Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([CH:13]=[N:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH:3]=1.[C:22]([Si](C)(C)C)#[N:23]>C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>[CH3:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][C:11]=1[CH3:12])[C:6](=[O:8])[N:14]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[CH:13]2[C:22]#[N:23]
Reactant: COC(=O)c1cc(C)c(C)cc1C=Nc1cccc(F)c1
Reactant: C[Si](C)(C)C#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: Cc1cc2c(cc1C)C(C#N)N(c1cccc(F)c1)C2=O
Yield: 78 %

Procedure:
The product of above-mentioned (25-b) (0.45 g, 1.6 mmol), cyanotrimethylsilane (0.40 ml, 3.2 mmol) and aluminum chloride (13 mg) were stirred in anhydrous benzene (5.5 ml) at 25° C. for 20 hrs under an argon atmosphere. The reaction solution was concentrated under reduced pressure, and the residue was washed with petroleum ether to give 0.35 g of 5,6-dimethyl-2-(3-fluorophenyl)-3-cyano-isoindolin-1-one. [IUPAC name: 2-(3-fluorophenyl)-5,6-dimethyl-3-oxo-1-isoindolinecarbonitrile].
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:14])=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[S:8][CH2:7][CH2:6][CH:5]2[OH:13].[CH2:15](O)[CH3:16]>S(=O)(=O)(O)O.O>[Br:1][C:2]1[C:3]([CH3:14])=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[S:8][CH2:7][CH2:6][CH:5]2[O:13][CH2:15][CH3:16]
Reactant: CCO
Reactant: Cc1cc(Br)c(C)c2c1SCCC2O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC1CCSc2c(C)cc(Br)c(C)c21

Procedure:
A 100 ml three-necked flask was charged with 5.9 g (0.022 mol) of 6-bromo-5,8-dimethylthiochroman-4-one, and then, 30 ml of methylene chloride and 10 ml of methanol were added and dissolved. The entire reaction system was cooled to 0° C. in an ice salt bath, and 0.42 g.(0.011 mol) of sodium borohydride was added by small portions. Thereafter, the mixture was allowed to react for 2 hours while it was cooled as above. The reaction mixture was poured into 100 ml of water, and the mixture was extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate, and methylene chloride was distilled off under reduced pressure to give 6.0 g of 6-bromo-5,8-dimethyl-4-hydroxythiochroman as a solid. Then, 6.0 g of this 6-bromo-5,8-dimethyl-4-hydroxythiochroman was charged into a 100 ml eggplant-shaped flask, and 20 ml of ethanol was added to form a solution. Then, 10 drops of concentrated sulfuric acid was added, and the mixture was refluxed under heat for 1 hour. The reaction mixture was allowed to cool and poured into 100 ml of water, and the mixture was extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate, and methylene chloride was distilled off under reduced pressure to give 5.8 g of 6-bromo-5,8-dimethyl-4-ethoxythiochroman as an oily substance.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:21]([OH:22])=[CH:20][C:7]2[C@H:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[CH:5]=1.[CH3:23][N:24]([CH3:28])[C:25](Cl)=[O:26]>C(COC)OC>[ClH:3].[Cl:3][C:4]1[C:21]([O:22][C:25]([N:24]([CH3:28])[CH3:23])=[O:26])=[CH:20][C:7]2[C@H:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[CH:5]=1
Reactant: CN1CCc2cc(Cl)c(O)cc2[C@H](c2ccccc2)C1
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CN1CCc2cc(Cl)c(OC(=O)N(C)C)cc2[C@H](c2ccccc2)C1
Product: Cl

Procedure:
Add in small portions with stirring, 360 mg of sodium hydride (50% in mineral oil) to a suspension of 2.16 g (0.0075 moles) of (S)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (as obtained in step E of Example 1) in 35 ml of anhydrous dimethoxyethane and stir until the evolution of gas ceases. Add dropwise a solution of 0.75 ml of dimethylcarbamyl chloride in 5 ml of anhydrous dimethoxyethane. Stir for 36 hours at room temperature and concentrate to dryness; dissolve the residue in 50 ml of ethyl ether and filter to remove the solid. Wash the filtrate twice with 30 ml of 0.5 N sodium hydroxide, dry the ether layer over anhydrous sodium sulfate, and precipitate (S)-7-chloro-8-dimethylaminocarbonyloxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride with 1 N ethereal hydrogen chloride. Obtain an analytical sample by crystallization from 2-propanol, m.p. 261°-263° C. [α]D26 =+23.1° (c=1, dimethylformamide).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27]Cl.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])[C:12]3[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: CN(C)CCCl
Reactant: COc1ccc([C@@H]2Sc3c(Cl)cccc3NC(=O)[C@@H]2O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc([C@@H]2Sc3c(Cl)cccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Yield: 75.5 %

