Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:9]1)C1C=CC=CC=1.[ClH:24].[H][H]>[C].[Pd].C(O)C>[ClH:24].[C:20]1([CH3:23])[CH:19]=[CH:18][C:17]([S:14]([O:13][C@@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)(=[O:16])=[O:15])=[CH:22][CH:21]=1
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCN(Cc3ccccc3)C2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CCNC2)cc1
Reaction time: 4.5 h

Procedure:
A mixed solution obtained by mixing 3.0 g of 100% pure (R)-1-benzyl-3-p-toluenesulfonyloxypyrrolidine with 3.0 ml of ethanol and adding dropwise 0.80 ml of 35% aqueous hydrochloric acid thereto with cooling on an ice-water bath was charged, together with 150 mg of moist 5% palladium-carbon (water content 52% by weight), into an autoclave, hydrogen was introduced thereinto and the autoclave was heated to raise the temperature to 60 and the pressure to 203 kPa, and the reaction was allowed to proceed for 4.5 hours. Hydrogen absorption came to an end in 2.5 hours after the start of hydrogen introduction. After completion of the reaction, the reaction mixture was treated in the same manner as in Example 4 to give 2.51 g (yield: 86 mole percent) of (R)-3-p-toluenesulfonyloxypyrrolidine hydrochloride.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:15]3[CH:23]=[CH:24][C:25]([C:27]([O:29][CH3:30])=[O:28])=[CH:26][C:14]=3[N:13]=2)=[C:8]([F:31])[CH:7]=1.[Cl:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1.C(=O)([O-])O.[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([C:2]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:3]=2[CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[C:15]4[CH:23]=[CH:24][C:25]([C:27]([O:29][CH3:30])=[O:28])=[CH:26][C:14]=4[N:13]=3)=[C:8]([F:31])[CH:7]=2)=[CH:42][CH:41]=1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc([N+](=O)[O-])ccc3Br)cc1F)n2C1CCCCC1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc([N+](=O)[O-])ccc3-c3ccc(Cl)cc3)cc1F)n2C1CCCCC1
Yield: 90.1 %

Procedure:
Methyl 2-[4-(2-bromo-5-nitrobenzyloxy)-2-fluorophenyl]-1-cyclohexylbenzimidazole-5-carboxylate (2.0 g) obtained in Example 336, 4-chlorophenylboronic acid (590 mg) and tetrakis(triphenylphosphine)palladium (396 mg) were suspended in dimethoxyethane (40 ml), and saturated aqueous sodium hydrogencarbonate solution (20 ml) was added, which was followed by refluxing under heating for 1 hr. The reaction mixture was allowed to cool, water was added and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (n-hexane:ethyl acatate=2:1) to give the title compound (1.9 g, yield 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:10][C:11]2[C:12](=O)[NH:13][CH:14]=[CH:15][C:16]=2[N:17]=1.P(Br)(Br)([Br:21])=O>CC#N>[Br:21][C:12]1[C:11]2[S:10][C:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])=[N:17][C:16]=2[CH:15]=[CH:14][N:13]=1
Reactant: O=c1[nH]ccc2nc(-c3c(Cl)cccc3Cl)sc12
Reactant: O=P(Br)(Br)Br
Solvent: CC#N
Product: Clc1cccc(Cl)c1-c1nc2ccnc(Br)c2s1
Temperature: 100 °C
Yield: 55.5 %

