Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[O:6]1[CH2:19][CH:7]1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1.C([O-])=O.[NH4+]>C1COCC1.[Pd]>[CH2:1]([NH:5][CH2:19][CH:7]([OH:6])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(OCC2CO2)cc1
Reactant: CC(C)CN
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)CNCC(O)COc1ccc(N)cc1
Yield: 100 %

Procedure:
Isobutylamine (5.1 ml, 51.2 mmol) was added to a solution of 4-(2,3-epoxypropoxy) nitrobenzene (obtained as described in Synthetic Communications, 1994, 24, 833; 1.0 g, 5.12 mmol) in THF (1 ml). The solution was heated under reflux for 3 hours and then volatile material was removed by evaporation. The residue was dissolved in methanol (5 ml) and 10% palladium on carbon (0.50 g) and ammonium formate (3.23 g, 51.2 mmol) were added. The mixture was heated under reflux for 3 hours and then filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to give the product as dark brown oil (1.22 g, 100%), which was used without further purification. MS (MH+): 238.9.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=O.[CH:20]1([C:23](=[O:28])[CH2:24][C:25](=O)[CH3:26])[CH2:22][CH2:21]1>C(O)(=O)C.S(=O)(=O)(O)O>[CH:20]1([C:23]([C:24]2[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[C:3]3[C:4]4[CH2:9][CH2:8][CH2:7][C:5]=4[S:6][C:2]3=[N:1][C:25]=2[CH3:26])=[O:28])[CH2:22][CH2:21]1
Reactant: COc1ccc(C(=O)c2c(N)sc3c2CCC3)cc1
Reactant: CC(=O)CC(=O)C1CC1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1ccc(-c2c(C(=O)C3CC3)c(C)nc3sc4c(c23)CCC4)cc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 21.3 %

Procedure:
To a stirred solution of 60 mg (0.22 mmol) (2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-(4-methoxy-phenyl)-methanone (the preparation of which is described in example 10) in 2 ml acetic acid was added 37 mg (0.29 mmol) of 1-cyclopropyl-butane-1,3-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 17 mg (22%) cyclopropyl-[4-(4-methoxy-phenyl)-2-methyl-6,7-dihydro-5H-cyclopenta[4,5]thieno [2,3-b]pyridin-3-yl)-methanone as a light brown solid. ES-MS m/e (%): 364 (M+H+, 100).
Reaction SMILES: [CH2:1]([C:5]1([N:33]([CH3:35])[CH3:34])[CH2:10][CH2:9][C:8]([C:22]2[N:23]([CH3:32])[C:24]3[C:29]([C:30]=2[CH3:31])=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:11]2[N:12]([CH3:21])[C:13]3[C:18]([C:19]=2[CH3:20])=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[Cl:36][Si](C)(C)C>C1CCCCC1>[ClH:36].[CH2:1]([C:5]1([N:33]([CH3:35])[CH3:34])[CH2:10][CH2:9][C:8]([C:22]2[N:23]([CH3:32])[C:24]3[C:29]([C:30]=2[CH3:31])=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:11]2[N:12]([CH3:21])[C:13]3[C:18]([C:19]=2[CH3:20])=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Si](C)(C)Cl
Agent: CCCCC1(N(C)C)CCC(c2c(C)c3ccccc3n2C)(c2c(C)c3ccccc3n2C)CC1
Solvent: C1CCCCC1
Product: Cl
Temperature: 24 °C
Reaction time: 0.5 h

