Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]([CH3:23])[C:9](=[O:22])[CH2:10][N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])=[CH:6][CH:5]=[C:4]([Cl:24])[C:3]=1[CH2:25][O:26]S(C)(=O)=O.O[C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:41]=1[N:40]=[C:39]([CH3:42])[CH:38]=[C:37]2[N:43]1[CH:47]=[CH:46][N:45]=[CH:44]1.C(=O)([O-])[O-].[K+].[K+].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([N:8]([C:9](=[O:22])[CH2:10][N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])[CH3:23])=[CH:6][CH:5]=[C:4]([Cl:24])[C:3]=1[CH2:25][O:26][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:41]=1[N:40]=[C:39]([CH3:42])[CH:38]=[C:37]2[N:43]1[CH:47]=[CH:46][N:45]=[CH:44]1
Reactant: Cc1cc(-n2ccnc2)c2cccc(O)c2n1
Reactant: CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)c(COS(C)(=O)=O)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(-n2ccnc2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a mixture of 2,6-dichloro-1-mesyloxymethyl-3-(N-methyl-N-phthalimidoacetylamino)benzene (2.35 g), tetrabutylammonium iodide (123 mg) and molecular sieves 4A (340 mg) in N,N-dimethylformamide (38 ml) were added 8-hydroxy-4-(imidazol-1-yl)-2-methylquinoline (750 mg) and potassium carbonate (2.3 g) under ice-cooling, and the mixture was stirred for 15 minutes at the same temperature and overnight at ambient temperature. Water and chloroform were added thereto, and the separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized with ethyl acetate to give 8-[2,6-dichloro-3-(N-phthalimidoacetyl-N-methylamino)benzyloxy]-4-(imidazol-1-yl)-2-methylquinoline (1.92 g) as colorless crystals.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[CH:20]=[CH:21][S:22][C:15]=12.[Br:23]C(F)(F)C(Br)(F)F>CCCCCC.O.O1CCCC1>[Br:23][C:21]1[S:22][C:15]2[C:16](=[N:17][CH:18]=[CH:19][C:14]=2[Cl:13])[CH:20]=1
Reactant: Clc1ccnc2ccsc12
Reactant: FC(F)(Br)C(F)(F)Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Clc1ccnc2cc(Br)sc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74.2 %

Procedure:
A solution of 90 mL of tetrahydrofuran and diisopropylamine (4.6 mL, 32.9 mmol) were cooled to −78° C. and n-butyllithium (12.2 mL, 30.3 mmol) in hexane was added dropwise. The solution was heated to 0 ° C. for 10 minutes, recooled to −78° C., and 7-chloro-thieno[3,2-b]pyridine (4.29 g, 25.2 mmol) was added. The anion was stirred 10 minutes and 1,2-dibromo-1,1,2,2-tetrafluoroethane (3.3 mL, 27.8 mmol) was added. The solution was stirred an additional 20 minutes then allowed to warm to room temperature. After 1 hour the reaction mixture was poured into water and extracted with chloroform (3×100 mL). The combined organic portions were dried over magnesium sulfate, filtered, and dried to afford 4.65 g (74%) of 2-bromo-7-chloro-thieno[3,2-b]pyridine. 1H NMR (400 MHz, DMSO) d 8.64 (d, 1H), 7.91 (s, 1H), 7.65 (d, 1H); LC-MS: 250 (MH+); HPLC RT: 5.49.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH3:21])[C:10]=1[CH3:22])C1C=CC=CC=1.[ClH:23]>C(O)(C)C>[ClH:23].[CH2:20]([O:19][CH2:18][CH2:17][CH2:16][N:11]1[CH:12]=[CH:13][C:14](=[O:15])[C:9]([OH:8])=[C:10]1[CH3:22])[CH3:21]
Reactant: CCOCCCn1ccc(=O)c(OCc2ccccc2)c1C
Agent: Cl
Solvent: CC(C)O
Product: CCOCCCn1ccc(=O)c(O)c1C