Procedure:
To a stirred solution of 2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4(5H)-one (0.32 g, 1.1 mmol) in CH3CN (50 ml) was added POBr3 (0.918 g, 3.21 mmol). The mixture was heated at 100° C. for 2 hours. The mixture was cooled to room temperature, quenched with ice (200 mL) and extracted with EtOAc (3×20 mL). The combined organic extract was washed with saturated NaHCO3 (100 mL) and brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with a 0-10% gradient of EtOAc/petroleum ether to give the desired product as a white solid (0.22 g, 56% yield). 1H NMR (500 MHz DMSO-d6): δ 8.59 (d, J=5.5 Hz, 1H), 8.26 (d, J=6.0 Hz, 1H), 7.76-7.74 (m, 2H), 7.71-7.68 (m, 1H). LCMS (ESI) m/z: 359.1 [M+H+].
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:38])[N:10]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([CH:27](OC)[O:28]C)[CH:19]=2)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.Cl>C1COCC1>[CH2:1]([O:8][C:9](=[O:38])[N:10]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([CH:27]=[O:28])[CH:19]=2)[CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)c1cc(Oc2cccc(N(C(=O)OCc3ccccc3)C3CCCCC3)c2)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cc(Oc2cccc(N(C(=O)OCc3ccccc3)C3CCCCC3)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 42 h

Procedure:
Cyclohexyl-[3-(3-dimethoxymethyl-4-nitro-phenoxy)-phenyl]-carbamic acid benzyl ester (0.0027 mol) was dissolved in THF (12 mL). Water (6 mL) and 12N HCl (3 mL) were added and the reaction mixture was stirred for 42 hours at room temperature. Water was added. This mixture was extracted with diisopropyl ether. The organic layer was separated, washed with a 10% aqueous NaHCO3 solution and then with water, dried (MgSO4) and filtered. The solvent was then evaporated to yield a residue that was used in the next reaction step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:4]=1[O:13][CH3:14].C([Li])CCC.[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>O1CCCC1.CCCCCC>[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:8]1[CH:7]=[CH:6][C:5]([C:9]([CH3:11])([CH3:10])[CH3:12])=[C:4]([O:13][CH3:14])[C:3]=1[O:2][CH3:1]
Reactant: COc1cccc(C(C)(C)C)c1OC
Reactant: BrCCCCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1c(CCCCCCBr)ccc(C(C)(C)C)c1OC
Reaction time: 3 h
Yield: 15 %

Procedure:
To 27.0 g (0.139 mole) of 1,2-dimethoxy-3(1,1-dimethylethyl)benzene in 350 mL of anhydrous tetrahydrofuran cooled in an ice-brine bath at -5° was added. 87 mL (0.139 mole) of 1.6M butyl lithium in hexane over 30 minutes. The reaction mixture was stirred at -5° for 3 hours and then at reflux for 1 hour. After cooling in an ice bath, 21.5 mL (0.139 mole) of 1,6-dibromohexane in 75 mL of tetrahydrofuran was added dropwise. The reaction mixture was then stirred at reflux for 17 hours. The solvent was removed under reduced pressure, 50 mL of 3N hydrochloric acid was added and the product was extracted with ether. The extract was washed with sodium bicarbonate solution, dried and concentrated at reduced pressure to an oil. Purification by HPLC using 20% toluene-hexane gave 7.6 g ((15% yield) of 1-(6-bromohexyl)-2,3-dimethoxy-4-(1,1-dimethylethyl)benzene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([CH3:22])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([CH3:22])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1N
Yield: 90.7 %

Procedure:
The 3-(3-Methyl-4-nitro-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (12.0 g, 43 mmol) was dissolved in 50 mL methanol and 50 mL ethyl acetate. An amount of 1.0 g of 10% wet Pd—C (50% w/w) was added. The reaction mixture was subjected to hydrogenation under 40 PSI of hydrogen for 3 hours. The solution was then filtered through Celite to remove catalyst. The filtrate was concentrated under reduced pressure to give the desired product (10.8 g, 39 mmol). 1H-NMR (400 MHz, CDCl3): δ=6.60 (m, 1H), 6.02 (m, 1H), 5.95 (m, 1H), 4.78 (m, 1H), 4.24 (m, 2H), 3.95 (m, 2H), 3.45 (br, 1H), 2.15 (s, 3H), 1.45 (s, 9H). MS: 301 (M++23).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15]
Reactant: BrCCCCCBr
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCCCBr)ccc2c1OCCC2=O