Procedure:
A mixture of 2.01 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-9-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 0.95 g of 2-(dimethylamino)ethyl chloride hydrochloride, 2.49 g of powdered potassium carbonate, 60 ml of acetone and 0.6 ml of water is refluxed for 23 hours. After the reaction is completed, insoluble materials are removed by filtration. The filtrate is evaporated to remove solvent. The residue is digested with isopropyl ether and the resultant crystals are collected by filtration and recrystallized from ethyl acetate. 1.84 g of (±)-cis-2-(4-methoxypheny)-3-hydroxy-5-[2-(dimethylamino)ethyl]-9-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained. Yield: 75.4%
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:15])=[CH:4][C:5]([C:8](O)(O)[C:9]([F:12])([F:11])[F:10])=[N:6][CH:7]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([CH3:15])=[CH:4][C:5]([CH:8]([N:23]=[CH:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[C:9]([F:12])([F:11])[F:10])=[N:6][CH:7]=1
Reactant: Cc1cc(C(O)(O)C(F)(F)F)ncc1Br
Reactant: COc1ccc(CN)cc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc(C=NC(c2cc(C)c(Br)cn2)C(F)(F)F)cc1
Temperature: 110 °C
Yield: 74.4 %

Procedure:
A solution of 1-(5-bromo-4-methylpyridin-2-yl)-2,2,2-trifluoroethane-1,1-diol (163.1 mg; 0.5702 mmol) in 2.0 mL toluene was added at room temperature to a solution of 4-methoxybenzylamine (118 μL; 0.858 mmol) and acetic acid (49 μL; 0.854 mmol) in 2.0 mL toluene. A scoop of oven-dried 3A molecular sieves was added, and the reaction mixture heated at 110° C. for 3 days. The mixture was poured into saturated aqueous sodium bicarbonate and extracted twice with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The crude product was purified via flash chromatography on silica gel (24 g silica, solvent gradient: 0-100% ethyl acetate in dichloromethane) to yield 164.2 mg of the title compound. LCMS (ESI): M-(4-methoxybenzaldehyde)+H=269.2; 1H NMR (400 MHz, DMSO) δ 8.69 (s, 1H), 8.57 (s, 1H), 7.80 (d, J=8.7 Hz, 2H), 7.66 (s, 1H), 7.05 (d, J=8.7 Hz, 2H), 5.28 (q, J=8.0 Hz, 1H), 3.82 (s, 3H), 2.41 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([CH3:12])[NH:9]2)=[CH:5][CH:4]=1.ClS([N:17]=[C:18]=O)(=O)=O.C([O-])(O)=O.[Na+]>C(#N)C.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:18]#[N:17])=[C:8]([CH3:12])[NH:9]2)=[CH:5][CH:4]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COc1ccc2cc(C)[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccc2c(C#N)c(C)[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
To a solution of 6-methoxy-2-methyl-1H-indole (3.9 g, 24 mmol) in acetonitrile (200 mL) and DMF (20 mL) was added dropwise a solution of ClSO2NCO (4 mL, 1.3 eq.) in acetonitrile (31 mL) at 0° C. After the addition, the mixture was stirred at room temperature for 3 h. Then it was poured into ice water and saturated NaHCO3 was added to it until it became basic. The aqueous phase was extracted with CH2Cl2 and then evaporated. The residue was purified with flash column chromatography on silica gel using EtOAc/petroleum ether (1/5) as eluent to yield 81% of 6-methoxy-2-methyl-1H-indole-3-carbonitrile.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[CH:11]=2)(=O)=O.ClC1C=C(C=CC=1)COC1C=C2C(C=C(CO)C=[N:39]2)=CC=1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O>C1COCC1>[Cl:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][O:17][C:12]1[CH:11]=[C:10]2[C:15]([CH:16]=[C:7]([CH2:6][NH2:39])[CH:8]=[N:9]2)=[CH:14][CH:13]=1
Reactant: OCc1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Reactant: CS(=O)(=O)OCc1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NCc1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
(7-((3-Chlorobenzyl)oxy)quinolin-3-yl)methyl methanesulfonate. To a solution of (7-((3-chlorobenzyl)oxy)quinolin-3-yl)methanol (Example 35, 55 mg, 0.18 mmol) in THF (1.8 mL) was added DIPEA (0.064 mL, 0.37 mmol), followed by methanesulfonyl chloride (0.014 mL, 0.18 mmol). The reaction was stirred at ambient temperature overnight. The crude reaction was loaded directly onto a column, purification (FCC, SiO2, 0-40%, EtOAc/hexanes) afforded the title compound as a white solid (44 mg, 76%). 1H NMR (400 MHz, CDCl3) δ 8.85 (d, J=2.3 Hz, 1H), 8.10 (s, 1H), 7.74 (d, J=9.0 Hz, 1H), 7.48 (d, J=9.4 Hz, 2H), 7.41-7.28 (m, 4H), 5.20 (s, 2H), 4.76 (s, 2H). [M+H]=318.2
