Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Mg]Br.O1CCC[CH2:5]1.C[Mg]Br.C(OCC)C.[CH2:17]([O:24][C@@H:25]1[C@@H:29]([CH2:30][O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:28][C@H:27]([O:39][CH3:40])[C:26]1=[O:41])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH2:17]([O:24][C@@H:25]1[C@@H:29]([CH2:30][O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:28][C@H:27]([O:39][CH3:40])[C@:26]1([CH3:5])[OH:41])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C1CCOC1
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)C1=O
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@]1(C)O
Temperature: 0 °C

Procedure:
92 mL of a 1 mol/L methyl magnesium bromide/tetrahydrofuran solution and 23 mL of a 3 mol/L methyl magnesium bromide/diethyl ether solution were added dropwise to a solution of 23.2 g of (2S,4R,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-2-methoxyoxolane-3-one in 100 mL of tetrahydrofuran at −40° C., and the obtained mixture was then stirred at the same temperature as described above for 30 minutes. Thereafter, the temperature of the reaction mixture was increased to 0° C. over 1 hour, and 500 mL of a saturated ammonium chloride aqueous solution and 500 mL of ethyl acetate were then added to the mixture. The organic layer was fractionated, and it was washed with 300 mL of a saturated sodium chloride aqueous solution and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography, so as to obtain 12.0 g of (2S,3R,4R,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-2-methoxy-3-methyloxolan-3-ol in the form of a colorless oily product.
Reaction SMILES: Cl[C:2]([O:4][CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:3].[NH2:10][C:11]1[CH:12]=[CH:13][C:14]2[O:19][CH2:18][CH2:17][N:16]([CH2:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=3[O:31][CH3:32])[C:15]=2[CH:33]=1.CN1CCOCC1>ClCCl>[CH:5]1([O:4][C:2]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[O:19][CH2:18][CH2:17][N:16]([CH2:20][C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=4[O:31][CH3:32])[C:15]=3[CH:33]=2)=[O:3])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C(Cl)OC1CCCC1
Reactant: COC(=O)c1ccc(CN2CCOc3ccc(N)cc32)c(OC)c1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)c1ccc(CN2CCOc3ccc(NC(=O)OC4CCCC4)cc32)c(OC)c1
Reaction time: 1 h
Yield: 52.2 %

Procedure:
Cyclopentyl chloroformate (0.5 g.) was added in a single portion to a stirred solution of methyl 4-(6-amino-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl)-3-methoxybenzoate (L) (1.0 g.) and N-methylmorpholine (0,314 g.) in dichloromethane (30 ml.), under an atmosphere of nitrogen. After one hour, the mixture was diluted with dichloromethane and washed successively with 1M hydrochloric acid, 5% w/v sodium bicarbonate solution, and saturated brine, then dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel (4 cm. diameter column), eluting with dichloromethane to give the title compound (0.7 g, 52%) as an oil; NMR (80 MHz, CDCl3): 1.69[m,8H, (CH2)4 ], 3.39(t,2H, OCH2CH2N), 3.90(s,3H, OCH3), 3.91 (s,3H, OCH3), 4.23(t,2H, OCH2CH2N) , 4.45(s,2H, CH2.Ar) , 5.10(m,1H, --CHO--) , 6.2(br s,1H, NHCO), 6.59-7.62(m,6H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH2:13][OH:14])[CH:3]=1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1>O1CCCC1.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH2:13][O:14][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1NC(CCO)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCC(Nc1cc(Cl)ccc1C#N)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
A solution of 4-chloro-2-[(3-hydroxy-1-phenylpropyl)amino]benzonitrile (2.3 g, 8 mmol) in dry tetrahydrofuran (50 ml) was treated with tert-butyldimethylsilylchloride (2.41 g, 2 eq.) and imidazole (1.09 g, 2 eq.) and stirred at room temperature for 1 h. The reaction mixture was diluted with water (200 ml) and the products extracted into diethyl ether (200 ml). The organic extract was dried over magnesium sulphate and concentrated to an oil. The crude product was purified on silica gel eluting with isohexane/diethyl ether (2:1) to afford the title compound as a colourless oil (2.3 g, 72%).
Reaction SMILES: [Cl:1][C:2]1[C:20](/[CH:21]=[CH:22]/[CH2:23][N:24]2C(=O)C3=CC=CC=C3C2=O)=[CH:19][CH:18]=[C:17]([Cl:35])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.CN>C(Cl)(Cl)Cl.CO>[NH2:24][CH2:23]/[CH:22]=[CH:21]/[C:20]1[C:2]([Cl:1])=[C:3]([C:17]([Cl:35])=[CH:18][CH:19]=1)[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(/C=C/CN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Agent: CN
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(/C=C/CN)c3Cl)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a solution of 8-[2,6-dichloro-3-((E)-3-phthalimido-1-propenyl)benzyloxy]-2-methylquinoline (43 mg) in chloroform (1 ml) was added 2M solution of methylamine in methanol (0.5 ml), and the mixture was stirred in the dark at ambient temperature overnight. The mixture was evaporated in vacuo, and the residue was purified by preparative thin layer chromatography to give 8-[3-((E)-3-amino-1-propenyl)-2,6-dichlorobenzyloxy]-2-methylquinoline (27 mg) as pale yellow amorphous.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]=2[CH3:22])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[Cl:42])[C:36](Cl)=[O:37]>ClCCl>[Cl:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[Cl:42])[C:36]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]=2[CH3:22])=[CH:23][CH:24]=1)=[O:37]
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccc(N)cc2)c2ccccc21
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1c(C)c(Cc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c2ccccc21
Yield: 79.8 %

