Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH2:18]2)[CH2:13][CH2:14][NH:15][OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH:33](OCC(F)(F)F)=[O:34]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH2:18]2)[CH2:13][CH2:14][N:15]([CH:33]=[O:34])[OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(CCNO)N2Cc3cccc(NC(=O)C(C)C)c3C2=O)ccc1OC
Reactant: O=COCC(F)(F)F
Solvent: C1CCOC1
Product: CCOc1cc([C@@H](CCN(O)C=O)N2Cc3cccc(NC(=O)C(C)C)c3C2=O)ccc1OC

Procedure:
(1R)—N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide was prepared by the procedure of Example 7 from N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-hydroxyamino-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide (1.6 g, 3.6 mmol) and 2,2,2-trifluoroethyl formate (5 g, 39 mmol) in THF (20 mL) to give a white solid (0.7 g, 41% yield): mp: 81-83° C. 1H NMR (DMSO-d6) δ 1.18 (d, J=7 Hz, 6H, 2CH3), 1.31 (t, J=7 Hz, 3H, CH3), 2.34-2.38 (m, 2H, CH2), 2.56-2.65 (m, 1H, CH), 3.39-3.51 (m, 2H, CH2), 3.73 (s, 3H, CH3), 3.96-4.05 (m, 2H, CH2), 4.16 (d, J=17 Hz, 1H, NCHH), 4.55 (d, J=17 Hz, 1H, NCHH), 5.25-5.29 (m, 1H, NCH), 6.93-6.97 (m, 3H, Ar), 7.18 (d, J=8 Hz, 1H, Ar), 7.50 (t, J=8 Hz, 1H, Ar), 7.83 (s, 0.5H, CH), 8.25 (s, 0.5H, CH), 8.28 (d, J=8 Hz, 1H, Ar), 9.63 (s, 0.5H, OH), 10.07 (s, 0.5H, OH), 10.47 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.69, 19.16, 19.21, 28.39, 28.60, 35.94, 43.35, 45.92, 46.26, 46.73, 51.17, 51.92, 55.44, 63.78, 111.97, 112.34, 116.55, 117.54, 117.58, 119.68, 131.54, 132.16, 151.12, 142.28, 147.94, 148.53, 157.36, 161.80, 168.37, 168.53, 174.93; Anal Calcd for C25H31N3O6+0.4 H2O: C, 62.98; H, 6.72; N, 8.81; H2O, 1.51. Found: C, 62.96; H, 6.80; N, 8.84; H2O, 1.48.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=1)[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].C(N(CC)CC)C.[C:32]1([C:38]2[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C)C=O.O>[C:38]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:39]=[CH:40][C:41]([C:42]([NH:2][C@@H:3]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=2)[CH2:4][C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6])=[O:43])=[CH:45][CH:46]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: N#Cc1cccc(OC[C@H](N)CC(=O)OCc2ccccc2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc(OC[C@@H](CC(=O)OCc2ccccc2)NC(=O)c2ccc(-c3ccccc3)cc2)c1
Reaction time: 0.5 h

Procedure:
310 mg (1.0 mmol) of benzyl (3R)-3-amino-4-(3-cyanophenoxy)butyrate hydrochloride was dissolved in 10 ml of dimethylformamide. 0.18 ml (1.3 mmol) of triethylamine was added to the solution. 282 mg (1.3 mmol) of 4-phenylbenzoyl chloride was added to the resultant mixture under cooling with ice, and they were stirred for 30 minutes. The temperature was elevated to room temperature, and the reaction mixture was stirred for additional 2 hours. The reaction liquid was diluted with water. After the extraction with ethyl acetate, the organic layer was successively washed with water, 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous NaCl solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][NH:13]C(=O)OC(C)(C)C)=[C:8]([CH:21]=O)[C:7]([CH3:23])=[C:6]([Cl:24])[CH:5]=1)(=[O:3])[CH3:2]>Cl.O1CCOCC1>[Cl:24][C:6]1[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[C:9]2[O:10][CH2:11][CH2:12][N:13]=[CH:21][C:8]=2[C:7]=1[CH3:23]
Reactant: CC(=O)c1cc(Cl)c(C)c(C=O)c1OCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)c1cc(Cl)c(C)c2c1OCCN=C2
Yield: 99.6 %

