Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]12[NH:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][CH2:13]2>CS(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([N:18]2[CH:12]3[CH2:17][CH2:16][CH:15]2[CH2:14][CH2:13]3)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Reactant: C1CC2CCC1N2
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N2C3CCC2CC3)cc1Br
Temperature: 80 °C
Reaction time: 24 h
Yield: 255.1 %

Procedure:
To a solution of 2-bromo-4-fluoro-1-nitro-benzene (250 mg, 1.14 mmol) in DMSO (2 mL) was added 7-azabicyclo[2.2.1]heptane (182 mg, 1.36 mmol) portion-wise. The reaction was stirred at 80° C. for 24 h. The reaction was quenched with water and the aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with 1 N HCl, dried over MgSO4, filtered and concentrated in vacuo to provide 7-(3-bromo-4-nitrophenyl)-7-azabicyclo[2.2.1]heptane (864 mg, 98% yield). LC/MS m/z 298.5 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][CH:19]=[O:20])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[CH:21]([Mg]Cl)([CH3:23])[CH3:22].Cl.O>O1CCCC1>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][CH:19]([OH:20])[CH:21]([CH3:23])[CH3:22])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(SCCC=O)cc(C(C)(C)C)c1O
Reactant: CC(C)[Mg]Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.0 g of the aldehyde of Example 4 was dissolved in 20 ml of dry tetrahydrofuran under argon and added to 8.5 ml of 2M isopropylmagnesium chloride in tetrahydrofuran that had previously been added under argon gas to a flask that had been dried in vacuo overnight. Reaction temperature was maintained at 10°-15° C. with an ice bath. When addition was complete, the reaction mixture was allowed warm to room temperature and stirred for 3 hours. 2N hydrochloric acid (2 ml) was added followed by 50 ml of water and the mixture extracted with ethyl acetate three times. The organic extracts were combined, washed with water twice and dried over sodium sulfate. The solvent was removed in vacuo after filtration and the crude product chromatographed on silica to give the title compound.
Reaction SMILES: [N+](C1C=CC(COC([N:12]2[CH2:16][CH2:15][C@@H:14]([NH:17][C:18]([C@@H:20]3[CH2:24][C@H:23]([S:25][C:26]4[C@H:27]([CH3:50])[C@@H:28]5[C@@H:45]([C@H:46]([OH:48])[CH3:47])[C:44](=[O:49])[N:29]5[C:30]=4[C:31]([O:33]CC4C=CC([N+]([O-])=O)=CC=4)=[O:32])[CH2:22][N:21]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:19])[CH2:13]2)=O)=CC=1)([O-])=O.[ClH:66]>O1CCCC1.O>[ClH:66].[NH:12]1[CH2:16][CH2:15][C@@H:14]([NH:17][C:18]([C@@H:20]2[CH2:24][C@H:23]([S:25][C:26]3[C@H:27]([CH3:50])[C@@H:28]4[C@@H:45]([C@H:46]([OH:48])[CH3:47])[C:44](=[O:49])[N:29]4[C:30]=3[C:31]([OH:33])=[O:32])[CH2:22][NH:21]2)=[O:19])[CH2:13]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N[C@@H]4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N[C@@H]4CCNC4)C3)[C@H](C)[C@H]12

Procedure:
500 mg of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-[(3R)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-3-ylaminocarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 20 ml of a 1:1 by volume mixture of tetrahydrofuran and water, after which 0.47 ml of 1N aqueous hydrochloric acid was added, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 1 g of 10% w/w palladium-on-charcoal. The reaction mixture was then worked up and purified by the same procedure as described in Example 18(b), to give 43 mg of the title compound as a powder.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:13])[CH2:5][CH2:6][O:7]2.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([OH:13])[CH2:5][CH2:6][O:7]2
Reactant: O=C1CCOc2cc(F)cc(F)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCOc2cc(F)cc(F)c21
Reaction time: 1 h
Yield: 67.3 %

