Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:9][C:10]1[CH:33]=[CH:32][C:31]([O:34]C(=O)C2C=CC=CC=2)=[CH:30][C:11]=1[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:13])(=O)C1C=CC=CC=1.Cl>C(O)C.[Pd]>[OH:9][C:10]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:11]=1[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:13]
Reactant: CCOC(=O)CCCCCCCCCCNC(=O)c1cc(OC(=O)c2ccccc2)ccc1OC(=O)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CCCCCCCCCCNC(=O)c1cc(O)ccc1O
Yield: 67.4 %

Procedure:
A solution containing 3.55 g (6.5 mmol) of ethyl 11-{N-[2,5-di(benzoyloxy)benzoyl]amino}undecanoate (compound of Example 9) in 95 ml of ethanol was adjusted to a pH value of 3 by adding concentrated hydrochloric acid, and hydrogenated in the presence of 1.3 g of 10% palladium-on-carbon catalyst under environmental pressure. After filtering off the catalyst, the solution was evaporated under reduced pressure, the residue was thoroughly triturated with 10 ml petroleum ether and dried to obtain 1.60 g (67.3%) of the aimed compound, m.p.: 72°-74° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[N:12]([CH3:13])[N:11]=[C:10]([CH3:14])[C:9]=2[CH:15]=[N:16]O)=[CH:5][CH:4]=1.[C:20]([NH:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([CH2:32]Cl)=[CH:28][CH:27]=1)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:20]([NH:24][C:25](=[O:34])[C:26]1[CH:27]=[CH:28][C:29]([CH2:32][N:16]=[CH:15][C:9]2[C:10]([CH3:14])=[N:11][N:12]([CH3:13])[C:8]=2[O:7][C:6]2[CH:18]=[CH:19][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:30][CH:31]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)NC(=O)c1ccc(CCl)cc1
Reactant: COc1ccc(Oc2c(C=NO)c(C)nn2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(Oc2c(C=NCc3ccc(C(=O)NC(C)(C)C)cc3)c(C)nn2C)cc1
Yield: 84.8 %

Procedure:
1.0 Gram (0.0038 mole) of 5-(4-methoxyphenoxy)-1,3-dimethylpyrazole-4-carbaldehyde oxime, 0.86 g (0.0038 mole) of N-tert-butyl-4-chloromethylbenzamide and 1.0 g (0.0072 mole) of potassium carbonate were added to 20 ml of acetonitrile, and the resulting mixture was heated under reflux for 6 hours. After completion of the reaction, acetonitrile was removed by evaporation under reduced pressure, after which water was added to the residue and extraction was carried out with ethyl acetate. The ethyl acetate extract was washed with water and dried, and ethyl acetate was removed by evaporation to obtain an oily product. This oily product was column-chromatographed on silica gel to obtain 1.4 g of the desired compound.
Reaction SMILES: [NH2:1]C(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][CH2:43]C)=[O:41])[CH2:36][CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.C(N)CN.NC1C=CC=CC=1>>[NH2:1][CH2:30][CH2:29][NH:28][C:26](=[O:27])[NH:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][CH3:43])=[O:41])[CH2:36][CH2:35]4)[N:32]=[CH:33][C:14]3=[C:13]([N:7]3[CH2:6][CH:5]4[O:12][CH:9]([CH2:10][CH2:11]4)[CH2:8]3)[N:18]=2)=[CH:20][CH:21]=1
Reactant: NC(N)=O
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Solvent: NCCN
Solvent: Nc1ccccc1
Product: COC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc(NC(=O)NCCN)cc4)nc32)CC1

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing ethylenediamine as the aniline component. (31%, MS=550.3 (M+H))
Reaction SMILES: O[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH3:12])[CH:4]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:33]>C1COCC1>[Br:33][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH3:12])[CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1cc(CO)ccc1C#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(CBr)ccc1C#N
Reaction time: 17 h

