Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]([OH:21])=O)[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:22][C@H:23]([C:32]([N:34]([CH2:44][C:45]1[C:46]2[CH:53]=[CH:52][CH:51]=[CH:50][C:47]=2[S:48][CH:49]=1)[C@@H:35]([CH3:43])[CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])=[O:33])[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>>[S:48]1[CH:49]=[C:45]([CH2:44][N:34]([C@@H:35]([CH3:43])[CH:36]([O:37][CH2:38][CH3:39])[O:40][CH2:41][CH3:42])[C:32](=[O:33])[C@@H:23]([NH:22][C:19](=[O:21])[CH2:18][N:2]([CH3:1])[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)[CH2:24][C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[C:46]2[CH:53]=[CH:52][CH:51]=[CH:50][C:47]1=2
Reactant: CN(CC(=O)O)NC(=O)NCc1cccc2ccccc12
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CC(=O)OC(C)(C)C
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CN(C)NC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(naphthalen-1-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-8) 93 mg (0.32 mmol) was coupled with (S)-tert-butyl 3-amino-4-((benzo[b]thiophen-3-ylmethyl)((S)-1,1-diethoxypropan-2-yl)amino)-4-oxobutanoate (Compound IV-18) 100 mg (0.22 mmol) to obtain the title compound.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH2:2]1.[OH:11]OS([O-])=O.[K+]>>[O:11]1[CH:8]2[CH2:7][CH2:6][C:5]3[C:10]([CH:9]12)=[CH:1][CH:2]=[CH:3][CH:4]=3
Reactant: C1=Cc2ccccc2CC1
Reactant: O=S([O-])OO
Agent: [K+]
Product: c1ccc2c(c1)CCC1OC21

Procedure:
36.5 g of 1,2-dihydronaphthalene (280.3 mmol) are treated with Oxone® according to the method described in Step A of Example 8 to yield the expected product in the form of an oil.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][C:27]([OH:29])=O)=[CH:20][CH:19]=3)[C:10]2=[S:30])=[CH:5][C:4]=1[C:31]([F:34])([F:33])[F:32])#[N:2].[CH2:35]([N:37](CC)CC)C.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.CN>C(Cl)Cl.O>[C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][C:27]([NH:37][CH3:35])=[O:29])=[CH:20][CH:19]=3)[C:10]2=[S:30])=[CH:5][C:4]=1[C:31]([F:34])([F:32])[F:33])#[N:2]
Reactant: CCN(CC)CC
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(CCCC(=O)O)cc3)C2=S)cc1C(F)(F)F
Agent: CN
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: ClCCl
Product: CNC(=O)CCCc1ccc(N2C(=S)N(c3cnc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of 4-(4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenyl)butanoic acid (Compound 227, 85 mg, 0.17 mmol) in DCM (2 mL) were added triethylamine (0.013 mL, 0.09 mmol) and 4-nitrophenyl chloroformate (15 mg, 0.07 mmol). The mixture was stirred at room temperature for 1 h and methylamine (0.3 mL, 2M in THF) was added. After 30 min, the mixture was diluted with water and extracted with EtOAc (2×). The organic layers were dried over magnesium sulfate and concentrated. Column chromatography on silica gel (Hexane:EtOAc=1:1) afforded 35 mg (40%) of 4-(4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenyl)-N-methylbutanamide as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.11 (d, 1H), 8.38 (d, 1H), 7.42 (d, 2H), 7.22 (d, 2H), 2.86-2.81 (m, 3H), 2.81-2.73 (t, 2H), 2.73-2.64 (m, 2H), 2.64-2.53 (m, 2H), 2.26 (t, 2H), 2.24-2.17 (m, 1H), 2.11-2.01 (m, 2H), 1.69 (m, 1H). LCMS [M+1]+ 502.0.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:21]=[CH:20][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=O)=[CH:7][CH:6]=1)=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:21]=[CH:20][C:8]([C:9](=[S:31])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(C(=O)Nc2ccccc2OC)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(=S)Nc2ccccc2OC)cc1
Temperature: 25 °C
Yield: 96.6 %

