Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH3:19])[C:6]([CH:8]=[CH:9][C:10](O)=[O:11])=O.C(=O)([O-])[O-].[K+].[K+].Cl.O.[NH2:28][NH2:29]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[CH:8]=[CH:9][C:10](=[O:11])[NH:28][N:29]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCOc1ccc(C(=O)C=CC(=O)O)cc1OC
Reactant: NN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCCOc1ccc(-c2ccc(=O)[nH]n2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.6 g of 3-(3-methoxy-4-n-propoxybenzoyl)acrylic acid and 6.1 g of potassium carbonate are dissolved in 100 ml of methanol and the solution is stirred overnight at room temperature. It is acidified with 7.4 ml of concentrated hydrochloric acid, 2.2 g of 100% pure hydrazine hydrate are added to the mixture and the mixture is boiled under reflux for 3 hours. It is then acidified to pH 1 with 1 ml of hydrochloric acid and 75 ml of methanol are distilled off in the course of 2 hours. The mixture is allowed to cool and the crystal mass is filtered off with suction, suspended several times in 50 ml of water each time, filtered off with suction and, finally, dried in vacuo. 6.6 g (63.7% of theory) of the title compound of m.p. 169°-171° are obtained. After recrystallization from ethanol/ethyl acetate, the m.p. rises to 172°.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[CH3:19][Mg]Br.[Cl-].[NH4+].O>O1CCCC1>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]([OH:16])[CH3:19])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: C[Mg]Br
Reactant: O=Cc1ccc(-c2cn3cc(I)ccc3n2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1ccc(-c2cn3cc(I)ccc3n2)cc1
Reaction time: 5 h

Procedure:
4-(6-Iodoimidazo[1,2-a]pyridin-2-yl)benzaldehyde (820 mg) was dissolved in tetrahydrofuran (25 mL), and the solution was stirred under ice cooling. Methyl magnesium bromide (787 mL) was added dropwise to the reaction mixture, followed by stirring for 15 minutes under ice cooling and then for 5 hours at room temperature. Aqueous saturated ammonium chloride solution (25 mL) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with dichloromethane-methanol. Subsequently, the solvent was evaporated, and the residue was purified through silica gel column chromatography (dichloromethane:methanol=97:3), followed by concentration under reduced pressure, to thereby yield the title compound (579 mg).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH3:23][NH:24][O:25][CH3:26].C(N(CC)CC)C>>[CH3:26][O:25][N:24]([CH3:23])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([S:2][CH3:1])[CH:4]=1
Reactant: CNOC
Reactant: CSc1cccc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cccc(SC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a stirred solution of 3-(methylthio)benzoic acid (15.4 g, 91.5 mmol), cooled to 0° C. with a brine/ice bath, was added N,N-dimethylformamide (0.35 mL, 4.6 mmol) followed by oxalyl chloride (8.79 mL, 100 mmol). The resulting mixture was stirred 2 h at room temperature, until gas evolution stopped and a clear solution was obtained. The mixture was cooled to 0° C. with a brine/ice bath, N,O-Dimethylhydroxylamine (10.7 g, 110 mmol) was added at once, followed by dropwise addition of triethylamine (43.4 mL, 311 mmol) through a dropping funnel, while keeping the internal temperature under 20° C. The resulting suspension was stirred overnight at room temperature, filtered over a pad of silica gel, and concentrated in vacuo to afford N-methoxy-N-methyl-3-(methylsulfanyl)benzamide as an oil [19.9 g, yield 83%; HPLC/MS: m/z=212 (M+H); logP(HCOOH)=1.89].
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.[Cl:12]N1C(=O)CCC1=O>CN(C)C=O>[Cl:12][C:11]1[C:2]([OH:1])=[CH:3][C:4]2[O:9][CH2:8][CH2:7][O:6][C:5]=2[CH:10]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Oc1ccc2c(c1)OCCO2
Solvent: CN(C)C=O
Product: Oc1cc2c(cc1Cl)OCCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.9 %

