Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(#N)C.[C:4]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Br)=[CH:8][CH:7]=1)#[N:5].[Na].[CH3:15][SH:16].O>C1(C)C=CC=CC=1>[CH3:15][S:16][CH2:10][C:9]1[CH:12]=[CH:13][C:6]([C:4]#[N:5])=[CH:7][CH:8]=1
Reactant: CS
Reactant: N#Cc1ccc(CBr)cc1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: O
Product: CSCc1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
To an acetonitrile solution (500 ml) of 4-cyanobenzyl bromide (50 g), 15% methyl mercaptan sodium salt (120 ml) was added at a room temperature and heated for 6 hours with refluxing. After cooling to a room temperature, water (1 l) and toluene (1 l) was added thereto. The organic layer was separated and washed successively with an aqueous 2N sodium hydroxide solution sulfate. After distilling off the solvent, 4-methylmercaptomethylbenzonitrile (38 g) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=3[O:13]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:21][C:14]=3[O:13]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1OC
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(C=C2Oc3cc(OC(=O)c4ccccc4)ccc3C2=O)cc1OC
Temperature: 25 °C

Procedure:
After 2-[(3,4-dimethoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.5 g was dissolved in pyridine 5 ml, benzoyl chloride 0.282 ml was added, and the mixture was refluxed for two hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml twice and with saturated sodium bicarbonate solution 50 ml. After the ethyl acetate solution was dehydrated with anhydrous magnesium sulfate, it was concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 294.6 mg.
Reaction SMILES: [CH3:1][C:2]([CH3:59])([CH3:58])[C@H:3]([N:44]1[CH2:48][CH2:47][N:46]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[N:51]=2)[C:45]1=[O:57])[C:4]([NH:6][C@@H:7]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:8][C@H:9]([OH:36])[C@@H:10]([NH:25]C(=O)OCC1C=CC=CC=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)=[O:5].Cl>CO.[OH-].[OH-].[Pd+2]>[NH2:25][C@@H:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[C@@H:9]([OH:36])[CH2:8][C@@H:7]([NH:6][C:4](=[O:5])[C@@H:3]([N:44]1[CH2:48][CH2:47][N:46]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[N:51]=2)[C:45]1=[O:57])[C:2]([CH3:1])([CH3:58])[CH3:59])[CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: Cc1ccc(-c2ccc(C[C@H](NC(=O)OCc3ccccc3)[C@@H](O)C[C@H](Cc3ccccc3)NC(=O)[C@@H](N3CCN(Cc4cccc(C)n4)C3=O)C(C)(C)C)cc2)cn1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2ccc(C[C@H](N)[C@@H](O)C[C@H](Cc3ccccc3)NC(=O)[C@@H](N3CCN(Cc4cccc(C)n4)C3=O)C(C)(C)C)cc2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution containing the product from Example 88A (0.079 g, 0.099 mmol) in methanol (1.5 mL) was treated with Pd(OH)2 on carbon (0.040 g, 20% Pd by wt.) and HCl solution (0.075 mL, 4N in dioxane), stirred under a hydrogen atmosphere (balloon pressure) at 25° C. for 16 hours, filtered through a bed of celite® and rinsed with methanol. The solvent was concentrated to give the title compound as the hydrochloride salt, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14](OCC)=[O:15])=[CH:12][N:11]=[C:10]([S:19][CH3:20])[N:9]=2)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:14][OH:15])=[CH:12][N:11]=[C:10]([S:19][CH3:20])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc(SC)nc1-c1ccc(F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CSc1ncc(CO)c(-c2ccc(F)cc2)n1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 57.3 %