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][C:11]([OH:13])=[O:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(Cl)Cl.Cl.C(N=C=N[CH2:26][CH2:27][CH2:28]N(C)C)C.[CH3:32][C:33]1[CH2:38][CH2:37][CH2:36][C:35]([CH3:40])([CH3:39])[C:34]=1/[CH:41]=[CH:42]/[C:43](/[CH3:52])=[CH:44]/[CH:45]=[CH:46]/[C:47](/[CH3:51])=[CH:48]/[CH2:49]O>CN(C)C=O>[CH3:51]/[C:47](/[CH:46]=[CH:45]/[CH:44]=[C:27](\[CH3:26])/[CH:28]=[CH:41]/[C:34]1[C:35]([CH3:39])([CH3:40])[CH2:36][CH2:37][CH2:38][C:33]=1[CH3:32])=[CH:48]\[CH2:49][O:15][C:14](=[O:16])[C@@H:9]([NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:10][C:11]([O:13][CH2:49]/[CH:48]=[C:47](\[CH3:51])/[CH:46]=[CH:45]/[CH:44]=[C:43](\[CH3:52])/[CH:42]=[CH:41]/[C:34]1[C:35]([CH3:40])([CH3:39])[CH2:36][CH2:37][CH2:38][C:33]=1[CH3:32])=[O:12]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/CO)C(C)(C)CCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/COC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)CCCC2(C)C)C(C)(C)CCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N-Boc aspartic acid (1.2 mg), methylene chloride 20 ml and minimum amount of dimethylformamide (DMF) were added to nitrogen filled, three mouth- round bottom flask and melted. The reaction mixture was cooled down into 0° C., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride [EDCI](1.36 g)were added slowly, and stirred for approximately 30 minutes. Retinol (0.51 g) was added into the reaction mixture, small amount of N,N′-dimethylaminopyridine (DMAP) were added immediately, and stirred for approximately 1˜3 hours. After the reaction was finished, eluent were removed under the low pressure, the residues were melted with ethyl acetate and washed several times with water and Brine. Organic phase were dried with anhydrous MgSO4, concentrated under low pressure and separated with column chromatography.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2[C:26](=[CH:27]C=CC=2)[C@@:25]2([C:43]3C(=CC4OCCOC=4[CH:42]=3)OC2)C1=O>>[CH2:27]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22])[CH2:26][CH2:25][CH2:43][CH3:42]
Reactant: O=C1Nc2ccccc2[C@@]12COc1cc3c(cc12)OCCO3
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Product: CCCCCN1C(=O)[C@]2(COc3cc4c(cc32)OCCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 7.3 and making non-critical variations using (R)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace (S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, (R)-1′-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (74%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.25-7.30 (m, 1H), 7.16-7.11 (m, 1H), 6.99-7.04 (m, 1H), 6.89 (d, J=7.8 Hz, 1H), 6.47 (s, 1H), 6.19 (s, 1H), 4.73 (ABq, 2H), 4.20-4.06 (m, 4H), 3.86-3.59 (m, 2H), 1.82-1.63 (m, 2H), 1.42-1.28 (m, 4H), 0.89 (t, J=6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ177.2, 155.2, 144.5, 142.4, 138.2, 132.5, 128.7, 123.9, 123.0, 121.2, 111.4, 108.5, 99.3, 80.1, 64.5, 63.9, 58.0, 40.3, 29.0, 27.1, 22.3, 14.0; MS (ES+) m/z 366.1 (M+1).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Si:11]([O:28][CH2:29][C@@H:30]1[C@@H:34]([CH2:35][O:36][Si:37]([C:50]([CH3:53])([CH3:52])[CH3:51])([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:33][CH2:32][C:31]1=[O:54])([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.P([O-])([O-])([O-])=O.C(Cl)Cl>C1(C)C=CC=CC=1.CCCCCC>[Si:11]([O:28][CH2:29][C@@H:30]1[C@@H:34]([CH2:35][O:36][Si:37]([C:50]([CH3:53])([CH3:52])[CH3:51])([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:33][CH2:32][C@@H:31]1[OH:54])([C:24]([CH3:25])([CH3:26])[CH3:27])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)[Si](OC[C@H]1CCC(=O)[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)[Si](OC[C@H]1CC[C@H](O)[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Reaction time: 0.25 h
Yield: 79902.2 %