Procedure:
To a solution of 6-hydroxy-1,4-benzodioxane (1.52 g, 10 mmol) in N,N-dimethylformamide (10 mL) was added N-chlorosuccinimide (1.33 g, 10 mmol) at ambient temperature. The solution was stirred at ambient temperature for 16 h and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 15% to 30% gradient of ethyl acetate in hexanes to afford 7-chloro-2,3-dihydrobenzo[b][1,4]dioxin-6-ol (1.79 g, 96%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.02 (s, 1H), 6.83 (s, 1H), 6.56 (s, 1H), 4.27-4.16 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([OH:17])=[CH:7][CH:8]=2)[N:3]=1.[CH2:18](Br)[CH:19]1[O:23][CH2:22][CH2:21][CH2:20]1>>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:17][CH2:18][CH:19]3[CH2:20][CH2:21][CH2:22][O:23]3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(N2CCCC2)c2ccc(O)cc2n1
Reactant: BrCC1CCCO1
Product: Cc1cc(N2CCCC2)c2ccc(OCC3CCCO3)cc2n1

Procedure:
In analogy to example 6 there was prepared: on reaction of 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with tetrahydro-furfuryl bromide, whereby the product was isolated as free base, (rac) 2-methyl-4-pyrrolidin-1-yl-7-(tetrahydro-furan-2-ylmethoxy)-quinoline as a yellow-brown waxy solid. ISP mass spectrum, m/e: 313.2 (M+1 calculated for C19H24N2O2: 313).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[S:16][C:15]2[C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[N:13][C:12]([CH3:23])=[N:11][C:10]=2[CH:9]=1)=[O:7].[NH:24]1[C:32]2[C:27](=C[CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1B(O)O>>[NH:24]1[C:32]2[C:27](=[C:23]([C:12]3[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:15]4[S:16][C:8]([C:6]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[O:7])=[CH:9][C:10]=4[N:11]=3)[CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25]1
Reactant: COCCNC(=O)c1cc2nc(C)nc(N3CCOCC3)c2s1
Reactant: OB(O)c1cc2ccccc2[nH]1
Product: COCCNC(=O)c1cc2nc(-c3cccc4[nH]ccc34)nc(N3CCOCC3)c2s1

Procedure:
2-Methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carboxylic acid (2-methoxyethyl)-amide was reacted with indole boronic acid in general procedure A. Purification on silica yielded 189. NMR: 400 MHz; CDCl3 3.44 (3H, s); 3.60 (2H, m); 3.70 (2H, m); 3.92 (4H, t, J=4.8 Hz); 4.15 (4H, t, J=4.8 Hz); 6.74 (1H, br t); 7.30 (1H, d, J=7.8 Hz); 7.35 (1H, m); 7.52 (1H, d, J=8.0 Hz); 7.57 (1H, s); 7.82 (1H, s); 8.20 (1H, d, J=7.4 Hz); 8.30 (1H, br s). MS: (ESI+) M+H (438)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:31]=[CH:30][C:17]4[O:18][CH2:19][C:20]5[C:27]([C:28]#[N:29])=[CH:26][CH:25]=[CH:24][C:21]=5[CH:22](O)[C:16]=4[CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1.[SH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36]>>[C:35]([CH2:34][CH2:33][S:32][CH:22]1[C:21]2[CH:24]=[CH:25][CH:26]=[C:27]([C:28]#[N:29])[C:20]=2[CH2:19][O:18][C:17]2[CH:30]=[CH:31][C:14]([O:13][CH2:12][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=3)=[CH:15][C:16]1=2)([OH:37])=[O:36]
Reactant: N#Cc1cccc2c1COc1ccc(OCc3ccc4ccc(Cl)cc4n3)cc1C2O
Reactant: O=C(O)CCS
Product: N#Cc1cccc2c1COc1ccc(OCc3ccc4ccc(Cl)cc4n3)cc1C2SCCC(=O)O