Procedure:
To a solution of ethyl 4-(4-fluorophenyl)-2-(methylsulfanyl)pyrimidine-5-carboxylate (21.0 g) in toluene (500 mL) was added diisobutylaluminum hydride (15% toluene solution, 124 mL) at −78° C. The reaction mixture was stirred at −78° C. for 1.5 hr, and the reaction was quenched with acetic acid. The reaction mixture was extracted with ethyl acetate, and the extract was washed successively with saturated aqueous sodium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (10.3 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:20][CH:21]=[CH:22][CH:23]=2)/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[C:31]1([S:37]([C:40]2[CH:41]=[C:42]([S:45](Cl)(=[O:47])=[O:46])[S:43][CH:44]=2)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>COCCOC>[O:17]=[C:11]1[NH:12][C:13]2[C:9](/[C:10]/1=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][CH:23]=1)=[C:8]([C:4]1[CH:3]=[C:2]([NH:1][S:45]([C:42]3[S:43][CH:44]=[C:40]([S:37]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)(=[O:39])=[O:38])[CH:41]=3)(=[O:46])=[O:47])[CH:7]=[CH:6][CH:5]=1)[CH:16]=[CH:15][CH:14]=2
Reactant: O=S(=O)(Cl)c1cc(S(=O)(=O)c2ccccc2)cs1
Reactant: Nc1cccc(-c2cccc3c2/C(=C/c2ccc[nH]2)C(=O)N3)c1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: O=C1Nc2cccc(-c3cccc(NS(=O)(=O)c4cc(S(=O)(=O)c5ccccc5)cs4)c3)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 35.7 %

Procedure:
A solution of (Z)-4-(3-aminophenyl)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (60 mg, 0.200 mmol) (from Example 4 supra), Et3N (28 μL , 0.201 mmol), and 4-benzenesulfonylthiophene-2-sulfonyl chloride (64.6 mg, 0.200 mmol) (Lancaster) in 7 mL of 1,2-dimethoxyethane (Fisher Scientific) was heated at reflux for 1 h. The reaction mixture was allowed to cool and then stirred at room temperature for 15 h. The reaction mixture was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 45% ethyl acetate-hexanes elution) provided pure (Z)-N-[3-[2,3-dihydro-2-oxo-3-[(1H-pyrrol-2-yl)methylene]-1H-indol-4-yl]phenyl]-4-(phenylsulfonyl)-2-thiophenesulfonamide (yield: 42 mg, 36%) as a yellow solid (mp 132-134° C.) (solid to gel).
Reaction SMILES: N1C(N)=C2C(N=CN2)=NC=1.[O:11]=[CH:12][C@@H:13]([C@H:15]([C@@H:17]([C@@H:19]([CH2:21][OH:22])[OH:20])[OH:18])[OH:16])[OH:14]>>[OH:22][CH2:21][C@@H:19]([C@H:17]([C@@H:15]([C@@H:13]([CH2:12][OH:11])[OH:14])[OH:16])[OH:18])[OH:20]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: Nc1ncnc2nc[nH]c12
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Reaction time: 24 h

Procedure:
Yeast (Zygosaccharomyces rouxii (obtained form Institute for Fermentation)) was inoculated in 5 ml of YPAD liquid culture medium (containing 10 g/liter of yeast extract, 20 g/liter of polypeptone, 0.4 g/liter of adenine and 20 g/liter of glucose), and was cultivated at 30° C. for 24 hours. The culture solution was centrifuged at 6,900×g for 3 minutes at 20° C. to collect the cells (hereinafter, the cells were collected under the same conditions). The obtained cells were suspended in 2 ml of a solution comprising 0.2-M Tris-HCl (pH 8.0) and 5 v/v % mercaptoethanol. The cell suspension was allowed to stand at 25° C. for 30 minutes while being gently stirred sometimes, and cells were then collected. Further, the collected cells were suspended 1 ml of a solution (pH 6.8) containing 2.5 mg/ml of Zaimolyeis-20T (obtained from SEIKAGAKU CORPORATION), 10 w/v % sorbitol and 5 w/v % KPO4. The suspension was allowed to stand at 30° C. for 90 minutes, and recentrifuged to collect the cells again. The collected cells were resuspended in 1 ml of a solution containing 0.2-M NaCl, 0.1-M EDTA, 5 w/v % SDS, 50-mM Tris-HCl (pH 8.5), and 20 Proteinase K were added to be 20 mg/ml thereto. The mixed solution was allowed to stand at 60° C. for 1 hour, then returned to room temperature, and extracted with a mixture of phenol and chloroform and then with chloroform to purify. To the thus-obtained supernatant was added in an equal volume of isopropanol to precipitate chromosomal DNA and plasmid pSR1. The mixture was centrifuged at 6,900×g for 10 minutes at 4° C. to collect the DNA, and the collected DNA was washed with 70 v/v % ethanol, then vacuum-dried and dissolved in 100 μl of TE.
Reaction SMILES: [CH2:1]([C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1)([CH2:6][CH3:7])[C:4]#[N:5])[CH3:2].O.O.NN>C(O)C>[NH2:14][C:10]1[CH:9]=[C:8]([C:3]([CH2:6][CH3:7])([CH2:1][CH3:2])[C:4]#[N:5])[CH:13]=[CH:12][CH:11]=1
Reactant: CCC(C#N)(CC)c1cccc([N+](=O)[O-])c1
Agent: NN
Solvent: O
Solvent: CCO
Product: CCC(C#N)(CC)c1cccc(N)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
A solution of 3.2 g (14.7 mmol) of 2-ethyl-2-(3-nitro-phenyl)-butyronitrile in 50 ml of ethanol was treated with 350 mg of water-wet Raney nickel and the mixture heated to 60° C. 10 ml of hydrazine hydrate was added dropwise over 20 minutes and the reaction stirred for a further 1 hour at 60° C. The cooled mixture was filtered through hyflo filter aid and evaporated to give 2.5 g (90%) of 2-(3-amino-phenyl)-2-ethyl-butyronitrile as an orange oil. [Mass spectrum (ESI) MH+ =189].
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][OH:9])=[CH:5][CH:4]=1)#[N:2].Cl>C(O)C.[Pd]>[OH:9][CH2:8][CH2:7][C:6]1[CH:10]=[CH:11][C:3]([CH2:1][NH2:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(CCO)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCc1ccc(CCO)cc1

