Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])O[CH2:3][CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[NH2:24]>>[C:4]([CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH:24][C:15]1[CH:16]=[CH:17][C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=1)#[CH:3]
Reactant: Nc1ccc2ccccc2c1
Reactant: O=C([O-])OCC=Cc1ccccc1
Product: C#CC(Nc1ccc2ccccc2c1)c1ccccc1
Reaction time: 16 h
Yield: 89.3 %

Procedure:
The general procedure was followed with cinnamyl carbonate (0.188 g, 0.979 mmol) and 2-napthylamine (0.170 g, 1.18 mmol). The reaction was conducted at room temperature for 16 h. 1H NMR analysis of the crude reaction mixture indicated the ratio of regioisomers to be 99/1. The mixture was purified by flash column chromatography on silica gel (1.5% ethyl acetate in hexanes) to give the title compound (0.225 g, 89%). [α]DRT=(c, CHCl3). 1H NMR (400.13 MHz, CDCl3) δ 7.53 (d, J=8.0 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.31-7.11 (m, 6H), 7.06 (t, J=7.6 Hz, 1H), 6.76 (dd, J=9.0, 2.2 Hz, 1H), 6.64 (d, J=2.0 Hz, 1H), 5.95 (ddd, J=17.2, 10.4, 6.0 Hz, 1H), 5.20 (d, J=17.6 Hz, 1H), 5.13 (d, J=9.6 Hz, 1H), 4.94 (d, J=5.6 Hz, 1H), 4.06 (br s, 1H). 13C NMR (100.59 MHz, CDCl3) δ 144.65, 141.52, 138.63, 134.90, 128.74, 128.73, 127.53, 127.48, 127.45, 127.14, 126.18, 125.99, 122.04, 118.02, 116.16, 105.82, 60.18. Anal. Calcd for C19H17N: C, 87.99; H, 6.61; N, 5.40. Found: C, 88.16; H, 6.58; N, 5.41.
Reaction SMILES: [NH2:1]/[C:2](=[C:4](\[C:11]([O:13][CH2:14][CH3:15])=[O:12])/[CH:5]=[CH:6]/[C:7](OC)=[O:8])/[CH3:3]>CN(C=O)C>[CH3:3][C:2]1[NH:1][C:7](=[O:8])[CH:6]=[CH:5][C:4]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(/C=C/C(=O)OC)=C(/C)N
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(=O)[nH]c1C
Temperature: 165 °C
Reaction time: 14 h
Yield: 55.2 %

Procedure:
5-Ethyl 1-methyl (2E,4Z)-4-(1-aminoethylidene)pent-2-enedioate (10 g, 50 mmol) and DMF (30 mL) were mixed in one 100 mL flask, and the mixture was stirred at 165° C. for 14 hrs. The reaction mixture was cooled to room temperature, then filtered to give the crude product, which was washed with DMF and small amount of methanol to give 5 g (60% yield) of the pure product. LC-MS found: 182.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:14]2[N:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[C:7]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:6]=2[N:5]=[C:4]([CH3:24])[N:3]=1.[CH2:25]([CH2:32][CH2:33][NH2:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CS(C)=O.[Cl-].[NH4+]>[CH2:25]([CH2:32][CH2:33][NH:34][C:2]1[C:14]2[N:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[C:7]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:6]=2[N:5]=[C:4]([CH3:24])[N:3]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCCCc1ccccc1
Reactant: Cc1cc(C)c(-c2c3nc(C)nc(Cl)c3n3ccccc23)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(-c2c3nc(C)nc(NCCCc4ccccc4)c3n3ccccc23)c(C)c1
Temperature: 110 °C

