Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:5]([CH:6]=O)[C:4]=1[OH:13].CC1(C)O[C:20](=[O:21])[CH2:19][C:17](=[O:18])[O:16]1>O>[CH3:12][O:11][C:10]1[C:3]([O:2][CH3:1])=[C:4]2[C:5]([CH:6]=[C:19]([C:17]([OH:18])=[O:16])[C:20](=[O:21])[O:13]2)=[CH:8][CH:9]=1
Reactant: COc1ccc(C=O)c(O)c1OC
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: O
Product: COc1ccc2cc(C(=O)O)c(=O)oc2c1OC
Temperature: 75 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
3,4-dimethoxy-salicylaldehyde (252.8 mg, 1.39 mmol) and Meldrum's acid (200 mg, 1.39 mmol) were combined in H2O (2 mL). The solution was stirred at 75° C. for 2 h. After cooling to room temperature, the precipitate was filtered and dried at suction to give 271.0 mg of 7,8-dimethoxy-3-carboxy-coumarin in an 78% yield.
Reaction SMILES: [C:1]1([O:11][CH2:12][C:13]([OH:15])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NC(N)CC(C)C)C.[NH2:39][C@H:40]([C:44]([NH:46][CH:47]([CH:56]([OH:59])[CH2:57][F:58])[CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[O:45])[CH:41]([CH3:43])[CH3:42]>CN(C)C=O.C(Cl)Cl>[C:1]1([O:11][CH2:12][C:13]([NH:39][C@H:40]([C:44]([NH:46][CH:47]([CH:56]([OH:59])[CH2:57][F:58])[CH2:48][C:49]([O:51][C:52]([CH3:53])([CH3:54])[CH3:55])=[O:50])=[O:45])[CH:41]([CH3:42])[CH3:43])=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)COc1cccc2ccccc12
Reactant: CC(C)[C@H](N)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Agent: CCN=C=NC(N)CC(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC(C)[C@H](NC(=O)COc1cccc2ccccc12)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Reaction time: 0.17 h
Yield: 62.6 %

Procedure:
To a solution of (1-naphthyloxy)acetic acid (0.202 g, 1.0 mmol) in in dimethylformamide(4.0 mL) —CH2Cl2 (6.0 mL) at 0° C. (ice bath) under nitrogen was added hydroxybenzotriazole hydrate (0.168 g) followed by 1-ethyl-3-(3′,3′-dimethyl-1′-aminopropyl)carbodiimide hydrochloride (0.249 g, 1.3 mmol). After stirring for 10 min, the mixture was treated with a solution of (3RS,4RS)-3-(valinyl)amino-5-fluoro-4-hydroxypentanoic acid, tert-butyl ester (0.319 g, 1.04 mmol) in CH2Cl2(8.0 mL). After stirring at 0° C. for 1 hr and at room temperature for 3 hrs, the mixture was partitioned between EtOAc-water. The organic phase was washed with water, 5% KHSO4, saturated NaHCO3 and saturated NaCl solutions, dried over anhydrous Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography on silica gel eluting with EtOAc-hexane (3:2) to give the title compound (0.307 g, 63%) as a white solid. TLC(MeOH—CH2Cl2; 1:9) Rf=0.69.
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([Cl:11])=[C:5]2[S:4][CH:3]=1.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1B(O)O.O1CCOCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:11][C:10]1[CH:9]=[CH:8][N:7]=[C:6]2[C:2]([C:16]3[CH:15]=[CH:14][C:13]([F:12])=[CH:18][C:17]=3[F:19])=[CH:3][S:4][C:5]=12
Reactant: Clc1ccnc2c(Br)csc12
Reactant: OB(O)c1ccc(F)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Fc1ccc(-c2csc3c(Cl)ccnc23)c(F)c1
Temperature: 90 °C
Yield: 360.6 %