Procedure:
4-hydroxymethyl-2-methoxy-benzonitrile (from L-819,538, step 2, 2.0 g, 12.3 mmol) was dissolved in THF (61.5 ml) and treated with Ph3P (4.82 g, 18.4 mmol) followed by CBr4 (6.1 g, 18.4 mmol). The reaction was mixture stirred at room temp. for 17 hours. The solvent was removed in vacuo and the residue was purified by flash chromatography (10% EtOAc/Hexane) to yield the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH2:16][F:17])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[C:19]([C:21]1[CH:22]=[CH:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=1)#[N:20]>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:24]3[CH:23]=[CH:22][C:21]([C:19]#[N:20])=[CH:26][N:25]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:18])([CH2:16][F:17])[N:9]=1
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: NC1=N[C@](CF)(c2cc(N)ccc2F)[C@@H](F)CO1
Product: N#Cc1ccc(C(=O)Nc2ccc(F)c([C@@]3(CF)N=C(N)OC[C@@H]3F)c2)nc1

Procedure:
The condensation of (4S,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-fluoromethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (A8.5) and 5-cyano-pyridine-2-carboxylic acid following procedure I yielded the title compound as a light yellow solid. MS (ISP): m/z=390.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[O:9][N:8]=[C:7]([C:10]2[O:14][N:13]=[C:12]3[C:15]4[C:20]([CH2:21][CH2:22][C:11]=23)=[CH:19][C:18]([CH:23]=C)=[CH:17][CH:16]=4)[C:6]=1[C:25]([F:28])([F:27])[F:26])[CH:2]([CH3:4])[CH3:3].[O:29]=[O+][O-].C(N(CC)CC)C>ClCCl>[CH2:1]([C:5]1[O:9][N:8]=[C:7]([C:10]2[O:14][N:13]=[C:12]3[C:15]4[C:20]([CH2:21][CH2:22][C:11]=23)=[CH:19][C:18]([CH:23]=[O:29])=[CH:17][CH:16]=4)[C:6]=1[C:25]([F:27])([F:26])[F:28])[CH:2]([CH3:3])[CH3:4]
Reactant: O=[O+][O-]
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(CC(C)C)c1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Cc1onc(-c2onc3c2CCc2cc(C=O)ccc2-3)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85 %

Procedure:
To a solution of 3-(5-isobutyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 5D, 0.045 g, 0.116 mmol) in dichloromethane (10 mL) at −78° C. was passed ozone from an ozone generator until the solution turned deep blue. The reaction mixture then was purged with oxygen until the blue color disappeared and then with nitrogen for 5 min. The reaction mixture was allowed to warm to room temperature, and triethylamine (0.016 mL, 0.116 mmol) was added. The reaction mixture was stirred at room temperature for 15 min. and then concentrated under pressure to give 3-(5-isobutyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (0.045 g, 85% yield) as a tan solid. The product had an HPLC ret. time=4.02 min. (condition B); LC/MS M+1=391.09.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH2:14][CH2:15][CH2:16][CH3:17])[C:9]=2[C:8](=[O:18])[NH:7][C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].Cl[CH2:21][P:22](=[O:25])([CH3:24])[CH3:23]>>[CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH2:14][CH2:15][CH2:16][CH3:17])[C:9]=2[C:8](=[O:18])[N:7]([CH2:21][P:22](=[O:25])([CH3:24])[CH3:23])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: CP(C)(=O)CCl
Reactant: CCCCn1cnc2c1c(=O)[nH]c(=O)n2CCCC
Product: CCCCn1cnc2c1c(=O)n(CP(C)(C)=O)c(=O)n2CCCC

Procedure:
The title substance was prepared from 5 g (0.0189 mol) of 3,7-dibutyl-xanthine and 2.9 g (0.0227 mol) of chloromethyldimethylphosphine oxide analogously to Example 67.
Reaction SMILES: O[CH:2]([NH:8][C:9](=[O:11])[CH3:10])[C:3]([Cl:7])([Cl:6])[CH2:4][Cl:5].S(Cl)([Cl:14])=O>>[Cl:14][CH:2]([NH:8][C:9](=[O:11])[CH3:10])[C:3]([Cl:7])([Cl:6])[CH2:4][Cl:5]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)NC(O)C(Cl)(Cl)CCl
Product: CC(=O)NC(Cl)C(Cl)(Cl)CCl