Procedure:
tert-Butyl [2-(6-acetyl-4-chloro-2-formyl-3-methylphenoxy)ethyl]carbamate (270 mg, 0.76 mmol) was stirred in 4.0 M hydrogen chloride in dioxane (5.0 mL) at room temperature for 1 hour and evaporated. Tetrahydrofuran was added and the mixture was evaporated to give the desired compound (180 mg, 100%). LCMS calculated for C12H13ClNO2 (M+H)+: m/z=238.1; found: 238.0.
Reaction SMILES: [C:1]1([C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH:9]2[CH2:18][CH2:17][N:16]3[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]3)[CH2:10]2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:25]>>[ClH:25].[C:1]1([C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]2[CH2:18][CH2:17][N:16]3[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]3)[CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCN2CCCCC2C1
Agent: Cl
Product: c1ccc(C(=C2CCN3CCCCC3C2)c2ccccc2)cc1

Procedure:
To 1.39 g. of α,α-diphenylquinolizidine-2-methanol was added 10 ml. of ethanolic hydrochloride. The resulting mixture was refluxed for 4 hrs. with stirring. The residue remained after the removal of the ethanol by distillation was dissolved in water. The solution was rendered alkaline with a potassium carbonate solution and extracted with chloroform. The chloroform layer was washed with water and dried. After the solvent was removed by distillation, light yellow liquid was obtained. The product was converted into the hydrochloride in a conventional manner. By recrystallization from acetone-ether, 0.47 g. of colorless needle 2-diphenylmethylenequinolizidine hydrochloride showing a melting point of 233° to 235° C. was obtained.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:16][C:17]([OH:19])=[O:18].Cl.[CH3:21]O>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:16][C:17]([O:19][CH3:21])=[O:18]
Reactant: CO
Reactant: O=C(O)Cc1ccc2c(c1)CCc1ccccc1S2
Agent: Cl
Product: COC(=O)Cc1ccc2c(c1)CCc1ccccc1S2

Procedure:
A solution of 950 mg. of 10,11-dihydrodibenzo[b.f]thiepin-2-acetic acid in 50 ml. of methanol is saturated with hydrogen chloride. After 2 hours the reaction mixture is evaporated under reduced pressure and the residue is chromatographed on silica gel using ethyl acetate:hexane (1:7) as eluant to yield methyl 10,11-dihydrodibenzo[b.f]-thiepin-2-acetate (XII, R1 = Me), which is dissolved in 10 ml. of benzene and treated with 900 mg. of 85% m-chloroperbenzoic acid dissolved in 10 ml. of dimethoxyethane. After 5 minutes, 3 ml. of saturated aqueous sodium sulfite is added, followed by 1 ml. of saturated aqueous potassium carbonate. The organic layer is separated, dried with anhydrous magnesium sulfate and filtered through a column of 20 g. of silica gel, eluting with benzene. Evaporation of the eluate under reduced pressure yields a residue which upon recrystallization from chloroform:hexane (1:1) yields 900 mg. of methyl 10,11-dihydrodibenzo[b.f]thiepin-2-acetate-S,S-dioxide (XV, R1 = Me), having a melting point of 103°-105° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][NH2:10])=[O:8])=[CH:5][CH:4]=1.[O:13](C(C(F)(F)F)=O)[C:14]([C:16]([F:19])([F:18])[F:17])=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][NH:10][C:14](=[O:13])[C:16]([F:19])([F:18])[F:17])=[O:8])=[CH:11][CH:12]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1ccc(C(=O)NN)cc1
Product: COc1ccc(C(=O)NNC(=O)C(F)(F)F)cc1

