Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OCC)=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([CH3:21])[N:15]=2)[CH:3]=1.CO.[NH3:24]>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:24])=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([CH3:21])[N:15]=2)[CH:3]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1ccc(C)c(C)n1
Reactant: N
Solvent: CO
Product: Cc1ccc(Nc2cc(Cl)nnc2C(N)=O)nc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
In a 50 mL round bottom flask, ethyl 6-chloro-4-(5,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxylate (929 mg, 3.03 mmol) was suspended in ammonia 7M in methanol (7.87 g, 10.0 mL, 70.0 mmol). The flask was sealed and stirred for 2 h at room temperature. Solvents evaporated and solid residue dried in high vacuum to give 6-chloro-4-(5,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxamide (841 mg, 100% yield) as an off-white solid. 1H NMR (CHLOROFORM-d) δ: 11.37 (br. s., 1H), 9.11 (s, 1H), 8.09 (br. s., 1H), 7.32 (d, J=8.3 Hz, 1H), 6.63 (d, J=8.1 Hz, 1H), 5.59 (br. s., 1H), 2.43 (s, 3H), 2.19 (s, 3H); LC-MS 278.0 [M+H]+.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(OCC)=O)C.C([O-])(C)(C)C.[Na+].[CH:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[C:27]([O:35][CH3:36])[CH:26]=1)=O.[Cl-].[NH4+]>O1CCCC1>[C:13]([O:12][C:10](/[CH:9]=[CH:23]/[C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[C:27]([O:35][CH3:36])[CH:26]=1)=[O:11])([CH3:14])([CH3:15])[CH3:16]
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: COC(=O)c1ccc(C=O)cc1OC
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(/C=C/C(=O)OC(C)(C)C)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 720 μL of tert-butyl diethylphosphonoacetate (1.1 equivalents) in 3 mL of tetrahydrofurane cooled to 0° C. under an inert atmosphere are added 307 mg of sodium tert-butanolate (1.15 equivalents). The whole is stirred for 30 minutes at 0° C. and then for 1 hour at room temperature. A solution cooled to 0-4° C. of 540 mg of aldehyde obtained in stage 3 in 1 ml of tetrahydrofurane is added dropwise to the previous mixture also cooled to 0° C. Stirring is maintained at this temperature for 30 minutes before letting the temperature rise back to room temperature for 2 hours. The medium is hydrolyzed with a saturated solution of ammonium chloride and extracted with ethyl acetate several times. The collected organic phases are washed with water, and then dried on magnesium sulfate, filtered and evaporated under reduced pressure. The reaction crude product is purified by chromatography on silica gel (petroleum ether/ethyl acetate: 95/5) leading to 500 mg of the expected product.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COc1ccnc(Br)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccnc(-c2ccc(F)cc2)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 85.2 %

Procedure:
To a suspension of 2-bromo-4-methoxypyridine (0.94 g), 4-fluorophenylboronic acid (909 mg) and tetrakis(triphenylphosphine)-palladium (289 mg) in 1,2-dimethoxyethane (20 ml) was added 2M aqueous solution of sodium carbonate (6.5 ml). The mixture was stirred at 80° C. for 4 hours under a nitrogen atmosphere, then cooled to room temperature and diluted with ethyl acetate. The organic layer was separated, washed with water and brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 50 g, 30% ethyl acetate in n-hexane) to give 4-(4-methoxypyridin-2-yl)fluorobenzene (0.866 g).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([CH3:26])=[N:9]2)=CC=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:40][CH2:39][CH:38]([C:41](O)=[O:42])[C:37]2=[O:44])=[CH:32][CH:31]=1>>[F:25][C:19]1[CH:20]=[C:21]([NH:24][C:41]([CH:38]2[CH2:39][CH2:40][N:36]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)[C:37]2=[O:44])=[O:42])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:8][N:9]=[C:10]([CH3:26])[C:11]=12
Reactant: O=C(O)C1CCN(c2ccc(F)cc2)C1=O
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Product: Cc1n[nH]c2nccc(Oc3ccc(NC(=O)C4CCN(c5ccc(F)cc5)C4=O)cc3F)c12