Procedure:
A mixture of 4-Chloro-2-methyl-10-(2,4,6-trimethylphenyl)pyrimido-[4,5-b]indolizine (15 mg) and N-benzylethylamine (0.04 mL) in DMSO (0.4 mL) is heated to 110° C. for 2 hours. The mixture is allowed to cool, diluted with aqueous ammonium chloride, and extracted twice with 50% ethyl ether in hexane. The combined extracts are washed with saturated brine, dried (Na2SO4), filtered, and concentrated in vacuo. Chromatography (10% to 20% ethyl acetate in hexane) gives 22 mg of the title compound (compound 5, Table 1) as a yellow oil: 1H nmr (400 MHz, CDCl3) d 1.17 (t, 3 H), 2.00 (s, 6 H), 2.38 (s, 3 H), 2.70 (s, 3 H), 3.40 (q, 2 H), 4.72 (s, 2 H), 6.68 (t, 1 H) 7.00 (s, 2 H), 7.03 (d, 1 H), 7.13 (d, 1 H), 7.29 (d, 1 H), 7.35 (t, 2 H), 7.41 (d, 2 H), 8.61 (d, 1 H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]([CH3:17])=[CH2:16])=[C:8]([Cl:18])[CH:7]=1.[OH-].[Na+]>ClCCl>[Br:5][C:6]1[CH:11]=[C:10]2[C:9](=[C:8]([Cl:18])[CH:7]=1)[O:12][CH2:13][CH2:14][C:15]2([CH3:17])[CH3:16]
Reactant: C=C(C)CCOc1ccc(Br)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)CCOc2c(Cl)cc(Br)cc21
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a mixture of aluminum chloride (403 mg, 3.03 mmol) and dichloromethane (10.0 mL) cooled to −78° C. was added 4-bromo-2-chloro-1-[(3-methylbut-3-en-1-yl)oxy]benzene (758 mg, 2.75 mmol) in dichloromethane (6.00 mL) via a cannula to give a light yellow solution. The reaction mixture was allowed to warm to room temperature, stirred for 5 minutes, and then poured into an Erlenmeyer flask containing a cold 10% NaOH solution (75.0 mL). The mixture was extracted with hexane (40.0 mL, 3×) and the combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The crude mixture was purified by silica gel chromatography eluting with 0-5% EtOAc/hexanes to afford the desired product as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[S:12][CH:11]=[N:10][C:9]=2[CH2:13][OH:14])[C:4]([CH3:7])=[CH:5][CH:6]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:7][C:4]1[N:3]([C:8]2[S:12][CH:11]=[N:10][C:9]=2[CH:13]=[O:14])[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: Cc1ccc(C)n1-c1scnc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1ccc(C)n1-c1scnc1C=O
Yield: 20.1 %

Procedure:
To a solution of (5-(2,5-dimethyl-1H-pyrrol-1-yl)thiazol-4-yl)methanol (86 mg, 0.41 mmol) in methylene chloride was added manganese dioxide (359 mg, 4.13 mmol). The reaction was warmed up to reflux for 3 h. The crude mixture was purified with silica gel chromatography to give an oil of 5-(2,5-dimethyl-1H-pyrrol-1-yl)thiazole-4-carbaldehyde (17 mg). 1H NMR (400 MHz, CDCl3) δ 9.72 (s, 1H), 8.87 (s, 1H), 5.98 (s, 2H), 2.05 (s, 6H). MS m/z 207.2 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:3]1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][CH:17]=1.C1COCC1.[H-].[Na+].Br[CH2:38][C:39]([O:41][CH3:42])=[O:40]>O>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][N:7]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[C:2](=[O:1])[CH:3]1[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:21]=1)=[O:9])([CH3:13])([CH3:14])[CH3:12]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1Cc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CN1CCN(C(=O)OC(C)(C)C)C(Cc2ccc(OCc3ccccc3)cc2)C1=O
Reaction time: 8 h

