Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[N:3]=1.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33].CCN(CC)CC.O>CCOC(C)=O>[C:32]([O:31][C:30]([NH:29][C@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@H:23]1[NH:22][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[N:3]=1)=[O:36])([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)c1c(C#N)cc(Cl)nc1Nc1cccc(C)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C#N)cc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc(C)c1
Yield: 79.5 %

Procedure:
A solution of methyl 6-chloro-4-cyano-2-(m-tolylamino)nicotinate (198 mg, 0.656 mmol), tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (562 mg, 2.62 mmol) and Et3N (0.402 mL, 2.89 mmol) was stirred at reflux overnight. To the resulting mixture were added H2O and EtOAc. The aqueous phase was extracted with EtOAc. The organic layers were combined, washed with brine, dried over MgSO4, and evaporated. The residue was triturated with EtOAc. The resulting solid was filtered, rinsed with EtOAc, and dried to give the title compound as a yellow solid (250 mg, 79%). 1H NMR (500 MHz, CDCl3) δ ppm 1.23-1.77 (m, 17H), 2.34 (s, 3H), 3.94 (br s, 3H), 3.98 (br s, 1H), 4.80 (s, 1H), 6.15 (s, 1H), 6.91 (d, J=5.37 Hz, 1H), 7.21 (t, J=7.81 Hz, 1H), 7.29 (s, 1H), 7.47-7.55 (m, 1H), 10.64 (br s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[C:20]([OH:26])=[C:19]([CH:27]([CH3:29])[CH3:28])[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.Cl[S:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[C:36]([OH:43])[CH:35]=1)(=[O:33])=[O:32]>>[Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[C:21]([CH:23]([CH3:24])[CH3:25])[C:20]([O:26][S:31]([C:34]3[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[C:36]([OH:43])[CH:35]=3)(=[O:33])=[O:32])=[C:19]([CH:27]([CH3:29])[CH3:28])[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: Cc1sc2c(Br)c3ccccc3c(-c3cc(C(C)C)c(O)c(C(C)C)c3)c2c1C
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Product: Cc1sc2c(Br)c3ccccc3c(-c3cc(C(C)C)c(OS(=O)(=O)c4ccc(C(=O)O)c(O)c4)c(C(C)C)c3)c2c1C

Procedure:
Using 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenol (0.291 g, 0.623 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.768 g, 3.24 mmol) the title compound was prepared according to the procedure in Example 1, step 9. Purification on Dynamax C18 eluting with 100% CH3CN (0.1% TFA added) gave 0.09 g (22%) of the title compound as a white solid, mp >225° C.; 1H NMR (DMSO-d6) δ 1.09 (t, 12 H), 1.54 (s, 3 H), 2.45 (s, 3 H), 3.14-3.22 (m, 2 H), 7.27 (s, 2 H), 7.41-7.46 (m, 2 H), 7.50-7.53 (m, 2 H), 7.65-7.69 (m, 1 H), 8.09 (d, 1 H), 8.21-8.23 (m, 1 H). IR (KBr) 3400, 2950, 1700, 1375 and 1180 cm-1. mass spectrum (-ESI), m/z 665/667 (M-H). Anal. Calcd. for C33H31BrO6S2.1.7H2O: C, 56.76; H, 4.97 N, 0.00. Found: C, 56.73; H, 4.81 N, 0.12.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[C@@H:14]([CH3:25])[CH2:13]2)(=[O:11])=[O:10])=[C:5]([CH3:26])[CH:4]=1)#[N:2].Cl.O1CCOCC1>C(Cl)Cl>[CH3:26][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[S:9]([N:12]1[CH2:17][CH2:16][NH:15][C@@H:14]([CH3:25])[CH2:13]1)(=[O:11])=[O:10])[C:1]#[N:2]
Reactant: Cc1cc(C#N)ccc1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc(C#N)ccc1S(=O)(=O)N1CCN[C@@H](C)C1
Reaction time: 2 h
Yield: 98.5 %