Procedure:
Prepared by a 2-step process from 3-fluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)aniline (prepared as in Example 5, Step D) and 1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid according to the procedure of Example 21, Steps A and B. The crude was purified by silica gel flash column chromatography (3% MeOH in CH2Cl2) to afford 4 mg (47% for 2-step process) of the desired product. LRMS (ESI pos) m/e 464.2 (M+1). 1H-NMR (400 MHz, CD3OD/CDCl3) δ 8.25 (d, 1H), 7.88 (dd, 1H), 7.64 (m, 2H), 7.46 (m, 1H), 7.36 (t, 1H), 7.14 (t, 2H), 6.27 (d, 1H), 3.97 (m, 2H), 3.81 (m, 1H), 2.71 (s, 3H), 2.61 (m, 1H), 2.49 (m, 1H); 19F NMR (376 MHz, CD3OD/CDCl3) δ −119.2, −130.1.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Cl[C:8]1[N:13]=[C:12]([N:14]=CN(C)C)[C:11]([C:19]#[N:20])=[N:10][C:9]=1[C:21]1[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH:28]([CH3:30])[CH3:29])[N:22]=1.[Br:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>O.O1CCOCC1.C(Cl)(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>[NH2:14][C:12]1[C:11]([C:19]#[N:20])=[N:10][C:9]([C:21]2[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH:28]([CH3:29])[CH3:30])[N:22]=2)=[C:8]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[Br:31])[N:13]=1
Reactant: OB(O)c1ccccc1Br
Reactant: CC(C)n1nc(-c2nc(C#N)c(N=CN(C)C)nc2Cl)ccc1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CC(C)n1nc(-c2nc(C#N)c(N)nc2-c2ccccc2Br)ccc1=O
Temperature: 102.5 °C
Reaction time: 4 h
Yield: 10.2 %

Procedure:
Under nitrogen atmosphere, a solution of Na2CO3 (427 mg) in water (8.8 ml) was added to a suspension of N′-[6-chloro-3-cyano-5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinyl]-N,N-dimethylimidoformamide (346 mg), (2-bromophenyl)boronic acid (503 mg) and tetrakis(triphenylphosphine)palladium (35 mg) in dioxane (22 ml) and the mixture was stirred at 100-105° C. for 4 hours. Dioxane was evaporated under reduced pressure to give a residue. The residue was dissolved in CHCl3, dried over MgSO4, concentrated under reduced pressure and purified by column chromatography on silica gel. By elution with a mixture of n-hexane and EtOAc (70:30 v/v) was obtained 3-amino-5-(2-bromophenyl)-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinecarbonitrile as a solid (42 mg) and by elution with a mixture of n-hexane and EtOAc (50:50 v/v) was obtained N′-[6-(2-bromophenyl)-3-cyano-5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinyl]-N,N-dimethylimidoformamide as a solid (360 mg).
Reaction SMILES: [CH2:1]([N:7]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>C(OCC)(=O)C.[Pd]>[CH2:17]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCN(CCCCCC)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCN(CCCCCC)c1ccc(N)cc1
Yield: 102.9 %

Procedure:
A solution of 25.0 grams of N,N-di-n-hexyl-N-(4-nitrophenyl)amine in 100 ml of ethyl acetate containing 3.02 grams of 10% palladium on activated charcoal was hydrogenated at 40 psi for 1.5 hours. The solution was filtered and concentrated in vacuo to yield 23.2 grams of product as a colorless oil. 1H NMR (CDCl3) δ 6.4(AB quartet, 4H), 3.3(bs, 2H), 3.15(t, 4H), 1.5(pent, 4H), 1.2-1.4(m, 12H), 0.9(t, 6H).
Reaction SMILES: [CH2:1]([C@H:8]([NH:39][C:40](=[O:66])[C@H:41]([CH2:43][C:44]([NH:46][C:47]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[NH2:42])[C@@H:9]([OH:38])[CH2:10][C@@H:11]([NH:25][C:26](=[O:37])[C@H:27]([C:33]([CH3:36])([CH3:35])[CH3:34])[NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:68]([O:70][CH3:71])=[O:69].C(N(CC)CC)C>O1CCOCC1>[CH2:1]([C@H:8]([NH:39][C:40](=[O:66])[C@H:41]([CH2:43][C:44]([NH:46][C:47]([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)([C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:45])[NH:42][C:68]([O:70][CH3:71])=[O:69])[C@@H:9]([OH:38])[CH2:10][C@@H:11]([NH:25][C:26](=[O:37])[C@H:27]([C:33]([CH3:34])([CH3:35])[CH3:36])[NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cl
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)(C)C
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Yield: 108.3 %

