Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[CH3:18][C:19]1[CH:23]=[CH:22][S:21][C:20]=1[CH:24]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(O)(=O)C.CN(C)C=O>[CH3:18][C:19]1[CH:23]=[CH:22][S:21][C:20]=1[CH2:24][N:8]1[CH2:7][CH2:6][C:5]2([CH2:1][N:2]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3][CH2:4]2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Reactant: Cc1ccsc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1ccsc1CN1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 15 h
Yield: 61.1 %

Procedure:
To a 1% acetic acid-dimethylformamide (10 mL) solution of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (1.28 g) and 3-methylthiophene-2-carboaldehyde (700 mg), sodium triacetoxyborohydride (1.96 g) was added. The reaction solution was stirred at room temperature for 15 hours. To the reaction solution, an aqueous 5N sodium hydroxide solution (10 mL) was added. The aqueous layer was washed twice with dichloromethane (100 mL) The combined organic layer was washed with saturated sodium chloride solution (50 mL) and then dried over anhydrous magnesium sulfate. After removing the anhydrous magnesium sulfate by filtration, the filtrate was concentrated. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:1→1:3) to obtain the title compound (1.14 g) having the following physical properties.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[C:9]([O:13][C:14](=[O:25])[NH:15][CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:17]O)([CH3:12])([CH3:11])[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:9]([O:13][C:14](=[O:25])[NH:15][C@@H:16]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:17][O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([CH3:10])([CH3:11])[CH3:12]
Reactant: Oc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)NC(CO)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](COc1cncc(Br)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 5-bromo-pyridin-3-ol (0.3 g, 1.7 mmol), (2-hydroxy-1-phenyl-ethyl)-carbamic acid tert-butyl ester (0.41 g 1.7 mmol), and triphenylphosphine (0.52 g, 2 mmol) in THF (15 mL) was stirred at 0° C. for 30 min. To the mixture was added a solution of di-t-butyl azidodicarboxylate (0.46 g, 2 mmol) in 5 ml of THF. The mixture was allowed to warm to room temperature then stirred at room temperature for 20 h. The THF was evaporated off and the residue was taken into ethyl acetate (75 ml), washed with saturated sodium bicarbonate (50 ml) water (50 ml) and brine (50 ml). The ethyl acetate was evaporated off and the residue was purified by flash column chromatography on silica gel, eluting with a solvent gradient of 1:4 to 1:2 ethyl acetate/hexane. Recovered 0.82 g of a mixture of product and di-tert-butyl azidodicarboxylate. MS (ESI) m/z 395 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]([C:15](CC)=[O:16])[CH3:14])[CH:5]=[CH:6][C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[NH2:19][C@H:20]([CH2:28][OH:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[CH2:21]([C@H:20]([NH:19][C:15](=[O:16])[C@H:13]([C:4]1[CH:5]=[CH:6][C:7]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[C:2]([F:1])[CH:3]=1)[CH3:14])[CH2:28][OH:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: CCC(=O)C(C)c1ccc(NS(C)(=O)=O)c(F)c1
Solvent: ClCCl
Product: C[C@H](C(=O)N[C@H](CO)Cc1ccccc1)c1ccc(NS(C)(=O)=O)c(F)c1

Procedure:
A mixture of 2-[3-fluoro-4-(methylsulfonylamino)phenyl]propion acid (100 mg, 0.234 mmol) and L-phenyl alaninol (71 mg, 0.468 mmol) in CH2Cl2 (3 mL) was refluxed for 3 h and concentrated in vacuo. The residue was dissolved in MeOH (2 mL) and purified by flash column chromatography on silica gel using EtOAc:hexanes (2:1) to EtOAc:MeOH (20:1) as eluant to afford N-[(1S)-1-Benzyl-2-hydroxyethyl]-(2S)-2-[3-fluoro-4-(methylsulfonylamino)phenyl]propionamide.
Reaction SMILES: Br[CH:2]([CH3:10])[C:3](=O)[CH2:4][C:5]([O:7][CH3:8])=[O:6].[C:11]([NH2:19])(=[S:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:8][O:7][C:5](=[O:6])[CH2:4][C:3]1[N:19]=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:18][C:2]=1[CH3:10]
Reactant: COC(=O)CC(=O)C(C)Br
Reactant: NC(=S)c1ccccc1
Product: COC(=O)Cc1nc(-c2ccccc2)sc1C
Yield: 70 %