Procedure:
A vessel capable of sealing was charged with a mixture of 3-bromo-7-chlorothieno[3,2-b]pyridine (110 mg, 0.443 mmol), 2,4-difluorophenylboronic acid (84 mg, 0.531 mmol), PdCl2(dppf)-CH2Cl2 adduct (18.1 mg, 0.022 mmol), dioxane (3 mL), and a 2.0 M aqueous solution of K3PO4 (0.66 mL, 1.328 mmol) and was purged with nitrogen for 10 min. The vessel was sealed and heated at 90° C. for 3 hours. Upon cooling, the reaction mixture was diluted with water and extracted with CH2Cl2. The combined organics were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by BIOTAGE® eluting with 30%-60% CH2Cl2/hexanes at 30 mL/min. Concentration of appropriate fractions provided the title compound (450 mg, 49% yield) as a white powder. LC/MS: Example 102A @ 3.60 min (RT) (Condition G). MS (ES): m/z=282.02/284.02, [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[CH2:2].Cl[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.F[K].C(P)(C)(C)C>C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd].O1CCOCC1>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(B(O)O)cc1
Reactant: Clc1ccccc1-c1ccccn1
Agent: [Pd]
Agent: CC(C)(C)P
Agent: F[K]
Solvent: C1COCCO1
Product: C=Cc1ccc(-c2ccccc2-c2ccccn2)cc1
Temperature: 80 °C
Yield: 50 %

Procedure:
This Example was carried out in the same manner as Example 10, except that 23.42 g (0.158 mol) of 4-vinyl-phenyl boronic acid, 20.0 g (0.1055 mol) of 2-(2-chloro-phenyl)pyridine, 500□ of 1,4-dioxane, 27.54 g (0.474 mol, 3.3 equivalent) of fluoro-potassium, 1.69 g (0.0084 mol, 5.3 mol %) of t-butylphosphine [P( t-Bu)3)], and 2.6 g (0.0028 mol, 1.8 mol %) of palladium tris(dibenzylidene acetone) [Pd2(dba)3] were used. Finally, after the resulting solution was heated to reflux at 80° C. for 24 hours, the 2-(4′-vinyl-biphenyl-2-yl)pyridine was isolated. The yield was 50%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([C:25]([N:27]3[CH2:32][CH2:31][CH2:30][CH:29]([CH2:33]OS(C)(=O)=O)[CH2:28]3)=[O:26])[CH2:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.O1C2C=CC(OCC3CCCN(C(C4(C5C=CC(Cl)=CC=5)CCC4)=O)C3)=CC=2OC1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([C:25]([N:27]3[CH2:32][CH2:31][CH2:30][CH:29]([CH2:33][O:1][C:2]4[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=4)[CH2:28]3)=[O:26])[CH2:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1
Reactant: Oc1cccnc1
Reactant: CS(=O)(=O)OCC1CCCN(C(=O)C2(c3ccc(Cl)cc3)CCC2)C1
Agent: O=C(N1CCCC(COc2ccc3c(c2)OCO3)C1)C1(c2ccc(Cl)cc2)CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C(N1CCCC(COc2cccnc2)C1)C1(c2ccc(Cl)cc2)CCC1
Yield: 52 %

Procedure:
Compound 85 was synthesized from 3-hydroxypyridine (0.25 g, 2.60 mmol), cesium carbonate (1.27 g, 3.89 mmol) and compound 43 (1.0 g, 2.60 mmol), using the method described for the synthesis of compound 44 to give 0.52 g of the desired product 85. C22H25ClN2O2, LRMS (m/z)=385 (MH+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11].[S:13]1[C:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22][C:16]=2[CH:15]=[CH:14]1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH3:8][C:6]1[NH:5][C:4](=[O:9])[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([N:20]2[CH2:21][CH2:22][C:16]3[CH:15]=[CH:14][S:13][C:17]=3[CH2:18][CH2:19]2)[N:7]=1
Reactant: Cc1nc(Br)c([N+](=O)[O-])c(=O)[nH]1
Reactant: c1cc2c(s1)CCNCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(N2CCc3ccsc3CC2)c([N+](=O)[O-])c(=O)[nH]1

Procedure:
According to the method described in example 1c 6-bromo-2-methyl-5-nitro-3H-pyrimidin-4-one (example 1a) was treated with 5,6,7,8-tetrahydro-4H-thieno-[2,3-d]azepine [J. Heterocycl. Chem. (1985), 22(4), 1011-16] in N,N-dimethylformamide in the presence of N-ethyl-di-isopropylamine at room temperature to yield the title compound as yellow solid; m.p.>200° C.; MS: [M−H]−=305.
Reaction SMILES: [C:1]([C:3](=[C:7](SC)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[N+:18]([C:21]1[CH:22]=[C:23]([NH:27][NH2:28])[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19].[OH-].[Na+]>>[NH2:2][C:1]1[N:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=2)[N:28]=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CSC(=C(C#N)C(N)=O)c1ccc(C)cc1
Reactant: NNc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(-c2nn(-c3cccc([N+](=O)[O-])c3)c(N)c2C(N)=O)cc1
Yield: 7.4 %