Procedure:
To a solution of 5,7-difluoro-2,3-dihydro-4H-chromen-4-one (14.2 g, 77.0 mmol, US 20050038032) in methanol (200 mL) was added sodium borohydride (3.50 g, 92.5 mmol) at 0° C. The reaction mixture was stirred at the same temperature for 1 hour, and evaporated to remove methanol. The residue was quenched with water, and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated in vacuum. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1 as an eluent) to afford the title compound as a pale gray solid (9.64 g, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[CH3:25][CH:26]1[S:31][CH2:30][CH2:29][NH:28][CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:28]1[CH2:29][CH2:30][S:31][CH:26]([CH3:25])[CH2:27]1)=[O:24])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: CC1CNCCS1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC1CN(C(=O)c2ccc(C(=O)NCc3nc4cc(Cl)ccc4[nH]3)cc2Cl)CCS1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, 2-methylthiomorpholine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.78 minutes; C21H20C12N4O2S (463.39); mass spectrum: (M+H)+=463.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:10]=2[N:11]=[C:12](S(C)(=O)=O)[N:13]=1.[NH2:28][CH:29]([CH2:32][OH:33])[CH2:30][OH:31]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:10]=2[N:11]=[C:12]([NH:28][CH:29]([CH2:32][OH:33])[CH2:30][OH:31])[N:13]=1
Reactant: NC(CO)CO
Reactant: CCC(CC)n1c(=O)ccc2c(-c3ccccc3F)nc(S(C)(=O)=O)nc21
Product: CCC(CC)n1c(=O)ccc2c(-c3ccccc3F)nc(NC(CO)CO)nc21

Procedure:
4-(2-Fluorophenyl)-8-(1-ethylpropyl)-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one, and serinol were reacted by the procedure of Example 60 to afford the title compound 4-(2-fluoro-phenyl)-8-(1-ethyl-propyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR: δ 0.82 (m, 6H), 1.32 (m, 4H), 1.90 (m, 2H), 2.32 (m, 2H), 3.71 (m, 2H), 4.24 (m, 1H), 5.38 (m, 0.5H), 5.69 (m, 0.5H), 5.71 (br s, 1H), 6.30 (br d, 1H, J=9.6), 7.13 (d, 1H, J=9.6 Hz), 7.30-7.55 (m, 4H). LC MS (m/e)=401 (MH+)
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(Cl)([Cl:23])=O>>[CH2:1]([Cl:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: O=C(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCCl
Yield: 99.9 %

Procedure:
The experimental method described in Example 1 is used, and 2,746 g (10 moles) of technical grade stearic acid and the catalyst phase (342 g) obtained in Example 1 are initially taken. 1,089 g (11 moles) of gaseous phosgene are then introduced. The product phase contains 2,930 g (99.9% yield) of stearyl chloride having a purity of 97% (determined by IR spectroscopy); the iodine color number is 30.
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].[OH-].[Na+].[Cl:9][C:10]1[CH:11]=[C:12]([N:17]=[C:18]=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:16]>O>[CH3:2][N:1]([CH2:3][C:4]([OH:6])=[O:5])[C:18]([NH:17][C:12]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([Cl:9])[CH:11]=1)=[O:19]
Reactant: CNCC(=O)O
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(CC(=O)O)C(=O)Nc1ccc(Cl)c(Cl)c1

Procedure:
To a stirred solution of 89 g. of sarcosine in 300 ml. of water containing 60 g. of sodium hydroxide were added portion-wise over thirty minutes 188 g. of 3,4-dichlorophenyl isocyanate. The reaction mixture was stirred for thirty minutes following the addition, and then was filtered. The filtrate was acidified with concentrated hydrochloric acid, whereupon a white solid precipitated. The solid was collected by filtration and air dried to give 1-methyl-1-(hydroxycarbonylmethyl)-3-(3,4-dichlorophenyl) urea. M.P. 103°-105° C.
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#[N:19]>C(Cl)Cl.[N-]=C=O>[C:18]([C:17]1[CH:16]=[C:15]([NH:14][C:12](=[O:13])[NH:11][C:8]2[CH:7]=[CH:6][C:5]([S:2]([Cl:1])(=[O:4])=[O:3])=[CH:10][CH:9]=2)[CH:22]=[CH:21][CH:20]=1)#[N:19]
Reactant: N#Cc1cccc(N)c1
Reactant: O=C=Nc1ccc(S(=O)(=O)Cl)cc1
Agent: [N-]=C=O
Solvent: ClCCl
Product: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)Cl)cc2)c1
Reaction time: 8 h
Yield: 94.8 %