Procedure:
1,1-Dimethylethyl (2S)-4-[(4-cyano-2-methylphenyl)sulfonyl]-2-methyl-1-piperazinecarboxylate (may be prepared as described in Intermediate 12; 5.52 g, 14.54 mmol) was dissolved in DCM (80 ml) and then 4M hydrochloric acid in dioxane (36.3 mL, 145 mmol) was added at room temperature and the reaction mixture was stirred for two hours. The solvent was removed under vacuum to give the title compound (4.0 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14].[F:19][C:20]1[C:25](B(O)O)=[CH:24][CH:23]=[C:22]([CH3:29])[N:21]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:25]3[C:20]([F:19])=[N:21][C:22]([CH3:29])=[CH:23][CH:24]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14]
Reactant: Cc1ccc(B(O)O)c(F)n1
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(Br)cccc12
Product: Cc1ccc(-c2cccc3c(N)c(C(=O)NC4CC4)nnc23)c(F)n1
Yield: 60.8 %

Procedure:
Using Method A, 4-amino-8-bromo-N-cyclopropyl-cinnoline-3-carboxamide (61 mg, 0.20 mmol) and 2-fluoro-6-methylpyridine-3-boronic acid (62 mg, 0.36 mmol) were reacted. After purification the title compound (41 mg, 60% yield) was obtained as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.52 (bm, 1H), 7.92 (a t, J=7.5 Hz, 2H), 7.85 (m, 1H), 7.75 (a t, J=7.7 Hz, 1H), 7.18 (a d, J=7.5 Hz, 1H), 2.96 (m, 1H), 2.58 (s, 3H), 0.88 (m, 2H), 0.65 (m, 2H). MS APCI, m/z=338, HPLC 2.17 min.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[NH:3][CH:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[C:9]([O:11]CC)=O.[CH3:15][S:16]([NH:19][C:20]1[CH:35]=[CH:34][C:23]2[NH:24][C:25]([CH2:30][C:31](O)=[O:32])=[N:26][S:27](=[O:29])(=[O:28])[C:22]=2[CH:21]=1)(=[O:18])=[O:17].CN1CCOCC1.[ClH:43].CN(C)CCCN=C=NCC>CN(C)C=O>[ClH:43].[CH3:14][N:2]([CH3:1])[N:3]1[C@@H:4]2[C@@H:5]([CH2:6][CH2:7][CH2:8]2)[C:9]([OH:11])=[C:30]([C:25]2[NH:24][C:23]3[CH:34]=[CH:35][C:20]([NH:19][S:16]([CH3:15])(=[O:18])=[O:17])=[CH:21][C:22]=3[S:27](=[O:28])(=[O:29])[N:26]=2)[C:31]1=[O:32]
Reactant: CCOC(=O)C1CCCC1NN(C)C
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN(C)N1C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)[C@@H]2CCC[C@@H]21
Yield: 52.4 %

Procedure:
Ethyl 2-(2,2-dimethylhydrazinyl)cyclopentanecarboxylate (0.16 g, 0.82 mmol) was dissolved in anhydrous N,N-dimethylformamide (8 mL). (7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.27 g, 0.82 mmol) was added followed by N-methylmorpholine (0.19 mL, 1.72 mmol). The mixture was stirred until everything dissolved, approximately 5 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.16 g, 0.86 mmol) was added and the mixture was stirred at 25° C. for 16 h. The reaction was quenched via addition of saturated aqueous sodium bicarbonate solution (20 mL). The mixture was extracted with ethyl acetate (3×30 mL). The organic layers were combined and washed with saturated aqueous brine solution (20 mL). The resulting solution was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a golden oil. The residue was triturated with ethyl acetate to afford the desired product, cis-N-[3-(1-dimethylamino-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl]-methanesulfonamide hydrochloride (0.22 g, 0.43 mmol, 52%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.48-1.73 (2H, m), 1.88-2.20 (4H, m), 2.82 (6H, s), 3.06 (3H, s), 4.01 (1H, s), 7.49-7.74 (3H, m), 10.18 (1H, s). LC-MS (ESI) calcd for C18H23N5O6S2 469.54, found 470.2 [M+H+].
Reaction SMILES: [CH:1]1([CH2:4][S:5]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-])=O)=[CH:17][C:16]=3[CH3:25])[CH:11]=[CH:10][C:9]=2[OH:26])(=[O:7])=[O:6])[CH2:3][CH2:2]1>CO>[NH2:22][C:18]1[CH:17]=[C:16]([CH3:25])[C:15]([O:14][C:12]2[CH:11]=[CH:10][C:9]([OH:26])=[C:8]([S:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)(=[O:7])=[O:6])[CH:13]=2)=[C:20]([CH3:21])[CH:19]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(O)c(S(=O)(=O)CC2CC2)c1
Solvent: CO
Product: Cc1cc(N)cc(C)c1Oc1ccc(O)c(S(=O)(=O)CC2CC2)c1
Reaction time: 3 h