Procedure:
The title compound (827 mg) was prepared from 1.0 g (4.78 mmol) of methyl 4-bromo-3-oxo-pentanoate and 2.6 g (19.14 mmol) of thiobenzamide according to the method of Intermediate 42 followed by purification via silica gel flash column chromatography using hexanes/EtOAc (3:1) as eluent: low resolution MS (ES) m/e 270 (MNa+), 248 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C@@H:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:12][CH2:13][CH3:14].Cl[CH2:24][C:25](Cl)=[O:26]>C(OCC)(=O)C>[C:19]([O:18][C:16]([N:15]1[C@@H:10]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[C:25](=[O:26])[CH2:24]1)=[O:17])([CH3:21])([CH3:20])[CH3:22]
Reactant: CCCC[C@@H](CNc1ccccc1C)NC(=O)OC(C)(C)C
Reactant: O=C(Cl)CCl
Solvent: CCOC(C)=O
Product: CCCC[C@H]1CN(c2ccccc2C)C(=O)CN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared essentially according to the procedure described in Example 39. Step D, except using N-(2-methylphenyl)-2(S)-(tert-butoxycarbonylamino)hexanamine (0.506 g, 1.65 mmol), chloroacetyl chloride (0.158 mL, 1.98 mmol) in ethyl acetate-saturated sodium bicarbonate at 0° C. The crude product thus obtained was dissolved in DMF (15 mL), cooled to 0° C. under nitrogen, and treated with cesium carbonate (1.61 g, 4.95 mmol). The reaction was stirred at 0° C. for 2 h, and at room temperature for 2 h. The reaction was quenched with saturated ammonium chloride, and extracted with ethyl acetate. The extracts were dried and evaporated to give the title compound.
Reaction SMILES: Cl.Cl.[NH:3]([C:5]1[N:6]=[N:7][C:8]([N:11]([CH3:13])[CH3:12])=[CH:9][CH:10]=1)[NH2:4].[CH3:14][C:15](=O)[CH2:16][CH2:17][C:18](=O)[CH3:19].C([O-])(=O)C.[Na+].C(OCC)C>C(O)(=O)C>[CH3:19][C:18]1[N:4]([NH:3][C:5]2[N:6]=[N:7][C:8]([N:11]([CH3:13])[CH3:12])=[CH:9][CH:10]=2)[C:15]([CH3:14])=[CH:16][CH:17]=1
Reactant: CC(=O)CCC(C)=O
Reactant: CN(C)c1ccc(NN)nn1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1ccc(C)n1Nc1ccc(N(C)C)nn1
Yield: 47 %

Procedure:
The product is obtained according to the procedure of example 19 by reacting 3-hydrazino-6-dimethylamino-pyridazine dihydrochloride and 2,5-hexanedione in acetic acid in the presence of sodium acetate. Yield 47%; m.p. 165°-167° C. (from ethyl ether).
Reaction SMILES: [CH2:1]([C:3]1([CH2:16][CH3:17])[C:8]2[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:7]=2[N:6]([CH3:14])[C:5](=[O:15])[O:4]1)[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25].C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][C:24]=1[F:25])[O:13][C:10]1[CH:11]=[CH:12][C:7]2[N:6]([CH3:14])[C:5](=[O:15])[O:4][C:3]([CH2:1][CH3:2])([CH2:16][CH3:17])[C:8]=2[CH:9]=1
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(O)cc21
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1(CC)OC(=O)N(C)c2ccc(Oc3ccc(F)c(Cl)c3)cc21
Temperature: 25 °C
Reaction time: 144 h
Yield: 8.6 %