Procedure:
In a dry reaction vessel, ethyl 2-[3-(4-aminobenzyl)-2-methyl-1H-indol-1-yl]acetate (1.0 g, 3.11 mmol) was added, and dissolved in 15 mL dichloromethane. Triethylamine (1.3 mL, 9.3 mmol) was added, and in an ice bath a dichloromethane solution dissolving 3,4-dichlorobenzoyl chloride (0.652 g, 3.11 mmol) was added slowly. After completion of dropwise addition, it was reacted in an ice bath for 4 h, and filtered. An aqueous solution of sodium bicarbonate was added, extracted with dichloromethane, rotate evaporated to dryness, chromatographed on a column to obtain a white solid 1.23 g, at a yield of 79.7%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10](OC)=[S:11].[N+:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])#[C-:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:10]2[S:11][CH:21]=[N:20][C:22]=2[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:14]=[CH:15][CH:16]=1
Reactant: COC(=S)c1cccc(OCc2cccc(Cl)c2)c1
Reactant: [C-]#[N+]CC(=O)OCC
Product: CCOC(=O)c1ncsc1-c1cccc(OCc2cccc(Cl)c2)c1
Yield: 77.8 %

Procedure:
In an analogous manner to that described in Example 1(C), 28.2 g (96.3 mmol) of O-methyl 3-[(3-chlorobenzyl)-oxy]thiobenzoate were reacted with ethyl isocyanoacetate and subsequently chromatographed on silica gel. Elution with 9:1, 8:2 and 1:1 mixtures of methylene chloride and ethyl acetate as well as ethyl acetate along yielded 28 g (77.8%) of ethyl 5-[3-[(3-chlorobenzyl)oxy]phenyl]-4-thiazolecarboxylate as an orange oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8]([CH3:14])([CH3:13])[CH2:7][CH2:6][C:5]2([CH3:16])[CH3:15].C1C(=O)N([Br:24])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH2:12][Br:24])[C:8]([CH3:14])([CH3:13])[CH2:7][CH2:6][C:5]2([CH3:16])[CH3:15]
Reactant: Cc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)CCC(C)(C)c2cc(CBr)c(Br)cc21

Procedure:
The mixture of 6-bromo-7-methyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (4.20 g, 15 mmol), NBS (3.20 g, 18 mmol), 2,2′-azobisisobutyronitrile (0.3 g, 1.8 mmol) and CCl4 (120 mL) was heated at reflux for 16 hours. The mixture was concentrated under reduced pressure to about 50 mL. The reaction was then filtered, and the solid was washed with Et2O (20 mL). The combined organic solution was then concentrated under vacuum to generate crude product. Crude 91.2 was generated as a brown oil and used directly in the next step without further purification.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[N:11]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:12](=[O:31])[CH2:13][C:14]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:17]=2[S:16](=[O:30])(=[O:29])[N:15]=1)=O)C.[O-]CC.[Na+]>C(O)C>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][N:11]2[C@@H:7]3[C@@H:6]([CH2:10][CH2:9][CH2:8]3)[C:4]([OH:3])=[C:13]([C:14]3[NH:19][C:18]4[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][C:17]=4[S:16](=[O:30])(=[O:29])[N:15]=3)[C:12]2=[O:31])=[CH:34][CH:35]=1
Reactant: CCOC(=O)C1CCCC1N(Cc1ccc(Cl)cc1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3CCC[C@@H]3N(Cc3ccc(Cl)cc3)C1=O)N2
Temperature: 60 °C
Reaction time: 16 h
Yield: 26.2 %