Procedure:
The amorphous 3-benzyloxy-1-(3-ethoxypropyl)-2-methyl-4(1H)-pyridinone so obtained is taken up in 100 ml of concentrated aqueous hydrochloric acid and refluxed for 3 minutes. The solution so obtained is diluted with isopropanol and evaporated to dryness. The residue is crystallised from isopropanol and washed with ethyl acetate, affording 1-(3-ethoxypropyl)-3-hydroxy-2-methyl-4(1H)-pyridinone hydrochloride which melts at 130°-131° C.
Reaction SMILES: [OH-].[K+:2].[CH3:3][NH:4][CH2:5][CH2:6][S:7]([OH:10])(=[O:9])=[O:8]>O>[K+:2].[CH3:3][NH:4][CH2:5][CH2:6][S:7]([O-:10])(=[O:9])=[O:8]
Reactant: CNCCS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CNCCS(=O)(=O)[O-]
Temperature: 27.5 °C
Reaction time: 1 h

Procedure:
In an aqueous solution of 3.0 kg (53.2 mol) of potassium hydroxide and 8.4 kg of water was dissolved 7.4 kg (53.2 mol) of N-methyltaurine obtained in Example 3, and the mixture was reacted under stirring at 25 to 30° C. for 1 hour to give 18.8 kg of a 50% aqueous solution of N-methyltaurine potassium salt.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1.O.[Cl-].[Na+]>[C:14]1([CH2:13][NH:20][C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][CH:2]=[CH:3]3)=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1)c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
Indole-5-carboxylic acid (3.0 g) in anhydrous terahydrofuran (THF) (25 ml) was treated with 1,1-carbonyldiimidazole (CDI) (3.35 g) with stirring at room temperature for 1 h. A further amount (1.0 g) of CDI was added and, after stirring for a further 1H, benzylamine (4.0 g) was introduced. Stirring was continued for 24 h. The solution was diluted with water (50 ml), saturated with sodium chloride, and the THF layer separated off. The organic solution was washed with 1N hydrochloride acid (3×50 ml), brine (2×50 ml), dried (MgSO4) and evaporated under reduced pressure to given an oil (6.0 g) which was chromatographed on silica (Merck 7734, 200 g) eluting with methylene chloride and then methylene chloride/methanol (50:1) to give a foam (4.0 g). Crystallization from ethyl acetate/petroleum/ether (b.p. 60°-80°) gave the title compound as a solid (2.05 g) m.p. 155°-160°.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[C:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:9])[CH:6]([CH3:8])[CH3:7]>O.C(O)(=O)C>[N:1](=[C:10]([C:5](=[O:9])[CH:6]([CH3:8])[CH3:7])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[OH:3]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(=NO)C(=O)C(C)C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
A solution of sodium nitrite (43.8 g.) in water (92 ml.) was added dropwise, with stirring, to a solution of ethyl isobutyrylacetate (100.3 g.) in acetic acid (80 ml.) at 0°. After stirring at 0° for 30 minutes then at room temperature for 3 hours, water (100 ml.) was added and the mixture extracted with ether. The extracts were washed with water, saturated sodium bicarbonate solution and water. After drying (CaSO4), the solution was evaporated to give ethyl 2-oximino-4-methyl-3-oxopentanoate (112 g.) as a crude oil.
Reaction SMILES: [CH3:1][C:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([NH:30]C(OC(C)(C)C)=O)=[CH:26][CH:25]=3)=[O:21])[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1([CH2:13][N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([NH2:30])=[CH:28][CH:29]=3)=[O:21])[CH2:18][CH2:19]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(COC(=O)N2CCN(CC3(C)Cn4cc([N+](=O)[O-])nc4O3)CC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(CN2CCN(C(=O)OCc3ccc(N)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.4 %