Procedure:
The 4-methoxycarbonyl-2'-methoxybenzanilide (123.2 g) obtained in (1) was dissolved in 400 ml of toluene, and 96.1 g of Lawesson's reagent was added. The mixture was refluxed for 2 hours. After the reaction, the reaction mixture was hot-filtered. The filtrate was left to stand until it cooled to room temperature. The precipitated crystals were collected by filtration and washed with a small amount of benzene to give 69.2 g of 4-methoxycarbonyl-2'-methoxybenzothioanilide.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH2:12].[Cl:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>ClCCCl.ClCCl>[Cl:13][CH2:14][CH2:15][C:16]([NH:12][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[Cl:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:17]
Reactant: Nc1cnc2ccccc2c1Cl
Reactant: O=C(Cl)CCCl
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(CCCl)Nc1cnc2ccccc2c1Cl
Temperature: 50 °C
Yield: 78.8 %

Procedure:
A solution of 4-chloroquinolin-3-amine (6.00 g, 33.59 mmol) and 3-chloropropionyl chloride (4.8 mL, 50.39 mmol) dissolved in 200 mL of 1,2-dichloroethane was heated to 50° C. in an oil bath. After 20 hrs the temperature of the oil bath was increased to 90° C. After an additional 26 hours the reaction was cooled to room temperature, diluted with dichloromethane, washed with saturated aqueous K2CO3, H2O, and brine, dried over Na2SO4, and concentrated under reduced pressure to give 7.12 g of 3-chloro-N-(4-chloroquinolin-3-yl)propanamide as a tan solid.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)C(OCC)=C)CCC.C([O:48][C:49]([C:51]1C(C2C=NC=NC=2)=CC(C(NC2C=CC(OC(F)(F)F)=CC=2)=O)=CN=1)=[CH2:50])C.Cl.C([O-])([O-])=O.[Na+].[Na+].C(C1C(C2C=NC=NC=2)=CC(C(NC2C=CC(OC(F)(F)F)=CC=2)=O)=CN=1)(=O)C.C[Mg+].[Br-].C1COCC1.C1(C)C=CC=CC=1.[NH4+].[Cl-]>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[OH:48][C:49]([C:2]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1)([CH3:51])[CH3:50]
Reactant: C=C(OCC)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2cncnc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: CC(=O)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1cncnc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CC(C)(O)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1cncnc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
6-Chloro-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Example 56, 100 mg, 0.253 mmol), tributyl(1-ethoxyvinyl)stannane (0.103 mL, 0.304 mmol), Pd(Ph3P)4 (29.3 mg, 0.025 mmol) and dioxane (1 mL) were added to a vial, which was sealed, evacuated/purged with argon and the RM was stirred at 110° C. for 2 h. The solvent was evaporated off under reduced the crude 6-(1-ethoxyvinyl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (100 mg, 0.232 mmol) was treated with 4 M HCl in dioxane (2 mL, 8.00 mmol), stirred at RT for 2 h and then treated with excess aq. Na2CO3 and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, 24 g, EtOAc/n-hexane from 50% to 70% EtOAc). The 6-acetyl-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (25 mg, 0.062 mmol) was dissolved in DCM (3 mL), cooled to −60° C. and treated dropwise with a solution of MeMgBr 1.4 M in THF/toluene (1:3) (0.089 mL, 0.124 mmol) at The RM was stirred for 1.5 h at −60° C., then treated with a sat. aq. NH4Cl solution and extracted with DCM. The combined extracts were dried over MgSO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by preparative SFC (Column NH2; gradient 12% to 17% in 6 min.) and lyophilized in water/MeCN to afford the title compound. UPLC-MS (Condition 2) tR 0.79-0.94 min, m/z=419.1 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 1.49 (s, 6H) 5.02 (br. s, 1H) 7.39 (d, J=8.40 Hz, 2H) 7.87 (d, J=9.10 Hz, 2H) 8.11 (d, J=2.19 Hz, 1H) 8.77 (s, 2H) 9.09 (d, J=2.20 Hz, 1H) 9.13 (s, 1H) 10.55 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:13])[CH:10]=[C:9]([CH3:11])[CH2:8][CH2:7][CH:6]([OH:12])[CH2:5]1.I[CH3:15]>C1(C)C=CC=CC=1>[CH3:15][O:12][CH:6]1[CH2:7][CH2:8][C:9]([CH3:11])=[CH:10][C:4]([CH3:13])([CH3:3])[CH2:5]1
Reactant: CI
Reactant: CC1=CC(C)(C)CC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC1CCC(C)=CC(C)(C)C1
Temperature: 98 °C

