Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:22]=[C:21]([CH2:23][N:24]([CH3:26])[CH3:25])[N:20]=[N:19]3)=[CH:14][CH:13]=2)=[N:4][CH:3]=1.[NH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29]>CN(C=O)C.O1CCOCC1.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>[CH3:25][N:24]([CH2:23][C:21]1[N:20]=[N:19][N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:5]3[C:6]4[N:7]([CH:8]=[CH:9][N:10]=4)[C:2]([C:33]4[CH:34]=[CH:35][C:30]([C:28]([NH2:27])=[O:29])=[CH:31][CH:32]=4)=[CH:3][N:4]=3)=[CH:13][CH:14]=2)[CH:22]=1)[CH3:26]
Reactant: CN(C)Cc1cn(-c2ccc(Nc3ncc(Br)n4ccnc34)cc2)nn1
Reactant: NC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CN(C)Cc1cn(-c2ccc(Nc3ncc(-c4ccc(C(N)=O)cc4)n4ccnc34)cc2)nn1
Yield: 6.8 %

Procedure:
In the same way as described for Compound 178, step 4, using (5-bromo-imidazo[1,2-a]pyrazin-8-yl)-[4-(4-dimethylaminomethyl-[1,2,3]triazol-1-yl)-phenyl]-amine (63 mg, 0.152 mmol), 4-(aminocarbonyl)phenylboronic acid (50.3 mg, 0.305 mmol) 1.5 M Na2CO3 (0.813 mL, 1.22 mmol) and Pd(PPh3)4 (44.0 mg, 0.0381 mmol) in (2:1) DMF-dioxane (1.8 mL). Purification of the crude material by Isolute FlashSilicaII Cartridge chromatography eluting with 95:5 DCM:NH3 (7M in MeOH) followed by reverse phase preparative HPLC, affords the title compound as a white solid (4.7 mg, 7%). LCMS: Rt 1.92 min (96%) m/z (APCI) 455 (M+H)+; 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 2.24 (6H, s), 3.61 (2H, s), 7.51 (1H, br s), 7.64 (1H, s), 7.80 (1H, s), 7.85-7.91 (4H, m), 8.08-8.12 (3H, m), 8.16 (1H, br s), 8.36 (2H, d), 8.66 (1H, s), 10.09 (1H, s).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Si:9]([O:16][CH2:17][CH:18]1[CH2:22][N:21]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=2[O:32][CH3:33])[C:20](=[O:34])[CH2:19]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].CN(C)P(N(C)C)(N(C)C)=O.I[CH2:47][C:48]#[C:49][CH2:50][CH2:51][CH2:52][C:53]([O:55][CH3:56])=[O:54]>C1COCC1>[CH3:56][O:55][C:53](=[O:54])[CH2:52][CH2:51][CH2:50][C:49]#[C:48][CH2:47][C@@H:19]1[C@@H:18]([CH2:17][O:16][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:22][N:21]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=2[O:32][CH3:33])[C:20]1=[O:34]
Reactant: COC(=O)CCCC#CCI
Reactant: COc1ccc(CN2CC(CO[Si](C)(C)C(C)(C)C)CC2=O)c(OC)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)CCCC#CC[C@H]1C(=O)N(Cc2ccc(OC)cc2OC)C[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.1 %

Procedure:
Lithium diisopropylamide (1.5 M in cyclohexane, 9.22 mL, 13.83 mmol) was added to a solution of 4-(tert-butyldimethylsilanyloxymethyl)-1-(2,4-dimethoxybenzyl)-pyrrolidin-2-one (2.63 g, 6.93 mmol) in THF (41 mL) at −78° C. under nitrogen. After 30 min at −78° C., hexamethylphosphoramide (3.61 mL, 20.7 mmol) was added dropwise. After 30 min at −78° C., methyl 7-iodohept-5-ynoate (5.52 g, 20.7 mmol) in THF (20 mL+3 mL) was added. The reaction mixture was allowed to warm to room temperature. After 18 h at room temperature, the reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (3×50 mL). Combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel (40% EtOAc/hexane) to afford 579 mg (16%) of 7-[(3R*,4R*)-4-(tert-butyldimethylsilanyloxymethyl)-1-(2,4-dimethoxybenzyl)-2-oxo-pyrrolidin-3-yl]-hept-5-ynoic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10](N)[CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=2)[CH:5]=[CH:4][N:3]=1.B(Br)(Br)Br.C(Cl)Cl.C([O-])(O)=[O:26].[Na+]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([OH:26])[CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(-c2cc(N)cc([N+](=O)[O-])c2)ccn1
Reactant: O=C([O-])O
Agent: BrB(Br)Br
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(-c2cc(O)cc([N+](=O)[O-])c2)ccn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 68 %