Procedure:
A solution of 0.74 g (0.005 mol) of p-cyanophenethyl alcohol in 50 ml of ethanol containing 10 ml of concentrated hydrochloric acid was hydrogenated at 30 psi using 0.1 g 5% Pd/C for 72 hours. The catalyst was removed by filtration and the solvent was removed under reduced pressure.
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:5]2=[N:4][C:3]=1[CH2:15][O:16][CH3:17].[F:18][C:19]1[CH:20]=[CH:21][C:22]2=[C:23]([CH:39]=1)[O:24][CH2:25][C:26]1[CH:36]=[C:35]([CH:37]=[O:38])[CH:34]=[CH:33][C:27]=1/[C:28]/2=[C:29](/[CH3:32])\[C:30]#[N:31]>>[F:18][C:19]1[CH:20]=[CH:21][C:22]2=[C:23]([CH:39]=1)[O:24][CH2:25][C:26]1[CH:36]=[C:35]([CH:37]([OH:38])[C:2]3[N:6]4[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:5]4=[N:4][C:3]=3[CH2:15][O:16][CH3:17])[CH:34]=[CH:33][C:27]=1/[C:28]/2=[C:29](/[CH3:32])\[C:30]#[N:31]
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Reactant: COCc1nc2c(C(F)(F)F)cccn2c1I
Product: COCc1nc2c(C(F)(F)F)cccn2c1C(O)c1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 81.9 %

Procedure:
[step 4] Using 3-iodo-2-(methoxymethyl)-8-(trifluoromethyl)imidazo[1,2-a]pyridine (700 mg, 1.97 mmol) obtained in step 3 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (288 mg, 0.98 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 8F, step 4, (E)-2-(3-fluoro-8-{hydroxy[2-(methoxymethyl)-8-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}dibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (420 mg, 82%) was obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](Cl)=[N:13][C:12]([CH2:19][O:20][CH3:21])=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>C(#N)C>[C:22]([C:26]1[CH:27]=[CH:28][C:29]([NH:32][C:14]2[C:15]3[CH2:16][CH2:17][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:9][C:10]=3[N:11]=[C:12]([CH2:19][O:20][CH3:21])[N:13]=2)=[CH:30][CH:31]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: COCc1nc(Cl)c2c(n1)CN(Cc1ccccc1)CC2
Solvent: CC#N
Product: COCc1nc2c(c(Nc3ccc(C(C)(C)C)cc3)n1)CCN(Cc1ccccc1)C2
Yield: 65.5 %