Procedure:
A solution of 5.00 g (1 eq.) of 4-chlorosulfonylphenylisocyanate in anhydrous DCM (40 ml) was added to a solution of 3-aminobenzonitrile (2.71 g, 1 eq.) in anhydrous isocyanate (60 ml) at rt under inert atmosphere and the mixture was stirred overnight. The precipitate was filtered off to yield 7.3 g (95%) of 4-[3-(3-cyanophenyl)-ureido]-benzenesulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20](O)=[O:21])[CH:9]=2)=[CH:4][C:3]=1[CH3:23].[F:24][C:25]([F:34])([F:33])[C:26]1[N:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:12][N:11]=[C:10]([C:20]([NH:32][CH2:31][C:29]3[O:28][N:27]=[C:26]([C:25]([F:24])([F:33])[F:34])[N:30]=3)=[O:21])[CH:9]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: NCc1nc(C(F)(F)F)no1
Reactant: Cc1cc(-c2cc(C(=O)O)ncc2OCC(F)(F)F)ccc1Cl
Product: Cc1cc(-c2cc(C(=O)NCc3nc(C(F)(F)F)no3)ncc2OCC(F)(F)F)ccc1Cl

Procedure:
The title compound was synthesized in analogy to Example 1 using 4-(4-chloro-3-methylphenyl)-5-(2,2,2-trifluoroethoxy)picolinic acid (example BN) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; LC-MS (UV peak area/ESI) 100%, 493.0499 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[CH2:14](Br)[CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:16]([O:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5])[CH:15]=[CH2:14]
Reactant: COC(=O)c1cccc(OC)c1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1c(OC)cccc1C(=O)O

Procedure:
The reaction of methyl 2-hydroxy-3-methoxy-benzoate and allyl bromide in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 2-Allyloxy-3-methoxy-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.18 (s, —CO2H); 7.10 (m, 3 arom. H); 5.97 (m, —CH═CH2); 5.28, 5.14 (2 d-like, CH═CH2); 4.43 (d-like, CH2—CH═CH2); 3.77 (s, OCH3). 13C-NMR (100 MHz, d6-DMSO): 167.42 (C═O); 153.06; 146.24; 134.49; 127.66; 123.94; 121.07; 117.10; 115.57; 73.88; 55.93.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([N:15]3[CH2:20][CH2:19][CH:18]([O:21]C4CCCCO4)[CH2:17][CH2:16]3)(=[O:14])=[O:13])=[CH:8][C:7]=2[C:28]2[C:29]3[CH:38]=[CH:37][NH:36][C:30]=3[C:31](=[O:35])[N:32]([CH3:34])[CH:33]=2)[CH2:3][CH2:2]1.C(O)(=O)C.O1CCCC1>O>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([N:15]3[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]3)(=[O:13])=[O:14])=[CH:8][C:7]=2[C:28]2[C:29]3[CH:38]=[CH:37][NH:36][C:30]=3[C:31](=[O:35])[N:32]([CH3:34])[CH:33]=2)[CH2:3][CH2:2]1
Reactant: Cn1cc(-c2cc(S(=O)(=O)N3CCC(OC4CCCCO4)CC3)ccc2OCC2CC2)c2cc[nH]c2c1=O
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cn1cc(-c2cc(S(=O)(=O)N3CCC(O)CC3)ccc2OCC2CC2)c2cc[nH]c2c1=O
Yield: 65.6 %

