Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:16]([OH:25])([CH:23]=[CH2:24])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1.[H-].[Na+].CI.Cl[CH2:31]Cl>C1COCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:16]([O:25][CH3:31])([CH:23]=[CH2:24])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1
Reactant: C=CC(O)(Cn1cncn1)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Reactant: ClCCl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: C=CC(Cn1cncn1)(OC)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-[2-chloro-4-(4-chlorophenoxy)phenyl]-1-(1,2,4-triazol-1-yl)but-3-en-2-ol (0.4 g) was dissolved in THF (10 mL) and sodium hydride (0.03 g) was added. The mixture was stirred for 30 min at room temperature and methyl iodide (0.08 mL) was added. The mixture was then heated for 10 h to reflux. Brine and dichloro methane were added, the organic phase was dried and evaporated to obtain the crude product. This was purified by column chromatography to obtain 0.04 g of the desired compound.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][C:6]2=[N:7][S:8][N:9]=[C:5]2[CH:4]=1.Br>>[N:7]1[S:8][N:9]=[C:5]2[CH:4]=[C:3]([OH:2])[CH:11]=[CH:10][C:6]=12
Reactant: COc1ccc2nsnc2c1
Agent: Br
Product: Oc1ccc2nsnc2c1
Temperature: 10 °C
Yield: 26.7 %

Procedure:
5-Methoxy-benzo-[2,1,3]-thiadiazole (4.09 g, 24.6 mmol) was stirred with hydrobromic acid (60 ml, 165 mmol, 30% in acetic acid) at 80° C. for 5 days. The mixture was cooled to 10° C. and filtered. The solids were purified by short column chromatography (50% ethyl acetate/hexane). Solvents were stripped in vacuo to afford 1.0 g of a yellow solid (27% yield).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[N:16]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:16]1([C:22]([O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=Cc1ccc(OC(=O)N2CCOCC2)cc1
Temperature: 25 °C
Yield: 74.8 %

Procedure:
To a 250 mL dry round bottom flask were added 4-hydroxybenzaldehyde (6.11 g, 50.0 mmol), anhydrous CH2Cl2 (80 mL) and pyridine (4.86 mL, 60.0 mmol). The mixture was stirred in an ice-water, then 4-morpholinecarbonyl chloride (6.12 mL, 52.5 mmol) was added. The mixture was stirred and warmed slowly to room temperature, then stirred at room temperature overnight. An aqueous solution of 5% NaHCO3 (100 mL) was added to the reaction mixture. The CH2Cl2 layer was separated, and the aqueous layer was extracted continually with CH2Cl2 (50 mL×2). The combined CH2Cl2 solution was dried over Na2SO4. Removal of the solvent gave 4-formylphenyl morpholine-4-carboxylate (8.80 g) as white solid. Yield: 75%. 1H NMR (CDCl3, 300 MHz): δ=9.97 (s, 1H), 7.90 (d, J=9.0 Hz, 2H), 7.30 (d, J=9.0 Hz, 2H), 3.77-3.57 (m, 6H). 13C NMR (CDCl3, 75.5 MHz, mixture of two isomers): δ=191.0, 156.0, 152.6, 133.6, 131.1, 122.3, 66.5, 66.4, 45.0, 44.2.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]C#N)=[CH:15][CH:14]=1.CC(C)([O-:25])C.[K+].OO.Cl>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[NH2:7][C:6]1[CH:8]=[C:2]([CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10])[C:19]([C:16]1[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=1)=[O:25]
Reactant: N#CCc1ccc(F)cc1