Procedure:
In an atmosphere of argon gas, 1M solution of diisobutylaluminum hydride in toluene (2.7 ml, 2.7 mmoles) was slowly added at -78° C. to solution of (2S,3S)-2,3-bis-(t-butyldiphenylsilyloxymethyl)-1-cyclopentanone (1.40 g, 2.25 mmoles) in toluene (23 ml), and the resulting mixture was stirred at that temperature for 15 minutes. Then, 0.2M phosphate buffer solution (pH 7) was added to the reaction mixture and stirred for a while, after which an excessive amount of methylene chloride was added and the inorganic matter was filtered off. The filtrate was subjected to extraction with methylene chloride and an extract solution was dried on anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane=1:10, v/v) to obtain (1S,2S,3S)-2,3-bis(t-butyldiphenylsilyloxymethyl)-1-cyclopentanol (1,120 g, Yield 80%):
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]([NH2:16])=[O:15])=[CH:8][CH:7]=1)([F:4])[F:3].[Cl:17][CH:18](Cl)[C:19](=O)[CH3:20]>C1(C)C=CC=CC=1>[Cl:17][CH2:18][C:19]1[N:16]=[C:14]([CH:13]=[CH:12][C:9]2[CH:8]=[CH:7][C:6]([S:5][C:2]([F:4])([F:3])[F:1])=[CH:11][CH:10]=2)[O:15][CH:20]=1
Reactant: CC(=O)C(Cl)Cl
Reactant: NC(=O)C=Cc1ccc(SC(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: FC(F)(F)Sc1ccc(C=Cc2nc(CCl)co2)cc1