Procedure:
Sodium hydride (60% in mineral oil) (5.4 gm) was added to 60 gm toluene in a stirred reaction flask and stirred under nitrogen. 3,3,5-Trimethyl-4-cyclohepten-1-ol (15.4 gm) was then added over 10 minutes at room temperature and stirred overnight. Iodomethane (21.3 gm) was added dropwise over 10 minutes followed by heating at 45° C. for six hours and four hours at 98° C. The reaction mixture was washed with 50 mL of saturated sodium bicarbonate solution and distilled through a short Vigreux column. A heart cut fraction, 3,3,5-trimethyl-4-cyclohepten-1-yl methyl ether, was obtained that weighed 13.9 gm and had a boiling point of 85° C. at 10 mm pressure. Its GC purity was 97%. The fraction was evaluated for its odor quality and characterized as fresh, spicy, saffron-like, floral, (marigold)-herbaceous-woody-powerful.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)[S:15][C:16]=1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[NH:29][C:28](=[O:30])[O:27][N:26]=2)=[C:21]([Cl:31])[CH:20]=1)C1C=CC=CC=1.B(Br)(Br)Br.CO>ClCCl>[Cl:31][C:21]1[CH:20]=[C:19]([O:18][CH2:17][C:16]2[S:15][C:14]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:40])([F:41])[F:39])=[CH:34][CH:33]=3)=[N:13][C:12]=2[CH2:11][CH2:10][CH2:9][OH:8])[CH:24]=[CH:23][C:22]=1[C:25]1[NH:29][C:28](=[O:30])[O:27][N:26]=1
Reactant: O=c1[nH]c(-c2ccc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3CCCOCc3ccccc3)cc2Cl)no1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=c1[nH]c(-c2ccc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3CCCO)cc2Cl)no1
Temperature: -60 °C
Reaction time: 0.75 h
Yield: 10.6 %

Procedure:
To a solution of 200 mg of 3-{4-[4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-chloro-phenyl}-4H-[1,2,4]oxadiazol-5-one in 6 ml of dichloromethane cooled to −70° C. was added 0.8 mL of a 1 M solution of boron tribromide in dichloromethane. After stirring for 45 minutes at −60° C., the solution was poured into a mixture of methanol and a saturated aqueous solution of sodium hydrogenocarbonate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient of dichloromethane/methanol from 100/0 to 90/10) then crystallized from dichloromethane/diisopropylether to give 18 mg of 3-{2-chloro-4-[4-(3-hydroxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-4H-[1,2,4]oxadiazol-5-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]#[N:14])=[C:11]([C:15]#[N:16])[N:10](CC3C=CC=CC=3)[C:9]2=[O:24])=[CH:4][CH:3]=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]#[N:14])=[C:11]([C:15]#[N:16])[NH:10][C:9]2=[O:24])=[CH:6][CH:7]=1
Reactant: N#Cc1c(C#N)n(-c2ccc(Cl)cc2)c(=O)n1Cc1ccccc1
Solvent: c1ccccc1
Product: N#Cc1[nH]c(=O)n(-c2ccc(Cl)cc2)c1C#N