Reactant: CC(C)(C)[O-]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Nc1cc(C(=O)c2ccc(F)cc2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a cold (0° C.) solution of 17.25 g (100 mmol) of 5-chloro-2-nitroaniline and 12 ml (100 mmol) of 4-fluorophenylacetonitrile in 200 ml of dimethylformamide, was added 22.44 g (200 mmol) of potassium t-butoxide, under nitrogen. The resultant reaction mixture was warmed to room temperature and reacted overnight. When the reaction was substantially complete, as indicated by TLC (eluent of 40% ethyl acetate in hexane), the reaction mixture was cooled to 0° C. followed by the addition of 30 ml of 30% hydrogen peroxide. When the reaction was substantially complete, as indicated by TLC (eluent of 40% ethyl acetate in hexane), the reaction mixture was poured into 1 liter of 1N hydrochloric acid (aqueous) which resulted in the formation of a yellow/orange precipitate. This precipitate was isolated by filtration. Yield: 23.3 g (89%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)=[CH:5][N:4]=[C:3]1[CH3:15].Cl.[NH2:17][OH:18]>N1C=CC=CC=1>[CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:17][OH:18])=[CH:5][N:4]=[C:3]1[CH3:15]
Reactant: NO
Reactant: Cc1ncc(C(=O)c2ccccc2)n1C
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ncc(C(=NO)c2ccccc2)n1C
Temperature: 50 °C
Reaction time: 3 h
Yield: 25.6 %

Procedure:
A solution of (1,2-dimethyl-1H-imidazol-5-yl)(phenyl)methanone (8.41 g, 42 mmol) and hydroxylamine hydrochloride (7.30 g, 105 mmol) in pyridine (60 mL) was stirred for 5 h at room temperature, and for 3 h at 50° C. Hydroxylamine hydrochloride (3.00 g, 43 mmol) was added again and the reaction mixture was stirred for 9.5 h at 50° C. After removal of the solvent in vacuo and addition of water (600 mL), the pH of the aqueous solution was adjusted to pH>7 by addition of aq. NaOH (1 M). After extraction with ethyl acetate (4×150 mL), the combined organic layers were washed with water (150 mL), dried over MgSO4 and concentrated in vacuo. Purification on silica gel afforded 1-(1,2-dimethyl-1H-imidazol-5-yl)-N-hydroxy-1-phenylmethanimine [2.31 g, yield 24%; HPLC/MS: m/z=216 (M+H); log P(HCOOH)=0.43].
Reaction SMILES: [C:1]([N:5]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[C:18][C:19]1[S:23][CH:22]=[N:21][CH:20]=1)[C:6](=[O:12])[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>O1CCOCC1.O>[C:1]([N:5]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[C:18][C:19]1[S:23][CH:22]=[N:21][CH:20]=1)[C:6](=[O:12])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)N(CCCCC#Cc1cncs1)C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)N(CCCCC#Cc1cncs1)C(=O)C(=O)O
Temperature: 50 °C
Reaction time: 1 h
Yield: 106.1 %

Procedure:
A solution of 180 mg of 17e in 2 ml of dioxane was mixed with a solution of 120 mg of KOH in 1 ml of water. The mixture was stirred for 1 hr at 50° C. The reaction mixture was cooled and diluted with 10 ml of water, acidified to pH 3 with 1N HCl and the product was extracted into ethyl acetate. The organic extract was washed twice with water, dried and concentrated, to provide 175 mg of 17f as a colorless oil.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].C[O:6][C:7]1[C:12]2[C:13](=[O:22])[C:14]3[CH:15]=[CH:16][N:17]=[CH:18][C:19]=3[C:20](=[O:21])[C:11]=2[C:10]([F:23])=[CH:9][CH:8]=1>C(Cl)Cl.O>[F:23][C:10]1[C:11]2[C:20](=[O:21])[C:19]3[CH:18]=[N:17][CH:16]=[CH:15][C:14]=3[C:13](=[O:22])[C:12]=2[C:7]([OH:6])=[CH:8][CH:9]=1.[Cl:1][C:10]1[C:11]2[C:20](=[O:21])[C:19]3[CH:18]=[N:17][CH:16]=[CH:15][C:14]=3[C:13](=[O:22])[C:12]=2[C:7]([OH:6])=[CH:8][CH:9]=1