Procedure:
A solution of the crude 2-{(4-chloro-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid ethyl ester in ethanol (20 mL) was treated with a 21% w/w solution of sodium ethoxide in ethanol (0.648 g) and stirred for 16 h at 60° C. Upon cooling, the reaction mixture was then quenched with 1.0 M aqueous hydrochloric acid solution (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered, and dried in vacuo. The residue was purified by prep-HPLC [Column ODS-A 5μ 100 Å, 150×21.2 mm, 5 micron, 50%-100% in 13.5 min @ 22 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, cis-N-{3-[1-(4-chloro-benzyl)-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 (72.1 mg, 0.131 mmol, 26.2% over two steps), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.44-1.62 (4H, m), 1.91-2.18 (3H, m), 3.06 (3H, s), 3.78-3.94 (1H, m), 4.39-4.62 (1H, m), 4.90 (1H, d, J=15.6 Hz), 7.35-7.64 (7H, m), 10.19 (1H, s). LC-MS (ESI) calcd for C23H23ClN4O6S2 550.07, found 551.4 [M+H+].
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[NH:37]1[CH2:42][CH2:41][CH:40]([N:43]2[CH2:48][CH2:47][N:46]([C:49](=[O:51])[CH3:50])[CH2:45][CH2:44]2)[CH2:39][CH2:38]1>>[C:49]([N:46]1[CH2:45][CH2:44][N:43]([CH:40]2[CH2:39][CH2:38][N:37]([C:13](=[O:14])[C@H:12]([NH:16][C:17]([N:19]3[CH2:20][CH2:21][CH:22]([N:25]4[CH2:31][CH2:30][C:29]5[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=5[NH:27][C:26]4=[O:36])[CH2:23][CH2:24]3)=[O:18])[CH2:11][C:5]3[CH:6]=[CH:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:1][CH3:2])[CH:4]=3)[CH2:42][CH2:41]2)[CH2:48][CH2:47]1)(=[O:51])[CH3:50]
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Reactant: CC(=O)N1CCN(C2CCNCC2)CC1
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C(C)=O)CC3)CC2)cc1CC

Procedure:
Prepared analogously to Example 9i) from 400 mg (0.81 mmol) (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 230 mg (1.09 mmol) 1-(4-piperidin-4-yl-piperazin-1-yl)-ethanone.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=[CH:11]OCC)[C:6]([O:8]CC)=[O:7])[CH3:2].Cl.NO.C([N:21](CC)CC)C.Cl>C(O)C.O>[CH2:1]([O:3][C:4]([C:5]1[C:6](=[O:7])[O:8][NH:21][CH:11]=1)=[O:15])[CH3:2]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCN(CC)CC
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c[nH]oc1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 65.8 %

Procedure:
2-Ethoxymethylene-malonic acid diethyl ester (5.00 g, 23.1 mmol), hydroxylamine hydrochloride (4.01 g, 57.8 mmol) and triethylamine (8.06 mL, 57.8 mmol) were dissolved in ethanol (100 mL), the solution was stirred at room temperature for 17 hours, then, the solution was stirred for 4.5 hours under reflux. The reaction solution was cooled to room temperature, water was added, and 1N hydrochloric acid was added until a salt precipitated. The precipitated salt was collected by filtration, and a hydrochloride salt of the title compound (2.39 g, 15.2 mmol, 66%) was obtained as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]2[CH:36]=[C:35]([CH3:37])[C:29]3[N:30]([CH3:34])[C:31](=[O:33])[O:32][C:28]=3[CH:27]=2)=[O:25])[CH:21]=[C:20](Cl)[N:19]=1>CN1C(=O)CCC1>[Cl:17][C:18]1[N:19]=[C:20]([N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:15]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[NH:9][C:8]3=[O:16])[CH2:5][CH2:6]2)[CH:21]=[C:22]([C:24]([C:26]2[CH:36]=[C:35]([CH3:37])[C:29]3[N:30]([CH3:34])[C:31](=[O:33])[O:32][C:28]=3[CH:27]=2)=[O:25])[CH:23]=1
Reactant: Cc1cc(C(=O)c2cc(Cl)nc(Cl)c2)cc2oc(=O)n(C)c12
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Solvent: CN1CCCC1=O
Product: Cc1cc(C(=O)c2cc(Cl)nc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)c2)cc2oc(=O)n(C)c12