Procedure:
4-(4-Amino-2,6-dimethyl-phenoxy)-2-cyclopropylmethanesulfonyl-phenol was prepared from 2-cyclopropylmethanesulfonyl-4-(2,6-dimethyl-4-nitro-phenoxy)-phenol according to a procedure analogous to that described in EXAMPLE 4, Step A. Methanol was used instead of ethanol as a co-solvent. Reaction mixture was hydrogenated for 3 hours. After the mixture was filtered through Celite® and concentrated, the title product of Step D was used in the next step without purification. MS (APCI−) Calc.: 347.4, Found: 346.0 (M−1).
Reaction SMILES: S([C:5]1C=CC(C)=C[CH:6]=1)(O)(=O)=O.[OH:12][CH2:13][C@@H:14]1[C@@H:20]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[CH2:19][C@H:18]2[N:29]([CH3:30])[C@@H:15]1[CH2:16][CH2:17]2.[O-]CC.[Na+]>C(O)C>[CH2:5]([O:12][CH2:13][C@@H:14]1[C@@H:20]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[CH2:19][C@H:18]2[N:29]([CH3:30])[C@@H:15]1[CH2:16][CH2:17]2)[CH3:6]
Reactant: CN1[C@H]2CC[C@@H]1[C@H](CO)[C@@H](c1ccc(Cl)c(Cl)c1)C2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC[C@@H]1[C@@H](c2ccc(Cl)c(Cl)c2)C[C@@H]2CC[C@H]1N2C
Yield: 96.9 %

Procedure:
(1R,2R,3S)-2-hydroxymethyl-3-(3,4-dichlorophenyl)tropane tosylate (2.5 g, 5.5 mmol) was dissolved in anhydrous ethanol (20 ml). Sodium ethoxide in ethanol (2.4 ml, 2.5 M, 6 mmol) was added and the reaction mixture was refluxed for 72 hours. The solvent was evaporated off. The residue was stirred with water and other and extracted three times with other (3×50 ml) and dried over MgSO4. Evaporation of the solvent yields 1.75 g of the title compound. The product was purified by column chromatography on silica using EtOAc:Et3N (99:1). Yield 1.24 g.
Reaction SMILES: Cl.[C:2]1([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[O:18]=[C:19]1[NH:28][C:27]2[N:26]=[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH:33]=O)[CH:24]=[C:23]([C:35]([F:38])([F:37])[F:36])[C:22]=2[CH2:21][CH2:20]1>>[C:2]1([N:12]2[CH2:17][CH2:16][N:15]([CH2:33][CH2:32][CH2:31][CH2:30][O:29][C:25]3[N:26]=[C:27]4[C:22]([CH2:21][CH2:20][C:19](=[O:18])[NH:28]4)=[C:23]([C:35]([F:37])([F:36])[F:38])[CH:24]=3)[CH2:14][CH2:13]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=CCCCOc1cc(C(F)(F)F)c2c(n1)NC(=O)CC2
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Agent: Cl
Product: O=C1CCc2c(C(F)(F)F)cc(OCCCCN3CCN(c4cccc5ccccc45)CC3)nc2N1