Procedure:
2-(7-Chloroquinolin-2-yl)methoxy-7-cyano-11-hydroxy-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][NH:6][C:7]1[CH:8]=[C:9]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14].[ClH:32]>ClCCl.C(OCC)C>[ClH:32].[Br:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][NH:6][C:7]1[CH:8]=[C:9]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(NCc3cccc(Br)c3)c2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(N2CCNCC2)cc1NCc1cccc(Br)c1
Reaction time: 4 h
Yield: 39 %

Procedure:
To a solution of t-butyl 4-(3-(3-bromobenzylamino)-4-nitrophenyl)piperazine-1-carboxylate (104 mg, 0.23 mmol) in dry dichloromethane (1.0 mL) was added a saturated solution of HCl in diethyl ether (15 mL). The reaction mixture was stirred for 4 hours. The solvent was evaporated and the precipitate was recrystallized from methanol (0.3 mL), dichloromethane (0.5 mL) and diethyl ether (5 mL). The product was collected by filtration and dried in vacuo to afford the title compound (35.0 mg, 39% yield after recrystallization). 1H NMR (400 MHz, CD3OD): δ 8.07 (d, 1H), 7.42 (s, 1H), 7.33 (m, 2H), 7.28 (m, 1H), 6.40 (d, 1H), 6.03 (s, 1H), 4.61 (s, 1H), 3.56 (m, 4H), 3.27 (m, 4H); MS (ESI) m/z: Calculated for C17H20ClN4O2: 347.13; Observed: 347.5 (M++1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.[C:11](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCCl>[C:11]([N:6]1[CH2:7][CH2:8][CH2:9][CH:5]1[C:4]([O:3][CH3:2])=[O:10])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)C1CCCN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
A solution of 3.00 g (18.1 mmol) of L-proline methyl ester hydrochloride, 5.05 g (18.1 mmol) of trityl chloride and 10 mL of triethylamine in 40 mL of 1,2-dichloroethane is stirred at 22° C. After a few minutes, a thick precipitate began to form. An additional 20 mL of 1,2-dichloroethane is added and the mixture is heated to 60° C. and stirred for 3 hrs. The reaction mixture is partitioned between water (100 mL) and CH2Cl2 (100 mL). The organic layer is washed with satd. NaHCO3 (50 mL), dried (MgSO4) and evaporated. The residue is recrystallized from hexane/EtOAc to give 5.76 g of 1-trityl-pyrrolidine-2-carboxylic acid, methyl ester as a white crystalline solid which is used directly in the next step.
Reaction SMILES: [CH:1]12[N:8]([C:9]3[N:14]=[C:13]([C:15]4[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=4)[N:12]=[C:11]4[N:22]([CH2:25][C:26]([F:29])([F:28])[F:27])[N:23]=[CH:24][C:10]=34)[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C1(N)CC1.[N:46]([C:49]1[CH:54]=[CH:53]C(C2N=C3N(CC(F)(F)F)N=CC3=C(N3C4CCC3COC4)N=2)=CC=1)=[C:47]=[O:48]>ClCCl.C(N(CC)CC)C>[CH:49]1([NH:46][C:47]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([C:13]3[N:12]=[C:11]4[N:22]([CH2:25][C:26]([F:28])([F:27])[F:29])[N:23]=[CH:24][C:10]4=[C:9]([N:8]4[CH:5]5[CH2:6][CH2:7][CH:1]4[CH2:2][O:3][CH2:4]5)[N:14]=3)=[CH:16][CH:17]=2)=[O:48])[CH2:54][CH2:53]1
Reactant: Nc1ccc(-c2nc(N3C4CCC3COC4)c3cnn(CC(F)(F)F)c3n2)cc1
Reactant: O=C=Nc1ccc(-c2nc(N3C4CCC3COC4)c3cnn(CC(F)(F)F)c3n2)cc1
Agent: NC1CC1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(-c2nc(N3C4CCC3COC4)c3cnn(CC(F)(F)F)c3n2)cc1)NC1CC1
Reaction time: 8 h
Yield: 41 %