Procedure:
30 ml of thionyl chloride were poured over 15 gm of N-(1-hydroxy-2,2,3-trichloro-n-propyl)-acetamide, and the mixture was refluxed until the solution became clear. Subsequently, the excess thionyl chloride was distilled off in vacuo, and the residue was recrystallized from benzene/petroleum ether. Upon washing of the crystallizate with petroleum ether, a colorless substance was obtained. Yield: 13.5 gm; m.p. 70°-72° C.
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([F:20])[C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([Br:8])[N:7]=1.[CH2:22]([O:29][CH2:30][CH2:31][S:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([NH2:42])([CH3:41])[CH3:40])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][CH2:30][CH2:31][S:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([NH:42][C:2]1[C:3](=[O:21])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([F:20])[C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([Br:8])[N:7]=1)([CH3:40])[CH3:41])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(Br)c2=O)c1
Reactant: CC(C)(N)c1ccccc1SCCOCc1ccccc1
Product: COC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(NC(C)(C)c3ccccc3SCCOCc3ccccc3)c2=O)c1

Procedure:
The subtitle compound was prepared using a similar method to Example 252h from methyl 3-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-5-fluoro-4-methylbenzoate (Example 252g) and 2-(2-{[2-(benzyloxy)ethyl]sulfanyl}phenyl)propan-2-amine (Example 320c).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]([F:33])([F:32])[C:19]1[CH:20]=[C:21]([N:29]=[C:30]=[O:31])[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1>>[F:17][C:18]([F:32])([F:33])[C:19]1[CH:20]=[C:21]([NH:29][C:30]([NH:16][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:3]3[N:4]([CH3:7])[N:5]=[CH:6][C:2]=3[Cl:1])[CH:9]=2)=[O:31])[CH:22]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:24]=1
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: COc1ccc(NC(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1-c1c(Cl)cnn1C
Yield: 32 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 3,5-Bis(trifluoromethyl)phenyl isocyanate in a similar manner as described in Example 1.53, providing 21.5 mg (32%) of Compound 82: LCMS m/z (%)=495 (M+H37Cl, 41), 493 (M+H35Cl, 100). 1H NMR (400 MHz, DMSO-d6) δ: 9.58 (s, 1H), 9.18 (s, 1H), 8.31 (s, 2H), 7.80 (s, 1H), 7.79 (s, 1H), 7.79 (dd, J1=8 Hz, J2=4 Hz, 1H), 7.59 (d, J=2 Hz, 1H), 7.36 (d, =8 Hz, 1H), 3.96 (s, 3H), 3.80 (s, 3H).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1.C(=O)(O)[O-].[Na+]>ClCCl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:5][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][O:6]1)[CH2:2][C:3]#[CH:4]
Reactant: C#CCCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C#CCCOC1CCCCO1
Yield: 81.9 %

Procedure:
A solution of 3-butyn-1-ol (50 g, 1 equiv, 713 mmol), p-toluenesulfonic acid monohydrate (1.36 g, 0.01 equiv, 7.13 mmol), and dihydropyran (71.7 mL, 1.10 equiv, 785 mmol) in dichloromethane (500 mL) is stirred at 25° C. for 24 hours. Saturated sodium bicarbonate solution (500 mL) is then slowly added, and the mixture is extracted with dichloromethane (500 mL). The organic extract is dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product, which is purified by vacuum distillation to afford the title compound (90 g, 82%): b.p.: 65° C., 1 mm Hg.
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:21]=[C:22]([CH:27]=[C:28]([O:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])[C:29]=1[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:23]([O:25][CH3:26])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C1CCCCC1>[C].[Rh].O1CCCC1>[CH2:1]([O:19][CH:20]1[CH:29]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH:28]([O:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])[CH2:27][CH:22]([C:23]([O:25][CH3:26])=[O:24])[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)OC)cc(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Agent: [Rh]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCCCCCCCCCCCCCCCCCOC1CC(C(=O)OC)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Yield: 8.2 %