Procedure:
Synthesis and isolation were same as I-benzoyl-2-trifluoroacetylhydrazine, using 1.8 g (10.8 mmol) of 4-methoxybenzoylhydrazine and 2.0 g (9.5 mmol) of (CF3CO)2O. Yield was 2.4 g (85%). MS (EI, m/e) calcd for C10H9F3N2O3 262, found 262 (M+, 8.0); mp 147-148° C.
Reaction SMILES: C1(N2C=NC3C2=NC(OCC)=NC=3N)CCCC=C1.[CH:20]1([N:26]2[CH:34]=[N:33][C:32]3[C:27]2=[N:28][C:29]([O:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[N:30][C:31]=3[NH2:35])[CH2:25][CH2:24][CH2:23][CH:22]=[CH:21]1>>[CH2:37]([O:36][C:29]1[N:28]=[C:27]2[C:32]([N:33]=[CH:34][N:26]2[CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[C:31]([NH2:35])[N:30]=1)[CH:38]([CH3:40])[CH3:39]
Reactant: CC(C)COc1nc(N)c2ncn(C3C=CCCC3)c2n1
Agent: CCOc1nc(N)c2ncn(C3C=CCCC3)c2n1
Product: CC(C)COc1nc(N)c2ncn(C3CCCCC3)c2n1
Yield: 60 %

Procedure:
The procedure of Example 8 was repeated except that the 9-(2-cyclohexenyl)-2-ethoxy-9H-adenine used therein was replaced by an equivalent weight of 9-(2-cyclohexenyl)-2-isobutoxy-9H-adenine. There was produced the title product in 60% yield; m.p. 123°-134° C. IR(neat): 3320, 3160, 2940, 1635, 1590, 1395, 1375 cm-1. UV: λmaxEtOH 253 nm (ε7000), 269 nm(ε11000). NMR(CDCl3): 1.05(6H, d, J=6.5 Hz), 1.90(11H, m), 4.05(2H, d, J=6.5 Hz), 4.24(1H, m), 6.14(2H, s), 7.55(1H, s).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=1[CH3:19])=[O:10])[NH:2]2.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[C:28]([C:33](O)=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=1>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[C:28]([C:33]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[N:13][C:12]=3[CH3:19])=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1
Reactant: O=C(O)c1ccccc1-c1ccccc1F
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1ccccc1-c1ccccc1F

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2′-fluoro-biphenyl-2-carboxylic acid. LC-MS (basic): tR=1.34 min; [M+H]+=475.2.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]34[CH2:21][CH:16]5[CH2:17][C:18]([NH2:20])([CH2:19]3)[CH:14]([CH2:15]5)[CH2:13]4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][C@H:33]1[C:37]#[N:38])=[O:31]>CS(C)=O.CCOC(C)=O>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]34[CH2:21][CH:16]5[CH2:17][C:18]([NH:20][CH2:29][C:30]([N:32]6[CH2:36][CH2:35][CH2:34][C@H:33]6[C:37]#[N:38])=[O:31])([CH2:19]3)[CH:14]([CH2:15]5)[CH2:13]4)=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Reactant: NC12CC3CC1CC(c1ccc(-n4cccc4)cc1)(C3)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(c1ccc(-n4cccc4)cc1)(C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.2 %