Reactant: COc1ccc(F)c2c1C(=O)c1ccncc1C2=O
Reactant: [Cl-]
Agent: [Al+3]
Solvent: O
Solvent: ClCCl
Product: O=C1c2ccncc2C(=O)c2c(Cl)ccc(O)c21
Product: O=C1c2ccncc2C(=O)c2c(F)ccc(O)c21
Reaction time: 0.17 h

Procedure:
Aluminum chloride (19.05 g) is added in one portion to a stirred refluxing solution of 6-methoxy-9-fluorobenzo[g]isoquinoline-5,10-dione (7.20 g) in methylene chloride (432 mL). After refluxing for 4 hours the reaction mixture is cooled and poured in water (1,300 mL). Methylene chloride (200 mL) is added and after stirring for 10 min the organic phase is separated. The aqueous solution is saturated with NaCl and further extracted with methylene chloride (3×400 mL). The combined organic solutions are washed with brine (1,000 mL), dried and the solvent removed by roto-evaporation. The brown solid obtained (6.5 g) is recrystallized from ethyl acetate/n-hexane 1/1 (65 mL) to yield a 9/1 mixture (1H-NMR evaluation) of 9-fluoro-6-hydroxybenzo[g] isoquinoline-5,10-dione and 9-chloro-6-hydroxybenzo[g] isoquinoline-5,10-dione respectively (6.00 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([NH:15][S:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=3)(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[C:5]([Cl:29])=[CH:4][N:3]=1>O.CO.C(O)(=O)C.[Fe]>[NH2:26][C:22]1[CH:21]=[C:20]([CH2:19][S:16]([NH:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][C:6]3[C:5]([Cl:29])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:10]=2)(=[O:17])=[O:18])[CH:25]=[CH:24][CH:23]=1
Reactant: O=[N+]([O-])c1cccc(CS(=O)(=O)Nc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: Nc1cccc(CS(=O)(=O)Nc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}-1-(3-nitrophenyl)methanesulfonamide (0.060 g, 0.13 mmol) in water (0.1 mL), methanol (0.5 mL) and acetic acid (0.20 mL) was added iron (0.030 g, 0.53 mmol) powder in one batch. The mixture was stirred at 0° C. for 0.5 h. The reaction was mixed with celite, filtered, and the cake was washed with EtOAc. The brown filtrate was concentrated and EtOAc and NaHCO3/water added. Water phase was extracted with EtOAc twice. The organics were combined, dried over Na2SO4 and concentrated to give the desired product as a yellow powder (0.050 g, 89%. LCMS for C17H15Cl2N5O2S (M+H)+: m/z=423.9, 426.0.
Reaction SMILES: C[OH:2].C(N)C[CH2:5][CH3:6].[S:8]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[C:26](=[O:27])C3C(=CC=CC=3)C2=O)[S:9]1>C1(C)C=CC=CC=1>[S:8]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:26](=[O:27])[O:2][CH2:5][CH3:6])[S:9]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCC1CCSS1
Reactant: CO
Reactant: CCCCN
Solvent: Cc1ccccc1
Product: CCOC(=O)NCCCCCC1CCSS1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
2 ml of methanol and 2 ml of butylamine were added to a solution of 1.6 mmol of 2-[5-(1,2-dithiolan-3-yl)pentyl]isoindole-1,3-dione in 3 ml of toluene. The resulting mixture was stirred at room temperature for 7 hours. At the end of this time, the reaction mixture was allowed to stand overnight at room temperature. The solvent was then removed from the reaction mixture by distillation under reduced pressure. Water was added to the resulting residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. 