Procedure:
A solution of 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline (30 mg, 0.074 mmol) in dichloromethane (1 mL) was treated with triethylamine (0.05 mL), followed by a solution of triphosgene (11 mg, 0.037 mmol) in dichloromethane (1 mL). After the passage of 5 minutes, the appropriate nucleophile—in the case, cyclopropylamine (17 mg, 0.30 mmol)—was added to the 8-(6-(4-isocyanatophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane (“isocyanate”) mixture. After being left overnight at room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Gemini 21 mm×100 mm column, running a gradient elution of 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 60% or 75% acetonitrile over 30 minutes to provide 1-cyclopropyl-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}urea (15 mg, 41%). MS (ES+): 488.2 (M+H)+
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]2[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=1.[F:39][CH:40]([F:55])[N:41]1[CH:45]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH:43]=[N:42]1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:39][CH:40]([F:55])[N:41]1[CH:45]=[C:44]([C:2]2[C:7]3[C:8](=[O:22])[N:9]([CH2:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=4[O:20][CH3:21])[CH2:10][C:6]=3[C:5]([F:23])=[C:4]([NH:24][C@@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]3[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=2)[CH:43]=[N:42]1
Reactant: CC1(C)OB(c2cnn(C(F)F)c2)OC1(C)C
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(-c4cnn(C(F)F)c4)c3C2=O)c(OC)c1
Yield: 89.2 %

Procedure:
A solution of tert-butyl (1S,2R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (35 mg, 0.064 mmol), 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (18.67 mg, 0.076 mmol) and bis(triphenylphosphine)palladium chloride (44.7 mg, 0.064 mmol) in dioxane (500 μL) and saturated aq Na2CO3 (500 μL) was heated at 85° C. for 2 h. After filtering out the solids, the solvent was removed and the residue was dissolved in MeOH and DCM and purified by preparative HPLC. The fractions were collected and ACN was removed via rotary evaporation. The resulting aq solution was neutralized with saturated aq NaHCO3, washed with EtOAc (2×200 mL), dried over Na2SO4, and filtered. The organic phase was stripped to dryness via rotary evaporation to yield the title compound (36 mg, 90%). [M+H] calc'd for C31H37F3N6O5, 631. found, 631.
Reaction SMILES: [N:1]([C@@H:4]([C@H:8]([C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=1)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=1)[C:5](O)=[O:6])=[N+]=[N-].[NH2:25][C:26]1[CH:56]=[CH:55][CH:54]=[C:53]([F:57])[C:27]=1[CH2:28][CH2:29][C@H:30]1[O:35][CH2:34][C@@H:33]([CH2:36][O:37][C:38](=[O:45])[NH:39][CH2:40][C:41]([F:44])([F:43])[F:42])[N:32](C(OC(C)(C)C)=O)[CH2:31]1>>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=2)[C@@H:4]([C:5]([NH:25][C:26]2[CH:56]=[CH:55][CH:54]=[C:53]([F:57])[C:27]=2[CH2:28][CH2:29][C@H:30]2[O:35][CH2:34][C@@H:33]([CH2:36][O:37][C:38](=[O:45])[NH:39][CH2:40][C:41]([F:44])([F:43])[F:42])[NH:32][CH2:31]2)=[O:6])[NH2:1])=[CH:18][CH:19]=1)#[N:24]
Reactant: N#Cc1ccc([C@H](c2ccc(F)c(F)c2)[C@H](N=[N+]=[N-])C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Product: N#Cc1ccc([C@H](c2ccc(F)c(F)c2)[C@H](N)C(=O)Nc2cccc(F)c2CC[C@@H]2CN[C@H](COC(=O)NCC(F)(F)F)CO2)cc1