Procedure:
To 0° C. flask charged with 65.B (2.85 g, 11.7 mmol) was added a solution of BBr3/CH2Cl2 (1.0 M, 25 mL). The solution was allowed to warm to rt and stirred for 45 mins. The resulting mixture was treated with MeOH (7 mL), neutralized with solid NaHCO3 to PH=7 and concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel using 0-10% of MeOH/CH2Cl2 for elution gave the title product 65.C as solid (1.83 g, 68%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:28][C:12]2=[CH:13][C:14]3[C:15](=[O:27])[N:16]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[C:17](=[O:21])[C:18]=3[C:19]([CH3:20])=[C:11]2[N:10]=1.[F:29][C:30]1[C:35]([F:36])=[CH:34][C:33]([F:37])=[C:32]([F:38])[C:31]=1[CH2:39][CH:40]([NH2:42])[CH3:41].CCN(C(C)C)C(C)C>C(O)CCC>[CH3:25][N:24]([CH3:26])[CH2:23][CH2:22][N:16]1[C:15](=[O:27])[C:14]2[CH:13]=[C:12]3[NH:28][C:9]([C:3]4[C:4](=[O:8])[NH:5][CH:6]=[CH:7][C:2]=4[NH:42][CH:40]([CH3:41])[CH2:39][C:31]4[C:32]([F:38])=[C:33]([F:37])[CH:34]=[C:35]([F:36])[C:30]=4[F:29])=[N:10][C:11]3=[C:19]([CH3:20])[C:18]=2[C:17]1=[O:21]
Reactant: CC(N)Cc1c(F)c(F)cc(F)c1F
Reactant: Cc1c2c(cc3[nH]c(-c4c(Cl)cc[nH]c4=O)nc13)C(=O)N(CCN(C)C)C2=O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c2c(cc3[nH]c(-c4c(NC(C)Cc5c(F)c(F)cc(F)c5F)cc[nH]c4=O)nc13)C(=O)N(CCN(C)C)C2=O
Yield: 42.8 %

Procedure:
A mixture of 2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(dimethylamino)ethyl)-4-methylimidazo[4,5-f]isoindole-5,7(1H,6H)-dione, (0.54 g, 1.35 mmol), 1-(2,3,5,6-tetrafluorophenyl)propan-2-amine (0.34 g, 1.62 mmol), Hunig's base (0.87 g, 6.75 mmol), and 12 mL of anhydrous 1-butanol was heated at reflux for 13-14 h under an argon atmosphere. Product was purified by a silica gel column using methylene chloride and methanol (9:1 v/v) as eluent to afford 0.33 g of the designed compound as yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 13.33 (s, 1H, NH), 11.29 (br s, 1H, NH), 11.00 (d, J=5.7 Hz, 1H, NH), 7.97 (s, ArH), 7.73-7.70 (m, 1H, ArH), 7.40 (d, J=7.6 Hz, 1H, ArH), 6.21 (d, J=7.6 Hz, 1H, ArH), 4.32-4.28 (m, 1H, CH), 3.65 (t, J=6.3 Hz, 2H, CH2), 3.08 (d, J=5.1 Hz, 2H, CH2), 2.72 (s, 3H, CH3), 2.19 (S, 6H, 2×CH3); 1.36 (d, J=6.3 Hz, 3H, CH3), 1.11 (t, J=6.3 Hz, 2H, CH2); Mass (ESI, negative) m/z 568.8 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([OH:12])=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1.[C:17]1(=[O:27])[O:22][C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.C1(C)C=CC=CC=1>C(OCC)C>[C:8]([C:6]1[CH:7]=[C:2]([NH:1][C:17]([C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[C:20]([OH:22])=[O:21])=[O:27])[CH:3]=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]=1[OH:12])([CH3:9])([CH3:10])[CH3:11]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(NC(=O)c2ccccc2C(=O)O)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
A solution of 5.60 g (0.03 mole) of the known compound 4-amino-2,6-di-t-butylphenol in 100 ml of diethyl ether was added dropwise over a period of twenty minutes to a solution of 4.44 g (0.03 mole) of phthalic anhydride in 200 ml of a 1:2 mixture of diethyl ether:toluene. The reaction mixture was stirred at room temperature for about sixteen hours. The resulting precipitate was collected, rinsed with a mixture of diethyl ether and hexane, and dried to give 6.8 g of a white solid. This material was recrystallized from a mixture of ethyl acetate and hexane to give 5.9 g of white solid 2-[N-(3,5-di-t-butyl-4-hydroxyphenyl)carbamoyl]benzoic acid, m.p. 191°-192° C. Analysis: Calculated for C22H27NO4 : %C, 71.5; %H, 7.4, %N, 3.8; Found: %C, 71.8; %H, 7.3; %N, 3.7.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH:24]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23][N:22]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:21][CH:20]2[CH2:44][OH:45])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:46](Cl)([CH3:49])(=[O:48])=[O:47]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH:24]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23][N:22]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH2:21][CH:20]2[CH2:44][O:45][S:46]([CH3:49])(=[O:48])=[O:47])=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(CO)C(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
By reacting tert-butyl (3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 148 (h)] with mesyl chloride according to a method known from the literature there was obtained tert-butyl (3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-methanesulphonyloxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [MS: 707 (M+NH4)+ ] as a colourless solid. Further reaction with diethylamine in acetonitrile at 50° C. analogously to Example 34 gave tert-butyl (3RS,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-diethylaminomethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a brown foam; MS: 667 (M+H)+.
Reaction SMILES: Cl[CH2:2][C@@H:3]([NH:13][C:14](=[O:16])[CH3:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.[CH3:17][S-:18].[Na+]>CN1CCCC1=O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C@H:3]([NH:13][C:14](=[O:16])[CH3:15])[CH2:2][S:18][CH3:17])=[CH:6][CH:7]=1
Reactant: COc1ccc(C[C@@H](CCl)NC(C)=O)cc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COc1ccc(C[C@@H](CSC)NC(C)=O)cc1
Reaction time: 2 h