Procedure:
In a manner similar to that of other examples above, 1-naphthalen-1-yl-piperazine hydrochloride was coupled by reductive amination to 4-(7-oxo-4-trifluoromethyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound. MS: APCI: M+1: 499.1 (Exact Mass: 489.22).
Reaction SMILES: Br[CH2:2][C:3](=[O:17])[CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH2:23].C(N(CC)C(C)C)(C)C>O1CCCC1>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH:23][CH2:2][C:3](=[O:17])[CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CBr)C(c1ccccc1)c1ccccc1
Reactant: COc1ccccc1CN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1CNCC(=O)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 3-bromo-1,1-diphenyl-2-propanone (0.5 g) in tetrahydrofuran (10 ml) was added to a mixture of (2-methoxy-benzyl)amine (1.13 ml) and N,N-diisopropylethylamine (0.602 ml) in tetrahydrofuran (12 ml) over 0.5 hour at room temperature. After being stirred at room temperature for 1.5 hours, the mixture was concentrated under reduced pressure to half volume and the resulting mixture was poured into ice-water (10 ml) and extracted with ethyl acetate (10 ml×2). The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 3-[(2-methoxybenzyl)amino]-1,1-diphenylpropan-2-one (483 mg) as a colourless syrup.
Reaction SMILES: [CH:1]([NH:3][CH:4]=[O:5])=[CH2:2].CC([O-])(C)C.[K+].Br[CH2:13][CH2:14][CH2:15][CH3:16]>C1COCC1>[CH2:13]([N:3]([CH:1]=[CH2:2])[CH:4]=[O:5])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCBr
Reactant: C=CNC=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CN(C=O)CCCC
Temperature: 15 °C
Reaction time: 0.75 h

Procedure:
Into a dry 500 mL three-necked round-bottomed flask equipped with magnetic stirring bar and dropping funnel were placed 11.67 g (0.164 mol) of N-vinylformamide and 200 mL of anhydrous THF. The mixture was cooled to 15° C. in an ice bath under nitrogen and a total of 18.8 g (0.167 mol) of t-BuOK was added in three portions with constant stirring over 45 minutes. 1-Bromobutane, 24.5 g (0.179 mol) was then added to the reaction mixture dropwise over 30 minutes. When addition was complete, the reaction was allowed to warm to ambient temperature and stirred overnight. After potassium bromide salt was removed, the reaction mixture was concentrated under reduced pressure and diluted with 200 mL of water. The organic layer was extracted three times with diethyl ether. The combined organic layers were washed twice with water and dried over anhydrous magnesium sulfate. The resulting product was recovered after concentration in vacuum and purification by chromatography on silica (diethyl ether/petroleum ether (v/v=3:7). yield: 11.7 g (56%). IR (NaCl, v: cm−1): 1693 (—NHC(═O)H); 1630 (C═C). 1H-NMR (CDCl3, δ: ppm): 8.31, 8.14 (2s, 1H, —C(═O)H); 7.25–7.16, 6.61–6.52 (m, 1H, H2C═CH—); 4.62–4.45 (m, 1H, HaHbC═CH—); 4.43–(s, 1H, HaHbC═CH—); 3.60–3.45 (t, 2H, —NCH2CH2—); 1.61–1.54 (m, 2H, —CH2CH2CH2—); 1.40–1.32 (m, 2H, —CH2CH2CH3); 0.99–0.94 (t, 3H, —NCH2CH2CH2CH3).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]2[C:3]3[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=3[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]2=3)=[CH:14][C:13]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: O=Cc1ccc(Cl)c(Oc2ccccc2)c1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1ccc(Cl)c(Oc2ccccc2)c1

Procedure:
Reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 4-chloro-3-phenoxybenzaldehyde in an analogous manner to that described in Example 1 gave 9-(4-chloro-3-phenoxyphenyl)-3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione. Crystallization from dimethylformamide/water gave a yellow crystalline solid of melting point 246-248° C.
Reaction SMILES: [CH2:1]([NH2:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:12]1([C:18]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[CH:19][C:20](Cl)=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCCC1>[CH2:1]([NH:11][C:20](=[O:21])[CH:19]=[C:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:23]1[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C(Cl)C=C(c1ccccc1)c1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCCCCCN
Solvent: C1CCOC1
Product: CCCCCCCCCCNC(=O)C=C(c1ccccc1)c1ccc([N+](=O)[O-])cc1