Procedure:
The title compound was prepared using the general procedure set forth in Example 2, above, using 7-benzyl-4-chloro-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidine (0.583 g, 1.92 mmol), 4-tert-butylbenzenamine (0.33 mL, 2.11 mmol) and acetonitrile (3 mL) to give 0.524 g (66%) of the title compound as an off-white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:10]=[C:11]([C:15](=[O:17])[CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[N+:25]([C:28]1[O:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1)([O-:27])=[O:26]>C(O)C>[F:24][C:21]1[CH:20]=[CH:19][C:18]([N:9]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:1]=[CH:32][C:31]4[O:34][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=4)=[CH:7][CH:6]=3)=[CH:16][C:15](=[O:17])[C:11]([C:12]([OH:14])=[O:13])=[CH:10]2)=[CH:23][CH:22]=1
Reactant: Nc1ccc(-c2cc(=O)c(C(=O)O)cn2-c2ccc(F)cc2)cc1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Solvent: CCO
Product: O=C(O)c1cn(-c2ccc(F)cc2)c(-c2ccc(N=Cc3ccc([N+](=O)[O-])o3)cc2)cc1=O
Temperature: 25 °C
Yield: 31.4 %

Procedure:
In 10 ml of ethanol were suspended 0.3 g of 6-(4-aminophenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinic acid and 0.15 g of 5-nitrofurfural, and the suspension was subjected to reaction at 80° C. for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and the insolubles were removed by filtration. The solvent was removed by distillation under reduced pressure. Then, 10 ml of diethyl ether was added to the residue, and the insolubles were collected by filtration to obtain 0.13 g of 1-(4-fluorophenyl)-6-[4-{(5-nitrofurfurylidene)amino}-phenyl]-4-oxo-1,4-dihydronicotinic acid having a melting point of 129°-131° C.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]1[C:12]2[CH2:11][O:10][C:9]([CH:13]=[CH2:14])=[CH:8][C:7]3=[CH:15][NH:16][CH:17]=[C:5]([C:6]=23)[CH2:4]1>CO.[H][H].[Pd]>[CH2:13]([C:9]1[O:10][CH2:11][C:12]2[CH:3]([N:2]([CH3:1])[CH3:18])[CH2:4][C:5]3=[CH:17][NH:16][CH:15]=[C:7]([C:6]=23)[CH:8]=1)[CH3:14]
Reactant: [H][H]
Reactant: C=CC1=CC2=CNC=C3CC(N(C)C)C(=C23)CO1
Agent: [Pd]
Solvent: CO
Product: CCC1=CC2=CNC=C3CC(N(C)C)C(=C23)CO1
Yield: 99 %

Procedure:
Compound (40) 242 mg was dissolved in methanol 4 ml and 5% palladium/C 60 mg was added. A mixture was stirred in hydrogen atmosphere at room temperature for 3 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in ethyl acetate:hexane (1:2) to give the titled compound as colorless crystals 241.6 mg. Yield 99%. This was recrystallized from acetone-hexane to give the titled compound as colorless crystals, m.p. 91-92° C.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([CH2:17][CH2:18][N:19]3[C@H:24]4[CH2:25][CH2:26][C@@H:20]3[CH2:21][CH:22]([N:27]3[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=5[N:29]=[C:28]3[CH3:36])[CH2:23]4)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:7]=[C:8]([F:10])[CH:9]=1.C(N(CC)CC)C.[Cl:44][C:45]1[CH:53]=[CH:52][C:48]([C:49](O)=[O:50])=[CH:47][C:46]=1[S:54](=[O:57])(=[O:56])[NH2:55].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[Cl:44][C:45]1[CH:53]=[CH:52][C:48]([C:49]([N:14]2[CH2:13][CH2:12][C:11]([C:6]3[CH:7]=[C:8]([F:10])[CH:9]=[C:4]([Cl:3])[CH:5]=3)([CH2:17][CH2:18][N:19]3[C@H:24]4[CH2:25][CH2:26][C@@H:20]3[CH2:21][CH:22]([N:27]3[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=5[N:29]=[C:28]3[CH3:36])[CH2:23]4)[CH2:16][CH2:15]2)=[O:50])=[CH:47][C:46]=1[S:54]([NH2:55])(=[O:57])=[O:56]
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cc(F)cc(Cl)c2)CCNCC1
Reactant: NS(=O)(=O)c1cc(C(=O)O)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cc(F)cc(Cl)c2)CCN(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.7 %