Procedure:
To a stirred mixture of the compound obtained from step II (0.41 g, 1.5 mmol) and K2CO3 (0.62 g, 4.5 mmol) in DMSO (6 mL) at ice bath temperature under N2 atmosphere was added (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.26 g, 1.5 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{N-[2-[4-(1H-pyrrol-1-yl)phenyl]hexahydro-2,5-methanopentalen-3a (1H)-yl]glycyl}pyrrolidine-2-carbonitrile as a white solid (0.2 g) in 32% yield as off-white solid. m/z (M+1) 415; 1H NMR (CDCl3) 300 MHz δ 7.38-7.26 (m, 4H), 7.10-7.05 (m, 2H), 6.36-6.32 (m, 2H), 4.84-4.78 (m, 1H), 3.75-3.40 (m, 2H), 3.50 (s, 2H), 2.50-2.42 (m, 1H), 2.38-2.28 (m, 2H), 2.25-2.0 (m, 6H), 2.0-1.70 (m, 7H).
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH3:11][N:12]([CH3:26])[C:13]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C1COCC1>[CH:2]1([NH:1][CH:16]2[CH2:15][CH2:14][C:13]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)([N:12]([CH3:26])[CH3:11])[CH2:18][CH2:17]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: NC1CCc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC(NC2CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.9 %

Procedure:
266 mg 1-aminoindane and 434 mg 4-dimethylamino-4-phenyl-cyclohexanone were dissolved in dry 1,2-dichloroethane (10 ml) and THF (10 ml) under argon. Glacial acetic acid (2 mmol) and sodium triacetoxyborohydride (600 mg) were added to this mixture and the mixture was stirred for 24 hours at RT. For working up, the mixture was concentrated and the residue was adjusted to pH 11 with five molar sodium hydroxide solution. The alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (5×20 ml). The combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product was chromatographed over silica gel with ethyl acetate/ethanol (1:1). 200 mg N′-indan-1-yl-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine were obtained as a white solid (m.p. 99-101° C.).
Reaction SMILES: C(C1[C:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=2[O:6][C:5]([CH3:17])([CH3:16])[CH:4]=1)#N.[C:18]([OH:21])(=[O:20])[CH3:19].S(=O)(=O)(O)O>O>[CH3:16][C:5]1([CH3:17])[CH:4]=[C:19]([C:18]([OH:21])=[O:20])[C:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=2[O:6]1
Reactant: CC1(C)C=C(C#N)c2cc([N+](=O)[O-])ccc2O1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC1(C)C=C(C(=O)O)c2cc([N+](=O)[O-])ccc2O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
MS: 230 (M+) ##STR41## A mixture of 13.0 g of 4-cyano-2,2-dimethyl-6-nitro-2H-1-benzopyran, 400 ml of acetic acid, 200 ml of water, and 100 ml of concentrated sulfuric acid was heated at reflux for 1.5 hours. After adding 100 ml of concentrated sulfuric acid, the refluxing was further continued for an additional period of 1 hour. The reaction mixture was poured into ice-water. The thus precipitated crystal was washed with water, dried, and recrystallized from a mixed solvent of acetonitrile and water to obtain 11.9 g of 2,2-dimethyl-6-nitro-2H-1-benzopyran-4-carboxylic acid represented by formula shown below.
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][C:3]1=[O:14].[H-].[Na+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[CH2:22]([O:1][C:2]1([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][C:3]1=[O:14])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC1=CC(=O)C(O)(CCC(C)C)c2ccccc21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1=CC(=O)C(CCC(C)C)(OCc2ccccc2)c2ccccc21
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of Example 11A (25 mg, 0.094 mmol) in N,N-dimethylformamide (1 mL) at 0° C. was added 60% wt sodium hydride (15.4 mg, 0.384 mmol). The reaction solution was stirred for 0.5 h and benzylbromide (0.046 mL, 0.384 mmol) was added. The solution was stirred 16 h at room temperature, quenched with saturated NH4Cl, and extracted with ethyl acetate. The organic extract was concentrated in vacuo. Column chromatography on silica (20% ethyl acetate/hexane) afforded the title compound as an oil (29 mg, 86%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.71 (dd, 6H), 0.80-1.03 (m, 2H), 1.19-1.38 (m, 1H), 1.69-2.04 (m, 2H), 3.85 (d, J=10.66 Hz, 1H), 3.98 (s, 3H), 4.04 (d, J=11.03 Hz, 1H), 5.84 (s, 1H) 7.19-7.39 (m, 5H), 7.40-7.57 (m, 1H), 7.58-7.71 (m, 2H), 7.85 (d, J=7.72 Hz, 1H); MS m/z 351.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH3:9])[CH2:3][C:4]1[NH:8][CH:7]=[N:6][CH:5]=1.[CH3:11][N:12]([CH3:17])[S:13](Cl)(=[O:15])=[O:14].CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][C:2]([CH3:10])([CH3:9])[CH2:3][C:4]1[N:8]=[CH:7][N:6]([S:13]([N:12]([CH3:17])[CH3:11])(=[O:15])=[O:14])[CH:5]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CC(C)(C)Cc1cnc[nH]1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)n1cnc(CC(C)(C)C)c1