Procedure:
0.33 g (1.5 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one and 0.20 g (0.49 mmol) 6-(2,6-dichloro-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one were stirred in 3 mL NMP for 3 h at 120° C. The reaction mixture was purified by preparative HPLC. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [Br-:1].C1(C(O)(C2C=CC=CC=2)C(O[CH:12]2[CH2:17][CH2:16][N+:15]([CH3:28])([CH2:18][C:19](=[O:27])[NH:20][C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[CH2:14][CH2:13]2)=O)CCCCC1.[CH:36]1([C:41]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([OH:45])[C:42]([OH:44])=[O:43])[CH2:40][CH2:39][CH2:38][CH2:37]1>>[Br-:1].[CH:36]1([C:41]([OH:45])([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:42]([O:44][CH:14]2[CH2:13][CH2:12][CH2:17][CH2:16][N+:15]2([CH3:28])[CH2:18][C:19](=[O:27])[NH:20][C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)=[O:43])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: O=C(O)C(O)(c1ccccc1)C1CCCC1
Reactant: C[N+]1(CC(=O)Nc2cnccn2)CCC(OC(=O)C(O)(c2ccccc2)C2CCCCC2)CC1
Agent: [Br-]
Product: C[N+]1(CC(=O)Nc2cnccn2)CCCCC1OC(=O)C(O)(c1ccccc1)C1CCCC1

Procedure:
This compound is prepared by an analogous method to 4-(2-cyclohexyl-2-hydroxy-2-phenyl-acetoxy)-1-methyl-1-(pyrazin-2-ylcarbamoylmethyl)-piperidinium bromide (Example 4) by replacing cyclohexyl-hydroxy-phenyl-acetic acid with cyclopentyl-mandelic acid.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].C(=O)([O-])[O-].[K+].[K+].[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1>CC(C)=O>[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:2][C:3](=[O:5])[CH3:4])=[CH:16][CH:15]=1
Reactant: CC(=O)CCl
Reactant: CSc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CSc1ccc(OCC(C)=O)cc1

Procedure:
A mixture of chloroacetone (10 ml), potassium carbonate (21 g), and 4-(methylthio)phenol (10 g) in acetone (200 ml) was heated under reflux for 6 h. The solvent was removed under reduced pressure and the residue partitioned between diethylether/water. The organics were separated, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 5-10% ethylacetate/iso-hexane. Yield 12.43 g
Reaction SMILES: C([N:9]1[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=2)[C:11](=[C:21](OC)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]1=[O:30])(=O)C1C=CC=CC=1.[NH2:31][C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=1.N>CN(C=O)C>[C:36]([C:35]1[CH:38]=[CH:39][C:32]([NH:31]/[C:21](=[C:11]2\[C:10](=[O:30])[NH:9][C:17]3[C:12]\2=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=3)/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:33][CH:34]=1)#[N:37]
Reactant: COC(=C1C(=O)N(C(=O)c2ccccc2)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: N#Cc1ccc(N)cc1
Agent: N
Solvent: CN(C)C=O
Product: N#Cc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 77 from 1-benzoyl-3-(1-methoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-aminobenzonitrile in DMF and subsequent treatment with methanolic ammonia.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[CH:18]2.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5])[CH:19]=[CH:18]2
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Reactant: Clc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cc(C(F)(F)F)ccc1-n1ccc2cc(Cl)ccc21
Temperature: 100 °C
Reaction time: 14 h
Yield: 98.1 %

Procedure:
A mixture of 2-fluoro-5-(trifluoromethyl)benzonitrile (1000 mg), 5-chloro-1H-indole (800 mg), potassium carbonate (1.8 g), and DMSO (10 ml) was stirred at 100° C. for 14 hours. The reaction mixture was cooled to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 2-(5-chloro-1H-indol-1-yl)-5-(trifluoromethyl)benzonitrile (1.66 g).
Reaction SMILES: [OH:1][CH2:2][C:3]12[CH2:10][O:9][P:6]([O:7][CH2:8]1)[O:5][CH2:4]2.[C:11](Cl)(=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(N(CC)CC)C>C1(C)C=CC=CC=1>[P:6]12[O:9][CH2:10][C:3]([CH2:2][O:1][C:11](=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH2:8][O:7]1)[CH2:4][O:5]2
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: OCC12COP(OC1)OC2
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCC(=O)OCC12COP(OC1)OC2
Temperature: 25 °C
Reaction time: 10 h