Procedure:
To a stirred solution of 4,4-diethyl-6-hydroxy-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (0.30 g, 1.28 mmol) and 3-chloro-4-fluorophenylboronic acid (0.67 g, 3.83 mmol) in methylene chloride (15 mL) was added triethylamine (0.6 mL, 4.3 mmol) and copper (II) acetate (0.46 g, 2.56 mmol). The reaction mixture was stirred at room temperature for 6 days and partitioned between ammonium chloride solution (sat.) and methylene chloride. The organic layer washed with 1N sodium hydroxide solution, dried over magnesium sulfate and concentrated to give 6-(3-chloro-4-fluorophenoxy)-4,4-diethyl-1-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one as a yellow oil (0.04 g, 9%). 1H NMR (DMSO-d6): δ 7.45 (t, J=9.1 Hz, 1H), 7.21 (dd, J=6.2, 3.0 Hz, 1H), 7.13 (d, J=8.7 Hz, 1H), 7.08 (m, 2H), 6.99 (m, 1H), 3.29 (s, 3H), 2.01 (m, 2H), 1.88 (m, 2H), 0.79 (t, J=7.3 Hz, 6H). MS (ESI) m/z 364/366 ([M+H]+); HRMS: calcd for C19H19ClFNO3, 363.1037. found (ESI+), 364.1106.
Reaction SMILES: [C:1]([NH:5]C(NCC1C=C(C2C=CC=C(C=O)C=2OCOCCOC)C(OCOCCOC)=CC=1)=O)(C)(C)C.Cl.[NH2:39][C:40]1[C:41](N)=[C:42]([CH:46]=[CH:47][CH:48]=1)[C:43]([NH2:45])=[NH:44].C1(=O)C=CC(=O)C=C1>CO>[NH:5]1[C:48]2[CH:47]=[CH:46][C:42]([C:43]([NH2:45])=[NH:44])=[CH:41][C:40]=2[N:39]=[CH:1]1
Reactant: N=C(N)c1cccc(N)c1N
Reactant: COCCOCOc1ccc(CNC(=O)NC(C)(C)C)cc1-c1cccc(C=O)c1OCOCCOC
Agent: Cl
Agent: O=C1C=CC(=O)C=C1
Solvent: CO
Product: N=C(N)c1ccc2[nH]cnc2c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
1-tert-Butyl-3-[3′-formyl-6,2′-bis-(2-methoxyethoxymethoxy)-biphenyl-3-ylmethyl]-urea (0.6 g, 1.15 mmol), prepared as in Reference 19, diaminobenzamidine hydrochloride (0.3 g, 1.6 mmol) and 1,4-benzoquinone (0.124 g, 1.15 mmol) were combined in methanol (15 mL) and the mixture was heated at 60° C. and stirred for 2 hours. The mixture was cooled to room temperature and the solvent was removed by evaporation to yield 2-[5′-3-tert-butylureidomethyl)-2,2′- bis-(2-methoxyethoxymethoxy)-biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine.
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([S:20](Cl)(=[O:22])=[O:21])[N:19]=[C:6]2[N:5]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:4]=1[CH3:34])#[N:2].[CH2:35]([NH2:37])[CH3:36].C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([S:20]([NH:37][CH2:35][CH3:36])(=[O:22])=[O:21])[N:19]=[C:6]2[N:5]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:4]=1[CH3:34])#[N:2]
Reactant: CCN
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(S(=O)(=O)Cl)nc2N1c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNS(=O)(=O)c1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon, abs. THF (3 ml) was stirred with molecular sieve (4 Å, 30 mg) for 30 min. (7R)-6-Cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonyl chloride (63%, 50 mg, 62 μmol), ethylamine (2 M solution in THF; 94 μl, 0.19 mmol, 3 eq.) and triethylamine (9 μl, 62 μmol, 1 eq.) were added, and the mixture was stirred at RT for 12 h. The reaction solution was then concentrated under reduced pressure, and the residue was purified by preparative HPLC (Reprosil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (29.9 mg, 93% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].C(Cl)Cl.C(Cl)(=O)C(Cl)=O.[NH3:24]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([NH2:24])=[O:13])[S:10][C:3]=12
Reactant: N
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: O=C(Cl)C(=O)Cl
Agent: [Li+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)c1cc2nccc(Cl)c2s1
Reaction time: 3 h

Procedure:
A 250 mL flask was charged with lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylate (3.00 g, 13.7 mmol) and CH2Cl2(100 ml) under nitrogen. DMF (cat)(0.100 ml) and oxalyl dichloride (1.49 ml, 17.1 mmol) were added dropwise, and the reaction mixture was stirred for 3 hours, and concentrated in vacuo. The brown solid was redissolved in CH2Cl2(100 ml) and ammonia (gas)(0.233 g, 13.7 mmol) was gently bubbled through the reaction mixture for 5 minutes. The flask was then capped and stirred at room temperature overnight under closed atmosphere. The brown suspension was concentrated in vacuo and the resulting solid was taken up in water (to dissolve the starting material), then collected by filtration to give 7-chlorothieno[3,2-b]pyridine-2-carboxamide. MS m/z=213 [M+H]+. Calc'd for C8H5ClN25OS: 212.66.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH2:17]([O:24][C:25](=[O:55])[C@H:26]([NH:38][C:39](=[O:54])[C:40]1[CH:45]=[CH:44][C:43]([N:46]2[CH2:51][CH2:50][CH:49]([CH:52]=O)[CH2:48][CH2:47]2)=[CH:42][CH:41]=1)[CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:17]([O:24][C:25](=[O:55])[C@H:26]([NH:38][C:39](=[O:54])[C:40]1[CH:45]=[CH:44][C:43]([N:46]2[CH2:51][CH2:50][CH:49]([CH2:52][NH:1][CH2:2][C@H:3]([OH:4])[C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[CH2:48][CH2:47]2)=[CH:42][CH:41]=1)[CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: O=CC1CCN(c2ccc(C(=O)N[C@H](CC(=O)OCc3ccccc3)C(=O)OCc3ccccc3)cc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCC2CCN(c3ccc(C(=O)N[C@H](CC(=O)OCc4ccccc4)C(=O)OCc4ccccc4)cc3)CC2)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.2 %