Procedure:
The N-[(1S)-2-chloro-1-(4-methoxybenzyl)ethyl]acetamide in solution in N-methylpyrrolidone prepared in the preceding stage is added to a suspension of sodium thiomethoxide (1.8 g) in 3.8 ml of N-methylpyrrolidone at 20° C. The reaction medium is brought to 40° C. for 2 hours. The product formed is precipitated by addition of 5.7 ml of water. After filtration and drying, 3.7 g of N-[(1S)-1-(4-methoxybenzyl)-2-(methylthio)ethyl]acetamide are isolated.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH2:7][C:8]#[CH:9].[CH2:17]([Sn:21](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>C1COCC1>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[O:10][CH2:6][CH2:7][C:8]#[C:9][Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: C#CCCOC1CCCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](C#CCCOC1CCCCO1)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.9 %

Procedure:
A solution of n-butyllithium in hexanes (1.6 M, 18.8 mL, 30 mmole) was added in a stream over 2 min to a solution of 2-(3-butynyloxy)tetrahydro-2H-pyran (4.7 mL, 30 mmole) in dry THF (60 mL) at 0° C. under argon. After 0.5 hr, tributyltin chloride (8.1 mL, 30 mmole) was added all at once, and the reaction was warmed to RT. After 3 hr, the reaction was diluted with hexanes (300 mL) and washed sequentially with H2O (2×60 mL), 10% KF (2×30 mL), and saturated brine (60 mL). Drying (Na2SO4), concentration, and silica gel chromatography (3% EtOAc/hexanes) gave the title compound (3.58 g. 27%) as a nearly colorless oil: TLC (5% EtOAc/hexanes) Rf0.37; 1H NMR (400 MHz, CDCl3) δ4.66 (narrow t, 1 H), 3.75-3.96 (m, 2 H), 3.49-3.62 (m, 2 H), 2.56 (app t, 2 H), 1.76-1.91 (m, 1 H), 1.65-1.78 (m, 1 H), 1.42-1.65 (m, 10 H), 1.22-1.41 (m, 6 H), 0.82-1.08 (m, 15 H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][OH:7].Cl.[N:9]([O-])=[O:10].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O>[N:9]([N:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][OH:7])=[O:10]
Reactant: OC[C@@H]1CCCN1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=NN1CCC[C@H]1CO
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.9 %