Procedure:
A mixture of 4-(tert-butoxycarbonylamino)-benzyl 4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate (340 mg, 0.66 mmol), trifluoroacetic acid (2 ml) and methylene chloride (10 ml) was stirred at room temperature for 2 hours, and then neutralized with a saturated sodium hydrogencarbonate solution. The organic phase was washed with water and a saturated saline solution in this order, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. To the residue, diethyl ether was added, and the precipitates were filtered off to afford 4-aminobenzyl 4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate (100 mg, yield 37%) as a light yellow powder.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH2:14])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1.Cl.[CH2:16]([S:18]([N:21]1[CH2:25][CH2:24][N:23]([C:26](Cl)=[O:27])[C:22]1=[O:29])(=[O:20])=[O:19])[CH3:17]>O1CCOCC1>[CH2:16]([S:18]([N:21]1[CH2:25][CH2:24][N:23]([C:26]([NH:14][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)[C:11]([OH:13])=[O:12])=[O:27])[C:22]1=[O:29])(=[O:20])=[O:19])[CH3:17]
Reactant: CCS(=O)(=O)N1CCN(C(=O)Cl)C1=O
Reactant: NC(C(=O)O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCN(C(=O)NC(C(=O)O)c2ccc(Cl)cc2)C1=O

Procedure:
Sufficient concentrated sodium hydroxide solution just to dissolve the acid was added to a suspension of 11.0 parts by weight of p-chloro-α-aminophenylacetic acid in 110 parts by volume of 50% strength aqueous dioxane. Dilute hydrochloric acid was then added with stirring until a pH of 7.5-8.0 was reached. 13.0 parts by weight of 3-ethylsulphonyl-imidazolidin-2-one-1-carbonyl chloride were then added in portions at about 0° C and the pH of the mixture was maintained at 7.5-8.0 by means of dilute sodium hydroxide solution. Thereafter the mixture was stirred further for as long as an occasional addition of sodium hydroxide solution was still necessary to maintain the pH of 7.5-8.0. The bulk of the dioxane was then removed in vacuo at pH 6.5, about 200 parts by volume of water were added, the mixture was extracted once with ether at pH 9.0 (the ether extract being discarded) and covered with fresh ether, and the pH was brought to 0.5 with stirring. The organic phase was then separated off, washed, dried and completely evaporated in vacuo. The residue was dissolved in hot ethyl acetate; thereafter the same amount of benzene and petroleum ether was added until there is turbidity which (only just) disappears again, and the mixture was left to crystallize.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[Cl:27][C:28]1[C:33](B(O)O)=[CH:32][CH:31]=[CH:30][N:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:33]2[C:28]([Cl:27])=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1cccnc1Cl
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(-c2cccnc2Cl)c1

Procedure:
By carrying out the operation analogously to example 1, starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to preparation IX, and 2-chloro-3-pyridineboronic acid, the desired product is obtained in the form of a white solid (yield=21%).
Reaction SMILES: [OH-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=2)[CH:7]=1>C(O)C>[N:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:17][CH:18]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccc(-n2cnnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(-n2cnnc2)cc1
Reaction time: 1 h
Yield: 90.9 %

Procedure:
5.5 ml of a 5N aqueous sodium hydroxide solution was added to a solution of 1.2 g of ethyl 4-(1,2,4-triazol-4-yl)benzoate in 15 ml of ethanol. The mixture was stirred at 50°-60° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. To the residue was added ice water. The mixture was made acidic with acetic acid. The resulting crystals were collected by filtration, water-washed, and dried to obtain 0.95 g of 4-(1,2,4-triazol-4-yl)benzoic acid as a white powder. Melting point: 300° C. or above
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:25]2[C:24]([CH3:26])=[C:23]([CH3:27])[N:22]=[C:21]([NH2:28])[C:20]=2[N:19]=[C:18]1[CH3:29]>>[NH2:28][C:21]1[C:20]2[N:19]=[C:18]([CH3:29])[N:17]([CH2:16][CH2:15][CH2:14][NH:13][C:10]([C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:11])[C:25]=2[C:24]([CH3:26])=[C:23]([CH3:27])[N:22]=1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: Cc1nc(N)c2nc(C)n(CCCN)c2c1C
Product: Cc1nc(N)c2nc(C)n(CCCNC(=O)[C@@H]3C[C@H]3c3ccccc3)c2c1C