Procedure:
The title compound was prepared from 2-cyano-3-methylthio-3-(4-tolyl)acrylamide (464 mg, 2.0 mmol), 3-nitrophenylhydrazine hydrochloride (417 mg, 2.2 mmol) and sodium hydroxide (88 mg, 2.2 mmol) following the procedure used for the compound of Example 12. The crude product was purified by column chromatography (SiO2, 50% ethyl acetate in hexane) and recrystallisation from ethyl acetate to give the title compound as white crystals (50 mg) m.p. 237-238°. δH (d6DMSO) 8.42 (1H, s), 8.21 (1H, d, J 7.8 Hz), 8.11 (1H, d, J 7.8 Hz), 7.79 (1H, t, J 8.2 Hz), 7.50 (2H, d, J 8.0 Hz), 7.30 (2H, d, J 8.1 Hz), 6.70 (2H, s), 5.50 (2H, br s) and 2.37 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].[NH2:13][CH2:14][C:15]([O-:17])=[O:16].[Na+:18]>CN(C=O)C.O>[Na+:18].[Cl:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:13][CH2:14][C:15]([O-:17])=[O:16])[CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: NCC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(NCC(=O)[O-])cc1Cl
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-chloro-4-fluoro-5-nitrotoluene (2.080 g, 10.97 mmol, as prepared above) in DMF (11.0 mL) at 70° C., was added dropwise, a solution of sodium glycinate (1.065 g, 10.97 mmol, Aldrich, used as received) in water (11.0 mL). The resulting suspension was stirred overnight at 70° C., cooled to room temperature, and the resulting red solid was filtered, washed with acetone (35 mL), and dried under vacuum to give 1.005 g (37%) of the pure (1H NMR) title compound as a red powder; 1H NMR (DMSO-d6): δ2.184 (s, 3H), 3.396 (d, 2H, J=4.2 Hz), 6.852 (s, 1H), 7.991 (s, 1H), 8.671 (s, 1H).
Reaction SMILES: S(Cl)([Cl:3])=O.N1C=CC=CC=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18](O)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH:18]([Cl:3])[C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=2)=[CH:21][CH:22]=1
Reactant: OC(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Clc1ccc(CC(Cl)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of of thionyl chloride in toluene is cooled to 0° C., and a catalytic amount of pyridine is added. A solution of 1,2-di(4-chlorophenyl)ethan-1-ol in toluene is then added drop wise. Upon completion addition of addition, the reaction mixture is allowed to warm to ambient temperature where it stirs for about 30 minutes. The reaction mixture is washed with water, dried with sodium sulfate, filtered, and concentrated under reduced pressure, yielding the subject compound.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][OH:7].C([O-])(O)=O.[Na+].[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH2:13]([O:20][C:21]([N:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][OH:7])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCC1CCCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCCC1CO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-Pyrrolidinemethanol (2 g, 20 mmol) was dissolved in CH2Cl2 (25 mL) followed by addition of saturated NaHCO3 (25 mL). To this vigorously stirred mixture was added benzylchloroformate via syringe slowly at 0° C. The reaction mixture was then stirred at room temperature for 4 h. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3×80 mL). The combined organic layer was washed with brine, and dried (Na2SO4). Removal of the solvent provided 4.7 g of the title compound, which was used, directly for next step. 1H NMR (CDCl3): δ 7.50-7.30 (aromatic Hs, 5H); 5.17 (s, 2H); 4.04 (brs, 1H); 3.66 (m, 2H); 3.57 (m, 1H); 3.42 (m, 1H); 2.04 (m, 1H); 1.89 (m, 1H); 1.83 (m, 1H); 1.62 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.C(N=C=N[CH2:34][CH2:35][CH2:36][N:37]([CH3:39])C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.N1CCCC1>C(Cl)Cl.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:19][CH2:20][CH:21]([C:24]([N:37]3[CH2:36][CH2:35][CH2:34][CH2:39]3)=[O:26])[CH2:22][CH2:23]2)=[O:17])=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1cc2ccccc2n1Cc1ccc(Cl)cc1)N1CCC(C(=O)N2CCCC2)CC1
Reaction time: 8 h