Procedure:
The product of Example 48, 1-(4-chlorophenyl)-4,5-dicyano-3-benzyl-1,3-dihydro-2H-imidazol-2-one, (XIII) (1.2 g, 3.6 mmol) was stirred in 50 mL of benzene. To this solution was added AlCl13 (1.9 g, 14.4 mmol) and the mixture was heated to reflux for one-half hour. The mixture was then poured onto water and extracted with ethyl acetate, then dried, filtered and evaporated via standard techniques. The residue was recrystallized from ethyl acetate/heptane to give 0.72 g of 1-(4-chlorophenyl)-4,5-dicyano-1,3-dihydro-2H-imidazol-2-one (XIV) (m.p. 242°-5° C.).
Reaction SMILES: [NH:1]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[CH2:9][CH2:8]2)[C:2]1=[O:18].[N+:19]([O-])([OH:21])=[O:20]>>[N+:19]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[C:3]1([CH2:4][CH2:5][C:6](=[O:7])[NH:1][C:2]1=[O:18])[CH2:8][CH2:9][C:10]2=[O:17])([O-:21])=[O:20]
Reactant: O=C1CCC2(CCC(=O)c3ccccc32)C(=O)N1
Reactant: O=[N+]([O-])O
Product: O=C1CCC2(CCC(=O)c3cc([N+](=O)[O-])ccc32)C(=O)N1
Temperature: 0 °C

Procedure:
A total of 14.1 grams (0.06 M) of 2,3-dihydrospiro-[naphthalene-1(4H),3'-piperidine]-2',4,6'-trione was added in small portions to 100 milliliters of nitric acid (d = 1.4) cooled to -5° to -10° C. This temperature was maintained for 15 minutes and then allowed to warm to 0° C. The reaction mixture was poured into an ice-water mixture and filtered. The precipitate was recrystallized from aqueous acetone and then from acetic acid and then from an acetone-isopropyl alcohol-ethyl acetate mixture. Recrystallization from dioxane followed by chromatrographic purification from a silica gel column (eluted by dioxane) gave 2,3-dihydro-6-nitrospiro-[naphthalene-1(4H),3'-piperidine]-2',4,6'-trione, melting point 273°-275° C.
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([CH2:6][NH2:7])[CH2:4][NH2:5].C[O-].[Na+].Cl.[NH2:12][C:13](N)=N>CO>[ClH:1].[CH3:2][CH:3]1[CH2:6][NH:7][C:13]([NH2:12])=[N:5][CH2:4]1
Reactant: CC(CN)CN
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC1CN=C(N)NC1
Temperature: 140 °C

Procedure:
To a solution containing 6.7 g (41.6 mmol) of 2-methyl-1,3-propanediamine hydrochloride (Tetrahedron (1994) 50(29), 8617-8632) in 50 ml of methanol was added 83 ml of a solution of sodium methylate in methanol (1 mmol/ml) and the resulting mixture was treated with 3.97 g (41.6 mmol) of guanidine hydrochloride. The reaction mixture was heated at 140° C. for 3 h. The solution was filtered, the solvent evaporated and the residue obtained was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O>ClCC(Cl)(Cl)Cl>[Br:12][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: ClCC(Cl)(Cl)Cl
Product: O=C(O)C(Br)c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
80.0 g (469 mmol) of 4-chlorophenylacetic acid are dissolved in 200 ml of tetrachloroethane under argon and heated under RF. While boiling, 100 g (563 mmol) of N-bromosuccinimide and 7.70 g (46.9 mmol) of 2,2′-azobis-2-methylpropanenitrile are added, and the mixture is heated under RF overnight. It is then cooled to 0° C. and filtered with suction, the precipitate is washed with cold tetrachloromethane, and the filtrate is concentrated. The residue is dissolved in diethyl ether and extracted three times with saturated aqueous bicarbonate solution. The combined aqueous phases are adjusted to a pH of 1 with concentrated hydrochloric acid and extracted four times with diethyl ether. The combined organic phases are dried over magnesium sulfate, filtered and concentrated to result in 83.0 g (71% of theory) of the product, which is reacted further without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17](Cl)=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: Clc1cnc2c(n1)OCCN(Cc1ccccc1)C2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(CN2CCOc3nc(N4CCOCC4)cnc3C2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
A suspension of 8-benzyl-3-chloro-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (322 mg), morpholine (0.13 mL), Pd2(dba)3 (22 mg), XPhos (45 mg) and sodium tert-butoxide (282 mg) in toluene (10 mL) was stirred under an argon atmosphere at 100° C. for 3 hr. Water was added to the reaction mixture, the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient: 16→100% ethyl acetate/hexane) to give the title compound (259 mg, 68%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4](Cl)[N:3]=1.[NH2:10][NH2:11]>O>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4]([NH:10][NH2:11])[N:3]=1
Reactant: NN
Reactant: Nc1nc(Cl)cc(=O)[nH]1
Solvent: O
Product: NNc1cc(=O)[nH]c(N)n1
Yield: 45.4 %