Procedure:
Using the method of Examples 78–92, trans-2-phenyl-1-cyclopropanecarbonyl chloride was reacted with 1-(3-aminopropyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired product. The observed accurate mass was 378.2298.
Reaction SMILES: [CH:1]1([CH:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C@H:18]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:19]1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH2:23][N:20]2[CH2:21][CH2:22][C@H:18]([NH:17][C:8](=[O:10])[CH:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:19]2)=[CH:26][CH:27]=1
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Reactant: O=C(O)C(C1CCCCC1)C1CCCCC1
Product: O=C(N[C@H]1CCN(CCc2ccc(F)cc2)C1)C(C1CCCCC1)C1CCCCC1
Yield: 26.5 %

Procedure:
Dicyclohexylacetic acid (0.45 g) and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine (0.42 g) were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)dicyclohexylacetamide (0.22 g), melting point 122-124° C.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].[Li+].[OH-].Cl.Cl[CH2:22][C:23]1[C:24]([NH:36][CH3:37])=[N:25][C:26]2[CH:27]=[C:28]3[O:35][CH2:34][O:33][C:29]3=[CH:30][C:31]=2[CH:32]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:22][C:23]2[C:24]([NH:36][CH3:37])=[N:25][C:26]3[CH:27]=[C:28]4[O:35][CH2:34][O:33][C:29]4=[CH:30][C:31]=3[CH:32]=2)=[C:5]([OH:17])[N:4]=1)[CH3:2]
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: CNc1nc2cc3c(cc2cc1CCl)OCO3
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCc1nc(O)c(Cc2cc3cc4c(cc3nc2NC)OCO4)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (284 mg, 1.22 mmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. LiOH solution (1.20 mL, 2.40 mmol) at RT followed by 7-(chloromethyl)-N-methyl-[1,3]dioxolo[4,5-g]quinolin-6-amine hydrochloride CCH 34158B (350 mg, 1.22 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (80 mL) and the organic solution was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:7 N NH3 solution in MeOH=100:0 to 95:5) gave 1-ethyl-6,7-dimethoxy-4-((6-(methylamino)-[1,3]dioxolo[4,5-g]quinolin-7-yl)methyl)isoquinolin-3-ol. This free base was dissolved in MeOH (6 mL) in a 25 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.19 M HCl solution in MeOH (5 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum. Recrystallization from a mixture of MeOH:Et2O afforded 1-ethyl-6,7-dimethoxy-4-((6-(methylamino)-[1,3]dioxolo[4,5-g]quinolin-7-yl)methyl)isoquinolin-3-ol dihydrochloride 61 as a pale brown solid (104 mg, 16% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][O:23]CCO)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[F:32][C:33]([F:38])([F:37])[CH2:34]C=O>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([OH:23])[CH2:34][C:33]([F:38])([F:37])[F:32])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(COCCO)nc3N21
Reactant: O=CCC(F)(F)F
Agent: [Li]C(C)(C)C
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(C(O)CC(F)(F)F)nc3N21

