Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:4][C:5]1[C:6]([S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])=[CH:7][S:8][CH:9]=1)[CH2:2][CH3:3].C([Li])CCC.[C:23](=[O:25])=[O:24].Cl>C1COCC1.CCCCCC>[CH2:1]([S:4][C:5]1[C:6]([S:10]([NH:13][C:14]([CH3:16])([CH3:15])[CH3:17])(=[O:12])=[O:11])=[C:7]([C:23]([OH:25])=[O:24])[S:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: CCCSc1cscc1S(=O)(=O)NC(C)(C)C
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCSc1csc(C(=O)O)c1S(=O)(=O)NC(C)(C)C
Temperature: 20 °C

Procedure:
A solution of 12.15 g 4-propylthio-3-N-(1,1-dimethylethyl)-3-thiophenesulfonamide in 150 mL THF was cooled to -30° C. and treated dropwise with 31.6 mL 2.69M n-butyllithium in hexane. The solution was warmed to 20° C. for 1.5 hours and then cooled to -80° C. 8.8 g Solid carbon dioxide was added in one portion, the mixture was warmed to 20° C. and poured over ice and hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated to a solid. The product was purified by recrystallization from butyl chloride to give 10.4 g of light yellow solid; m.p. 123°-126° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-])=O)=[C:5]2[C:15]([F:18])([F:17])[F:16].O.O.Cl[Sn]Cl.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([NH2:12])=[C:5]2[C:15]([F:17])([F:16])[F:18]
Reactant: O=[N+]([O-])c1cnc2ccc(Cl)cc2c1C(F)(F)F
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cnc2ccc(Cl)cc2c1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.3 %

Procedure:
To a solution of 6-chloro-3-nitro-4-(trifluoromethyl)quinoline (5.53 g, 20 mmol) (prepared according to the procedures described by Tarby, C. M., in WO 2003062238) in EtOAc (100 mL) was added SnCl2.2H2O (18 g, 80 mmol). The resulting mixture was stirred at RT for 18 h, then at 80° C. for 6 h. After cooling to RT, saturated aqueous K2CO3 (5 mL) was added. The reaction mixture was stirred at RT for 30 min, and then solid K2CO3 (16.6 g, 120 mmol) was added stirring was continued at RT for 4 more hours. EtOAc (200 mL) was added, the resulting mixture was filtered, and the filtrate concentrated in vacuo to give the title compound (4.8 g, 97% yield) as an off-white solid.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([CH2:41][OH:42])[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl.[CH3:44][N:45]([CH3:52])[CH2:46][CH2:47][CH2:48][C:49](O)=[O:50].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:44][N:45]([CH3:52])[CH2:46][CH2:47][CH2:48][C:49]([O:42][CH2:41][CH:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:20][O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:50]
Reactant: CCCCCCCC/C=C\CCCCCCCCOCC(CO)OCCCCCCCC/C=C\CCCCCCCC
Reactant: CN(C)CCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCCOCC(COC(=O)CCCN(C)C)OCCCCCCCC/C=C\CCCCCCCC
Reaction time: 8 h
Yield: 87.1 %

Procedure:
In 6 ml of methylene chloride-N,N-dimethylformamide (1:2) was dissolved 120 mg (0.20 mmol) of 1,2-O-dioleylglycerol, followed by addition of 168 mg (1 mmol) of 4-dimethylaminobutyric acid hydrochloride. Then, 206 mg (1 mmol) of N,N'-dicyclohexylcarbodiimide (DCC) and 25 mg (0.2 mmol) of 4-dimethylaminopyridine were further added and the reaction was conducted at ambient temperature overnight. The precipitated byproduct urea was filtered off using a glass filter and the filtrate was concentrated to dryness under reduced pressure and treated with methylene chloride-saturated aqueous sodium hydrogen carbonate solution. After phase separation, the methylene chloride layer was dried over sodium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography (silica gel/methylene chloride-methanol) to provide 123 mg (87%) of the title compound of the invention.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH2:12]([O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)[CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:12]([O:17][C:18]1[CH:19]=[CH:20][C:21]([NH:22][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])=[CH:23][CH:24]=1)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCOc1ccc(N)cc1
Reactant: O=C(O)Cc1ccccc1Br
Product: CCCCCOc1ccc(Nc2ccccc2CC(=O)O)cc1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 4-pentyloxyaniline to yield 2-[(4-pentyloxyphenyl)amino]phenylacetic acid.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:23][CH3:24])[CH:10]([C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]=1)[OH:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@@H:9]([CH2:23][CH3:24])[CH:10]([C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]=1)[OH:11]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(O)c1nc(-c2ccccc2)no1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](N)C(O)c1nc(-c2ccccc2)no1
Reaction time: 1 h