Procedure:
A stirred suspension of 15.0 g (103 mmol) of 1 in 250 mL water was added 12 g (375 mmol) of anhydrous hydrazine, and the mixture was heated at reflux for 3 h. The resulting clear solution was cooled, and the precipitate which separated was collected by filtration, washed with water followed by ethanol and dried to give 6.6 g (46%) of white solid. mp decomposes at 313° C. (Literature mp 314-315° C., see Taylor, E. C.; Cocuzza, J. A. Synthesis and Properties of 7-Azaxanthopterin. J. Org. Chem. 1979, 44, 1125-1128.).
Reaction SMILES: [Na].C(O[C:5](=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH3:12][CH:13]([CH3:17])[C:14](=[O:16])C>C(O)C>[CH2:9]([O:8][C:6](=[O:7])[CH2:5][C:14](=[O:16])[CH:13]([CH3:17])[CH3:12])[CH3:10]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)C(C)C
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CC(=O)C(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 102.3 %

Procedure:
Sodium pellets (3.39 g, 148 mmol) were dissolved in ethanol (100 ml) under nitrogen at room temperature and a solution of diethyloxalate (20 ml, 147 mmol) in 3-methyl-2-butanone (18.9 ml, 177 mmol) was added dropwise at room temperature over 30 minutes. The reaction was diluted with ethanol (100 ml), heated to 60° C. and stirred at this temperature for 2 hours. After cooling to room temperature the reaction was poured onto ice-cold 2N HCl (200 ml) and extracted with diethylether (300 ml) and ethyl acetate (300 ml). The combined organic extracts were dried over MgSO4, concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of pentane:ethyl acetate (99:1 changing to 95:5, by volume) to give 4-methyl-3-oxo-pentanoic acid ethyl ester (23.8 g) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ=14.40-14.80 (1H, brs), 6.40 (1H, s), 4.30-4.39 (2H, quart), 260-2.71 (1H, quin), 1.35-1.40 (3H, t), 1.15-1.20 (6H, d) ppm. LRMS (electrospray): m/z [M−H]+ 185.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[N:6][NH:5][C:4](=[O:15])[CH2:3]1.[CH3:16][N:17]=[C:18]=[O:19]>CS(C)=O>[CH3:1][CH:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:18]([NH:17][CH3:16])=[O:19])=[N:12][CH:13]=2)=[N:6][NH:5][C:4](=[O:15])[CH2:3]1
Reactant: CC1CC(=O)NN=C1c1ccc(N)nc1
Reactant: CN=C=O
Solvent: CS(C)=O
Product: CNC(=O)Nc1ccc(C2=NNC(=O)CC2C)cn1
Yield: 48 %