Procedure:
A mixture of 0.413 g (2.00 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, 3.0 g (13.05 mmol) of 1,5-dibromopentane, 1.4 g (10.13 mmol) of anhydrous granular potassium carbonate and 31 mL of 2-butanone was stirred and refluxed for 18 hr. The resulting slurry was filtered with suction and the solids were washed thoroughly with ethyl acetate. The filtrate and washes were combined and concentrated in vacuo and the residue was purified by flash chromatography on 75 g of silica gel, eluting with 4:1 hexane-ethyl acetate giving 0.627 g (88%) of the title compound as a white solid, mp 47°-48° C.
Reaction SMILES: [H-].[Na+].CS(C)=O.Cl.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH3:16])[C:10]=1[CH3:17].Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][CH:20]=1>O>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][CH:20]=[C:19]2[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH2:8])=[C:10]([CH3:17])[C:11]=1[CH3:16]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1c(N)ccc(O)c1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
Sodium hydride (60 wt %, 0.72 g) was added to dimethyl sulfoxide (10 ml). The mixture was stirred at 50° C. for 30 min and was then cooled to room temperature. 4-Amino-2,3-dimethylphenol hydrochloride (1.55 g) was added to the cooled mixture, and the mixture was stirred at room temperature for 10 min. Next, 4-chloro-6,7-dimethoxyquinoline (1.00 g) was added thereto, and the mixture was stirred at 100° C. overnight. Water was added to the reaction solution, followed by extraction with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and methanol was added to the residue. The precipitated crystal was collected by suction filtration to give 0.94 g (yield 65%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:23])=[CH:4][N:3]=1
Reactant: Brc1ccc(Sc2ccccc2)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: O=S(c1ccccc1)c1ccc(Br)nc1

Procedure:
Following the procedure of Example 7 2-bromo-5phenylthiopyridine is converted to 2-bromo-5-(phenylsulfinlyl) pyridine with m-chloroperbenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[C:10](Cl)(=[O:13])[CH2:11][CH3:12].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:10](=[O:13])[CH2:11][CH3:12])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: CCC(=O)Cl
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Nc1ccc(F)c(Cl)c1
Reaction time: 2 h
Yield: 95.8 %

Procedure:
3-chloro-4-fluoroaniline (10 g, 67.32 mmol) dissolved in CH2Cl2 was added with propionyl chloride (6.6 mL, 74.10 mmol) and triethyl amine (10.2 mL, 73.58 mmol) dropwise under water bath, and the mixture was stirred for 2 h. The resulting solution was washed with water (2×50 mL) and saturated aqueous NaHCO3 solution (12 mL). The CH2Cl2 layer dried over MgSO4 was evaporated to give title compound as light purple solid (13.01 g, 96.3%). 1H NMR (400 MHz, DMSO-d6) δ 1.06 (t, J=7.6 Hz, 3H), 2.30 (q, J=7.6 Hz, 2H), 7.31 (dd, J=9.2 and 8.8 Hz, 1H), 7.44 (ddd, J=8.8 and 4 and 2.8 Hz, 1H), 7.91 (dd, J=7.2 and 2.8 Hz, 1H), 10.04 (br s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 9.4, 29.4, 116.6, 116.8, 118.8, 119.0, 119.1, 120.2, 136.55, 136.58, 151.5, 153.9, 172.1;
Reaction SMILES: Br[C:2]1[C:15]2[C@:14]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:12]=3)[O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30].[C:33]([Zn]C#N)#[N:34].CN(C=O)C>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:20][C:17]1[O:18][CH2:19][C@@:14]2([N:16]=1)[C:15]1[C:2]([C:33]#[N:34])=[C:3]([O:27][CH2:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH:4]=[CH:5][C:6]=1[O:7][C:8]1[C:13]2=[CH:12][C:11]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:10][CH:9]=1
Reactant: N#C[Zn]C#N
Reactant: CC(C)(C)COc1ccc2c(c1Br)[C@]1(COC(N)=N1)c1cc(-c3cccnc3)ccc1O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)COc1ccc2c(c1C#N)[C@]1(COC(N)=N1)c1cc(-c3cccnc3)ccc1O2