Procedure:
A solution of N-[5-(2-amino-1-{R}-hydroxyethyl)-2-hydroxyphenyl]-methane-sulfonamide (0.104 g, 0.421 mmol), (2R)-2-{[4-(4-(formyl)piperidin-1-yl)benzoyl]-amino}butanedioic acid dibenzyl ester (0.4 mmol) and glacial acetic acid (0.024 g, 0.421 mmol) in 5 mL methanol was stirred for 1 hour over 4A molecular sieves. In one portion sodium cyanoborohydride (0.028 g, 0.421 mmol) was added and the mixture stirred overnight at ambient temperature. The sieves were filtered and the filtrate was preabsorbed on silica gel. The solids were purified by flash chromatography (CH2Cl2—CH3OH, 19:1). to give the product (0.110 g).
Reaction SMILES: [N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:12]/[C:13]1[C:18](Cl)=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:14]=1[Cl:23])=[N+:2]=[N-:3].[NH2:24][C:25]1C(Cl)=CC([N+]([O-])=O)=CC=1C#N>>[N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:12]/[C:13]1[C:14]([Cl:23])=[CH:15][C:16]([N+:20]([O-:22])=[O:21])=[CH:17][C:18]=1[C:25]#[N:24])=[N+:2]=[N-:3]
Reactant: N#Cc1cc([N+](=O)[O-])cc(Cl)c1N
Reactant: [N-]=[N+]=Nc1c(F)cncc1/C=N/c1c(Cl)cc([N+](=O)[O-])cc1Cl
Product: N#Cc1cc([N+](=O)[O-])cc(Cl)c1/N=C/c1cncc(F)c1N=[N+]=[N-]
Temperature: 25 °C

Procedure:
Following the procedure described for [1-(4-azido-5-fluoropyridin-3-yl)-meth-(E)-ylidene]-(2,6-dichloro-4-nitrophenyl)-amine (Example 99, Step 1), 2-amino-3-chloro-5-nitrobenzonitrile was stirred at room temperature to afford the title compound which was used without purification (6.07 g, quantitative yield). LCMS (Method C): RT=3.69 min, m/z: 318 [M+H+−N2].
Reaction SMILES: [C-:1]#[N:2].[K+].[C:4]1([CH:14]=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.C(O)(=O)C>CCOCC>[OH:15][CH:14]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)[C:1]#[N:2]
Reactant: O=Cc1cccc2ccccc12
Reactant: [C-]#N
Agent: [K+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: N#CC(O)c1cccc2ccccc12
Temperature: 25 °C
Yield: 91 %