Procedure:
To a solution of t-boc-(4-benzyloxybenzyl) piperazinone 3a (2.66 g, 6.72 ×10-3 mole) and dry THF (20 ml) under argon at room temperature is added portionwise NaH (0.30 g, 7.4 ×10-3 mole, 59% oil dispersion). After stirring 1/2hour at room temperature a solution of methyl α-bromoacetate (0.62 ml, 7.4 ×10-3 mole) is added via syringe. After stirring overnight the reaction mixture is poured into water which is subsequently extracted with Et2O (3 times). The combined ethereal extracts are washed with saturated aqueous NaCl before being dried over Na2SO4. Filtration of the drying agent and evaporation of the filtrate affords a viscous oil which after column chromatography (silica gel, 10% EtOAc/CHCl3)gives a clear, colorless oil. After standing in the refrigerator this oil crystallizes. The resulting solid is triturated with hexane and collected by filtration affording 4a as colorless matted needles: 2.3 g (74%), m.p. 84°-87° C.
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.[F:22][C:23]1[C:28]([O:29][CH3:30])=[CH:27][C:26]([O:31][CH3:32])=[CH:25][C:24]=1[C:33]1[N:38]=[CH:37][C:36]2[C:39]([I:48])=[N:40][N:41]([CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)[C:35]=2[CH:34]=1>C(#N)C>[F:22][C:23]1[C:28]([O:29][CH3:30])=[CH:27][C:26]([O:31][CH3:32])=[C:25]([F:21])[C:24]=1[C:33]1[N:38]=[CH:37][C:36]2[C:39]([I:48])=[N:40][N:41]([CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)[C:35]=2[CH:34]=1
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.2 %

Procedure:
1-(Chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (97 mg, 0.27 mmol) was added a stirring solution of 6-(2-fluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (88 mg, 0.18 mmol) in acetonitrile (5 mL). The mixture was stirred at r.t. for 1 h then concentrated. The solid was filtered out and the filtrate was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (30 mg). LCMS (M+H)+=502.0.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([C:24]([F:27])([F:26])[F:25])[O:13][CH:11]([OH:12])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[C:28]([O:12][CH:11]1[O:13][C@@H:14]([C:24]([F:27])([F:26])[F:25])[C@@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:10]1)(=[O:30])[CH3:29]
Reactant: OC1C[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H](C(F)(F)F)O1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC1C[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H](C(F)(F)F)O1

Procedure:
Step (9'): The 1-hydroxyl group of Compound 74 is then acetylated with acetic anhydride to produce 1-O-acetyl-3,4-di-O-benzyl-2,6-dideoxy-6,6,6-trifluoro-L-lyxo-hexopyranose [Compound 75] of the formula ##STR115##
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][CH2:14][C:15]([CH3:17])=[CH2:16])=[C:8]([Cl:18])[CH:7]=1.[OH-].[Na+]>ClCCl>[Br:5][C:6]1[CH:11]=[C:10]2[C:9](=[C:8]([Cl:18])[CH:7]=1)[S:12][CH2:13][CH2:14][C:15]2([CH3:17])[CH3:16]
Reactant: C=C(C)CCSc1ccc(Br)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)CCSc2c(Cl)cc(Br)cc21
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a mixture of aluminum chloride (0.58 g, 4.34 mmol) and dichloromethane (23.2 mL) cooled to −78° C. was added 4-bromo-2-chloro-1-[(3-methylbut-3-en-1-yl)sulfanyl]benzene (1.15 g, 3.94 mmol) in dichloromethane (6.00 mL) via a cannula to give a light yellow solution. The reaction mixture was allowed to warm to room temperature, stirred for 5 minutes, and then poured into an Erlenmeyer flask containing a cold 10% aqueous NaOH solution (75.0 mL). The mixture was extracted with dichloromethane (2×, 40.0 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was purified by silica gel chromatography eluting with 0-20% EtOAc/hexanes to afford the desired product as a pale-yellow oil.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[O:13][C:14]2[CH:20]=[C:19]([CH2:21][N:22]([CH3:24])[CH3:23])[CH:18]=[CH:17][C:15]=2[CH:16]=1)SC)#[N:2].[CH3:25][NH2:26]>C(O)C>[C:1]([NH:3][C:4]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[O:13][C:14]2[CH:20]=[C:19]([CH2:21][N:22]([CH3:24])[CH3:23])[CH:18]=[CH:17][C:15]=2[CH:16]=1)=[N:26][CH3:25])#[N:2]
Reactant: CN
Reactant: CSC(=NCCSCc1cc2ccc(CN(C)C)cc2o1)NC#N
Solvent: CCO
Product: CN=C(NC#N)NCCSCc1cc2ccc(CN(C)C)cc2o1
Reaction time: 3 h
Yield: 84 %