Procedure:
A solution of Example 168B (24 mg, 0.027 mmol) in dioxane (0.25 mL) was treated with methyl chloroformate (3.2 μL, 0.041 mmol) and triethylamine (7.5 μL, 0.054 mmol) at 25° C. for 0.5 h. The solvents were evaporated to give the crude title compound (27.7 mg, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=1)[CH3:2].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH3:35][O:36][C:37]1[CH:47]=[CH:46][C:45](/[CH:48]=[CH:49]/[C:50](=[O:63])[C:51]2[CH:56]=[C:55]([O:57][CH3:58])[C:54]([O:59][CH3:60])=[C:53]([O:61][CH3:62])[CH:52]=2)=[CH:44][C:38]=1[O:39][CH2:40][C:41](O)=[O:42]>ClCCl.O>[CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH:11][C:41](=[O:42])[CH2:40][O:39][C:38]3[CH:44]=[C:45](/[CH:48]=[CH:49]/[C:50](=[O:63])[C:51]4[CH:52]=[C:53]([O:61][CH3:62])[C:54]([O:59][CH3:60])=[C:55]([O:57][CH3:58])[CH:56]=4)[CH:46]=[CH:47][C:37]=3[O:36][CH3:35])[S:10][C:6]=2[CH:5]=1)[CH3:2]
Reactant: COc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)O
Reactant: CCOc1ccc2nc(N)sc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCOc1ccc2nc(NC(=O)COc3cc(/C=C/C(=O)c4cc(OC)c(OC)c(OC)c4)ccc3OC)sc2c1
Yield: 781.2 %

Procedure:
To a solution of 6-ethoxy-2-aminobenzothiazole (194 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxy phenyl)-1-propenyl]phenoxy}acetic acid (2) (402 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (9h) (452 mg, 80% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:8]=2[C:9]#[N:10])[C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2.[Cl:20][S:21](O)(=[O:23])=[O:22]>C(Cl)Cl>[Cl:15][C:12]1[CH:13]=[CH:14][C:7]([N:4]2[CH2:5][CH2:6][O:1][C:2]3[CH:19]=[C:18]([S:21]([Cl:20])(=[O:23])=[O:22])[CH:17]=[CH:16][C:3]2=3)=[C:8]([C:9]#[N:10])[CH:11]=1
Reactant: N#Cc1cc(Cl)ccc1N1CCOc2ccccc21
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: N#Cc1cc(Cl)ccc1N1CCOc2cc(S(=O)(=O)Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.4 %

Procedure:
To a solution of 2-(2h-benzo[b][1,4]oxazin-4(3h)-yl)-5-chlorobenzonitrile (480 mg, 1.77 mmol) in DCM (5 mL) was added chlorosulfonic acid (0.47 mL, 7.11 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h. After completion, reaction mixture was poured into ice water (10 mL), quenched with solid sodium bicarbonate (pH˜9-10) and extracted with ethyl acetate (2×15 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to provide 4-(4-chloro-2-cyanophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (480 mg, 73.3%) as yellow solid. The compound was used in the next step without further purification. LCMS (ESI) m/z: 367.98 (M+H).
Reaction SMILES: O=C=[N:3]C1CC(C)(C)CC(C)(CN=C=O)C1.[C:17]([O:21][CH2:22][CH2:23]O)(=[O:20])[CH:18]=[CH2:19].C(O)(=O)C=C>>[C:17]([OH:21])(=[O:20])[CH:18]=[CH2:19].[NH2:3][C:17]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Reactant: C=CC(=O)OCCO
Agent: C=CC(=O)O
Product: CCOC(N)=O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
In a flask equipped with a stirrer, a thermometer and a reflux condenser, 222 parts of isophorone diisocyanate was charged. After heating to 70° C. while stirring, 116 parts of hydroxyethyl acrylate was added dropwise over one hour and reacted to obtain an intermediate. Then, in a flask equipped with a stirrer, a thermometer and a reflux condenser, 144 parts of acrylic acid was added to 376 parts of a bisphenol A epoxy resin (epoxy equivalent: 118 g/eq) and the reaction was conducted at 100° C. for 8 hours. To the reaction product, 338 parts of the above intermediate was added and the reaction was conducted at 80° C. for 5 hours to obtain a urethane acrylate (H-2) as a radical polymerizable oligomer (A1).
Reaction SMILES: C([O:9][C@@H:10]1[CH2:17][N:16]2[C@:12]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][CH:31]=3)([C:13]([CH2:27][CH3:28])=[C:14]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)[C:15]2=[O:18])[CH2:11]1)(=O)C1C=CC=CC=1.[OH-].[Na+]>C1COCC1.CO>[Br:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][C@:12]23[C:13]([CH2:27][CH3:28])=[C:14]([C:19]4[CH:20]=[C:21]([Cl:26])[CH:22]=[C:23]([Cl:25])[CH:24]=4)[C:15](=[O:18])[N:16]2[CH2:17][C@@H:10]([OH:9])[CH2:11]3)=[CH:35][CH:34]=1
Reactant: CCC1=C(c2cc(Cl)cc(Cl)c2)C(=O)N2C[C@@H](OC(=O)c3ccccc3)C[C@@]12Cc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC1=C(c2cc(Cl)cc(Cl)c2)C(=O)N2C[C@@H](O)C[C@@]12Cc1ccc(Br)cc1
Reaction time: 5 h
Yield: 42 %