Procedure:
To a stirred mixture of (S)-(+)-2-pyrrolidinemethanol (6.52 g, 64.4 mmol) in THF (120 mL) and 3N hydrochloric acid (33 mL, 99 mmol) at 3° C. was added dropwise a solution of sodium nitrite (5.80 g, 84 mmol) in water (25 mL) over 20 minutes. The reaction mixture was warmed to room temperature and stirred for 15 hours. After being basified with aqueous sodium carbonate, the mixture was extracted with EtOAc twice, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, EtOAc) to give the title compound (8.04 g, 96% yield) as a liquid. 1H NMR (300 MHz, CDCl3) δ 4.53-4.31 (m, 1H), 4.30-4.27 (m, 1H), 4.02-3.93 (m, 2H), 3.70-3.52 (m, 2H), 2.23-1.89 (m, 4H). 13C NMR (75 MHz, CDCl3) δ 63.4, 62.6, 45.9, 26.2, 20.5, LRMS (API-TIS) m/z 131 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[N:15]=[N+]=[N-])=[CH:4][CH:3]=1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH2:15])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=N[C@H]1CCCC[C@H]1Oc1ccc(Br)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: N[C@H]1CCCC[C@H]1Oc1ccc(Br)cc1
Reaction time: 18 h

Procedure:
A solution of (1R,2S)-2-azidocyclohexyl 4-bromophenyl ether from the previous step (2.85 g, 9.62 mmol) in tetrahydrofuran (59 mL) and water (4.6 mL) was treated with polymer-supported triphenylphosphine (3 mmol/g, 7.87 g, 23.6 mmol). The reaction was stirred for 18 hours, then filtered through Celite®. The filter pad was rinsed with tetrahydrofuran (250 mL), then with ethyl acetate (400 mL), and the combined filtrates were concentrated in vacuo, and azeotroped with ethanol. The residue was purified by chromatography on silica gel (Gradient: 0% to 10% methanol in dichloromethane) to afford (1S,2R)-2-(4-bromophenoxy)cyclohexanamine as a yellow oil. Yield: 1.82 g, 6.74 mmol, 70%. 1H NMR (400 MHz, CDCl3) δ 1.33-1.55 (m, 4H), 1.66-1.75 (m, 3H), 2.00 (m, 1H), 2.07 (br s, 2H), 2.97 (m, 1H), 4.39 (m, 1H), 6.85 (d, J=9.0 Hz, 2H), 7.36 (d, J=9.0 Hz, 2H).
Reaction SMILES: [Mg].II.Br[CH:5]([CH2:7][CH2:8][CH3:9])[CH3:6].[CH2:10]([N:17]1[CH2:21][CH:20]([CH2:22]I)[CH2:19][C:18]1=[O:24])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([N:17]1[CH2:21][CH:20]([CH2:22][CH:5]([CH3:6])[CH2:7][CH2:8][CH3:9])[CH2:19][C:18]1=[O:24])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCCC(C)Br
Reactant: O=C1CC(CI)CN1Cc1ccccc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCC(C)CC1CC(=O)N(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
To a suspension of magnesium turnings (0.50 g, 0.021 mol) in 15 mL of dry THF under nitrogen, was added an iodine crystal and 2-bromopentane (2.88 g, 0.019 mol). After an exothermic reaction which was periodically cooled in an ice bath, the reaction was stirred at room temperature for 2 hours. Eight milliliters of Li2CuCl4 (made from 84 mg LiCl and 134 mg CuCl2 in 10 mL of dry THF) was added at 0° C. followed by dropwise addition of 1-Benzyl-4-iodomethyl-pyrolidine-2-one 75 in 15 mL dry THF, and the resulting suspension was let stir at 0° C. for 3 hours. Stirring was continued at room temperature for 1 hour before quenching with a saturated solution of ammonium chloride. Water was added to dissolve the precipitate formed, and the solution was then extracted with ether and dried over magnesium sulfate. The solvent was evaporated under vacuum and the residue chromatographed on silica eluting with 1:1 acetone/hexane to give 1.13 g, 69% of the 1-benzyl-4-(2-methyl-pentyl)-pyrrolidin-2-one 76. 1H NMR (CDCl3) δ 7.30 (m, 5H), 4.44 (m, 2H), 3.32 (m, 1H), 2.86 (m, 1H), 2.56 (m, 1H), 2.40 (m, 1H), 2.10 (m, 1H), 1.30 (m, 6H), 1.10 (m, 1H), 0.90 (m, 6H). MS, m/z (relative intensity): 261 [M+2H, 100%], 301 [M−H+CH3CN, 82%], 260 [M+H, 72%].
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:13][CH2:12][C:5]2(C(=O)CCC2=O)[CH2:4][CH2:3]1.CC(C)=[O:17]>Cl>[F:1][C:2]1([F:14])[CH2:13][CH2:12][C:5](=[O:17])[CH2:4][CH2:3]1
Reactant: O=C1CCC(=O)C12CCC(F)(F)CC2
Reactant: CC(C)=O
Agent: Cl
Product: O=C1CCC(F)(F)CC1