Procedure:
This compound was prepared in analogy to Example 38 intermediate, from (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 5, intermediate b), tert-butyllithium and 3,3,3-trifluoropropanal.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH2:14]([N:17]([CH3:31])[CH2:18][CH2:19][CH2:20]/[C:21](/[CH3:30])=[CH:22]/[CH2:23][CH2:24]/[C:25](/[CH3:29])=[CH:26]/[CH:27]=[O:28])[CH:15]=[CH2:16]>C1COCC1.CCCCCC>[CH2:14]([N:17]([CH3:31])[CH2:18][CH2:19][CH2:20]/[C:21](/[CH3:30])=[CH:22]/[CH2:23][CH2:24]/[C:25](/[CH3:29])=[CH:26]/[CH:27]([C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1)[OH:28])[CH:15]=[CH2:16]
Reactant: Brc1ccc(Br)cc1
Reactant: C=CCN(C)CCC/C(C)=C/CC/C(C)=C/C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCN(C)CCC/C(C)=C/CC/C(C)=C/C(O)c1ccc(Br)cc1
Reaction time: 1 h
Yield: 23.3 %

Procedure:
A solution of 6.4 g of 1,4-dibromobenzene in 50 ml of absolute THF is cooled -78° C. and treated within 30 min. with 15.3 ml of 1.6M butyllithium in hexane. After 1 hr. 3.0 g of (2E,6E)-10-(allyl-methyl-amino)-3,7-dimethyl-deca-2,6-dienal (Ex. 57.1.A) in 12 ml of THF are added dropwise. After 1 1/2 hr. at -78° C. the bath is removed until the suspension has dissolved. Subsequently, 4.5 ml of acetic acid in 6 ml of ether are added dropwise at -78° C. Then, the mixture is poured into saturated ammonium chloride solution/ethyl acetate. The organic phase is washed with saturated sodium bicarbonate solution and 10% sodium chloride solution, dried and evaporated. After silica gel chromatography with methylene chloride/methanol (95:5) there are obtained 1.14 g of (2E,6E)-(RS)-10-(allyl-methyl-amino)-1-(4-bromo-phenyl)-3,7-dimethyl-deca-2,6-dien-1-ol. This is dissolved in ethanol with 0.29 g of fumaric acid, evaporated and converted with ethyl acetate/ether into 0.91 g of (2E,6E)-(RS)-10-(allyl-methyl-amino)-1-(4-brom-phenyl)-3,7-dimethyl-deca-2,6-dien-1-ol.fumarate (1:1), MS: m/e 406 (M+H+, 1Br).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:12]([OH:14])=O)[CH3:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[CH3:16][O:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH2:20]>>[CH3:16][O:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH:20][C:12](=[O:14])[CH:10]([CH3:11])[NH:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: CC(Nc1cc(Cl)cc(Cl)c1)C(=O)O
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Product: COC(=O)[C@H](C)NC(=O)C(C)Nc1cc(Cl)cc(Cl)c1

Procedure:
Following General Procedure D and using N-(3,5-dichlorophenyl)-D,L-alanine (from Example B above) and L-alanine methyl ester hydrochloride (Sigma), the title compound was prepared as a oil. The reaction product was purified by silica gel chromatography using 50% ethyl acetateihexane.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:13]=[C:12]([C:14](=[O:16])[CH3:15])[CH:11]=[CH:10][C:9]=1[OH:17].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:6][O:7][C:8]1[CH:13]=[C:12]([C:14](=[O:16])[CH3:15])[CH:11]=[CH:10][C:9]=1[O:17][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(C(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To dimethylformamide (200 ml) are added 2-methoxy-4-acetylphenol (20 g), ethyl α-bromoacetate (15 ml) and potassium carbonate (18.3 g), and the mixture is stirred at room temperature overnight. After the reaction is complete, water is added to the mixture, and the mixture is extracted with ethyl acetate. The extract is washed with aqueous sodium hydrogen carbonate solution, and dried over magnesium sulfate, and concentrated under reduced pressure to remove the solvent. The resulting crystals are collected, and washed with n-hexane-diethyl ether to give ethyl α-(2-methoxy-4-acetylphenoxy)acetate (23.86 g).
Reaction SMILES: I[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH2:15][N:16]3[C:20]([CH3:22])([CH3:21])[C:19](=[O:23])[NH:18][C:17]3=[O:24])[N:8]=2)=[CH:4][CH:3]=1.[C:25]1([SH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:21][C:20]1([CH3:22])[N:16]([CH2:15][CH2:14][NH:13][C:9]2[N:8]=[C:7]([C:5]3[S:6][C:2]([S:31][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:3][CH:4]=3)[CH:12]=[CH:11][N:10]=2)[C:17](=[O:24])[NH:18][C:19]1=[O:23]
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2ccc(I)s2)n1
Reactant: Sc1ccccc1
Product: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2ccc(Sc3ccccc3)s2)n1