Procedure:
(2S,7aS)-7a-(4-Bromobenzyl)-6-(3,5-dichlorophenyl)-7-ethyl-5-oxo-2,3,5,7a-tetrahydro-1H-pyrrolizin-2-yl benzoate VIIb (5 mg, 0.01 mmol) was suspended in THF (1 mL) and treated with 1N aqueous NaOH (50 uL). The reaction was stirred for 5 h, diluted with MeOH (1 mL) and purified on preparative HPLC using MeOH, H2O, TFA(0.1%) as the eluant to give (6S, 7aS)-7a-(4-Bromobenzyl)-2-(3,5-dichlorophenyl)-1-ethyl-6-hydroxy-5,6,7,7a-tetrahydro-3H-pyrrolizin-3-one VIII, (2 mg, 42%) LCMS, (m/z) 480/482 (M++H), HPLC Retention Time/Condition 1: 2.03 min.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:25])[CH:7]=[CH:8][C:9]=1[CH:10]([CH3:24])[C:11]([OH:23])([C:16]1[CH:21]=[CH:20][N:19]=[C:18]([CH3:22])[CH:17]=1)[C:12]([F:15])([F:14])[F:13].Br[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([O:25][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:7]=[CH:8][C:9]=1[CH:10]([CH3:24])[C:11]([C:16]1[CH:21]=[CH:20][N:19]=[C:18]([CH3:22])[CH:17]=1)([OH:23])[C:12]([F:15])([F:13])[F:14]
Reactant: BrCCc1ccccc1
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(O)(C(C)c2ccc(OCCc3ccccc3)cc2Cl)C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in mineral oil, 20.4 mg) was added to abs. DMF (2 mL). To this mixture was added a solution of 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(2-methyl-pyridin-4-yl)-propyl]-phenol (Example 73, 80 mg) in DMF (2 mL) over 15 minutes. The mixture was then allowed to stir for 30 min at RT. The mixture was cooled to 0° C. and a solution of 2-bromoethylbenzene ((0.033 mL) in DMF (1 mL) was added within 10 minutes. The mixture was then heated to 50° C. over night. The reaction mixture was poured into ice/water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) to give the title compound as a colorless oil (12 mg). MS (m/e)=450.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]([C:17]([O:19][CH3:20])=[O:18])[N:4](C)[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14]Cl)[CH:9]=2)=[CH:6][N:7]=1.[CH2:21]([OH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>[Ag]=O>[NH2:1][C:2]1[C:3]([C:17]([O:19][CH3:20])=[O:18])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][O:28][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:9]=2)=[CH:6][N:7]=1
Reactant: OCc1ccccc1
Reactant: COC(=O)C1C(N)=NC=C(c2cccc(CCl)c2)N1C
Agent: O=[Ag]
Product: COC(=O)c1nc(-c2cccc(COCc3ccccc3)c2)cnc1N
Temperature: 110 °C
Yield: 28 %

Procedure:
Methyl 3-amino-6-(3-chloromethylphenyl)-N-methylpyrazine-2-carboxylate (18 mg, 0.06 mmol) and silver oxide (15 mg, 0.06 mmol) were added to benzyl alcohol (2 mL) and the mixture was heated to 110° C. over 15 hours. The benzyl alcohol was removed in vacuo and the residue purified by silica gel flash chromatography using ethyl acetate:hexanes (1:1) as eluent. The pure fractions were combined and concentrated then dried ill vacuo to give methyl 3-amino-6-(3-{[(phenylmethyl)oxy]methyl}phenyl)pyrazine-2-carboxylate (5.8 mg, 28% yield) as a yellow solid: MS (EI) for C20H20N3O3: 350 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=O)[C:10]=2[CH:11]=1.O.NN.C(O)COCCO.[OH-].[Na+]>O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: Cc1cnc2c(c1)C(=O)CCC2
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: Cc1cnc2c(c1)CCCC2
Reaction time: 1 h
Yield: 93.1 %