Procedure:
A solution of Example 354e (54 mg, 0.10 mmol), acetic acid (4 mL, 69.9 mmol), tetrahydrofuran (2 mL) and water (1 mL) was stirred at 45° C. for 2.5 hours. The reaction mixture was concentrated to dryness and the residue was dried overnight (in-vacuo). The crude product was triturated with diethyl ether, filtered and dried (in-vacuo) to afford the title compound (30 mg, 66% yield). 1H NMR (300 MHz, DMSO-d6) ppm 0.25-0.31 (m, 2H) 0.44-0.51 (m, 2H) 1.08-1.17 (m, 1H) 1.38-1.51 (m, 2H) 1.70-1.80 (m, 2H) 2.70-2.80 (m, 2H) 3.10-3.18 (m, 2H) 3.51-3.56 (m, 1H) 3.57 (s, 3H) 3.97 (d, J=6.78 Hz, 2H) 4.66 (d, J=4.07 Hz, 1H) 6.12 (t, J=2.71, 2.03 Hz, 1H) 7.27-7.32 (m, 2H) 7.36 (s, 1H) 7.64-7.70 (m, 2H) 12.04 (brs, 1H). MS (ESI+) m/z 458 [M+H]+.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C([O-])(=O)C.[Na+].C(O)C.Cl.[NH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([OH:30])=[CH:22][CH:21]=1>O>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[N:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([OH:30])=[CH:22][CH:21]=1
Reactant: Nc1ccc(O)c2ccccc12
Reactant: O=Cc1ccccc1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Oc1ccccc1C=Nc1ccc(O)c2ccccc12
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 82.5 %

Procedure:
To a 500 milliliter round bottom flask equipped with a water condenser, magnetic stirrer and drying tube was added 5.50 grams (0.045 moles) of salicylaldehyde, 4.10 grams (0.050 moles) of sodium acetate and 40 milliliters of ethanol. The resulting mixture was then heated to a temperature of 50° C. and a solution consisting of 7.83 grams (0.040 moles) of 4-amino-1-naphthol hydrochloride in 20 milliliters of water was added thereto. The resulting reaction mixture was stirred for 15 minutes at a temperature of 50° C. and then cooled to room temperature forming a precipitate. The precipitate was removed from the reaction mixture by filtration, washed with water and dried over magnesium sulfate to give 8.68 grams (0.033 moles) of 4-(2-hydroxybenzylideneamino)-1-naphthol in the form of reddish-brown crystals having a melting point of 153.5°-157° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:12]2[N:13]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH:14]=[C:15]([CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][CH3:20])[N:16]=2)([OH:11])[CH3:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:35][S:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O.O>CN(C)C=O.O>[CH3:21][C:18]([CH3:22])([CH2:19][CH3:20])[CH2:17][C:15]1[N:16]=[C:12]([C:9]([OH:11])([CH3:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[S:36][CH3:35])=[CH:3][CH:4]=2)[N:13]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH:14]=1
Reactant: CSc1ccccc1B(O)O
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(Br)cc2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(-c3ccccc3SC)cc2)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (61 mg, 0.075 mmol) was added to a degassed, ambient temperature solution of 2-[2-(4-bromophenyl)-1-hydroxy-1-methylethyl]-4-(2,2-dimethylbutyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (Intermediate 11) (354 mg, 0.75 mmol), sodium carbonate (239 mg, 2.25 mmol) and [2-(methylthio)phenyl]boronic acid (252 mg, 1.5 mmol) in N,N-dimethylformamide/water (2:1) (22.5 mL). After stirring at 80° C. overnight, the reaction mixture was cooled, poured into water and extracted with diethyl ether. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-40% ethyl acetate/hexane afforded 4-(2,2-dimethylbutyl)-2-{1-hydroxy-1-methyl-2-[2′-(methylthio)biphenyl-4-yl]ethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: [CH:1]([CH:3]1[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH:4]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=O.[CH3:20][CH:21]([CH2:44][CH2:45][CH2:46][CH3:47])[C:22]([C:24]1C=CC=CC=1P(=C)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:23]>O1CCCC1>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:4]1[CH:3]([CH:1]=[CH:24][C:22](=[O:23])[CH:21]([CH3:20])[CH2:44][CH2:45][CH2:46][CH3:47])[CH2:11][CH2:10][C:5]21[O:9][CH2:8][CH2:7][O:6]2
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1C(=O)C(C)CCCC
Reactant: O=CC1CCC2(OCCO2)C1CCCCCCCO
Solvent: C1CCOC1
Product: CCCCC(C)C(=O)C=CC1CCC2(OCCO2)C1CCCCCCCO
Yield: 101.8 %