2 ml of anhydrous tetrahydrofuran were added to the residue, and then 0.33 ml of triethylamine and 0.23 ml of ethyl chloroformate were added dropwise, whilst ice-cooling. The resulting mixture was stirred at room temperature for 2 hours. The solvent was then removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 1:3 and 1:2 by volume mixtures of ethyl acetate and hexane as eluent, followed by reverse phase preparative silica gel column chromatography, using a 1:1 by volume mixture of acetonitrile and water as eluent. Acetonitrile was removed from the eluate so obtained by distillation under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilised, to give 75 mg of the title compound as a red oil having an Rf value of 0.46 (silica gel thin layer chromatography; using a 1:2 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: NCC1C=NC=CC=1.[S:9]1[C:13]([CH2:14][NH2:15])=[CH:12][N:11]=[CH:10]1.[F:16][C:17]1([F:36])[CH2:19][CH:18]1[CH2:20][N:21]1[CH2:25][CH2:24][N:23]([C:26]2[S:27][C:28]([C:32]([OH:34])=O)=[C:29]([CH3:31])[N:30]=2)[C:22]1=[O:35]>>[F:36][C:17]1([F:16])[CH2:19][CH:18]1[CH2:20][N:21]1[CH2:25][CH2:24][N:23]([C:26]2[S:27][C:28]([C:32]([NH:15][CH2:14][C:13]3[S:9][CH:10]=[N:11][CH:12]=3)=[O:34])=[C:29]([CH3:31])[N:30]=2)[C:22]1=[O:35]
Reactant: NCc1cncs1
Reactant: Cc1nc(N2CCN(CC3CC3(F)F)C2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1nc(N2CCN(CC3CC3(F)F)C2=O)sc1C(=O)NCc1cncs1
Yield: 68 %

Procedure:
Following the procedure as describe in Example 16, making variations as required to replace 3-(aminomethyl)pyridine with (thiazole-5-yl)methylamine to react with 2-(3-((2,2-difluorocyclopropyl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colourless solid in 68% yield: mp 182-184° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.61 (t, J=6.0 Hz, 1H), 7.74 (s, 1H), 4.53 (d, J=6.0 Hz, 1H), 4.01-3.95 (m, 2H), 3.64-3.47 (m, 3H), 3.19-3.12 (m, 1H), 2.44 (s, 3H), 2.04-1.88 (m, 1H), 1.67-1.55 (m, 1H), 1.37-1.26 (m, 1H); MS (ES+) m/z 414.9 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH2:9][CH2:8][CH:7]=[C:6]([CH3:10])[CH2:5][CH2:4][CH:3]=1.CC1CCC(C)=CCCC=1.[FH:21].C([O-])(=O)C.[K+]>O1CCCC1.CO.O>[CH3:10][C:6]12[CH:3]([F:21])[C:2]([CH3:1])([CH2:4][CH2:5]1)[CH2:9][CH2:8][CH2:7]2
Reactant: CC1=CCCC(C)=CCC1
Reactant: F
Agent: CC(=O)[O-]
Agent: CC1=CCCC=C(C)CC1
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC12CCCC(C)(CC1)C2F
Yield: 86.5 %

Procedure:
A mixture of 13.6 g (0.1 mol) 1,5-dimethyl-1,5-cyclooctadiene and 1,6-dimethyl-1,5-cyclooctadiene (ratio 80/20 was dissolved in a mixture of tetrahydrofuran (15 ml) and methanol (5 ml). The resulting mixture was added dropwise under stirring and cooling to 50 ml anhydrous hydrogen fluoride. The temperature was kept at about -10° C. during the addition (45 min). After the addition, the reaction mixture was stirred for a further period of 15 minutes at 0° C. and then poured into a cooled saturated solution of potassium acetate in water. The upper layer was then decanted and the aqueous layer was extracted several times with pentane. The upper layer and the pentane solutions were combined and washed with water and an aqueous diluted solution of sodium bicarbonate (5%). The pentane layer was then treated as described in Example 1a which resulted in 10.8 g of 1,5-dimethyl-8-fluorobicyclo-[3,2,1]octane (b.p. 68°-69° C./22 mm Hg) or a yield of 86.5% based on the starting 1,5-dimethyl-1,5-cyclooctadiene. The purity of the product according to gas-liquid chromatography was more than 98%.
