=7.4 Hz), 2.22 (t, 2H, J=7.4 Hz), 1.80-1.90 (m, 2H).