Procedure:
A solution of N-cyano-N'-[2-(6-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]-S-methylisothiourea (8.8 g., 0.024 mole) and methylamine (31 g.) in ethanol (90 ml.) is allowed to stand at room temperature for 3 hours. The solvent is evaporated at reduced pressure. The residual oil gradually crystallizes, m.p. 62°-65° C. Two crystallizations of this product from acetonitrile-ether gives 7.0 g, (84%) of N-cyano-N'-[2-(6-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]-N"-methylguanidine as white needles, m.p. 115.5°-117.5° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28][NH:27]1.C(#N)C>C(Cl)Cl>[O:14]1[C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:12]([C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[O:5][CH2:4][CH2:3][CH2:2][N:27]2[CH2:28][CH2:29][C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:26]2)=[N:13]1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Reactant: c1ccc2c(c1)CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: c1cc(OCCCN2CCc3ccccc3C2)cc(-c2noc3ccsc23)c1

Procedure:
The title compound is prepared from 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 1,2,3,4-tetrahydroisoquinoline and acetonitrile essentially as described above in example 48 except that the crude product is dissolve in DCM and purified by using a step gradient of 50% ethyl acetate in heptane, to 100% ethyl acetate. Purity by LC/MS (APCI)=96%, [M+H]+=391.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]3[C:15]4[C:20]([CH2:21][CH2:22][C:11]=23)=[CH:19][C:18]([OH:23])=[CH:17][CH:16]=4)=[CH:6][CH:5]=1)[CH2:2][CH3:3].CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[F:40][C:41]([F:56])([S:52](F)(=[O:54])=[O:53])[C:42]([F:51])([F:50])[C:43]([F:49])([F:48])[C:44]([F:47])([F:46])[F:45]>ClCCl>[F:56][C:41]([F:40])([S:52]([O:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[C:12]1=[N:13][O:14][C:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=3)=[C:11]1[CH2:22][CH2:21]2)(=[O:54])=[O:53])[C:42]([F:50])([F:51])[C:43]([F:49])([F:48])[C:44]([F:47])([F:46])[F:45]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCc1ccc(-c2onc3c2CCc2cc(O)ccc2-3)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1ccc(-c2onc3c2CCc2cc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)ccc2-3)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 72.1 %

Procedure:
To a solution of 3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-ol (Example 9, 115 mg, 0.377 mmol), dimethylaminopyridine (4.60 mg, 0.038 mmol), and triethylamine (0.262 mL, 1.883 mmol) in anhydrous dichloromethane (2 mL) was added perfluoro-1-butanesulfonyl fluoride (0.102 mL, 0.565 mmol) dropwise at room temperature under nitrogen. The mixture was stirred at room temperature for 4.5 hr and allowed to stand in the freezer overnight and quenched by the addition of saturated aqueous sodium bicarbonate solution (3 mL). The dichloromethane layer was separated and the aqueous layer was re-extracted with dichloromethane (2 mL). The combined organic solutions were dried over sodium sulfate, filtered through a silica gel pad and concentrated under reduced pressure to give 3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (160 mg, 0.272 mmol, 72.3% yield) as a white solid. LC/MS M+1=588
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[C:23]3[O:22][CH2:21][CH2:20][O:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)=[O:13])[CH2:3]1.[CH3:24][C:25]1[S:26][C:27]([C:33]2[CH:34]=[C:35]([CH3:39])[CH:36]=[CH:37][CH:38]=2)=[C:28]([C:30](O)=[O:31])[N:29]=1>>[CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][N:6]([C:30]([C:28]3[N:29]=[C:25]([CH3:24])[S:26][C:27]=3[C:33]3[CH:34]=[C:35]([CH3:39])[CH:36]=[CH:37][CH:38]=3)=[O:31])[C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[C:23]3[O:22][CH2:21][CH2:20][O:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)=[O:13])[CH2:3]1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Reactant: CC1C[C@H]2CN[C@H](CNC(=O)c3cccc4c3OCCO4)[C@H]2C1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2cccc3c2OCCO3)c1