Procedure:
The title compound was prepared from 1-{2-[4-(5-iodothiophen-2-yl)pyrimidin-2-ylamino]ethyl}-5,5-dimethyl-imidazolidine-2,4-dione and thiophenol in a manner analogous to Example 259. MS (M+H)+ 440.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([CH:20]=[O:21])[C:15]=2[O:16][CH2:17][O:18][CH3:19])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OCC)C.[CH:27]([Mg]Br)([CH3:29])[CH3:28].[Cl-].[NH4+]>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([CH:20]([OH:21])[CH:27]([CH3:29])[CH3:28])[C:15]=2[O:16][CH2:17][O:18][CH3:19])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[Mg]Br
Reactant: COCOc1c(C=O)csc1-c1ccc(C(C)(C)C)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCOc1c(C(O)C(C)C)csc1-c1ccc(C(C)(C)C)cc1
Reaction time: 2.5 h
Yield: 34 %

Procedure:
To a solution of 2-(4-t-butylphenyl)-3-methoxymethyloxy-4-formylthiophene (3.0 g, 10 mmol) in THF (2.5 mL), 2.0 M ethyl ether solution (6.0 mL, 12 mmol) of isopropylmagnesium bromide was added dropwise under cooling with ice, followed by stirring for 2.5 hours under cooling with ice. A saturated ammonium chloride aqueous solution was added to the reaction solution, and then extraction was carried out with ethyl acetate, and the organic layer was washed with a saturated sodium chloride solution and then dried over anhydrous sodium sulfate. The obtained organic layer was concentrated, and then purification was carried out with a silica gel column chromatography (n-hexane/ethyl acetate=3/1) to obtain the desired product as a pale yellow oil (1.18 g, yield 34%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=1[C:17]([F:20])([F:19])[F:18].O[N:22]=[C:23]([C:25]1[CH:33]=[CH:32][C:28]2[NH:29][CH:30]=[N:31][C:27]=2[CH:26]=1)[NH2:24]>>[CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]2[O:14][N:22]=[C:23]([C:25]3[CH:33]=[CH:32][C:28]4[NH:29][CH:30]=[N:31][C:27]=4[CH:26]=3)[N:24]=2)=[CH:10][C:9]=1[C:17]([F:19])([F:18])[F:20]
Reactant: NC(=NO)c1ccc2[nH]cnc2c1
Reactant: C[C@@H]1CCCCN1c1ccc(C(=O)O)cc1C(F)(F)F
Product: C[C@@H]1CCCCN1c1ccc(-c2nc(-c3ccc4[nH]cnc4c3)no2)cc1C(F)(F)F

Procedure:
Title compound was prepared following general procedure 3 starting from Intermediate 26 (300 mg; 1.04 mmol; 1 eq.), and Intermediate 1 (183.98 mg; 1.04 mmol; 1 eq.). After evaporation of the solvents, the solid residue was triturated with ACN, filtered and dried under vacuum to give the title compound as an off-white solid. 1H NMR (DMSO-d5) δ 12.78 (br m, 1H), 8.50-8.26 (m, 2H), 8.04-7.68 (m, 3H), 3.16 (m, 1H), 3.02-2.90 (m, 1H), 2.69-2.55 (m, 1H), 1.87-1.20 (m, 6H), 0.78 (d, J=6.1 Hz, 3H). HPLC (Method A), Rt 5.03 min (Purity: 98.4%). LC/MS (Method B): 426.3 (M+H)−; 428.1 (M+H)+.