Procedure:
1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (100 mg, 0.252 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (97 mg, 0.504 mmol), and 1-Hydroxybenzotriazole (68 mg, 0.504 mmol) were dissolved in 3.0 mL of DCM. The reaction was allowed to stir for 10 minutes before N,N-Diisopropylethylamine (88 μL, 0.504 mmol) and pyrrolidine (41.7 μL, 0.504 mmol) were added. The reaction was allowed to stir overnight. The reaction was diluted with water and ethyl acetate. The layers were separated and the organic layer was washed with another aliquot of water. The ethyl acetate layer was washed with saturated citric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude material was purified in silica gel using the gradient 100% DCM to 5% 7M NH3 in methanol diluted with 95% DCM. After purification, pure white solid was obtained. Yield: 83 mg (White solid)
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([CH3:20])=[C:15]([CH:19]=2)[C:16]([OH:18])=[O:17])=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:28](O)[CH3:29]>>[CH2:28]([O:17][C:16](=[O:18])[C:15]1[CH:19]=[C:11]([CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:22][CH:21]=2)[CH:12]=[CH:13][C:14]=1[CH3:20])[CH3:29]
Reactant: Cc1ccc(CCNC(=O)c2ccc(Cl)cc2)cc1C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(CCNC(=O)c2ccc(Cl)cc2)ccc1C

Procedure:
6 Grams of 5-(2-[4-chloro-benzamido]-ethyl)-2-methyl-benzoic acid in 50 ml of ethanol are boiled for 4 hours with 1.5 ml of concentrated sulfuric acid at the reflux condenser. Subsequently the alcohol is distilled off for the most part, the residue is mixed with ice, the precipitate is filtered off with suction, is treated with diluted ammonia in order to remove the acid still present and is recrystallized from diluted ethanol. The 5-(2-[4-chloro-benzamido]-ethyl)-2-methyl-benzoic acid-ethylester obtained melts at a temperature in the range of from 116° to 118° C.
Reaction SMILES: [O:1]=[C:2]1[C@@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:6][CH2:5][CH2:4][NH:3]1.[CH3:16]I>>[CH3:16][N:3]1[CH2:4][CH2:5][CH2:6][C@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1=O
Reactant: CI
Product: CN1CCC[C@H](NC(=O)OC(C)(C)C)C1=O

Procedure:
(S)-tert-butyl 1-methyl-2-oxopiperidin-3-ylcarbamate was prepared from (S)-tert-butyl 2-oxopiperidin-3-ylcarbamate (Example 7) and methyl iodide according to the general procedure of Example 9. The crude product was purified by column chromatography, eluting with 100% ethyl acetate, to provide compound (2c) in 31% yield.
Reaction SMILES: [CH2:1]([SH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1C=CC=CC=1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(#N)C>[C:26]1([NH:32][C:33](=[O:34])[S:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCS
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCSC(=O)Nc1ccccc1
Temperature: 25 °C
Yield: 86.4 %