Procedure:
To a solution of 5-(2,2-dimethylpropyl)-1H-imidazole, dimethylsulfamoyl chloride (25 mL), Et3N (45 mL) in CH2Cl2 (300 mL) was added DMAP (0.8 g). The reaction mixture was refluxed overnight. The solvent was concentrated and the residue was purified by silica gel chromatography to give the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.O.[C:21]([OH:25])(=[O:24])[CH:22]=O.[BH3-]C#N.[Na+]>CCO>[CH2:8]([C:6]1[CH:7]=[C:2]([NH:1][CH2:22][C:21]([OH:25])=[O:24])[C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:4][CH:5]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1ncc(Cc2ccccc2)cc1N
Reactant: O=CC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ncc(Cc2ccccc2)cc1NCC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 3-amino-5-benzylpyridine-2-carboxylate (0.543 g, 2.12 mmol) and glyoxylic acid monohydrate (0.254 g, 2.76 mmol) in EtOH (6 mL) was heated at reflux for 1 h. The mixture was allowed to cool to rt and NaCNBH3 (266 mg, 4.23 mmol) was added. After stirring 2 h at rt, the reaction was quenched with water and the EtOH was removed at reduced pressure. The aqueous mixture was extracted with CH2Cl2 and the organic layers were dried and concentrated. Trituration of the remaining material with EtOAc/hexanes and filtration afforded the product as a beige solid: 1H NMR (d6-DMSO) δ 13.2 (1H, br), 7.92 (1H, br t, J=4.8 Hz), 7.76 (1H, s), 7.26 (4H, m), 7.17 (1H, t, J=7 Hz), 7.00 (1H, s), 4.24 (2H, q, J=7 Hz), 3.90 (2H, s), 3.86 (2H, br), 1.27 (3H, t, J=7 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](O)=[O:19])[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:43][O:44][C:45](=[O:63])[C@@H:46]([NH2:62])[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[CH:58][N:57]=[C:56]([CH3:60])[C:55]=2[CH3:61])=[CH:50][CH:49]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl.C(Cl)CCl>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:19])[NH:62][C@H:46]([C:45]([O:44][CH3:43])=[O:63])[CH2:47][C:48]2[CH:49]=[CH:50][C:51]([C:54]3[CH:59]=[CH:58][N:57]=[C:56]([CH3:60])[C:55]=3[CH3:61])=[CH:52][CH:53]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccnc(C)c2C)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(3R,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester (260 mg), (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride (190 mg), EDC (106 mg), and HOBt (78 mg) were suspended in 2 mL DCM and NMM (0.214 mL) added. The resulting mixture stirred at room temperature for 4 hours and loaded directly onto silica. The residue was purified by silica gel flash chromatography (hexanes to 1:1 hexanes/EtOAc to 1:1 hexanes/EtOAc+1% MeOH) to give 320 mg after drying under vacuum. LCMS: m/z 853.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][O:10][CH2:11][C:12]([CH2:14]Cl)=[CH2:13])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Cl:16][C:17]1[N:25]=[C:24]([NH2:26])[N:23]=[C:22]2[C:18]=1[NH:19][CH:20]=[N:21]2.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:6]([O:5][P:4]([CH2:9][O:10][CH2:11][C:12](=[CH2:13])[CH2:14][N:21]1[CH:20]=[N:19][C:18]2[C:22]1=[N:23][C:24]([NH2:26])=[N:25][C:17]=2[Cl:16])([O:3][CH2:1][CH3:2])=[O:8])[CH3:7]
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: C=C(CCl)COCP(=O)(OCC)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(COCP(=O)(OCC)OCC)Cn1cnc2c(Cl)nc(N)nc21
Temperature: 20 °C
Reaction time: 48 h