Procedure:
prepared by reaction of 3,4-dihydro-benzo[1,4]dioxine-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[NH2:11][CH:12]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=1)[CH2:13][NH:14][C:15](=[O:37])[CH2:16][N:17]1[C:21](=[O:22])[N:20]([CH2:23][C@H:24]([OH:29])[C:25]([F:28])([F:27])[F:26])[C:19]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[N:18]1.[C:48](OC(=O)C)(=[O:50])[CH3:49]>ClCCl>[C:48]([NH:11][CH:12]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=1)[CH2:13][NH:14][C:15](=[O:37])[CH2:16][N:17]1[C:21](=[O:22])[N:20]([CH2:23][C@H:24]([OH:29])[C:25]([F:28])([F:27])[F:26])[C:19]([C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)=[N:18]1)(=[O:50])[CH3:49]
Reactant: NC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
20 μl (0.11 mmol) of N,N-diisopropylethylamine were added to a solution of 60 mg (0.10 mmol) of the compound of Example 58A in 1 ml of dichloromethane. The mixture was cooled to 0° C., 10 μl (0.10 mmol) of acetic anhydride were then added and stirring was continued at 0° C. for 1 h. The volatile components were then removed on a rotary evaporator. The residue was dissolved in a little DMSO and separated by preparative HPLC [Method 8]. The product-containing fraction was freed from the solvent on a rotary evaporator and the residue was dried under high vacuum. This gave 50 mg (83% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:32](Cl)(=[O:35])[CH:33]=[CH2:34]>>[C:32]([N:27]1[CH2:28][CH2:29][CH2:30][CH2:31][C@H:26]1[C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]2=[C:10]([C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[N:9]=1)(=[O:35])[CH:33]=[CH2:34]
Reactant: Nc1nccn2c([C@@H]3CCCCN3)nc(-c3ccc(C(=O)Nc4ncccn4)cc3)c12
Reactant: C=CC(=O)Cl
Product: C=CC(=O)N1CCCC[C@H]1c1nc(-c2ccc(C(=O)Nc3ncccn3)cc2)c2c(N)nccn12
Yield: 26.2 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 1, from (S)-4-(8-amino-3-(piperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyrimidin-2-yl)benzamide (intermediate 27) and acryloylchloride, to afford the title compound (5.9 mg, 26.2%). Data: UPLC(C) Rt: 1.70 min; m/z 469.3 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH:3]([N:6]([CH:24]([CH3:26])[CH3:25])[CH2:7][CH2:8][NH:9][CH:10]([C:16]1[CH:17]=[N:18][C:19]([CH3:23])=[CH:20][C:21]=1[CH3:22])[NH:11][C:12](=[O:15])[O:13][CH3:14])([CH3:5])[CH3:4].CI.[C:29](O)(=O)C>C1(C)C=CC=CC=1.CS(C)=O.O>[CH3:29][N:11]([CH:10]([NH:9][CH2:8][CH2:7][N:6]([CH:3]([CH3:4])[CH3:5])[CH:24]([CH3:26])[CH3:25])[C:16]1[CH:17]=[N:18][C:19]([CH3:23])=[CH:20][C:21]=1[CH3:22])[C:12](=[O:15])[O:13][CH3:14]
Reactant: COC(=O)NC(NCCN(C(C)C)C(C)C)c1cnc(C)cc1C
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)N(C)C(NCCN(C(C)C)C(C)C)c1cnc(C)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 50% sodium hydride in mineral oil (2.0 g, 42 mmol) in dry toluene (100 ml) under a nitrogen atmosphere is added a solution of methyl N-(2-diisopropylaminoethylamino-4,6-dimethyl-3-pyridylmethyl)carbamate (13.5 g, 40 mmol) in dry dimethyl sulfoxide (12 ml) and dry toluene (60 ml) in one portion. This mixture is stirred for one hour at room temperature and then methyliodide (2.52 ml, 40 mmol) is added dropwise. After stirring an additional three hours, acetic acid (6.0 ml) is added, followed by water. The aqueous layer is separated, washed with benzene and made basic with sodium carbonate. The product is extracted into methylene chloride, dried and evaporated to give 11.1 g of crude title A product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([C:9]([NH:12][S:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])([CH3:11])[CH3:10])#[N:8].Cl.[NH2:20][OH:21]>CCO>[CH3:16][C:15]([CH3:18])([S:13]([NH:12][C:9]([CH3:11])([CH3:10])[C:7](=[N:20][OH:21])[NH2:8])=[O:14])[CH3:17]
Reactant: NO
Reactant: CC(C)(C#N)NS(=O)C(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(NS(=O)C(C)(C)C)C(N)=NO
Temperature: 60 °C
Yield: 84.9 %