Procedure:
The product of Step A, 8,8-difluoro-1,4-dioxospiro[4.5]decane was dissolved in acetone (90 ml) and 3N HCl (900 ml), and stirred until the reaction finished. Then, the reaction mixture was extracted with DCM, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The obtained residue was used in the next reaction without further purification.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl>>[C:1]1([CH:7]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH:18]3[CH2:19][O:20]3)=[CH:13][CH:14]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(c1ccccc1)c1ccc(O)cc1
Reactant: ClCC1CO1
Product: CC(c1ccccc1)c1ccc(OCC2CO2)cc1

Procedure:
The title compound was prepared from 4-(1-phenyl-ethyl)-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C([Li])CCC.[I:22]I>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[O:10][C:9]([I:22])=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2occc2n1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Clc1nc(N2CCOCC2)c2oc(I)cc2n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To a solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine 38 (50 mg, 1.0 eq) dissolved in THF (2.1 ml) at −78° C. was added 1.6M solution of n-butyllithium (0.17 ml, 1.3 eq, 1.6M in hexanes). Reaction mixture was stirred at −78° C. for 30 minutes. A solution of iodine (159 mg, 3.0 eq) in THF (0.6 ml) was added and reaction mixture was allowed to slowly warm up to room temperature and stirred for 45 minutes. The reaction mixture was quenched with saturated aq. Na2S2O3, and extracted with dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated. The crude reaction mixture was purified by flash chromatography to yield 2-chloro-6-iodo-4-morpholinofuro[3,2-d]pyrimidine 45 (63 mg, 83%): MS (Q1) 366 (M)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30]>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:30])([F:31])[F:32])[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: FC(F)(F)c1ccccc1CBr
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3ccccc3C(F)(F)F)C2=O)cn1
Yield: 37 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 1-(bromomethyl)-2-(trifluoromethyl)benzene. Yield: 37%. MS M+H calculated 434.1; found 434.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.2 uM.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[CH2:12]([O:14][C:15]([C:17]1([NH2:26])[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1)=[O:16])[CH3:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:12]([O:14][C:15]([C:17]1([NH:26][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[C:3]=2[OH:11])[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1)=[O:16])[CH3:13]
Reactant: O=C(O)c1cccc(Cl)c1O
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc(Cl)c2O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
To a solution of 3-chloro-2-hydroxy-benzoic acid (413 mg, 2.4 mmol), 2-Amino-indan-2-carboxylic acid ethyl ester (500 mg, 2.4 mmol), HATU (1.1 g, 2.9 mmol) in anhydrous DMF (10 mL) is added DIPEA (0.88 ml, 5.3 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (50 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 10%-80% EtOAc in heptane) to give a pure product (14) as white solid (420 mg, 49%).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][C:14]1[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:15]=1[N+:22]([O-:24])=[O:23].[CH2:25]([NH2:35])[C:26]1[CH:34]=[CH:33][C:32]2[O:31][CH2:30][O:29][C:28]=2[CH:27]=1>>[O:31]1[C:32]2[CH:33]=[CH:34][C:26]([CH2:25][NH:35][C:19]([C:17]3[S:18][C:14]([CH3:13])=[C:15]([N+:22]([O-:24])=[O:23])[CH:16]=3)=[O:21])=[CH:27][C:28]=2[O:29][CH2:30]1
Reactant: Cc1sc(C(=O)O)cc1[N+](=O)[O-]
Reactant: NCc1ccc2c(c1)OCO2
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1sc(C(=O)NCc2ccc3c(c2)OCO3)cc1[N+](=O)[O-]
Yield: 97.6 %

Procedure:
The title compound was prepared according to the procedure described for Example 2 using carbonyldiimidazole (0.7 g, 4.3 mmol), 5-methyl-4-nitro-thiophene-2-carboxylic acid (0.6 g, 3.2 mmol), and piperonyl amine (0.5 g, 3.3 mmol). Acidification of the aqueous workup mixture with dilute hydrochloric acid prior to filtration afforded 1 g of 5-methyl-4-nitro-thiophene-2-carboxylic acid (1,3-benzodioxol-5-ylmethyl)-amide. A sample was dissolved in ethyl acetate and filtered through a short column of silica gel to give 5-methyl-4-nitro-thiophene-2-carboxylic acid (1,3-benzodioxol-5-ylmethyl)-amide; mp 181-183° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[CH3:21][O:22][C:23]1[CH:28]=[C:27]([C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: COc1cccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc12
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2nc(Nc3cc(C)[nH]n3)cc3c(OC)cccc23)c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-methoxy-phenylboronic acid to give [1-(3-methoxy-phenyl)-5-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 361(MH+).