Procedure:
A vial was charged with (S)—1′-bromo-2′-(neopentyloxy)-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (68.1 mg, 0.138 mmol), dicyanozinc (81 mg, 0.689 mmol), tetrakis(triphenylphosphine)palladium(0) (31.8 mg, 0.028 mmol), and DMF (689 μL). The vial was sealed and placed in a 120° C. oil bath for 12 hours. The mixture was diluted with water and extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was chromatographed on a 25-g SNAP column, eluting with a 90:10:1 mix of DCM/MeOH/NH4OH in DCM. This gave ca. 40 mg of a white powder that was impure by HPLC. The solid was combined with 104487-6-2 in DMSO/MeOH and purified by reverse-phase HPLC (10-90% CH3CN/H2O with 0.1% TFA). The fractions containing product were combined in saturated aq. sodium bicarbonate solution with the aid of methanol and extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to give (S)-2-amino-2′-(neopentyloxy)-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-1′-carbonitrile as an off-white powder after evaporation from DCM/hexane.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]=1[C:12]([OH:14])=[O:13].[Cl:15][C:16]1[C:17]([N:22]2[C:26]([C:27](O)=O)=[CH:25][C:24]([C:30]([F:33])([F:32])[F:31])=[N:23]2)=[N:18][CH:19]=[CH:20][CH:21]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>O1CCCC1>[Cl:15][C:16]1[C:17]([N:22]2[C:26]([C:27]3[O:13][C:12](=[O:14])[C:3]4[C:4]5[C:9](=[N:8][CH:7]=[CH:6][CH:5]=5)[CH:10]=[CH:11][C:2]=4[N:1]=3)=[CH:25][C:24]([C:30]([F:33])([F:31])[F:32])=[N:23]2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: Nc1ccc2ncccc2c1C(=O)O
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2ccc3ncccc3c12
Temperature: 0 °C
Reaction time: 48 h

Procedure:
To a suspension of 240 mg (1.28 mmol) of 6-amino-quinoline-5-carboxylic acid in 9.60 mL of anhydrous tetrahydrofuran at 10° C., is added 372 mg (1.28 mmol) of 2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid followed by 5134 (6.38 mmol) of pyridine. Then the suspension is cooled to 0° C. and 398 μL (5.10 mmol) of methanesulfonyl chloride are added dropwise. The mixture is stirred at ambient temperature for 48 hours. Then the solvent is evaporated and the residue is precipitated with a minimum of ethyl acetate and washed with ethyl acetate. After filtration, water is added to the filtrate and the new suspension formed is filtrated again. After drying on high vacuum pump 303 mg (54%) of solid are obtained; LC/MS:444/446 (M+H)+.
Reaction SMILES: B(F)(F)F.CCOCC.[C:10](#[N:14])[CH2:11][C:12]#[N:13].[N+](=[CH:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19])=[N-]>C(Cl)Cl>[C:20]1([C:18]2[O:19][C:12]([CH2:11][C:10]#[N:14])=[N:13][CH:17]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: [N-]=[N+]=CC(=O)c1ccccc1
Reactant: N#CCC#N
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: N#CCc1ncc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
BF3.Et2O (1.1 mL, 8.5 mmol) was added dropwise to a solution of malononitrile (2.26 g, 34.2 mmol) in dry CH2Cl2 (20 mL) at 0° C., followed by addition of 2-diazo-1-phenylethanone (0.5 g, 3.4 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 1 h and then quenched with aqueous 10% NaOH solution. The organic product was extracted with EtOAc and the combined extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 5-10% EtOAc in petroleum ether) to get 2-(5-phenyloxazol-2-yl)acetonitrile (200 mg, yield 32%) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 7.66-7.63 (m, 2H), 7.47-7.38 (m, 3H), 7.32 (s, 1H), 4.02 (s, 2H). MS (ESI) m/z: Calculated for C11H8N2O: 184.06. found: 185.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]([CH:9]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[O:8])[CH:4]=[CH2:5].Br[CH2:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1.O>CN(C=O)C>[CH2:3]([O:6][C:7]([C:9]([CH2:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1)([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[O:8])[CH:4]=[CH2:5]
Reactant: C=CCOC(=O)C(CCCCC(=O)OCC)C(=O)OCC=C
Reactant: N#Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)C(CCCCC(=O)OCC)(Cc1ccc(C#N)cc1)C(=O)OCC=C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1.69 g (70.43 mmol) of sodium hydride are added in portions to a solution of 20 g (64.03 mmol) of 1-allyl 7-ethyl 2-allyloxycarbonylheptanedioate in 140 ml of DMF at 0° C. The reaction mixture is then allowed to reach room temperature and is stirred for 30 min. The reaction solution is cooled to 0° C. again and, after addition of 16.32 g (83.24 mmol) of 4-bromomethylbenzonitrile in 140 ml of DMF, stirred at this temperature for 30 min. The mixture is then stirred at room temperature overnight. Water is added dropwise to the reaction mixture and, after extraction three times with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is concentrated to dryness in vacuo. The resulting crude product is purified by flash chromatography an silica gel (mobile phase: cyclohexane/ethyl acetate 10:1→4:1→1:1). 20.08 g (46.97 mmol, 73% of theory) of a colorless solid are obtained.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[CH:8]1([NH:11][C:12]2[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[C:17]([F:24])[C:13]=2[C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1>CO.C(Cl)Cl>[CH3:1][O:15][C:14](=[O:16])[C:13]1[C:17]([F:24])=[CH:18][CH:19]=[C:20]([N+:21]([O-:23])=[O:22])[C:12]=1[NH:11][CH:8]1[CH2:9][CH2:10]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1c(F)ccc([N+](=O)[O-])c1NC1CC1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1c(F)ccc([N+](=O)[O-])c1NC1CC1
Reaction time: 0.25 h
Yield: 98 %