Procedure:
To a solution of potassium cyanide in ether (100 mL) at 0° C. was added dropwise a mixture of 1-naphthalenecarboxaldehyde (1.56 g, 10 mmol) and acetic acid (1.41 g, 23.5 mmol) in ether (10 mL). The resulting mixture was warmed to 25° C. for 20 h, the precipitate was filtered and the filtrate was concentrated affording the title compound as a clear oil (1.67 g, 9.14 mmol, 91%): LCMS (ES) m/z 184 (M+H)+.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=O)[CH2:3][CH2:2]1.[CH:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:9]=1.O=S(Cl)Cl>C1(C)C=CC=CC=1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:10]2[CH:11]=[CH:12][C:13]([N:14]3[C:1](=[O:7])[CH2:2][CH2:3][C:4]3=[O:6])=[CH:8][CH:9]=2)=[CH:17][CH:18]=1
Reactant: O=C1CCC(=O)O1
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C1CCC(=O)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A mixture of succinic anhydride (250 mg, 2.50 mmol) and 4-amino-4′-chloro diphenylether (500 mg, 2.27 mml) in toluene is heated to 110° C. for 14 h. and cooled down to room temperature. SOCl2 (1.5 mL) is added into the mixture and stirred at room temperature for 8 h. After the solvent is removed under vacuum, the residue is treated with saturated NaHCO3 aqueous solution (20 mL) and extracted with CHCl3 (3×50 mL). The combined organic layer is washed with brine and dried (MgSO4). After filtering the drying agent, the filtrate is concentrated and purified by flash column chromatography (silica gel, EtOAc/hexane 30%˜80%) to provide 1-[4-(4-chloro-phenoxy)-phenyl]-pyrrolidine-2,5-dione as white solid (570 mg, 83%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[O:16][N:15]=2)=[CH:10][CH:9]=1)(C)(C)C.C(OC(=O)NC1C=CC(C(=N)NO)=CC=1)(C)(C)C.FC(F)(F)OC1C=CC(C=O)=CC=1>C(O)(=O)C.C(Cl)(Cl)Cl>[F:29][C:26]([F:27])([F:28])[O:25][C:22]1[CH:21]=[CH:20][C:19]([C:17]2[O:16][N:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([NH2:7])=[CH:9][CH:10]=3)[N:18]=2)=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2noc(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: CC(C)(C)OC(=O)Nc1ccc(C(=N)NO)cc1
Agent: O=Cc1ccc(OC(F)(F)F)cc1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Nc1ccc(-c2noc(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 15 %

Procedure:
{4-[5-(4-Trifluoromethoxyphenyl)-[1,2,4]oxadiazol-3-yl]-phenyl}-carbamic acid tert-butyl ester. To a stirred solution of tert-butyl-4-(N-hydroxycarbamimidoyl)-phenylcarbamate (Ace Synthesis) (500 mg; 1.99 mmol) dissolved in 2.5 mL of acetic acid was added 4-trifluoromethoxybenzaldehyde (1.7 mL; 11.94 mmol), and the reaction mixture was stirred at room temperature for 4 d. The mixture was diluted with CHCl3 (20 mL) and filtered through a pad of Celite®. The pad was washed with CHCl3 (20 mL). Heptane (20 mL) was then added to the solution and the solution was concentrated under reduced pressure. This procedure was repeated twice. The residue was purified via radial chromatography using a 3:1 hexane/EtOAc solution as the eluent. Two fractions were isolated. The first fraction isolated (Rf=0.42) was shown to be the title compound (127 mg; 15%). 1H NMR (300 MHz, CDCl3) δ 8.26 (d, J=8.9 Hz, 2H), 8.09 (d, J=8.9 Hz, 2H), 7.52 (d, J=8.6 Hz, 2H), 7.39 (d, J=8.3 Hz, 2H), 6.70 (s, 1H), 1.54 (s, 9H); EI/MS 421 [M]+. The second fraction isolated (Rf=0.11) was shown to be the 4,5-dihydro-1,2,4-oxadiazole (96 mg; 11%). 1H NMR (300 MHz, CDCl3) δ 8.40 (d, J=8.9 Hz, 2H), 8.00 (d, J=8.9 Hz, 2H), 7.51 (d, J=8.9 Hz, 2H), 7.22-7.31 (m, 3H), 6.87 (s, 1H), 1.54 (s, 9H); EI/MS 423 [M]+.
Reaction SMILES: [OH:1][C:2]1[CH:8]2[CH:6]([CH2:7]2)[C:5]([CH3:11])([S:9][CH3:10])[C:4](=[O:12])[C:3]=1[C:13]([C:15]1[C:16]([CH3:25])=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=1)=[O:14].I([O-])(=O)(=O)=[O:27].[Na+]>CO>[OH:1][C:2]1[CH:8]2[CH:6]([CH2:7]2)[C:5]([S:9]([CH3:10])=[O:27])([CH3:11])[C:4](=[O:12])[C:3]=1[C:13]([C:15]1[C:16]([CH3:25])=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=1)=[O:14]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSC1(C)C(=O)C(C(=O)c2ccc(C(F)(F)F)nc2C)=C(O)C2CC21
Agent: [Na+]
Solvent: CO
Product: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(O)C2CC2C(C)(S(C)=O)C1=O