Procedure:
To methyl 3,4,5-tris(octadecyloxy)benzoate (1 g, 10.6 mmol) was added cyclohexane, 5% rhodium-carbon (0.8 g) was added, and hydrogenation was performed at 80° C., 10 atm. Tetrahydrofuran (10 ml) was added, and the catalyst was filtered off. The filtrate was concentrated, methanol (8 ml) was added, and the mixture was stirred. The precipitate was collected by filtration and dried to give methyl 3,4,5-tris(octadecyloxy)cyclohexylcarboxylate (820 mg, 0.87 mmol, 82%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)([NH:8]C(=O)C1C=CC=CC=1)[C:4]([F:7])([F:6])[F:5]>S(=O)(=O)(O)O.O.O>[F:7][C:4]([F:5])([F:6])[C:3]([NH2:8])([C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)[C:2]([F:25])([F:24])[F:1]
Reactant: O=C(NC(c1ccc(F)cc1)(C(F)(F)F)C(F)(F)F)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: NC(c1ccc(F)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 110 °C
Yield: 106272.4 %

Procedure:
The benzamide (0.866 mg) was suspended in a mixture of 98% sulfuric acid/water (10:1, v/v, 11 mL) and heated to reflux (110° C.) for 6 hours. After diluting with water (15 mL), the solution was extracted thoroughly with diethylether (5×20 mL). The organic extracts were washed with 1N aqueous sodium hydrogen carbonate, with saturated aqueous sodium chloride and dried over sodium sulphate. The crude obtained after evaporating the solvent was purified by flash chromatography on silica gel (eluant: n-hexane/ethyl acetate 9:1) to afford 658 mg of the title compound.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C:51]4([C:55]([O:57][CH3:58])=[O:56])[CH2:54][CH2:53][CH2:52]4)[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[F:59][C:60]([F:71])([F:70])[C:61]1[CH:69]=[CH:68][C:64]([C:65](Cl)=[O:66])=[CH:63][CH:62]=1>>[O:50]=[C:47]1[C:48]2[C:44](=[CH:43][CH:42]=[C:41]([C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:65](=[O:66])[C:64]4[CH:68]=[CH:69][C:61]([C:60]([F:59])([F:70])[F:71])=[CH:62][CH:63]=4)=[CH:40][CH:39]=3)[CH:49]=2)[CH2:45][N:46]1[C:51]1([C:55]([O:57][CH3:58])=[O:56])[CH2:52][CH2:53][CH2:54]1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C1(N2Cc3ccc(-c4ccc(N)cc4)cc3C2=O)CCC1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)C1(N2Cc3ccc(-c4ccc(NC(=O)c5ccc(C(F)(F)F)cc5)cc4)cc3C2=O)CCC1
Yield: 83 %

Procedure:
The compound of example 579 was prepared analogous to compound of example 97 by reaction of compound of example 574 with 4-trifluoromethyl benzoyl chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][O:9][C:10]([NH:12][CH2:13][CH2:14][SH:15])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:19][C:20]([CH2:22][C@H:23]1[NH:26][C:25](=[O:27])[C@@H:24]1[C@H:28]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH3:29])=[O:21].O1CCCC1.C([Li])CCC>CCCCCC.C(OCC)(=O)C.C(O)(=O)C>[Si:31]([O:30][C@@H:28]([C@@H:24]1[C@@H:23]([CH2:22][C:20]([CH2:19][S:15][CH2:14][CH2:13][NH:12][C:10]([O:9][CH2:8][C:7]2[CH:16]=[CH:17][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:11])=[O:21])[NH:26][C:25]1=[O:27])[CH3:29])([C:34]([CH3:37])([CH3:35])[CH3:36])([CH3:33])[CH3:32]
Reactant: O=C(NCCS)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)CSCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 76.3 %