Procedure:
A mixture of 1-((1R,5S)-8-{2-[4-(3-chloro-5-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole dihydrochloride (0.40 g, 0.78 mmol), triethylamine (0.35 mL, 2.5 mmol) and 4-chloro-3-sulfamoylbenzoic acid (184 mg, 0.78 mmol) in dimethylformamide (2.5 mL) was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (327 mg, 0.86 mmol) and the resulting mixture was stirred for 1 h at rt. The mixture was diluted with water and the resulting precipitate was collected, washed with saturated sodium bicarbonate solution and water, dried and purified by chromatography on silica gel eluting with a gradient of chloroform:methanol:ammonium hydroxide 400:15:1 to 200:15:1 to give 2-chloro-5-[(4-(3-chloro-5-fluoro phenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)carbonyl]benzenesulfonamide as a solid (0.20 g, 36%). 1H NMR (400 MHz, CD3OD) δ 8.09 (s, 1H), 7.67 (m, 1H), 7.60 (m, 1H), 7.51 (m, 1H), 7.42 (m, 1H) 7.30 (s, 1H), 7.10-7.21 (m, 4H), 4.72 (m, 1H), 4.06 (m, 1H), 3.57 (m, 1H), 3.47 (m, 1H), 3.30 (m, 3H), 2.52 (s, 3H), 2.40-2.48 (m, 4H), 2.27 (m, 1H), 2.14 (m, 1H), 1.83-2.04 (m, 10H), 1.70 (m, 2H). HRMS C35H38Cl2FN5O3S m/z 698.2134 (M+H)Cal., 698.2161 (M+H)Obs..
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[S:4][CH:5]=[C:6]([C:8](=[O:11])[CH2:9]Br)[N:7]=1.[C:14]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH2:28])=[CH:22][CH:21]=1)([O:16][CH3:17])=[O:15]>>[C:14]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH:28][CH2:9][CH:8]([OH:11])[C:6]2[N:7]=[C:3]([C:2]([F:13])([F:12])[F:1])[S:4][CH:5]=2)=[CH:22][CH:21]=1)([O:16][CH3:17])=[O:15]
Reactant: O=C(CBr)c1csc(C(F)(F)F)n1
Reactant: COC(=O)COc1ccc(CCN)cc1
Product: COC(=O)COc1ccc(CCNCC(O)c2csc(C(F)(F)F)n2)cc1

Procedure:
Prepared analogously to Example 3 by reaction of 2-trifluoromethyl-4-bromoacetyl-thiazole with 2-(4-carbomethoxymethoxyphenyl)ethanamine, followed by reduction.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Br.[CH2:12]([O:14][P:15]([O:19]CC)[O:16][CH2:17][CH3:18])[CH3:13]>>[Br:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][P:15](=[O:19])([O:16][CH2:17][CH3:18])[O:14][CH2:12][CH3:13]
Reactant: BrCCc1ccccc1CBr
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccccc1CCBr)OCC
Yield: 69.1 %

Procedure:
In a round bottom flask equipped for distillation, 15.0 g (54 mmol) of 2-(2-bromoethyl)benzyl bromide and 9.0 g (54 mmol) of triethylphosphite were heated on an oil bath with stirring at 90°-100° C. When ethyl bromide ceased distilling off (1 h) the remaining volatile by-products and triethylphosphite were removed from the mixture by distillation under vacuum. The viscous oil which remained was chromatographed on a column of silica gel with hexane-ethyl acetate (1:1) as eluant. The combined fractions were concentrated under reduced pressure to yield 12.5 g (70%) of the product as a yellow oil. IR(neat): 2987, 1249, 1170, 1064, 964, 802 cm-1. 1H NMR(CDCl3) δ 1.2 (t, 6H); 3.0-4.35 (m, 10H); 7.2 (s, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@@H:13]([C:15]3[O:19][NH:18][C:17](=[O:20])[CH:16]=3)[CH2:12][CH2:11][N:10]2C(OC)=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Br>>[Cl:8][C:6]1[CH:5]=[C:4]([C@H:9]2[CH2:14][C@@H:13]([C:15]3[O:19][NH:18][C:17](=[O:20])[CH:16]=3)[CH2:12][CH2:11][NH:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1cc(Cl)cc(Cl)c1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](c3cc(Cl)cc(Cl)c3)C2)o[nH]1
Reaction time: 8 h
Yield: 72.1 %