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C:7]([CH3:13])([CH:10]([CH3:12])[CH3:11])[C:8]#[N:9].[Cl:14][C:15]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:16]=1[O:17][C@H:18]([CH3:22])[C:19](Cl)=[O:20].[OH-].[Na+]>O.C1(C)C=CC=CC=1>[C:8]([C:7]([NH:6][C:19](=[O:20])[CH:18]([O:17][C:16]1[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:15]=1[Cl:14])[CH3:22])([CH3:13])[CH:10]([CH3:12])[CH3:11])#[N:9]
Reactant: CC(C)C(C)(N)C#N
Reactant: C[C@@H](Oc1ccc(Cl)cc1Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(Oc1ccc(Cl)cc1Cl)C(=O)NC(C)(C#N)C(C)C
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
A stirred mixture of sodium bicarbonate (1.446 kg; 17.2 mol) in water at -3° to 3° C. is treated with a toluene solution of 2-amino-2,3-dimethylbutyronitrile (1.51 kg, 13.46 mol) over a 15 minute period, then treated sequentially with a toluene solution of (R)-2-(2,4-dichlorophenoxy)propionyl chloride (3.346 kg, 13.2 mol) over a 1.5 hour period at ice bath temperatures, stirred for 0.5 hours, treated with 50% NaOH (0.396 kg), heated to 55° C. and stirred for 0.5 hours. The resultant mixture is separated. The organic phase is washed with 5% NaOH and distilled at temperatures up to 80° C. at 10 mm Hg to remove the toluene. The pot residue is crystallized in isopropanol/water to afford the title product as a white solid, 4.131 kg (94.8% yield), characterized by HPLC analysis. The product is 99.7% pure. The isomer ratio is: 94.8% RR, RS and 5.2% SS, SR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH2:23]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[CH2:24][CH2:25][CH3:26]>C(N(CC)CC)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:32]([C:31]2[CH:35]=[CH:36][C:28]([O:27][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:29][CH:30]=2)=[O:33])=[CH:20][CH:21]=1
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOc1ccc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1
Temperature: 25 °C
Reaction time: 30 h
Yield: 41 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) was suspended in triethylamine/methylene chloride (3 ml/2 ml), commercially available 4-butoxybenzoyl chloride (0.07 ml) was added, and the admixture was stirred at room temperature for 30 hours. The reaction mixture was then purified in the same manner as described in Example 62 to obtain 34 mg of the title compound (yield: 41%).
Reaction SMILES: CC(C)([O-])C.[K+].[I:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([OH:18])=[CH:13][CH:12]=2.[CH3:19][O:20][C:21](=[O:26])[CH:22](Br)[O:23][CH3:24].[I-].[K+]>C(O)(C)(C)C.C(Cl)(Cl)Cl>[CH3:19][O:20][C:21](=[O:26])[CH:22]([O:18][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([I:7])=[CH:17]2)[O:23][CH3:24]
Reactant: Oc1ccc2ncc(I)cc2c1
Reactant: COC(=O)C(Br)OC
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)(C)O
Product: COC(=O)C(OC)Oc1ccc2ncc(I)cc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of potassium t-butoxide (1.36 g) in t-butyl alcohol (50 mL) was added a solution of 3-iodo-quinolin-6-ol (3 g) in t-butyl alcohol (5 mL). The reaction mixture was stirred at room temperature for 15 minutes. Bromo-methoxy-acetic acid methyl ester (4.0 g) and a solution of potassium iodide (catalytic quantity) in t-butyl alcohol (5 mL) were then added. The reaction mixture was stirred at room temperature for 18 hours. The mixture was poured on water and chloroform was added. The mixture was stirred. The two layers were separated, the aqueous layer was extracted with chloroform (twice). The organic layers were combined, washed with brine (twice), dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude (4.3 g) was used directly in the next step without purification.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([CH2:11][CH3:12])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:13]([N:21]=[C:22]=[S:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(C)=O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:22]([NH:21][C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[S:23])[N:7]([CH2:11][CH3:12])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCn1nc(C(C)(C)C)cc1N