Procedure:
The title compound was prepared from the product of step 1 and the product of step 4 of Example 99 using the procedures given in steps 2-4 of Example 93. MS (ES) m/z=664 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:4][CH2:3]1.[CH3:17]I>C(O)(C)(C)C>[CH3:16][C:2]1([CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:17])([C:12](=[O:15])[CH2:13][CH3:14])[CH2:4][CH2:3]1
Reactant: CCC(=O)C1CCC(C)(C)c2ccccc21
Reactant: CI
Solvent: CC(C)(C)O
Product: CCC(=O)C1(C)CCC(C)(C)c2ccccc21
Temperature: 5 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
5.6 g of potassium tert.butylate are placed in 42.5 ml of tert.butanol and 10.8 g of 1,1-dimethyl-4-propionyl-tetralin are added dropwise thereto. The mixture is stirred for 1 hour, cooled to 5° C. and 8.5 g of methyl iodide are added. The mixture is stirred for a further 3 hours, a further 4.2 g of methyl iodide are added, the cooling source is removed and the mixture is stirred for a further 15 hours. The bulk of the tert.butanol is then removed by evaporation, the residue is taken up in ether, washed neutral with water, dried over sodium sulphate, evaporated and distilled. There are obtained 6 g of 1,1,4-trimethyl-4-propionyl-tetralin of boiling point 79° C./0.05 mmHg; nD20 =1.5249; yield 52%. Odour: fruity, woody.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[C:5]2[N:6]=[CH:7][CH:8]=[C:9]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[N:4]2[N:3]=1.[Cl:17]N1C2C=CC=CC=2N=N1>>[Cl:17][C:16]1[C:2]([CH3:1])=[N:3][N:4]2[C:9]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][CH:7]=[N:6][C:5]=12
Reactant: Cln1nnc2ccccc21
Reactant: Cc1cc2nccc(-c3cccnc3)n2n1
Product: Cc1nn2c(-c3cccnc3)ccnc2c1Cl

Procedure:
As for Example 34, 2-methyl-7-(3-pyridyl)pyrazolo[1,5-a]pyrimidine is reacted with N-chlorobenzotriazole to give the product of the example.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8](C(O)=O)=[N:9][CH:10]=1.C1(P([N:28]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>C(O)(C)(C)C>[NH2:28][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][CH3:1])=[CH:10][N:9]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCCCc1ccc(C(=O)O)nc1
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: CCCCc1ccc(N)nc1

Procedure:
Fusaric acid (2 g), diphenylphosphoryl azide (2.4 mL) and triethylamine (1.6 mL) in t-butanol (70 mL) were refluxed overnight. The contents were concentrated in vacuo and treated with 25% aqueous HBr (20 mL) for 24 hours. After neutralizing with 50% NaOH, contents were extracted with CH2Cl2, dried (MgSO4) and concentrated in vacuo to give 2-amino-5-(n-butyl)pyridine as an oil (1.1 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[OH:12][C:13]1[C:18]([CH2:19][CH2:20][CH3:21])=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=1[C:23](=[O:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[OH:12][C:13]1[C:18]([CH2:19][CH2:20][CH3:21])=[C:17]([O:22][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=2)[CH:16]=[CH:15][C:14]=1[C:23](=[O:25])[CH3:24]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(OCc2cccc([N+](=O)[O-])c2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add 3-bromomethyl nitrobenzene (10.00 g, 46.3 mmol) to a solution of 1-(2,4-dihydroxy-3-propyl-phenyl)-ethanone (8.99 g, 46.3 mmol) in dimethylformamide (60 mL). After 10 minutes add potassium carbonate (9.60 g, 69.4 mmol) and cesium carbonate (15.08 g, 46.3 mmol). Stir at room temperature for one hour, then heat to 70° C. for 1.5 hours. Cool and add water (250 mL). Triturate for 15 minutes. Filter. Wash the solid with water several times, and then wash with hexanes. Dry to afford the title compound as an off white/light gray powder (12.9 g, 85%): 1H NMR (DMSO-d6) δ 0.91 (t, 3H), 1.52 (m, 2H), 2.58 (s, 3H), 2.63 (m, 2H), 5.42 (s, 2H), 6.72 (d, 1H), 7.73 (t, 1H), 7.83 (d, 1H), 7.90 (d, 1H), 8.21 (d, 1H), 8.34 (s, 1H), 12.88 (bs, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C@H:10]([C:25](O)=[O:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[F:68][C:69]1[CH:81]=[CH:80][C:72]([CH2:73][C@@H:74]2[CH2:79][CH2:78][CH2:77][NH:76][CH2:75]2)=[CH:71][CH:70]=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C@H:10]([C:25]([N:76]2[CH2:77][CH2:78][CH2:79][C@@H:74]([CH2:73][C:72]3[CH:71]=[CH:70][C:69]([F:68])=[CH:81][CH:80]=3)[CH2:75]2)=[O:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(C[C@@H]2CCCNC2)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@H](C(=O)O)C1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@H](C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)C1
Reaction time: 0.08 h
Yield: 83.2 %