Procedure:
1-butyl-4,4-bis-(1,3-dimethyl-1H-indol-2-yl)-N,N-dimethylcyclohexylamine (39 mg, 0.083 mmol) was dissolved in cyclohexane (10 ml). The solution was mixed with chlorotrimethyl silane (20 μl, 0.156 mmol) at 24° C. The clear reaction mixture immediately became cloudy. The mixture was stirred for 30 min at 24° C. The white precipitate was aspirated. The solid was washed with cyclohexane (3×0.5 ml) and then dried. The hydrochloride (40 mg, 95%, melting point 153-157° C.) was obtained as a white solid.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[F:22][C:23]([F:38])([F:37])[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([N:30]2[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]2)[CH:25]=1>CN(C=O)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:36][CH:33]2[CH2:34][CH2:35][N:30]([C:26]3[CH:25]=[C:24]([C:23]([F:38])([F:37])[F:22])[CH:29]=[CH:28][N:27]=3)[CH2:31][CH2:32]2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NC1CCN(c2cc(C(F)(F)F)ccn2)CC1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)N1C(=O)C(NC2CCN(c3cc(C(F)(F)F)ccn3)CC2)=C(c2ccccc2)S1(=O)=O
Temperature: 130 °C
Yield: 38 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.175 g, 0.58 mmol), 1-[4-(trifluoromethyl)pyridin-2-yl]piperidin-4-amine dihydrochloride (0.220 g, 0.69 mmol) and TEA (0.23 g, 2.31 mmol) was dissolved in dry DMF (3 ml) and heated in a microwave reactor at 130° C. for 30 mins. The reaction mixture was purified by preparative HPLC to yield the title compound (0.112 g, 38%). 1H NMR (500 MHz, CDCl3): δ 8.28-8.23 (m, 1H), 7.59-7.52 (m, 2H), 7.51-7.44 (m, 3H), 6.79-6.74 (m, 1H), 6.74-6.70 (m, 1H), 5.27-5.17 (m, 1H), 4.17-4.07 (m, 2H), 3.24-3.13 (m, 1H), 2.57-2.48 (m, 2H), 1.83-1.69 (m, 2H), 1.75 (s, 9H), 1.42-1.31 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 159.8, 149.3, 134.1, 131.9, 130.2, 129.0, 125.3, 108.5, 107.4, 102.9, 61.9, 50.5, 43.9, 32.0, 27.8; Mass Spectrum: M−H+ 509.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[C@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@@:5]1([CH3:29])[C:17]1[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[CH:18]=1.COC[C@H]1[C@H](C=O)[C@]1(C)C1C=C(C(C)C)C=C(C(C)C)C=1>>[CH3:1][O:2][CH2:3][C@H:4]1[C@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@@:5]1([CH3:29])[C:17]1[CH:18]=[C:19]([CH:26]([CH3:27])[CH3:28])[CH:20]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:22]=1
Reactant: CCOC(=O)/C=C(C)/C=C/[C@H]1[C@@H](COC)[C@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Agent: COC[C@H]1[C@H](C=O)[C@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Product: CCOC(=O)/C=C(C)/C=C/[C@H]1[C@H](COC)[C@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Yield: 85 %

Procedure:
Following a procedure similar to that for the preparation of Compound 24 but using Intermediate 47a as the starting material afforded the title compound (19 mg, 85% yield) as a white solid:
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:14][OH:15]>C1CCCCC1>[CH:1](=[N:14][OH:15])[CH:2]=[CH:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: NO
Reactant: CCCCCCC/C=C\CCC=O
Solvent: C1CCCCC1
Product: CCCCCCC/C=C\C=CC=NO
Reaction time: 8 h