Procedure:
To a stirred solution of 5.89 g. of decylamine in 25 ml. of tetrahydrofuran was added a solution of 4.89 g. of 3-phenyl-3-(4-nitrophenyl)propenoyl chloride in 25 ml. of tetrahydrofuran, dropwise, during 20 minutes, at ice-bath temperature. The solvent was removed by evaporation in vacuo and the residue was partitioned between ethyl acetate and water. The layers were separated, and the ethyl acetate layer was washed with water, dried using sodium sulfate, and then evaporated in vacuo. This afforded 5.6 g. of the title compound, m.p. 91°-93° C.
Reaction SMILES: ClC1C=C(C=CC=1Cl)N.C(OCC)(=O)C(C)=O.C([O:20][C:21](=[O:33])[CH:22]([CH3:32])[NH:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=1)C>>[Cl:31][C:26]1[CH:25]=[C:24]([NH:23][CH:22]([C:21]([OH:33])=[O:20])[CH3:32])[CH:29]=[CH:28][C:27]=1[Cl:30]
Reactant: CCOC(=O)C(C)Nc1ccc(Cl)c(Cl)c1
Agent: CCOC(=O)C(C)=O
Agent: Nc1ccc(Cl)c(Cl)c1
Product: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O

Procedure:
Alternatively, following General Procedure A above and using 3,4-dichloroaniline (Aldrich) and ethyl pyruvate (Aldrich), N-(3,4-dichlorophenyl)-D,L-alanine ethyl ester was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.4 in 25% EtOAc/Hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/Hexanes as eluent).
Reaction SMILES: C1(CO[C:9]([NH:11][C@H:12]([C:17]([NH:19][C@H:20]([CH2:24][OH:25])[CH:21]([CH3:23])[CH3:22])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])C=CC=CC=1.O.C(=O)([O-])[O-].[Na+].[Na+].[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1C(Cl)=O>CO.C(OCC)(=O)C.[C].[Pd]>[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C:9]([NH:11][C@H:12]([C:17]([NH:19][C@H:20]([CH2:24][OH:25])[CH:21]([CH3:22])[CH3:23])=[O:18])[CH2:13][CH:14]([CH3:15])[CH3:16])=[O:10]
Reactant: O=C(Cl)c1ccco1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](CO)C(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)c1ccco1)C(=O)N[C@H](CO)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
30 mg of 10% palladium-carbon was added to a solution of 350 mg (1 mmol) of N—[N-[(phenylmethoxy)carbonyl]-L-leucyl]-L-valinol obtained in Reference example 178 in 10 ml of methanol, and the mixture was stirred under a hydrogen atmosphere at room temperature overnight. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure. 10 ml of ethyl acetate, 10 ml of water and further 159 mg (1.5 mmol) of sodium carbonate were added to the residue. A solution of 131 mg (1 mmol) of 2-furancarbonyl chloride in 3 ml of ethyl acetate was added to the mixture solution under ice-cooling. The reaction solution was returned to room temperature and stirred overnight. The aqueous layer of reaction solution was separately collected and extracted with ethyl acetate. The organic layer was combined and after it was washed with 10% potassium hydrogensulfate, and then saturated brine, it was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, ether was added to the residue, and the crystal was washed to obtain 268 mg (86%) of the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1.[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1I>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:6]1[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1
Reactant: Brc1ccccc1I
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2ccccc2Br)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-formylbenzeneboronic acid (1.19 g, 7.96 mmol) and Na2CO3 (1.68 g, 15.8 mmol) in water (60 mL) was added p-dioxane (60 mL). This mixture was treated sequentially with 2-bromo iodobenzene (2.25 g, 7.95 mmol) and palladium (II) acetate (159 mg, 0.708 mmol) and allowed to stir at ambient temperature for 16 hours. The solvent was evaporated in vacuo. To the residue was added EtOAc (400 mL) and water (300 mL). The aqueous layer was extracted with EtOAc (2×200 mL). The organic extracts were combined, washed with brine (200 mL), 5% aq. Na2S2O3 (200 mL), brinel (200 mL), dried, (Na2SO4) and the solvent evaporated in vacuo to afford the title compound which was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N:17]3[N:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:23]=4)[C:18]3=[O:31])[C:12]=2[CH2:32][O:33]C(=O)C)=[N:8][C:7]=1[CH3:37])=O)C.[NH3:38].CO>>[C:27]([C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:31])[N:17]([C:13]1[C:12]([CH2:32][OH:33])=[C:11]([C:9]3[O:10][C:6]([C:4]([NH2:38])=[O:3])=[C:7]([CH3:37])[N:8]=3)[CH:16]=[CH:15][CH:14]=1)[N:26]=[CH:25]2)([CH3:29])([CH3:28])[CH3:30]
Reactant: CCOC(=O)c1oc(-c2cccc(-n3ncc4cc(C(C)(C)C)ccc4c3=O)c2COC(C)=O)nc1C
Reactant: N
Solvent: CO
Product: Cc1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)ccc4c3=O)c2CO)oc1C(N)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 68 %