Procedure:
0.87 g (2.3 mmol) of 5-hydroxy-2-methyl-2-methylsulfanyl-4-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)bicyclo[4.1.0]hept-4-en-3-one (compound A2-D 113), dissolved in 8 ml of methanol, is warmed for 3 hours at a temperature of 50° C. in the presence of 0.56 g of sodium periodate. The mixture is then partitioned between ethyl acetate and sodium chloride solution, concentrated, and the crude product is purified by chromatography (mobile phase: ethyl acetate/methanol 19:1). Pure 5-hydroxy-2-methanesulfinyl-2-methyl-4-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)bicyclo[4.1.0]hept-4-en-3-one is obtained as tautomer and isomer mixture of melting point 159.5-160° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:11][C:3]1[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[CH:9]=[CH:10][C:2]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: OB(O)c1ccccc1
Product: Cc1cc(C(=O)O)ccc1-c1ccccc1

Procedure:
The title compound was prepared from 4-bromo-3-methylbenzoic acid and benzeneboronic acid using a similar procedure to Description 15, as a pale yellow solid (89%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1.[C:28](Cl)(=[O:38])[O:29][C@@H:30]1[CH:35]2[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]2)[CH2:31]1.O>N1C=CC=CC=1>[C:22]1([C@H:3]([NH:2][C:28]([O:29][C@@H:30]2[CH:35]3[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]3)[CH2:31]2)=[O:38])[C:4]2[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=2)[O:7][CH2:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1ccc(COc2cccc([C@@H](N)c3ccccc3)c2)cc1
Reactant: O=C(Cl)O[C@H]1CN2CCC1CC2
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccc(COc2cccc([C@@H](NC(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a stirred solution of (S)-methyl 4-((3-(amino(phenyl)methyl)phenoxy)methyl)-benzoate hydrochloride (I13, 12.0 g, 31.3 mmol) in pyridine (100 mL) at 0° C. was added portion-wise (R)-quinuclidin-3-yl carbonochloridate (8.50 g, 37.5 mmol, prepared as previously reported for Int 6, Step 6). The reaction was stirred at 0° C. for 1 hour and then allowed to warm to RT for 16 h. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate (×3). The combined extracts were washed with brine, dried over sodium sulfate, filtered and the solvent was removed in vacuo. The crude material was purified by chromatography on a KP-NH Biotage cartridge eluting with 0-20% methanol in ethyl acetate to afford the title compound (10.3 g, 66%).
Reaction SMILES: [S:1]1[C:5]([CH2:6][C:7]2[C:8]([CH3:25])=[C:9]([CH3:24])[C:10]([OH:23])=[C:11]([CH:13]3[CH:18]([OH:19])[CH:17]([OH:20])[CH2:16][CH:15]([CH2:21][OH:22])[O:14]3)[CH:12]=2)=[CH:4][C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]1=2.[C:30]([O-])([O-])=O.[Cs+].[Cs+].CI>CC(C)=O>[S:1]1[C:5]([CH2:6][C:7]2[C:8]([CH3:25])=[C:9]([CH3:24])[C:10]([O:23][CH3:30])=[C:11]([CH:13]3[CH:18]([OH:19])[CH:17]([OH:20])[CH2:16][CH:15]([CH2:21][OH:22])[O:14]3)[CH:12]=2)=[CH:4][C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]1=2
Reactant: O=C([O-])[O-]
Reactant: Cc1c(Cc2cc3ccccc3s2)cc(C2OC(CO)CC(O)C2O)c(O)c1C
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(C2OC(CO)CC(O)C2O)cc(Cc2cc3ccccc3s2)c(C)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
A 20 ml vial was charged with 22 (38.2 mg, 0.09 mmol) and Cs2CO3 (45 mg, 0.14 mmol) and to which was added 1 ml of dry acetone, followed by methyl iodide (12 μL, 0.18 mmol). The resulting mixture was stirred at room temperature for 16 h and the solid was filtered of, washed with acetone. The solvent was evaporated and the crude residue was purified by flash column chromatography on silica gel (4 g column, EtOAc/heptane: 0>>>100%) to afford 28.4 mg (71.8%) of 23 as a white solid. 1H NMR (CD3OD) δ 7.71 (d, J=7.58 Hz, 1H), 7.60 (d, J=7.58 Hz, 1H), 7.14-7.28 (3H), 6.87 (s, 1H), 4.52 (d, J=9.60 Hz, 1H), 4.22 (s, 2H), 3.76 (s, 3H), 3.65-3.75 (m, 2H), 3.49-3.59 (m, 3H), 2.23 (s, 3H), 2.20 (s, 3H), 2.02 (m, 1H), 1.50 (q, J=11.62 Hz, 1H). MS (ES) 451.1 (M+Na+).