Procedure:
A mixture of 7-formyl-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane (3.88 g.) and 2-methylhexanoyl-methylenetriphenylphosphorane (6.0 g.) in dry tetrahydrofuran (30 ml.) was heated to reflux under nitrogen for 18 hours. The solvent was removed in vacuo and the residue triturated with petroleum ether (b.p. 60°-80° C.), allowed to stand at 0° C., filtered to remove triphenylphosphine oxide and the filtrate evaporated to give 6-(7-hydroxyheptyl)-7-(4-methyl-3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonane (5.56 g), νmax 1620 cm-1, 1660 cm-1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N)cc2)CC1
Temperature: 30 °C
Yield: 66.5 %

Procedure:
A solution of 4-(4-nitro-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (2.82 g, 8.77 mmol) was hydrogenated on an H-Cube apparatus with a 5% Pd/C cartridge under the following conditions: flow rate=1 mL/min, heating column temperature=30° C., H2 pressure=40 bar. The material was passed through the column twice more in order to complete the reaction. Solvents were evaporated in vacuo. Purification of the residue on a 50-g Isolute SPE column on a FlashMaster system with 25-50% EtOAc-hexane afforded the title compound (1.70 g, 67%) as a yellow solid. Mass spectrum (ESI, m/z): Calcd. for C16H25N3O2, 292.2 (M+H). found 292.1.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]([O:20]CC)=[O:19])[C:9]2=[O:23])[O:4][N:3]=1.O.[OH-].[Li+]>C(O)C.O>[CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]([OH:20])=[O:19])[C:9]2=[O:23])[O:4][N:3]=1
Reactant: CCOC(=O)c1nc2ccccc2n(Cc2cc(C)no2)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(Cn2c(=O)c(C(=O)O)nc3ccccc32)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
3.0 g (9.58 mmol) of ethyl 1-[(3-methylisoxazol-5-yl)methyl]-2-oxo-1,2-dihydroquinoxaline-3-carboxylate and 0.46 g (11.5 mmol) of lithium hydroxide monohydrate were dissolved in a solvent mixture of ethanol (30 mL) and water (30 mL), and the solution was stirred for 2 hours at room temperature. The reaction solution was concentrated to a half the original volume, and water was added to the residue. The mixture was acidified using 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated, to obtain 2.3 g (yield: 84%) of 1-[(3-methylisoxazol-5-yl)methyl]-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid as a white powder.
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11]=[CH2:12])[C:5](=[O:9])[CH:6](Br)[CH3:7])[CH:2]=[CH2:3].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24](=[O:25])[C:23]3[CH2:26][CH2:27][CH2:28][CH2:29][C:22]=3[C:21]2=[O:30])=[CH:16][C:15]=1[OH:31].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:21](=[O:30])[C:22]3[CH2:29][CH2:28][CH2:27][CH2:26][C:23]=3[C:24]2=[O:25])=[CH:16][C:15]=1[O:31][CH:6]([C:5](=[O:9])[N:4]([CH2:1][CH:2]=[CH2:3])[CH2:10][CH:11]=[CH2:12])[CH3:7]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Br)c(O)c1
Reactant: C=CCN(CC=C)C(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCN(CC=C)C(=O)C(C)Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Br