Procedure:
The above 2-[2-acetoxymethyl-3-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-phenyl]-4-methyl-oxazole-5-carboxylic acid ethyl ester was dissolved in 10 mL of NH3/MeOH. The reaction was stirred at room temperature for two days. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=1:1) to give 2-[3-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-4-methyl-oxazole-5-carboxylic acid amide (47 mg, yield 68% for two steps) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 8.57 (s, 1H), 8.24 (d, J=8.1 Hz, 1H), 8.20 (dd, J=2.1, 8.4 Hz, 1H), 8.06-8.00 (m, 2H), 7.66-7.58 (m, 2H), 4.73-4.57 (m, 2H), 2.46 (s, 3H), 1.41 (s, 9H). LC-MS calcd for C24H24N4O4 (m/e) 432.18, obsd 433 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[CH:13]=O.[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([CH2:21][C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1.N1CCCC1>CO>[CH3:1][O:2][C:3](=[O:15])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1/[CH:13]=[C:21]1\[C:22](=[O:26])[NH:23][C:24]2[C:20]\1=[CH:19][CH:18]=[C:17]([Cl:16])[CH:25]=2
Reactant: COC(=O)COc1ccc(Cl)cc1C=O
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNC1
Product: COC(=O)COc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Yield: 74.6 %

Procedure:
In a manner similar to the method described in Example 227b, (4-chloro-2-formyl-phenoxy)-acetic acid methyl ester (34 g, 149 mmol) was reacted with 6-chlorooxindole (20.7 g, 124 mmol) and pyrrolidine (10.58 g, 149 mmol) in methanol to give title compound as a yellow solid (35 g).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]2[C:14](=[O:22])[C:15]([C:17]([O:19]CC)=[O:18])=[CH:16][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:23].C(O)(=O)C.Cl>O>[F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]2[C:14](=[O:22])[C:15]([C:17]([OH:19])=[O:18])=[CH:16][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:23]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)c(F)c3c1=O)CCN2C
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CN1CCc2c(F)c(F)c(F)c3c(=O)c(C(=O)O)cn1c23
Temperature: 100 °C
Yield: 80.2 %

Procedure:
30 mg of the compound (198) obtained in Example 69 was added to 0.4 ml of acetic acid and 0.1 ml of 12 N hydrochloric acid, and the solution was heated at 100° C. for 2 hours. After air-cooling, water was added to the reaction solution, and deposited solids were filtered off and washed with water, ethanol and ether in this order to obtain 22 mg of the subject compound (199) in a 81% yield.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9])=[O:2].OS(O)(=O)=O.[CH2:18](Cl)Cl.O>CO>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:12])=[C:7]([CH:11]=1)[C:8]([O:10][CH3:18])=[O:9])=[O:2]
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Reactant: ClCCl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(C=O)ccc1O
Temperature: 50 °C

Procedure:
To a solution of 5-formyl-2-hydroxybenzoic acid (3 g, 18.06 mmol) in methanol (10 ml) was added H2SO4 (0.5 ml, 9.38 mmol). The solution was heated at 50° C. for 18 hours. The solution was cooled, and DCM (30 ml) and water (20 ml) were added. The organic layer was separated, washed with NaHCO3 (10 ml), dried (MgSO4) and the solvent removed in vacuo to yield the title compound as a yellow solid. 3.1 g.