Procedure:
16.4 g (0.1 mol) of 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2,2,2]octane are dissolved in 150 ml of toluene by warming. 30.2 g (0.1 mol) of stearic acid chloride, followed by 10.1 g (0.1 mol) of triethylamine, are added dropwise at room temperature. After the slight evolution of heat has died away, the mixture is stirred for 10 hours under nitrogen at room temperature and the precipitated triethylamine hydrochloride is then filtered off. The filtrate is evaporated with exclusion of moisture, a yellowish oil remaining, which crystallises on being triturated with methanol. After filtering off under suction and drying, stearic acid 1-phospha-2,6,7-trioxabicyclo[2,2,2]oct-4-yl-methyl ester (Stabiliser No. 9), melting point 49°C, is obtained.
Reaction SMILES: [C:1]([C:6]1[C:7](=O)[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[CH:16]=[CH2:17])(=[O:5])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:21])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:16]=[CH2:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: C=Cc1cccc2cc(C(=O)CCC)c(=O)[nH]c12
Solvent: ClC(Cl)Cl
Product: C=Cc1cccc2c(Cl)c(C(=O)CCC)cnc12
Yield: 38.5 %

Procedure:
3-Butyryl-8-vinylquinolone (23 g, 95 mmol) was heated under reflux in a mixture of phosphoryl chloride (I00 ml) and chloroform (100 ml) for 45 minutes. The solvent was evaporated and the residue was mixed with ice, neutralized with ammonia solution and extracted into dichloromethane. The organic solution was washed successively with sodium hydrogen carbonate solution and brine, dried (anhyd. MgSO4), filtered and evaporated. Chromatography (silica gel, 2% methanol in dichloromethane) afforded 3-butyryl-4-chloro-8-vinylquinoline as a brown oil (9.5 g, 38.5%).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[CH:8][N:9]=1)(=[O:3])[CH3:2].[C:10]1([CH2:16][C@H:17]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:18]2[O:23][C:22](=[O:24])[C:21]3[CH:25]=[CH:26][CH:27]=[C:28]([C:29]([F:32])([F:31])[F:30])[C:20]=3[N:19]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1.C([Li])CCC.CCCCCC>[O:24]=[C:22]([C:21]1[CH:25]=[CH:26][CH:27]=[C:28]([C:29]([F:31])([F:32])[F:30])[C:20]=1[NH:19][C:18]([C@@H:17]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:23])[CH2:2][C:1](=[O:3])[NH:4][C:5]1[S:6][CH:7]=[CH:8][N:9]=1
Reactant: CC(=O)Nc1nccs1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)c1nc2c(C(F)(F)F)cccc2c(=O)o1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F
Yield: 103 %

Procedure:
Using the procedure of Step B of Example 7, a solution of 9.09 g of 2-acetylaminothiazole in 280 ml of tetrahydrofuran, 91 ml of n-butyllithium in solution in hexane and 13.9 g of product of Step A in 100 ml of tetrahydrofuran were reacted to obtain 19 g of 1,1-dimethylethyl N-[(S) 1-[[2-[1,3-dioxo-3-(2-thiazolylamino)-propyl]-6-(trifluoromethyl)-phenyl]-amino-carbonyl]-2-(phenyl)-ethyl]-carbamate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:15][CH3:16])=[C:6]([CH:8]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]2=[O:14])[CH:7]=1>C(O)(=O)C.[Zn]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:15][CH3:16])=[C:6]([CH:8]2[C:12](=[O:13])[CH2:11][CH2:10][C:9]2=[O:14])[CH:7]=1
Reactant: CCc1ccc(Br)cc1C1C(=O)C=CC1=O
Agent: [Zn]
Solvent: CC(=O)O
Product: CCc1ccc(Br)cc1C1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of zinc dust (13.9 g, 214 mmol) in acetic acid (270 ml) is added a solution of 2-(5-bromo-2-ethylphenyl)cyclopent-4-ene-1,3-dione (8.544 g, 31 mmol) in acetic acid (70 ml). The reaction mixture is stirred at room temperature for 18 hours, then filtered through diatomaceous earth and washed with acetic acid and concentrated under reduced pressure. The crude oil is azeotroped with toluene (×2) then concentrated in vacuo and purified by flash column chromatography on silica gel to afford 2-(5-bromo-2-ethylphenyl)cyclopentane-1,3-dione.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1)=[O:3].[N+:11]([O-])([O-:13])=[O:12].[K+]>S(=O)(=O)(O)O>[CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)=[O:3]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
Concentrated sulfuric acid (200 ml) is cooled to 5° C. 4-Fluoroacetophenone (20 ml, 0.16 mol) is added keeping the temperature below 10° C. The mixture is cooled to 0-5° C. and potassium nitrate (25 g, 0.25 mol) is added portionwise over 2 hours keeping the temperature within this range. Following the addition the mixture is stirred in the cold for additionally 2 hours. The mixture is poured on ice (600 g) and the crude product is filtered off. Column-chromatographic purification on silica gel using a mixture of ethyl acetate and petroleum ether (1:9) as the eluent affords pure 1 g (18.2 g, 60%). Mp 48-49° C.