Procedure:
In a 250 ml three-necked flask containing 20 g of (Z)-4-dodecenal in 50 ml of cyclohexane were added 8.4 ml of NH2OH (50% aqueous solution) over 30 minutes. The reaction was left overnight. The organic layer was decanted, washed with water and the solvent removed in vacuum to yield the oxime as a mixture 55/45 of 1-E and 1-Z.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([CH:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[CH3:24][O:25][C:26]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:27]=1[CH2:28]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:23])[CH:4]([CH:16]1[CH2:20][C:19](=[O:21])[N:18]([CH2:28][C:27]2[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:26]=2[O:25][CH3:24])[C:17]1=[O:22])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)C1CC(=O)NC1=O
Reactant: COc1ccc(CO)c(OC)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(NC(=O)OCc1ccccc1)C1CC(=O)N(Cc2ccc(OC)cc2OC)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 100 ml of tetrahydrofuran were dissolved 3.2 g of benzyloxycarbonyl-2-(2,5-dioxopyrrolidin-3-yl)glycine methyl ester, 1.8 g of 2,4-dimethoxybenzyl alcohol and 3.9 g of triphenylphosphine and under ice-cooling 2 ml of diethyl azodicarboxylate was added. The mixture was stirred at room temperature for one hour and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with 5% sodium hydrogen carbonate and 10% phosphoric acid in that order and dried over sodium sulfate. The solution was concentrated under reduced pressure and the concentrate was chromatographed on a silica gel column, elution being carried out with toluene-ethyl acetate (7:3). The eluate was concentrated under reduced pressure and to the residue was added petroleum ether. The precipitate was collected by filtration and dried. Yield 1.2 g.
Reaction SMILES: CS(C)=O.C(N(CC)CC)C.[Si:12]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[Cl-].[NH4+]>CCCCCC.ClCCl>[Si:12]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[O:25])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCO
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCCC=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
Under a nitrogen atmosphere and at 0° C., dimethylsulfoxide (7.81 ml, 110 mmol), triethylamine (9.60 ml, 69.0 mmol), and a sulfur trioxide-pyridine complex (4.39 g, 27.6 mmol) were added to a dichloromethane solution (80 ml) of 5-(t-butyldimethylsilyloxy)pentanol (3.00 g, 13.8 mmol). The resulting mixture was stirred at 0° C. for 30 minutes and then, at room temperature for further 3 hours. After cooling to 0° C., a saturated aquoeus ammonium chloride solution was added. Dichloromethane was distilled off under reduced pressure. To the residue was added ethyl acetate. After the water layer was separated, the organic layer was washed with water and brine, dried over magnesium sulfate and then, concentrated. The residue thus obtained was subjected to chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate=20:1 eluate was concentrated, whereby the title compound (2.42 g, 11.2 mmol, 81%) was obtained as a colorless oil.
Reaction SMILES: O[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].O[N:18]1C(=O)[CH2:21][CH2:20][C:19]1=O.C(N)C=C.[Al].C(#N)C>CN(C=O)C.O>[CH2:19]([NH:18][C:2](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)[CH:20]=[CH2:21]
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: O=C1CCC(=O)N1O
Agent: [Al]
Solvent: O
Solvent: C=CCN
Solvent: CN(C)C=O
Product: C=CCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 25 °C

Procedure:
In an argon-purged 100 ml flask, biotin-N-hydroxy-succinimide (251 mg, 0.735 mmol; Compound 1, Sigma-Aldrich) was dissolved in 26.7 ml dry DMF and mixed with allylamine (50 μl, 0.668 mmol; Nacalai Tesque, Inc., Japan), followed by stirring at room temperature with the flask covered with aluminum foil for light shielding. The progress of the reaction was monitored by C18 reversed-phase HPLC (HPLC conditions; column: μ-Bondsphere φ19×150 mm (Waters); mobile phase: 20% acetonitrile in H2O; elution speed: 10 ml/min; detection: UV absorption (200 nm)). At 3 hours after initiation of the reaction, it was confirmed that the source material biotin-N-hydroxysuccinimide was almost completely converted into Compound 2. This reaction solution was used directly in the subsequent reaction.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.Br[C:13]1[CH:14]=[CH:15][C:16]([O:33][CH2:34][CH3:35])=[C:17]([C:19]2[NH:20][C:21](=[O:32])[C:22]3[N:27]([CH3:28])[N:26]=[C:25]([CH2:29][CH2:30][CH3:31])[C:23]=3[N:24]=2)[CH:18]=1.O.O.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.[Na].[Na].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O.[Cl-].[Zn+2].[Cl-].CO>[CH2:34]([O:33][C:16]1[CH:15]=[CH:14][C:13]([C:8]2[N:7]([CH3:6])[CH:11]=[CH:10][N:9]=2)=[CH:18][C:17]=1[C:19]1[NH:20][C:21](=[O:32])[C:22]2[N:27]([CH3:28])[N:26]=[C:25]([CH2:29][CH2:30][CH3:31])[C:23]=2[N:24]=1)[CH3:35]
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(Br)ccc3OCC)nc12
Reactant: Cn1ccnc1
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(-c4nccn4C)ccc3OCC)nc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.1 %