Procedure:
4.45 g (18.0 mmol) 3-(4-trifluoromethylsulfanyl-phenyl)-acrylamide, 2.79 g (22.0 mmol) dichloro acetone and 50.0 ml toluene were kept at reflux temperature for 30 h with continuous removal of water by use of a Dean-Stark trap (a water separator used in chemical reactions). The reaction mixture was cooled for 30 min. in an ice bath and the precipitated amide (1.2 g) was removed by filtration and discarded. After removal of solvents in vacuo, the residue (5.92 g) was purified by chromatography on silica gel (eluent: heptane/ethyl acetate 1:1). All fractions containing the product were concentrated to a volume of 10 ml, n-heptane added and the crystallized material isolated by filtration, washed with cold heptane and dried. 2.02 g (35%) 4-Chloromethyl-2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-oxazole.
Reaction SMILES: [F:1][C:2]1[C:11]([CH:12]([N:14]2C(=O)C3C(=CC=CC=3)C2=O)[CH3:13])=[C:10]([F:25])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.O.NN>CO>[F:1][C:2]1[C:11]([CH:12]([NH2:14])[CH3:13])=[C:10]([F:25])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(c1c(F)cc2ncccc2c1F)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CO
Product: CC(N)c1c(F)cc2ncccc2c1F
Temperature: 50 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
To a solution of 2-(1-(5,7-difluoroquinolin-6-yl)ethyl)isoindoline-1,3-dione (2.6 g, 7.7 mmol) in CH3OH (50 mL) was added hydrazine monohydrate (0.38 g, 7.7 mmol). The solution was heated at 50° C. and stirred overnight. After cooling and evaporating, the residue was purified by silica gel and eluted with hexane/EtOAc to give the title compound (1.0 g, 60%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.95 (d, 1H), 8.45 (d, 1H), 7.65 (d, 1H), 7.60 (dd, 1H), 4.49 (q, 1H), 2.20 (bs, 2H), 1.48 (d, 3H).
Reaction SMILES: [CH2:1]([C:3]1[C:4](CC)=NC=C([CH:11]=1)C(O)=O)C.C([O:18][C:19](=[O:29])[C:20]1[CH:25]=[C:24](Cl)[C:23]([CH:27]=[CH2:28])=[N:22][CH:21]=1)(C)(C)C>>[CH2:27]([C:23]1[C:24]([CH2:1][CH:3]([CH3:4])[CH3:11])=[CH:25][C:20]([C:19]([OH:18])=[O:29])=[CH:21][N:22]=1)[CH3:28]
Reactant: C=Cc1ncc(C(=O)OC(C)(C)C)cc1Cl
Reactant: CCc1cc(C(=O)O)cnc1CC
Product: CCc1ncc(C(=O)O)cc1CC(C)C

Procedure:
6-Ethyl-5-isobutyl-nicotinic acid is prepared in analogy to 5,6-diethyl-nicotinic acid from 5-chloro-6-vinyl-nicotinic acid tert.-butyl ester and 2,4,6-tri-(2-methyl-propenyl)-cycloboroxane pyridine complex (prepared in analogy to a procedure given by F. Kerins, D. F. O'Shea, J. Org. Chem. 67 (2002) 4968-4971); LC-MS: tR=0.64 min, [M+1]+=207.98.
Reaction SMILES: [C:1]([CH2:4][N:5]([S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28])[C:6]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:7]=1[O:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)([OH:3])=[O:2].C1(S(NC2C=CC(C(F)(F)F)=C[C:47]=2[O:48][CH2:49]C2C=CC(C(OC)=O)=CC=2)(=O)=O)C=CC=CC=1.COCCl.C(N(CC)CC)C>CN(C=O)C.O>[CH3:47][O:48][CH2:49][O:2][C:1]([CH2:4][N:5]([S:27]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)(=[O:28])=[O:29])[C:6]1[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:19][C:7]=1[O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:17][CH:18]=1)=[O:3]
Reactant: COC(=O)c1ccc(COc2cc(C(F)(F)F)ccc2NS(=O)(=O)c2ccccc2)cc1
Reactant: O=C(O)CN(c1ccc(C(F)(F)F)cc1OCc1ccc(C(=O)O)cc1)S(=O)(=O)c1ccccc1
Agent: COCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COCOC(=O)CN(c1ccc(C(F)(F)F)cc1OCc1ccc(C(=O)O)cc1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-[2-(N-carboxymethyl-phenylsulfonylamino)-5-trifluoromethyl-phenoxymethyl]benzoic acid (446 mg) prepared by the same procedure as Example 17→Example 2 by using methyl 4-(2-phenylsulfonylamino-5-trifluoromethylphenoxymethyl)benzoate (prepared in Example 15) was dissolved in DMF (5 ml). To the solution, methoxymethyl chloride (160 μl) and triethylamine (300 μl) were added dropwise. The mixture was stirred for 2 hours at room temperature. Water was added thereto. The mixture was extracted with ethyl acetate, washed, dried over, filtered and concentrated to give the title compound (476 mg) having the following physical data.
Reaction SMILES: [CH:1]1[CH:6]=[N:5][C:4]2N(O)N=N[C:3]=2[CH:2]=1.C[CH2:12][N:13]=C=NCCCN(C)C.CCN(CC)CC.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH:40]([N:42]2[C:51]3[CH:50]=[CH:49][CH:48]=[C:47]([Cl:52])[C:46]=3[C:45]3=[N:53][O:54][C:55]([CH3:56])=[C:44]3[C:43]2=[O:57])[CH2:39][CH:38]([C:58](O)=[O:59])[CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:29]([O:33][C:34]([N:36]1[CH2:37][CH:38]([C:58](=[O:59])[NH:13][CH2:12][C:3]2[CH:4]=[N:5][CH:6]=[CH:1][CH:2]=2)[CH2:39][CH:40]([N:42]2[C:51]3[CH:50]=[CH:49][CH:48]=[C:47]([Cl:52])[C:46]=3[C:45]3=[N:53][O:54][C:55]([CH3:56])=[C:44]3[C:43]2=[O:57])[CH2:41]1)=[O:35])([CH3:31])([CH3:32])[CH3:30]
Reactant: CCN=C=NCCCN(C)C
Reactant: On1nnc2cccnc21
Reactant: Cc1onc2c1c(=O)n(C1CC(C(=O)O)CN(C(=O)OC(C)(C)C)C1)c1cccc(Cl)c21
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1onc2c1c(=O)n(C1CC(C(=O)NCc3cccnc3)CN(C(=O)OC(C)(C)C)C1)c1cccc(Cl)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.3 %