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: CCn1nc(C(C)(C)C)cc1NC(=S)NC(=O)c1ccccc1
Temperature: 60 °C

Procedure:
To a solution of compound 23 (5.0 g, 29.9 mmol) in 40 mL of acetone at 0° C. was added dropwise benzoyl isothiocynate (4.88 g, 29.9 mmol). The reaction mixture was gradually warmed up and stirred in an oil bath of 60° C. until TLC indicated there was no starting material remained. Concentration of the reaction mixture on rotavapor gave a yellow solid, which was further triturated with ethyl ether to yield the desired product 24.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([O:15][CH2:16][CH2:17][CH:18]([OH:24])[C:19]([CH3:23])([CH3:22])[C:20]#[N:21])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.CCOCC>[CH2:8]([O:15][CH2:16][CH2:17][CH:18]([O:24][C:1](=[O:3])[CH3:2])[C:19]([CH3:22])([CH3:23])[C:20]#[N:21])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C#N)C(O)CCOCc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)OC(CCOCc1ccccc1)C(C)(C)C#N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
14.56 g (42.64 mmol) of acetic acid anhydride is added at 0° C. to a solution that consists of 25.6 g (109.7 mmol) of 5-benzyloxy-2,2-dimethyl-3-hydroxy-pentane-nitrile of the title compound of Example 1a, 14.43 g (142.64 mmol) of triethylamine and 200 mg of 4-dimethylaminopyridine (DMAP), dissolved in 128 ml of MTB-ether, and it is stirred for 5 hours at room temperature. The reaction mixture is poured onto 21 of ice water and extracted twice with 300 ml each of MTB-ether. The combined MTB-phases are washed once with 300 ml of 5% hydrochloric acid and then with water. It is evaporated to the dry state in a vacuum.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.Br[C:20]1[CH:36]=[CH:35][C:23]([C:24]([C@@H:26]2[CH2:30][CH2:29][CH2:28][C@H:27]2[C:31]([O:33]C)=[O:32])=[O:25])=[CH:22][CH:21]=1.FC1C=C(C2C=CC(C([C@@H]3CCC[C@H]3C(O)=O)=O)=CC=2)C=CC=1NC1SC2C=C(OC(F)(F)F)C=CC=2N=1>>[CH3:18][C:15]1[CH:16]=[CH:17][C:11]2[O:10][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([C:20]4[CH:21]=[CH:22][C:23]([C:24]([C@@H:26]5[CH2:30][CH2:29][CH2:28][C@H:27]5[C:31]([OH:33])=[O:32])=[O:25])=[CH:35][CH:36]=4)=[CH:3][CH:4]=3)=[N:13][C:12]=2[CH:14]=1
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(Br)cc1
Reactant: Cc1ccc2oc(Nc3ccc(Br)cc3)nc2c1
Agent: O=C(O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(OC(F)(F)F)cc4s3)c(F)c2)cc1
Product: Cc1ccc2oc(Nc3ccc(-c4ccc(C(=O)[C@@H]5CCC[C@H]5C(=O)O)cc4)cc3)nc2c1
Yield: 17 %

Procedure:
This compound was prepared from N-(4-bromophenyl)-N-(5-methyl-1,3-benzoxazol-2-yl)amine (0.50 g, 1.65 mmol), methyl (1R,2R)-2-(4-bromobenzoyl)cyclopentanecarboxylate (0.57 g, 1.83 mmol, 94.5% ee) in a similar manner to the method described for (1R,2R)-2-({3′-fluoro-4′-[(6-trifluoromethoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylic acid. Yield: 17%. 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.05 (d, 2H), 7.75-7.90 (m, 6H), 7.35 (d, 1H), 7.25 (s, 1H), 6.95 (d, 1H), 4.05 (q, 1H), 3.20 (s, 1H), 2.40 (s, 3H), 2.15 (m, 1H), 2.00 (m, 1H), 1.55-1.80 (m, 4H). LC-MS m/z 441.3 (MH+), ret. time 3.48 min.