Procedure:
3-tert-Butoxycarbonylamino-2-hydroxy-pentanoic acid (500 mg, 2.14 mmol) was combined with EDC (600 mg, 3.14 mmol), HOBt (600 mg, 3.92 mmol), and N-hydroxy-benzamidine (292 mg, 2.14 mmol). Dichloromethane (10 mL) was added and then 4-methylmorpholine (1 mL). The reaction mixture was stirred at ambient temperature for 16 h. After dilution with ethyl acetate (200 mL), the solution was washed with water (30 mL), saturated aqueous NaHCO3 solution and brine, dried with MgSO4 and evaporated under vacuum. The crude product was dissolved in pyridine (10 mL) and heated at 80° C. for 15 h. The pyridine was evaporated under vacuum and the residue was purified by flash chromatography on silica gel (eluent:ethyl acetate) to yield 2(S)-tert-butoxycarbonylamino-1-(3-phenyl-[1.2.4]oxadiazol-5-yl)butan-1-ol (290 mg, 0.83 mmol). 2(S)-tert-butoxycarbonylamino-1-(3-phenyl-[1.2.4]oxadiazol-5-yl)butan-1-ol (145 mg, 0.41 mmol) was dissolved in CH2Cl2 (4 mL) and TFA (4 mL) was added. After stirring for 1 h, the reaction mixture was evaporated to dryness to yield 2(S)-amino-1-(3-phenyl-[1.2.4]oxadiazol-5-yl)-butan-1-ol.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[N:6]=[CH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=1)([CH3:13])[CH3:12]
Reactant: O=Cc1ccccn1
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1N=Cc1ccccn1
Temperature: 25 °C
Yield: 39.9 %

Procedure:
2,6-Diisopropylaniline (2.0 g, 11.3 mmol) was added to a solution of picolinaldehyde (1.2 g, 11.3 mmol) in toluene (200 mL) in a round bottom flask equipped with a Dean-Stark trap, followed by the addition of a catalytic amount of p-toluenesulfonic acid (0.1 g). The reaction mixture was refluxed for 18 h to remove water. The reaction mixture was cooled to rt, and then washed once with water (100 mL), and the toluene was removed under reduced pressure. The resulting residue was purified by chromatography on silica gel to give the desired product (1.2 g, 40% yield) as a pale green solid.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=[O:4].[CH3:27][CH:28]([NH2:33])[C:29]([F:32])([F:31])[F:30]>>[F:30][C:29]([F:32])([F:31])[C@@H:28]([NH:33][C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=[O:4])[CH3:27]
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nn1C
Reactant: CC(N)C(F)(F)F
Product: C[C@H](NC(=O)c1cc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nn1C)C(F)(F)F
Yield: 17 %