Procedure:
0.536 g. of 2-(p-nitrobenzyloxycarbonylamino)ethylmercaptan was added to a mixture of 0.635 g. of bromomethylazetidin-2-one (48) and 20 ml. of dry tetrahydrofuran. The mixture was cooled to -78° C. and a solution of 1.18 ml of n-butyllithium in n-hexane was added thereto. The mixture was stirred at that temperature for 1.5 hours. Acetic acid (0.22 ml) was added to the reaction mixture. The mixture was then diluted with 380 ml of ethyl acetate and washed successively with water and an aqueous solution of sodium chloride, and was then dried over sodium sulphate. The solvent was distilled off under reduced pressure and the resulting oily residue was subjected to rapid chromatography using silica gel eluted with a 1:4 by volume mixture of benzene and ethyl acetate, to afford 0.718 g. (yield 76.3%) of the desired azetidin-2-one (49).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@@H:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([N:28]1[CH2:33][CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH2:30][CH2:29]1)(=[O:27])=[O:26]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@@H:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:31]4[CH2:32][CH2:33][N:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:29][CH:30]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC([C@H]2Cc3cc(Cl)ncc3O2)CC1
Reactant: CC1(C)OB(C2=CCN(S(C)(=O)=O)CC2)OC1(C)C
Product: CC(C)(C)OC(=O)N1CCC([C@H]2Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1

Procedure:
The title compound is prepared from (R)-4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 1-methanesulfonyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,6-tetrahydro-pyridine following a procedure analogous to that described for Intermediate 10. LC (method 3): tR=1.10 min; Mass spectrum (ESI+): m/z=464 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[NH:6][N:5]=[C:4]2[CH2:9][O:10][C:11]3[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[C:14]([CH:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)=[CH:13][C:12]=3[N:3]12>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][CH:2]1[C:7](=[O:8])[NH:6][N:5]=[C:4]2[CH2:9][O:10][C:11]3[CH:16]=[C:15]([C:17]([F:18])([F:20])[F:19])[C:14]([CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[CH:13][C:12]=3[N:3]12
Reactant: CC1C(=O)NN=C2COc3cc(C(F)(F)F)c(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1C(=O)NN=C2COc3cc(C(F)(F)F)c(C4CCNCC4)cc3N21

Procedure:
A solution of tert-butyl 4-(1-methyl-2-oxo-8-(trifluoromethyl)-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)piperidine-1-carboxylate (0.01 g, 0.021 mmol) in DCM (5 mL) and TFA (1 mL) was stirred for 1 h at ambient temperature. The solvent was removed in vacuo to give 1-methyl-9-(piperidin-4-yl)-8-(trifluoromethyl)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one trifluoacetic acid salt as a pale yellow solid (0.01 g, 97%). LC/MS (Table 1, Method 5) Rt=3.057 min.; MS m/z: 369 [M+H]+.
Reaction SMILES: [C:1]([C:6]1[CH2:7][CH:8]([CH:16]=[CH2:17])[O:9][C:10]=1[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([O:3][CH2:4][CH3:5])=[O:2]>C(OCC)(=O)C>[C:1]([C:6]1[CH2:7][CH:8]([CH2:16][CH3:17])[O:9][C:10]=1[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: C=CC1CC(C(=O)OCC)=C(CCCCC)O1
Solvent: CCOC(C)=O
Product: CCCCCC1=C(C(=O)OCC)CC(CC)O1
Yield: 98 %