Procedure:
A mixture of (2-chloromethyl-2-propenyloxymethyl)-phosphonic acid diethylester (0.285 g, 1.1 mmol), 6-chloro-2-aminopurine (0.25 g, 1.5 mmol) and potassium carbonate (0.24 g, 1.5 mmol) in anhydrous dimethylformamide is stirred 2 days at 20° C. Then the reaction mixture is concentrated in vacuo and the title product is obtained by flash chromatography on silica gel (0.22 g, 51%).
Reaction SMILES: CN(C([O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([N+:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)=O)C.[CH3:17][N:18]1[C@@H:22]2[CH2:23][C@@H:24]([O:26][C:27]([CH:29]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:30][OH:31])=[O:28])[CH2:25][C@H:19]1[CH2:20][CH2:21]2>>[CH3:17][CH2:14][N+:13]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:6])[CH:12]=1)([CH3:16])[CH3:15].[CH3:17][N:18]1[C@@H:22]2[CH2:23][C@@H:24]([O:26][C:27]([CH:29]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:30][OH:31])=[O:28])[CH2:25][C@H:19]1[CH2:20][CH2:21]2
Reactant: CN(C)C(=O)Oc1cccc([N+](C)(C)C)c1
Agent: CN1[C@@H]2CC[C@H]1C[C@@H](OC(=O)C(CO)c1ccccc1)C2
Product: CC[N+](C)(C)c1cccc(O)c1

Procedure:
Compared to neostigmine (0.043 mg/kg) and atropine (15 mg/kg), the simultaneous administration of edrophonium (0.5 mg/kg) and atropine (74 g/kg) resulted in minimal changes in heart rate or MAP.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([S:14][CH2:15][CH2:16][C@@H:17]([C:29]([NH:31][C@H:32]([C:42]([O:44][CH3:45])=[O:43])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][OH:41])=[O:30])[NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])(=[O:13])[CH3:12].CCN(CC)CC>C(Cl)Cl.CCOC(C)=O>[C:11]([S:14][CH2:15][CH2:16][C@@H:17]([C:29]([NH:31][C@H:32]([C:42]([O:44][CH3:45])=[O:43])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH:40]=[O:41])=[O:30])[NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])(=[O:13])[CH3:12]
Reactant: COC(=O)[C@H](Cc1ccccc1CO)NC(=O)[C@H](CCSC(C)=O)NC(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)[C@H](Cc1ccccc1C=O)NC(=O)[C@H](CCSC(C)=O)NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 97.9 %

Procedure:
To a solution of oxalyl chloride (192 μL, 2.2 mmol) in CH2Cl2 (3 mL) cooled at −78° C. was added DMSO (312 μL, 4.4 mmol). After stirring at −78° C. for 5 minutes, a solution of the title compound of step (I) (790 mg, 1.572 mmol) in CH2Cl2 (9 mL) was added dropwise. The resultant white suspension was stirred at −78° C. for 30 minutes, before Et3N (0.964 mL, 6.916 mmol) was added. The reaction mixture was warmed up at −30° C. and stirred for 1 hour. The mixture was diluted with EtOAc (100 mL), washed with 5% KHSO4 (2×), sat. NaHCO3 (1×), H2O (2×), brine, dried (MgSO4), filtered and concentrated in vacuo to give 0.77 g (98%) of the title compound of this step as a white foam.