Procedure:
As described for example 100f, 5-[3-(4-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.27 mmol) was converted, using L-2,2,2-trifluoro-1-(methyl)ethylamine instead of isopropylamine, to the title compound (21 mg, 17%) which was obtained as a colorless gum. MS: m/e=459.3 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)([CH3:12])[CH3:11])=[CH:6][CH:5]=1.Cl[CH2:21][C@H:22]1[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]1>CN(C)C=O>[CH3:27][C:24]1([CH3:28])[O:23][C@@H:22]([CH2:21][O:3][C:4]2[CH:5]=[CH:6][C:7]([C:10]([C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)([CH3:12])[CH3:11])=[CH:8][CH:9]=2)[CH2:26][O:25]1
Reactant: CC1(C)OC[C@H](CCl)O1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](COc2ccc(C(C)(C)c3ccc(O)cc3)cc2)O1
Yield: 23.7 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 1750 mg, 43.80 mmol, 1.0 equiv) was added slowly to a stirred solution of Bisphenol A (10000 mg, 43.80 mmol, 1 equiv) in anhydrous dimethyl formamide (30 mL), at room temperature, and the contents were stirred under an atmosphere of argon for 20 min. (R)-(+)-4-chloromethyl-2,2-dimethyl-1,3-dioxolane 98% (7.10 mL, 52.56 mmol, 1.2 equiv) was added via syringe and the mixture was allowed to react at 70-80° C. for 40 h. Then, the reaction was quenched by the addition of a saturated solution of ammonium chloride (10 mL), and the mixture was extracted with ethyl acetate (3×20 mL). The organic layer was washed with deionized water (25 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 10% ethyl acetate in hexane) to provide the title compound (3560 mg, 24%, 25-30% conversion) as a foam.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][N:16]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:32])=O>O>[Cl:32][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CO)cn1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a mixture of 2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine-5-methanol (12.2 g) and toluene (200 ml) was added thionyl chloride (5.39 g), and the mixture was stirred at room temperature for 1 hr. Iced water was added to the reaction mixture, and after neutralization with saturated aqueous sodium hydrogencarbonate, the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to give crystals (11.7 g, yield 90%) of 5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 86-87° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16]Br)[N:11]=1>CN(C)C=O>[CH3:8][O:7][C:5](=[O:6])[CH2:4][O:3][CH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([Br:9])[N:11]=1
Reactant: BrCc1cccc(Br)n1
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COCc1cccc(Br)n1
Reaction time: 5 h

Procedure:
To a suspension of sodium hydride (0.50 g, 12.38 mmol) in N,N-dimethylformamide (20 mL) at 0° C. was added a mixture of methyl hydroxyacetate (1.0 g, 11.25 mmol) and 2-bromo-6-(bromomethyl)pyridine (Example 190, Step 1) (3.4 g, 13.5 mmol) dropwise. After stirring for 5 hours, the reaction was quenched with iso-propanol/methanol solution. The reaction mixture was poured onto iced water and extracted with ether. The organic phase was dried over MgSO4, filtered and evaporated. The crude mixture was purified by silica gel column and eluted with ethyl acetate:petroleum ether (1:10) to afford the title compound. 1H NMR (400 MHz, CDCl3): δ 7.55 (t, 1H), 7.48 (d, 1H), 7.39 (d, 1H), 4.71 (s, 2H), 4.22 (s, 2H), 3.77 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:31]/[O:32][C:33]2([C:36]([O:38][CH:39]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH2:35][CH2:34]2)/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][N:24]2[N:28]=[C:27]([CH2:29][OH:30])[CH:26]=[N:25]2)=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:61][S:62](Cl)(=[O:64])=[O:63]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:31]/[O:32][C:33]2([C:36]([O:38][CH:39]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[O:37])[CH2:34][CH2:35]2)/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][N:24]2[N:28]=[C:27]([CH2:29][O:30][S:62]([CH3:61])(=[O:64])=[O:63])[CH:26]=[N:25]2)=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2ncc(CO)n2)cs1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2ncc(COS(C)(=O)=O)n2)cs1
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a solution of benzhydryl 1-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2R,3S)-2-((4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylate (178 mg, 0.25 mmol) and DIPEA (65 μL, 0.37 mmol) in DCM (2.5 mL) at 0° C. was added MsCl (25 μL, 0.32 mmol). After 1 h at 0° C., the reaction mixture was diluted with DCM (10 mL), washed with 0.2 N HCl and saturated NaHCO3 (aq). The organic layer was dried over Na2SO4, concentrated in vacuo to afford the title compound (190 mg, 96%). The crude residue was used as such in the following step. LCMS: Rt=1.05 min, m/z=795.4 (M+1) Method 2m_acidic.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:7]=1[F:18])(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][O:28][CH3:29]>C(#N)C>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:13][CH2:14][N:15]([CH2:26][CH2:27][O:28][CH3:29])[CH2:16][CH2:17]2)[C:7]=1[F:18])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Oc1cccc(C2CCNCC2)c1F
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCN1CCC(c2cccc(OS(C)(=O)=O)c2F)CC1