Procedure:
n-Butyllithium (1.6M solution in hexane, 9.6 ml, 0.0153 mol) was added to a stirred solution of 1-methylimidazole (0.628 g, 0.0077 mol) in dry tetrahydrofuran (10 ml) at -78° C., and the resulting solution stirred for 0.25 hours. A solution of anhydrous zinc chloride (2.08 g, 0.0153 mol) in dry tetrahydrofuran (15 ml) was added, the mixture allowed to warm to room temperature, then 5-(5-bromo-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (1.0 g, 0.0026 mol) and tetrakis(triphenylphospine)palladium(0) (0.036 g, 0.031 mmol) were added and the mixture heated under reflux for 18 hours. A further quantity of anhydrous zinc chloride (2.08 g, 0.0153 mol) was added and the resulting mixture heated under reflux for a further 60 hours, then cooled; methanol (2 ml) was added and the solvent removed by evaporation under vacuum. The residue was heated with a solution of disodium ethylenediaminetetraacetic acid dihydrate (23.0 g, 0.0618 mol) in water (100 ml) to 100° C. for 0.2 hour, then the resulting solution basified to pH 8 with saturated aqueous sodium carbonate solution and extracted with dichloromethane (6×100 ml). The organic extracts were combined, dried (Na2SO4) and evaporated under vacuum to give a yellow solid, purification of which by chromatography on silica gel (13 g), using a methanol-dichloromethane elution gradient (0-3% methanol), followed by crystallisation from ethyl acetate, gave the title compound as an off-white solid (0.542 g, 53%), m.p. 199°-202° C. Found: C,64.45; H,6.27; N,21.56. C21H24N6O2 requires C,64.27; H,6.16; N,21.42%.
Reaction SMILES: Br[CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].CN(C)CCN(C)C.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([Mg]Br)=[CH:29][CH:28]=1>C1COCC1>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:29][CH:28]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: CCCCCCCCCC(Br)CCCCC
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: CCCCCCCCCC(CCCCC)c1ccc(OC)cc1

Procedure:
The title compound (34.8 g) was prepared from 6-bromo-pentadecane (Example 12, 34 g), N,N,N′,N′-tetramethyletane-1,2-diamine (14.92 g), THF (35 ml) and (4-methoxyphenyl)magnesium bromide (0.5M in THF, 226.5 ml) using the procedure of Example 7.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[C:16]([F:17])=[CH:15][C:14]([NH:18][C:19]([C:21]3([C:24]([OH:26])=O)[CH2:23][CH2:22]3)=[O:20])=[C:13]([F:27])[CH:12]=2)[CH:7]=[CH:6][N:5]=1)(=[O:3])[NH2:2].[F:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>O1CCCC1>[NH2:2][C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[C:16]([F:17])=[CH:15][C:14]([NH:18][C:19]([C:21]3([C:24]([NH:33][C:32]4[CH:34]=[CH:35][C:29]([F:28])=[CH:30][CH:31]=4)=[O:26])[CH2:23][CH2:22]3)=[O:20])=[C:13]([F:27])[CH:12]=2)[CH:7]=[CH:6][N:5]=1)=[O:3]
Reactant: NC(=O)c1cc(Oc2cc(F)c(NC(=O)C3(C(=O)O)CC3)cc2F)ccn1
Reactant: Nc1ccc(F)cc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a suspension of 1-[4-(2-carbamoylpyridin-4-yl)oxy-2,5-difluorophenylaminocarbonyl]cyclopropanecarboxylic acid (100 mg) and 4-fluoroaniline (0.051 ml) in tetrahydrofuran (4 ml) was added 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (157 mg), followed by stirring at room temperature 23 hr. The reaction mixture was partitioned between ethyl acetate and an aqueous solution of sodium hydrogencarbonate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:2, ethyl acetate, then ethyl acetate:methanol=10:1), and fractions containing the target compound were concentrated under reduced pressure. The residue was dried under reduced pressure to provide the titled compound as a white solid (133.5 mg, quant.).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].C(N(CC)CC)C.Br[CH2:16][C:17]#[CH:18]>C1C=CC=CC=1>[CH2:18]([NH:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])[C:17]#[CH:16]
Reactant: COC(CN)OC
Reactant: C#CCBr
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C#CCNCC(OC)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(2,2-Dimethoxyethyl)amine (23 grams), triethylamine (31 ml) and benzene (100 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. 1-Bromo-2-propyne (16.5 grams) was added dropwise with stirring to the reaction mixture at room temperature. After the addition was completed stirring was continued for a period of about 1 hour. After this time the reaction mixture was filtered and stripped of solvent. The residue was then distilled to yield the desired product N-propargyl-N-(2,2-dimethoxyethyl)amine having a boiling point of 70° C. at 1 mm of Hg pressure.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[Cl-].[K+].Cl.C[CH2:17][O:18]CC>[C-]#N.[Zn+2].[C-]#N>[OH:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:17]=[O:18]
Reactant: Oc1cc2ccccc2cc1O
Reactant: CCOCC
Agent: Cl
Agent: [C-]#N
Agent: [Cl-]
Product: O=Cc1c(O)c(O)cc2ccccc12
Yield: 85.7 %