Procedure:
In a flask (3R,4R)-4-benzyloxycarbonylamino-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (3.93 g, 10.4 mmol) was dissolved in dichloromethane (200 mL) and then benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate (6.48 g, 12.5 mmol) and triethylamine (3.3 mL, 23.7 mmol) were added. After stirring for 5 minutes, (S)-3-(4-fluorobenzyl)-piperidine (2.21 g, 11.4 mmol) was added. The mixture was stirred for 16 hours. The reaction mixture was extracted with water (50 mL) and brine (50 mL). The organic layer was dried with magnesium sulfate, filtered, and concentrated in vacuo to give a crude orange glass (10.49 g). Purification by flash column chromatography (50-70% ethyl acetate/hexanes) provided a colorless oil (4.79 g, 83%). 1H NMR (300 MHz, CDCl3), δ: 7.32 (m, 2H), 7.26 (m, 3H), 7.07 (m, 2H), 6.95 (m, 2H), 5.04 (m, 2H), 4.41 (d, 1H, J=13), 4.12 (bm, 2H), 3.83 (bm, 2H), 3.06 (bm, 1H), 2.76 (bs, 2H), 2.60 (dd, 2H, J=14, J′=6), 2.37 (m, 2H), 1.90 (bs, 1H), 1.63 (bm, 2H), 1.45 (m, 9H), 1.12 (m, 3H), 0.87 (m, 1H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([N:27]([CH2:31][CH3:32])[C:28](Cl)=[O:29])[CH3:26]>>[CH2:25]([N:27]([CH2:31][CH3:32])[C:28]([N:10]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[C:9]1[S:18][C:19]([F:23])([F:24])[CH:20]([F:22])[F:21])=[O:29])[CH3:26]
Reactant: FC(F)C(F)(F)Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: CCN(CC)C(=O)Cl
Product: CCN(CC)C(=O)n1c(SC(F)(F)C(F)F)nc(-c2ccccc2)c1-c1ccccc1
Yield: 55.4 %

Procedure:
A mixture of 2.0 g (0.006 mole) of 4,5-diphenyl-2-(1,1,2,2-tetrafluoroethylthio)imidazole and 10.0 g (0.074 mole) of diethylcarbamoyl chloride was heated at reflux for two hours. Excess diethylcarbamoyl chloride was removed under high vacuum. The residue was chromatographed on silica gel, eluting with toluene, to give 1.5 g of product, mp 108°-9° (from methylcyclohexane).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[N:28]1([CH2:34][C:35]([N:37]([CH3:45])[C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)=[O:36])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[N:28]1([CH2:34][C:35]([N:37]([C:38]2[CH:43]=[CH:42][C:41]([NH:44]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:40][CH:39]=2)[CH3:45])=[O:36])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: CN(C(=O)CN1CCOCC1)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(C)C(=O)CN2CCOCC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-(morpholinyl-methylcarbonyl)-N-methyl-p-phenylenediamine Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C30H30N4O5