Procedure:
Preparation according to Example 1: 2-fluoro-3-piperidin-4-ylphenyl methanesulfonate (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and 1-bromo-2-methoxyethane (0.01 g). MS m/z (rel. intensity, 70 eV) 331 (M+, 1), 288 (6), 287 (15), 286 (bp), 207 (47).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=1>>[Cl:38][C:39]1[CH:44]=[C:43]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:10]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[O:11])=[CH:20][CH:19]=3)[CH:15]=[C:16]2[C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])[CH:42]=[CH:41][CH:40]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(=O)(=O)N5CCCCC5)CC4)cc3c2)CC1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(S(=O)(=O)N4CCCCC4)CC2)n3-c2cccc(Cl)c2)CC1
Yield: 54 %

Procedure:
The title compound was synthesized in analogy to example 5, from [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-[4-(piperidine-1-sulfonyl)-piperazin-1-yl]-methanone (example 2) and 3-chlorophenylboronic acid to afford the desired product as a colorless foam (54%). MS (ISP): 641.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)[C:10](=[O:19])[CH:9]=2)[CH:7]=1.[NH2:22][C:23]1[CH:35]=[CH:34][C:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([NH:22][C:23]3[CH:35]=[CH:34][C:26]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])=[CH:25][CH:24]=3)=[O:17])[C:10](=[O:19])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
76 mg (purity 83%, 0.21 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) and 1.1 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 43 mg (43% of theory)
Reaction SMILES: [Cl:1][CH2:2][S:3]([NH:6][C:7]1[C:35]([O:36]C)=[CH:34][C:10]2[C@H:11]([N:18]([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)C(=O)OC(C)(C)C)[C@@H:12]([OH:17])[C:13]([CH3:16])([CH3:15])[O:14][C:9]=2[CH:8]=1)(=[O:5])=[O:4].B(Br)(Br)Br.O>ClCCl>[Cl:1][CH2:2][S:3]([NH:6][C:7]1[C:35]([OH:36])=[CH:34][C:10]2[C@H:11]([NH:18][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@@H:12]([OH:17])[C:13]([CH3:16])([CH3:15])[O:14][C:9]=2[CH:8]=1)(=[O:4])=[O:5]
Reactant: COc1cc2c(cc1NS(=O)(=O)CCl)OC(C)(C)[C@H](O)[C@H]2N(CCc1ccccc1)C(=O)OC(C)(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC1(C)Oc2cc(NS(=O)(=O)CCl)c(O)cc2[C@H](NCCc2ccccc2)[C@H]1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of t-butyl(3R*,4S*)-7-{[(chloromethyl)sulfonyl]amino}-3-hydroxy-6-methoxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-yl(2-phenylethyl)carbamate (400 mg, 0.72 mmol) in dichloromethane (4.0 mL), 1 mol/L solution of boron tribromide in dichloromethane (3.61 mL, 3.61 mmol) was added below freezing point, and the resulting mixture was stirred at 0° C. for 1 hour. Water was added, and the resulting mixture was further stirred for 30 minutes. The resulting solid was filtered off, washed with water and then with chloroform. The solid was dried at 60° C. for 3 hours under reduced pressure, and the aimed product was quantitatively obtained.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:16](N1C=CN=C1)(=[O:18])[CH3:17]>>[C:16]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:8]1)(=[O:18])[CH3:17]
Reactant: c1ccc2c(Cn3ccnc3)c[nH]c2c1
Reactant: CC(=O)n1ccnc1
Product: CC(=O)n1cc(Cn2ccnc2)c2ccccc21
Yield: 42.5 %