Procedure:
The reaction mixture was washed with water and dried and the solvent was distilled off to obtain 3.8 g. of N,N-diallyl α-bromopropionamide. The product was admixed with 3.5 g. of N-(4-bromo-3-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide, 2.2 g. of potassium carbonate, 1.8 g. of potassium iodide and 50 ml. of acetone.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]#[N:12].[CH2:15](N)[CH2:16][NH2:17]>>[F:1][C:2]([F:13])([F:14])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]1[NH:17][CH2:16][CH2:15][N:12]=1
Reactant: N#CCc1ccccc1OC(F)(F)F
Reactant: NCCN
Product: FC(F)(F)Oc1ccccc1CC1=NCCN1

Procedure:
2-(2-Trifluoromethoxy-benzyl)-4,5-dihydro-1H-imidazole was prepared from (2-trifluoromethoxy-phenyl)-acetonitrile and ethylene diamine in analogy to Example 19 b): yellow powder; MS (ISP): 245.0 ((M+H)+.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[C:18]([C:20]1[O:24][C:23]([C:25](Cl)=[O:26])=[CH:22][CH:21]=1)#[N:19].CCN(C(C)C)C(C)C>>[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:25]([C:23]2[O:24][C:20]([C:18]#[N:19])=[CH:21][CH:22]=2)=[O:26])=[C:3]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:4]=1)(=[O:11])[CH3:10]
Reactant: N#Cc1ccc(C(=O)Cl)o1
Reactant: CC(=O)Nc1ccc(N)c(N2CCCCC2)c1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(NC(=O)c2ccc(C#N)o2)c(N2CCCCC2)c1
Yield: 38 %

Procedure:
Using a procedure similar to Example 3, step (d), N-(4-amino-3-piperidin-1-yl-phenyl)-acetamide (40 mg, 0.17 mmol, as prepared in the previous step) was allowed to react with 5-cyano-furan-2-carbonyl chloride (27 mg, 0.17 mmol) in the presence of DIEA (65 μL, 0.37 mmol) to afford 23 mg (38%) of the title compound as a yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 9.64 (s, 1H),), 8.36 (d, 1H, J=8.5 Hz), 7.70 (br s, 1H), 7.27 (br s, 1H), 7.22 (d, 1H, J=3.8 Hz), 7.14 (br s, 1H), 7.02 (dd, 1H, J=6.6, 8.9 Hz), 2.85 (br s, 4H), 2.18 (s, 3H), 1.80 (br s, 4H), 1.65 (br s, 2H); Mass spectrum (ESI, m/z): Calcd. for C19H20N4O3, 353.1 (M+H), found 353.2.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:10]=[CH:9][C:6]([O:7][CH3:8])=[CH:5][CH:4]=1.[C:11]([OH:17])(=O)[CH2:12][C:13]([OH:15])=O.[OH-].[Na+]>>[OH:15][C:13]1[C:10]2[C:3](=[CH:4][CH:5]=[C:6]([O:7][CH3:8])[CH:9]=2)[N:2]([CH3:1])[C:11](=[O:17])[CH:12]=1
Reactant: CNc1ccc(OC)cc1
Reactant: O=C(O)CC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2c(c1)c(O)cc(=O)n2C
Temperature: 90 °C
Yield: 43.9 %

Procedure:
To a mixture of N-methyl-p-anisidine (2.8 g, 20 mmol) and malonic acid (4.3 g, 40 mmol) was added POC13 (17 mL). After heating at 90° C. for 1.5 hr, the reaction mixture was poured over ice and basified with 6N NaOH to a pH of 14. The solution was then filtered and the filtrate was acidified with 6N HCl to pH 3. The precipitate was filtered and dried to afford a brown solid (1.8 g, 50%). 1H NMR (300 MHz, MeODd4) 8 3.65 (3H, s), 3.86 (3H, s), 5.97 (1H, s), 7.28 (1H, dd, J=2.8, 9.3 Hz), 7.49 (2H, d, J=9.3 Hz).