Procedure:
4-Carbethoxy-5-pentyl-2-vinyl-2,3-dihydrofuran prepared in accordance with the procedure of Example I was hydrogenated to obtain 4-carbethoxy-2-ethyl-5-pentyl-2,3-dihydrofuran. For the reaction, 13 grams of the 4-carbethoxy-5-pentyl-2-vinyl-2,3-dihydrofuran and 75 mls ethyl acetate were charged to the reactor of a Parr apparatus. The system was thoroughly purged with nitrogen and 0.65 gram of a hydrogenation catalyst (5 percent palladium on carbon) was added under a nitrogen atmosphere. After additional nitrogen purging, shaking was begun and the system was pressurized with hydrogen to 15 psig. The system was repressurized as necesary until no futher hydrogen uptake was noted. The reaction mixture was then filtered through Dicalite® to remove the catalyst. Ethyl acetate was removed under reduced pressure. Gas chromatographic analysis indicated 98 percent yield crude 4-carbethoxy-2-ethyl-5-pentyl-2,3-dihydrofuran. The crude product was fractionated using a spinning-band distillation apparatus to obtain essentially pure 4-carbethoxy-2-ethyl-5-pentyl-2,3-dihydrofuran (B.P. 112°-114° C. Ε 1 mm Hg. nD≅° 1.4636). The structure ##STR11## was confirmed by infrared and nuclear magnetic resonance spectroscopy.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH:5]([CH3:7])[CH2:4][N:3]1[CH2:8][CH2:9][CH2:10][NH2:11].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[S:20](Cl)(=[O:22])=[O:21]>C1C=CC=CC=1>[CH3:1][CH:2]1[CH2:6][CH:5]([CH3:7])[CH2:4][N:3]1[CH2:8][CH2:9][CH2:10][NH:11][S:20]([C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[Cl:12])(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: CC1CC(C)N(CCCN)C1
Solvent: c1ccccc1
Product: CC1CC(C)N(CCCNS(=O)(=O)c2cc(Cl)ccc2Cl)C1
Temperature: 25 °C
Reaction time: 96 h
Yield: 67 %

Procedure:
2,4-Dimethyl-1-(3-aminopropyl) pyrrolidine in (4.7 g, 0.03 mol) benzene (30 ml) was added dropwise at room temperature to a solution of 2,5-dichlorobenzenesulphonylchloride (7.3 g, 0.03 ml) in benzene (100 ml). Thereafter, the mixture was stirred for 4 days at room temperature until the reaction was complete. Finally, the reaction product was obtained as a viscous, oily paste. The benzene mother liquor was decanted. The residue was dissolved in water, the solution was adjusted to pH 9.8 with 10% NaOH and extractes with petroleum ether (40°-60°) (4×100 ml). The combined extracts were dried over Na2SO4 and evaporated. The residue (5 g) was recrystallised twice from 100 ml petroleum ether to yield the product (3.7 g as white needles), m.p. 65°-67° C. Yield=67% of theoretical
Reaction SMILES: [NH:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH:3]1[NH:14][C:15]([NH:17][C:18]([O:20][CH3:21])=[O:19])=[S:16].I[CH2:23][CH2:24][CH2:25][CH3:26].CN(C)C=O.[OH-].[Na+]>O>[NH:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH:3]1[NH:14][C:15](=[N:17][C:18]([O:20][CH3:21])=[O:19])[S:16][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCI
Reactant: COC(=O)NC(=S)NC1C(=N)C=CC=C1Cc1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCSC(=NC(=O)OC)NC1C(=N)C=CC=C1Cc1ccco1
Reaction time: 0.5 h

Procedure:
To 5.0 g (0.0165 mole) of 1-imino(2-furylmethyl)-2-(3-carbomethoxythioureido)benzene and 3.6 g (0.01975 mole) of iodobutane in 80 ml. of N,N-dimethylformamide is added 0.7 g (0.0175 mole) of sodium hydroxide in 20 ml of water. The resulting mixture is stirred for 1/2 hour and the yellow precipitate that formed is separated by filtration, washed with 50 ml of water and dried to give 3.4 g of crude product, m.p. 86°-7° C. Recrystallization from ether-hexane affords 1-imino(2-furylmethyl)-2-(3-carbomethoxy-S-butylisothioureido)benzene m.p. 84°-85° C.