Procedure:
Trimethylsilyldiazomethane (2M in hexane, 2.6 mL, 5.21 mmol) was added dropwise to a solution of 2-cyclopropylamino-6-fluoro-3-nitrobenzoic acid (836 mg, 3.48 mmol) in MeOH (4 mL) and DCM (16 mL) at 0° C. The solution was stirred for 15 min then the volatiles were removed under reduced pressure to afford the title compound (867 mg, 98%). LCMS (Method C): RT 3.50 min [M+H]+ 255.10
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]([S:15]([NH2:18])(=[O:17])=[O:16])[C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C)C=O.O>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C:5]1([S:15]([NH2:18])(=[O:16])=[O:17])[C:4]2[CH:3]=[C:2]([Cl:1])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH3:27]
Reactant: NS(=O)(=O)C1c2ccccc2-c2ccc(Cl)cc21
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC1(S(N)(=O)=O)c2ccccc2-c2ccc(Cl)cc21
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
Under nitrogen, (21) (2.6 g, 9.3 mmoL) was added portionwise to a stirred suspension of sodium hydride (465 mg of a 60% mineral oil dispersion, 1.25 eq) in dry dimethylformamide (60 mL , from CaH2). After 30 minutes, ethyl bromoacetate (1.3 g, 11.6mmoL, 1.25 eq) was added and stirring was continued overnight. The reaction was then diluted with water (200 mL), neutralized, and extracted with ethyl acetate (3×200 mL). The combined organic phases were washed with brine (3×200 mL), dried (MgSO4), and concentrated. The crude solid was recrystallized twice from ethyl acetate/hexane to provide 1.7 g(50%) of product (22): mp 189°-191° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.B(O)(O)[C:24]1[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)=[CH:17][CH:16]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(-c2ccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)cc2)cc1
Yield: 74.5 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methylbiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), p-tolylboronic acid (0.025 g; 0.176 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 10% ethyl acetate in dichloromethane) furnished 0.051 g (74%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methylbiphenyl-4-carboxamide as a white solid.