Procedure:
A mixture of 0.4 g. (2 mmole) 4,5-dihydro-5-methyl-6-(2-amino-5-pyridyl)-3(2H)-pyridazinone, 10 ml. dimethyl sulphoxide and 0.24 ml. (4 mmole) methyl isocyanate was stirred for 16 hours at ambient temperature, evaporated in a vacuum and the residue triturated with water. There were obtained 0.25 g. of the title compound (48% of theory); m.p. 257°-259° C.
Reaction SMILES: Br[C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[O:4][CH:5]([CH3:13])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[CH2:19]([S:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)[CH3:20]>>[Cl:18][C:16]1[CH:15]=[CH:14][C:3]([O:4][CH:5]([CH3:13])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:2]([C:25]2[CH:26]=[CH:27][C:22]([S:21][CH2:19][CH3:20])=[CH:23][CH:24]=2)[CH:17]=1
Reactant: CCSc1ccc(B(O)O)cc1
Reactant: CC(Oc1ccc(Cl)cc1Br)C(=O)OC(C)(C)C
Product: CCSc1ccc(-c2cc(Cl)ccc2OC(C)C(=O)OC(C)(C)C)cc1

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using the product from step (i) and 4-(ethylthio)benzeneboronic acid, yield 1.2 g.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][CH2:6]Br)[CH3:2].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C([O-])([O-])=O.[Na+].[Na+]>CCO>[CH2:1]([O:3][C:4](=[O:8])[CH2:5][CH2:6][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[CH3:2]
Reactant: CCOC(=O)CCBr
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCN1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.5 %

Procedure:
Ethyl-3-bromoproprionate (3.20 ml; 25 mmol) was added to a mixture of morpholine (2.20 ml; 25 mmol) and Na2CO3 (2.78 g; 26 mmol) in 4.5 ml of EtOH at RT. The mixture was stirred for 30 min at RT and 4 h at reflux. After cooling to RT and filtering, the filtrate was concentrated and the residue was dissolved in H2O. The pH was adjusted to ~1.5 with saturated KHSO4 and the acidic mixture was washed with Et2O. Solid K2CO3 was added to the aqueous layer until a pH of ~9 was reached. The basic mixture was extracted with CH2Cl2, dried (MgSO4) and concentrated to afford 4.75 g (100+%; contained trace solvent) of ethyl-3-morpholinoproprionate as a colorless liquid. A solution of this ester (935 mg; 5 mmol) in 20 ml of Et2O was added to a suspension of LiAlH4 (400 mg; 10 mmol) in 80 ml of Et2O at 0° C. After stirring for 30 min at 0° C., the reaction was quenched by the careful addition of 0.42 ml of H2O followed by 0.42 ml of 15% NaOH and 1.26 ml of H2O. MgSO4 was added and the suspension was filtered and concentrated to afford 531 mg (73%) of Compound 201a as a colorless liquid. ##STR383##
Reaction SMILES: [Na].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:23])[CH:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([OH:16])=O)=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[N+:46]([C:49]1[CH:54]=[CH:53][C:52]([C@@H:55]([NH2:57])[CH3:56])=[CH:51][CH:50]=1)([O-:48])=[O:47]>CN(C=O)C>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:23])[CH:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([NH:57][CH:55]([C:52]2[CH:51]=[CH:50][C:49]([N+:46]([O-:48])=[O:47])=[CH:54][CH:53]=2)[CH3:56])=[O:16])=[CH:9][CH:10]=1)(=[NH:4])[NH2:3]
Reactant: N=C(N)c1ccc(NC(=O)C(C(=O)O)c2ccccc2)cc1
Reactant: C[C@H](N)c1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(NC(=O)C(C(=O)Nc1ccc(C(=N)N)cc1)c1ccccc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
75 mg (0.235 mmol) of the sodium salt from example 2 were dissolved in 2.5 ml DMF. 85 mg (0.265 mmol) TOTU in 2.5 ml DMF were added and stirred for 30 min at rt. Then 34 μl (0.265 mmol) NEM and 53.7 mg (0.265 mmol) of (S)-1-(4-nitrophenyl)-ethylamine in 0.5 ml of DMF was added and the mixture stirred at rt overnight. After filtration, the filtrate was evaporated to dryness and purified by prep. RP-HPLC.