Procedure:
120 g of 2,3-dihydroxynaphthalene, 132 g of ZN(CN)2 (zinc cyanide) and 1.32 g of potassium chloride in 1200 ml of absolute ether were placed in a 2.5 l sulfonation flask equipped with inlet-tube, stirrer, thermometer, reflux condenser and calcium chloride tube. Hydrogen chloride gas was introduced for 6 hours while cooling with ice and stirring. Subsequently, the ether was decanted and destroyed with sodium hydroxide. In order to remove the residual ether, the oily residue was evacuated hot, then treated with 800 ml of water and stirred at 60° C. on a steam-bath. The cooled mixture was filtered under suction and the material on the suction filter was dried at 40 ° C. in vacuo. The crude product was dissolved in acetonitrile while warming, filtered and, after concentration in vacuo, crystallized. There were obtained 121.3 g (85.7% of theory) of 2,3-dihydroxy-naphthaldehyde of melting point 132°-133° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]([C:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14])[CH2:5][C:6](=O)[NH:7]2.[N+:20]([CH2:22][C:23]1[N:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[O:25][N:24]=1)#[C-:21]>>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]([C:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14])[CH2:5][C:6]1[N:7]2[CH:21]=[N:20][C:22]=1[C:23]1[N:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[O:25][N:24]=1
Reactant: [C-]#[N+]Cc1noc(C(C)C)n1
Reactant: O=C1CN(C(=O)N2CCCC2)c2c(F)cccc2N1
Product: CC(C)c1nc(-c2ncn3c2CN(C(=O)N2CCCC2)c2c(F)cccc2-3)no1

Procedure:
Following the general procedure of EXAMPLE 30 and making non-critical variations but using 5-fluoro-1,2,3,4-tetrahydro-4-[(pyrrolidino)carbonyl]quinoxalin-2-one (XXXII, EXAMPLE 29, 0.978 g) and 3-isocyanomethyl-5-isopropyl-1,2,4-oxadiazole (0.673 g) are converted to the title compound, mp 169°-170°; MS (m/z) at 396; IR (mineral oil) 1657, 1495, 1216, 1614 and 785 cm-1 ; NMR (CDCl3) 1.47, 1.86, 3.30, 3.34, 5.13, 7.08, 7.22, 7.38 and 8.12 δ.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:18]([OH:20])=[O:19])[CH2:12][C:13]1[N:17]=[CH:16][NH:15][CH:14]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6].C([O-])(O)=O.[Na+].[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>O.O1CCOCC1>[NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:18]([OH:20])=[O:19])[CH2:12][C:13]1[N:17]=[CH:16][N:15]([S:33]([C:30]2[CH:31]=[CH:32][C:27]([CH3:26])=[CH:28][CH:29]=2)(=[O:35])=[O:34])[CH:14]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:6])[OH:7]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N[C@@H](CCC(=O)O)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cnc(C[C@H](NC(=O)[C@@H](N)CCC(=O)O)C(=O)O)c2)cc1
Temperature: 25 °C