Procedure:
Potassium carbonate (2.94 g, 21.2 mmol) was added to a stirring solution of N-(2-cyanopropan-2-yl)-2-methylpropane-2-sulfinamide (1.0 g, 5.3 mmol) and hydroxylamine hydrochloride (738 mg, 10.6 mmol) in EtOH (18 mL) at rt. The reaction was heated to 60° C. for 16 h. The reaction was then concentrated and the resulting residue was diluted with EtOAc and washed with water, and sat NaCl aq. The organic phase was dried over Na2SO4, filtered and concentrated azeotroping with toluene to give the expected product 2-(1,1-dimethylethylsulfinamido)-N′-hydroxy-2-methylpropanimidamide (1.0 g, 4.5 mmol, 85% yield) as a white solid consistent by LCMS and NMR. LC-MS retention time: 0.35 min; m/z (MH+): 222. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. 1H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 5.27 (s, 1H), 5.25 (s, 2H), 1.36 (d, J=5.0 Hz, 6H), 1.12 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([CH2:13][NH:14][C:15]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)=[O:16])[O:10][C:9]2=[O:23])=[CH:4][CH:3]=1.[Cl:24][CH2:25][CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29].C(N(CC)CC)C>ClCCl>[Cl:22][C:19]1[S:18][C:17]([C:15]([NH:14][CH2:13][CH:11]2[O:10][C:9](=[O:23])[N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:28]([CH2:27][CH2:26][CH2:25][Cl:24])(=[O:30])=[O:29])=[CH:3][CH:4]=3)[CH2:12]2)=[O:16])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Nc1ccc(N2CC(CNC(=O)c3ccc(Cl)s3)OC2=O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC1CN(c2ccc(NS(=O)(=O)CCCCl)cc2)C(=O)O1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
35 mg (0.1 mmol) of N-{[3-(4-aminophenyl)-2-oxo-1,3-oxazolidin-5-yl]-methyl}-5-chloro-2-thiophenecarboxamide (from Example 149) are added to an ice-cooled solution of 26.4 mg (0.15 mmol) of 3-chloro-1-propanesulfonyl chloride and 0.03 ml (0.2 mmol) of triethylamine in 3.5 ml of absolute dichloromethane. After 30 min, the ice cooling is removed and the mixture is stirred at room temperature overnight before adding 150 mg (approx. 5.5 eq) of PS-trisamine (Argonaut Technologies) and 0.5 ml of dichloromethane. The suspension is stirred gently for 2 h and filtered (the resin is washed with dichloromethane/methanol), and the filtrate is concentrated. The product is purified by preparative RP-HPLC. Yield: 19.6 mg (40% of theory),
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)#[N:2].[N-:16]=[N+:17]=[N-:18].[Na+].[NH4+].[Cl-].Cl>O.CN(C=O)C>[NH:16]1[C:1]([CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)=[N:2][N:18]=[N:17]1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)Cc1ccc(OCC#N)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(OCc2nnn[nH]2)cc1
Temperature: 125 °C
Yield: 57.1 %

Procedure:
A mixture of methyl 4-(cyanomethoxy)phenylacetate (2.5 g, 12 mmol), NaN3 (0.87 g), NH4Cl (0.72 g, 13 mmol) and DMF (20 ml) was heated at 125° C. for 24 hours. The reaction mixture was cooled, water was added and the mixture was stripped in vacuo without allowing the solution to be stripped to dryness. This procedure was repeated (2×) and then water was added, followed by 2N HCl. The product crystallized from the solution and was collected by filtration, and washed with water and air dried to afford 1.7 g (60%) of methyl 4-(5-tetrazolylmethoxy)phenylacetate.