Procedure:
(2R,4S)-Methyl 2-(3,5-dichlorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1 g, 2.69 mmol) was dissolved in hydrogen bromide (33% in AcOH, 4.67 mL, 80.82 mmol). Stirred overnight and evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(3,5-dichlorophenyl)piperidin-4-yl)isoxazol-3(2H)-one (607 mg, 72%). 1H NMR (600 MHz, dmso) δ 1.32 (q, 1H), 1.44 (dq, 1H), 1.84-1.89 (m, 1H), 1.97-2.03 (m, 1H), 2.70 (dt, 1H), 2.80-2.87 (m, 1H), 3.06-3.12 (m, 1H), 3.67 (dd, 1H), 5.75 (s, 1H), 7.42 (d, 2H), 7.44 (t, 1H). HRMS Calculated for [C14H14Cl2N2O2+H]+: 313.0511. Found: 313.0513
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=1.CN(C=[O:25])C.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[O:25])[N:15]=1
Reactant: Cc1cccc(F)n1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: O=Cc1cccc(F)n1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of diisopropylamine (6.54 mL, 1.2 equiv) in 30 mL of THF at 0° C., a solution of n-butyllithium (17.1 mL, 2.5M in hexanes) is added dropwise. Stirring is continued for 15 minutes at 0° C., the reaction is then cooled to −78° C. 2-Fluoro-6-methylpyridine (4.00 mL, 38.9 mmol) is added dropwise to the cold solution. The reaction mixture is stirred at −78° C. for 1 hours and then quenched with DMF (4.52 mL, 1.5 equiv). The reaction is maintained at −78° C. for 30 minutes and then warmed to 0° C. The cold solution is added to a mixture of sodium periodate (24.9 g) in 120 mL of water at 0° C. The reaction mixture is allowed to gradually warm to room temperature over 1 hours and then stirred at room temperature for 24 hours. The reaction mixture is filtered through a plug of celite to remove the precipitate and the plug is washed with ether. The organic layer is separated, washed with aqueous sodium bicarbonate (1×40 mL), then with 0.25M KH2PO4 (1×40 mL) and then brine (1×40 mL). The organic solution is dried (NaSO4) and concentrated in vacuo.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.[Al].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>[C:4]([C:3]1[CH:8]=[CH:9][CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:2]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][CH3:15])([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Reactant: COc1ccccc1B(O)O
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: [Al]
Solvent: C1CCOC1
Product: COC(=O)c1cccc([N+](=O)[O-])c1-c1ccccc1OC
Yield: 69.5 %

Procedure:
A solution of methyl 2-chloro-3-nitrobenzoate (2.16 g, 10.0 mM), 2-methoxybenzeneboronic acid (1.64 g, 10.5 mM), tetrakis(triphenylphosphine)palladium (0) (584 mg, 0.5 mM), and 2 M aqueous sodium carbonate (10.5 mL, 21.0 mM) in 50 mL of THF was wrapped in aluminum foil and stirred at reflux for 27 hours. The THF was removed in vacuo and the residue dissolved in ethyl acetate. The mixture was washed with with H2O, 1 N HCl, H2O, sat. NaHCO3, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The resultant light brown oil was purified by column chromatography on silica (elution with gradient toluene/ethyl acetate) to afford 2.0 g (69%) of 2-carbomethoxy-6-nitro-2′-methoxy-biphenyl as a yellow-orange solid. 1H NMR (CDCl3) δ8.05 (d, 1H, J=8 Hz), 7.95 (d, 1H, J=8 Hz), 7.55 (t, 1H, J=8 Hz), 7.35 (t, 1H, J=8 Hz), 7.05 (d, 1H, J=8 Hz), 7.0 (t, 1H, J=8 Hz), 6.9 (d, 1H, J=8 Hz), 3.7 (s, 3H), and 3.6 (s, 3H). IR (KBr, cm−1) 1730, 1538, 1499, 1366, 1298, 1271, 1130, 774, 765, 759, 752, and 707. MS (ES) m/e 288.