Procedure:
3 g (10 mmols) of Glu-His-OH and 2.3 g of NaHCO3 are dissolved in 20 ml of water and, while stirring at room temperature, a solution of 2.1 g (10% excess) of p-toluene sulfochloride in about 10 ml of dioxane is slowly added drop by drop. When the addition is terminated, stirring of the mixture is continued for a further hour, whereupon it is extracted twice with ether. The aqueous phase is acidified to pH 2 with 2 N HCl and the precipitate is filtered off with suction. It is washed with water and the filer residue is dried over P2O5 under reduced pressure. Yield 2.2 g.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:28]([C:29]3[N:33](COCC[Si](C)(C)C)[N:32]=[CH:31][CH:30]=3)=[CH:27][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)=[O:12])=[CH:9][N:8]=2)[CH2:3]1.C=C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>>[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:28]([C:29]3[NH:33][N:32]=[CH:31][CH:30]=3)=[CH:27][C:10]([C:11]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:26])([F:25])[C:21]([F:22])([F:23])[F:24])=[CH:18][CH:19]=3)=[O:12])=[CH:9][N:8]=2)[CH2:3]1
Reactant: C[Si](C)(C)CCOCn1nccc1-c1cc(C(=O)Nc2ccc(C(F)(F)C(F)(F)F)cc2)cnc1N1CC[C@@H](O)C1
Agent: C=C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(F)(F)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccn[nH]2)c1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A mixture of (R)-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(perfluoroethyl)phenyl)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)nicotinamide (Stage 16.1, 68 mg, 0.114 mmol) and ethylene damien (38.4 μL, 0.569 mmol) in a MW vial and sealed under an argon atmosphere 1 M TBAF in THF (1.707 mL, 1.707 mmol) was added and the RM was stirred at 80° C. for 20 h. The solvent was evaporated off under reduced pressure and the residue was dissolved in EtOAc (40 mL), washed 3 times with sat. aq. NaHCO3 and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column Diol, isocratic 27% in 9 min) to afford the title compound as an off-white solid. UPLC-MS (Condition 3) tR=0.98 min, m/z=468.2 [M+H]+, m/z=466.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.78 (m, 1H) 1.83 (dd, J=8.80, 4.40 Hz, 1H) 2.96 (d, J=11.74 Hz, 1H) 3.19-3.29 (m, 2H) 3.40-3.50 (m, 1H) 4.20 (br. s, 1H) 4.83 (br. s, 1H) 6.39 (d, J=1.96 Hz, 1H) 7.65 (d, J=8.80 Hz, 2H) 7.77 (br. s, 1H) 8.02 (d, J=9.05 Hz, 2H) 8.05 (d, J=2.45 Hz, 1H) 8.76 (d, J=2.20 Hz, 1H) 10.33 (s, 1H) 12.91 (br. s, 1H).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C>C1COCC1>[N+:11]([C:5]1[CH:4]=[CH:3][C:2]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8])([O-:13])=[O:12]
Reactant: NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: C1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Yield: 93.4 %

Procedure:
To 5-Fluoro-2-nitro-benzamide (850 mg, 4.07 mmol) in THF (100 mL), was added piperdine (381 mg, 4.47 mmol) and diisopropyl ethyl amine (780 mL, 4.07 mmol) and the solution was heated to 70 C in a sealed tube for 12 h. The resulting yellow precipitate was collected to give 2-Nitro-5-piperidin-1-yl-benzamide 948 mg (100% yield) HPLC tr=3.58 min (100%), FIA m/e 250.2(M+H) 248.8 (M−H); 1HNMR (500 MHz, dmso): δ 7.95 (1H, d), 7.85 91H, bs), 7.50 (1H, bs), 6.97 (1H, d), 6.80 (1H, s), 3.50 (4H, m), 1.70–1.50 (6H, m).