Procedure:
A mixture of cyclohexane-1,3-dione (11.2 g. 0.1 m), 3-amino-2-methylacrolein (8.5 g. 0.1m) triethylamine (5 ml.) and ammonium acetate (100 mg) were heated with stirring at 120° in an oil bath for 12 hours. The cooled reaction mixture was diluted with ether (50 ml.) and the solution washed with 2N HCl (3 × 15 ml.) The combined washings were adjusted to pH 9.0 with sodium carbonate and extracted with ether (3 × 50 ml.) The combined extracts were dried, evaporated in vacuo and the residual oil distilled at 0.2 mm Hg to give the 3-methyl-7,8-dihydro-5(6H)-quinolone as a colorless crystalline solid b.p. 80° (7.5 g. 48%). A mixture of 3-methyl-7,8-dihydro-5(6H)-quinolone (20 g.), hydrazine hydrate (14 ml), diethylene glycol (150 ml.) and sodium hydroxide (14 g) was heated at reflux with stirring for 1 hour. The condenser was replaced by a Dean and Stark Water Separator and the heating continued for a further 3 hours. The cooled reaction mixture was diluted with water (200 ml.) and extracted with ether (3 × 150 ml.). The combined extracts were dried (MgSO4) and the solvent removed in vacuo and the residual oil distilled at 15 mm Hg to give the title compound as a colourless oil b.p.116° (17 g, 93%) G.L.C. (3% SE30, T=150°) RF =3.5 min.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]([NH:9][C:10](=[S:27])[NH:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[NH:19][C:20]([NH:22][C:23]([O:25][CH3:26])=[O:24])=[S:21])[NH2:15])=[O:8].C(=O)(O)[O-].[Na+].O>CC(C)=O>[C:1]([NH:15][C:14]1[CH:16]=[CH:17][C:18]([NH:19][C:20]([NH:22][C:23]([O:25][CH3:26])=[O:24])=[S:21])=[C:12]([NH:11][C:10]([NH:9][C:7]([O:6][CH3:5])=[O:8])=[S:27])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COC(=O)NC(=S)Nc1ccc(N)cc1NC(=S)NC(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)NC(=S)Nc1ccc(NC(C)=O)cc1NC(=S)NC(=O)OC
Reaction time: 6 h

Procedure:
Acetyl chloride (1.66 g; 0.0212 mole) was added dropwise during five minutes to a stirred suspension of 3,4-bis-(3-methoxycarbonyl-2-thioureido)aniline (4.0 g; 0.0112 mole) and sodium bicarbonate (1.78 g; 0.0212 mole) in dry acetone (50 ml). The temperature of the reaction mixture rose spontaneously to 30° C. After completion of the addition, the mixture was refluxed with stirring for 6 hours, cooled and poured into water. The solid which separated was filtered off, washed well with water and crystallised from ethanol to give 4-acetamido-1,2-bis-(3-methoxycarbonyl-2-thioureido)benzene, m.p. 183°-185° C. (with decomposition).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:18]([O:20]CC)=O)=[C:13]([CH:17]=1)[C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([NH:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:24]([CH3:27])([CH3:26])[CH3:25].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(=O)([O-])[O-].[K+].[K+].C(Br)C1C=CC=CC=1.C(O)C.[O-]CC.[Na+].Cl>CN(C)C=O.O>[CH2:1]([O:8][C:9]1[CH:17]=[C:13]2[C:12]([C:18]([OH:20])=[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:28]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[C:14]2=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(OCc2ccccc2)cc1C(=O)O
Reactant: CCOC(=O)CNCC(C)(C)C
Agent: BrCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CC[O-]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(O)c2ccc(OCc3ccccc3)cc2c(=O)n1CC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 5-benzyloxy-2-(ethoxycarbonyl)benzoic acid (21.86 g, 120 mmol), ethyl 2-(neopentylamino)acetate (20.79 g, 120 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (28.76 g, 150 mmol) and 1-hydroxybenzotriazole (22.97 g, 150 mmol) in N,N-dimethylformamide (200 ml) was stirred at room temperature for 3 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (300 ml), and potassium carbonate (33.17 g, 240 mmol) and benzyl bromide (35.7 ml, 300 mmol) were added. The mixture was stirred at room temperature for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol (50 ml) and 20% sodium ethoxide ethanol solution (34.04 g, 100 mmol) was added. The mixture was stirred at room temperature for 1 h. The reaction mixture was poured into 1N hydrochloric acid (150 ml) and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and the component eluted earlier was concentrated to give ethyl 7-benzyloxy-4-hydroxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate as an oil. To a solution of the obtained ethyl 7-benzyloxy-4-hydroxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (3.26 g, 8 mmol), 1-butanol (1.1 ml, 12 mmol) and tributylphosphine (4.0 ml, 16 mmol) in tetrahydrofuran (30 ml) was added 1,1′-(azodicarbonyl)dipiperidine (4.04 g, 16 mmol) and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give ethyl 7-benzyloxy-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (3.61 g, 97.0%) as an oil.