Procedure:
Add HOAt (30 mg, 0.22 mmol), EDCI (41 mg, 0.22 mmol), Et3N (0.075 mL, 0.54 mmol), and DMAP (5 mg, cat.) to a solution of 5-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (83 mg, 0.18 mmol) in DMF (5 mL). Stir overnight at room temperature and concentrate to dryness. Dissolve in 20% iPrOH/CHCl3. Wash 2× sat. aq NaHCO3, wash 2× with brine, dry over Na2SO4, filter, and concentrate to dryness. Purify by radial chromatography using a MeOH/CHCl3 gradient as eluant and concentrate to dryness. Slurry the residue in ether/hexanes and concentrate to dryness to afford the title compound (44 mg, 50%) as a white foam as a mixture of cis isomers. MS(IS) 552.2 (M+); HPLC (100% EtOH 0.2% DMEA on a Chiralpak AD (0.46×25 cm) 1.0 mL/min flow; 20 μL Inj. Vol.; 225 nM) Rt=6.291 min (67.8%), 13.156 min (24.4%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]=[C:13]3[C:26](=[O:32])[C:27]([O:29]CC)=[O:28])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[K+]>C1COCC1.O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]=[C:13]3[C:26](=[O:32])[C:27]([OH:29])=[O:28])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccc(C(C)=O)cc3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(-c2ccc3c(c2)c(C(=O)C(=O)O)cn3Cc2ccccc2)cc1

Procedure:
[5-(4-Acetylphenyl)-1-benzyl-1H-indol-3-yl](oxo)acetic acid was prepared from ethyl [5-(4-acetylphenyl)-1-benzyl-1H-indol-3-yl](oxo)acetate (0.225 g, 0.529 mmol), and potassium hydroxide (0.104 g, 1.85 mmol) in THF (7 mL) and water (7 mL) according to the procedure described in Step 4 of Example 5. After drying for 15 hours at 96° C., the title compound was obtained as a tan solid (0.166 g, 79%), mp: 213-214° C. (dec.). Mass spectrum (−APCI, [M−H]−) m/z 396; 1HNMR (400 MHz, DMSO-d6): δ 8.75 (s, 1H), 8.5 (d, 1H, J=1.7 Hz), 8.05 (d, 2H, J=8.3 Hz), 7.8 (d, 2H, J=8.3 Hz), 7.7 (d, 1H, J=8.8 Hz), 7.65 (dd, 1H, J=8.7 Hz and 1.6 Hz), 7.25-7.4 (m, 5H), 5.65 (s, 2H), and 2.6 ppm (s, 3H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:12](Cl)=[N:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH2:24].[Na]>>[CH2:1]([NH:8][C:9]([C:11]1[C:12]([SH:24])=[N:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S
Reactant: O=C(NCc1ccccc1)c1cnc(-c2ccccc2)nc1Cl
Agent: [Na]
Product: O=C(NCc1ccccc1)c1cnc(-c2ccccc2)nc1S
Yield: 65.2 %

Procedure:
Using the procedure from Preparation 34, 5.8 g (17.9 mmol) of 4-chloro-2-phenyl-pyrimidine-5-carboxylic acid benzylamide was reacted with 5.1 g (72 mmol) of sodium hydrogen sulfide to give 3.75 g of the title compound, mp 189°-193° C.