Procedure:
A mixture consisting of 3-(imidazol-1-ylmethyl)indole (0.97 g) and 1-acetylimidazole (1.10 g) was heated on a steam bath for a period of 3.5 hours to give an orange oil, which soon solidied on cooling. The resulting solid product was then chromatographed on silica gel. Elution with chloroform first gave some minor impurity, followed by the pure product. The product-containing fractions were then combined and subsequently evaporated to dryness while under reduced pressure to afford a solid residue, which was thereafter crystallized from ethyl acetate to yield pure 1-acetyl-3-(imidazol-1-ylmethyl)indole (yield, 0.50 g.), m.p. 122° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][CH:6]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:26]=1[O:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>ClCCl>[OH:5][CH:6]([O:24][C:25]1[CH:30]=[C:29]([N+:1]([O-:4])=[O:2])[CH:28]=[C:27]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:26]=1[O:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCCCCCCOc1cccc(OC(O)CCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOc1cc([N+](=O)[O-])cc(OC(O)CCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Reaction time: 0.25 h
Yield: 76.2 %

Procedure:
Dispersed was 63 g of silica gel into 21 g of nitric acid and 150 ml of dichloromethane was added. Into the resulting dispersion, added was a solution dissolving 5.0 g of 1-(1′-hydroxyoctadecyloxy)-2,3-dioctadecyloxybenzene in 30 ml of dichloromethane. After stirring for 15 minutes, silica gel was filtered off. After the filtrate was concentrated under reduced pressure, 300 ml of methanol was added and stirred. Resulting precipitant was filtered off to obtain 4.0 g of 3-(1′-hydroxyoctadecyloxy)-4,5-dioctadecyloxy nitrobenzene (yield: 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[N:6]=[C:5]2O.P(Cl)(Cl)([Cl:19])=O.C(N(CC)CC)C>C(Cl)Cl>[Cl:19][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[N:6]=1
Reactant: Oc1nc(C(F)(F)F)nc2ccc(Cl)cc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: FC(F)(F)c1nc(Cl)c2cc(Cl)ccc2n1
Yield: 55.2 %

Procedure:
6-Chloro-2-trifluoromethyl-quinazolin-4-ol (1.35 g, 5.43 mmol, 1 eq.), phosphorous oxychloride (4.88 mL, 52.4 mmol, 9.64 eq.) and triethylamine (2.43 mL, 17.4 mmol, 3.21 eq.) were refluxed for 2 hours. Stripped 3× from methylene chloride then dissolved in methylene chloride and rinsed 3× with saturated sodium bicarbonate, 1× with brine. Dried and stripped in vacuo to give an amber oil. Purified over silica gel in 9:1 Hexanes/EtOAc. Obtained 800 mg of off-white solids as product. The product was used immediately in Example 1 Part C.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([O:26]C(=O)C)=[C:8]2[C:16]([Cl:17])=[CH:15][N:14]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:30][CH2:31][C:32]([OH:34])=[O:33].C[O-].[Na+].CO>>[Cl:17][C:16]1[C:8]2[C:9](=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:5])[C:7]=2[OH:26])[N:14]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[CH:15]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2-c2ccc(OC)cc2)c1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-n2cc(Cl)c3c(O)c(C(=O)NCC(=O)O)nc(C#N)c32)cc1

Procedure:
Prepared in analogy to that of Example 1(e) from 4-acetoxy-3-chloro-7-cyano-1-(4-methoxy-phenyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 401 (M+H)+.