Procedure:
To a mixture of 15.69 g (54.8 mmol) of octadecanethiol, 250 ml of acetonitrile, and 5 ml (4.9 g, 62 mmol) of pyridine and under a nitrogen atmosphere, 6.52 g (0.54.8 mmol) of phenylisocyanate were added all at once. The mixture was heated to reflux for 2 hours, then cooled to room temperature. The product crystallized, was collected by filtration, and was recrystallized from acetonitrile to give 19.19 g of S-octadecyl phenylcarbamothioate (Compound PS-1), mp 85.5–86.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:45][O:46][C:47](=[O:50])[CH2:48][NH2:49].CCN(C(C)C)C(C)C>O.CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([NH:49][CH2:48][C:47]([O:46][CH3:45])=[O:50])=[O:19])[CH2:10][CH:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCOCC1)C(=O)O
Reactant: COC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CNC(=O)[C@H](CC1CCOCC1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
A 100-mL round-bottomed flask was charged with N-(tert-butoxycarbonyl)-3-(tetrahydro-2H-pyran-4-yl)-L-alanine (3.11 g, 11.38 mmol), HATU (5.41 g, 14.22 mmol), glycine methyl ester hydrochloride (1.714 g, 13.65 mmol, Sigma-Aldrich, St. Louis, Mo.), and 10 mL of DMF. To this was added Hünig's base (4.37 mL, 25.03 mmol). After 30 min at room temperature, the mixture was diluted with water (100 mL) and extracted with EtOAc (2×200 mL). The layers were separated and the organic extracts were washed with water (2×100 mL) and brine (50 mL), dried (MgSO4), filtered and concentrated to give methyl N-(tert-butoxycarbonyl)-3-(tetrahydro-2H-pyran-4-yl)-L-alanylglycinate (3.00 g) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:19][CH:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][C:27]=4[CH:32]=[O:33])[CH2:22][CH2:21]3)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-]#N.[Na+].[C:37](O)(=[O:39])C>C(Cl)(Cl)Cl.CO.[O-2].[O-2].[Mn+4]>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:19][CH:20]3[CH2:21][CH2:22][N:23]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][C:27]=4[C:32]([O:39][CH3:37])=[O:33])[CH2:24][CH2:25]3)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(OCC3CCN(c4ccncc4C=O)CC3)cc2C1
Agent: [Mn+4]
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cnccc1N1CCC(COc2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a soution of 7-[1-(3-formylpyridin-4-yl)piperidin4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (50 mg) in a mixture of chloroform (0.5 ml) and methanol (0.2 ml) were added sodium cyanide (8 mg), manganese dioxide (250 mg) and acetic acid (0.003 ml), and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was filtrated and the solvent was evaporated. The obtained residue was purified by preparative thin layer chromatography (chloroform:methanol=15:1) and dried under reduced pressure to give the title compound (50 mg).
Reaction SMILES: Br.[NH2:2][C:3]1[C:4]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]3([C:30]4[C:21](=[CH:22][C:23]5[O:28][CH2:27][CH2:26][O:25][C:24]=5[CH:29]=4)[O:20][CH2:19]3)[C:11]2=[O:31])=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].N1C=CC=CC=1>ClCCl>[O:31]=[C:11]1[C:12]2([C:30]3[C:21](=[CH:22][C:23]4[O:28][CH2:27][CH2:26][O:25][C:24]=4[CH:29]=3)[O:20][CH2:19]2)[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]1[CH2:9][C:4]1[C:3]([NH:2][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccnc1CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Agent: Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccnc1CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.5 %

Procedure:
A 50 mL round-bottom flask was charged with 1′-[(3-aminopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1H)-one hydrobromide (0.56 g, 1.0 mmol), methanesulfonyl chloride (0.12 g, 1.1 mmol), pyridine (0.25 g, 3.0 mmol) and dichloromethane (20 mL). The reaction mixture was stirred under nitrogen at ambient temperature for 16 h and diluted with dichloromethane (50 mL). The organic phase was washed with water (2×50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 0% to 100% gradient of ethyl acetate in dichloromethane, followed by recrystallization from methanol (10 mL) to afford N-{2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-yl}methanesulfonamide (0.18 g, 38%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 9.64 (s, 1H), 8.27 (dd, J=4.6, 1.2 Hz, 1H), 7.78 (dd, J=8.0, 1.4 Hz, 1H), 7.34 (dd, J=8.0, 4.7 Hz, 1H), 7.21-7.10 (m, 2H), 6.96 (t, J=7.4 Hz, 1H), 6.77 (d, J=7.8 Hz, 1H), 6.48 (s, 1H), 6.46 (s, 1H), 5.17 (ABq, 2H), 4.73 (ABq, 2H), 4.18-4.05 (m, 4H), 3.14 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 177.6, 154.9, 151.0, 147.1, 144.5, 143.2, 138.1, 134.5, 132.6, 132.2, 132.1, 129.0, 123.8, 123.2, 122.2, 112.3, 109.4, 99.0, 79.6, 64.6, 64.1, 57.8, 41.8, 40.6; MS (ES+) m/z 479.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)=[N:19][N:20]=2)[C@@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:35](Cl)(=[O:39])[CH2:36][CH2:37][CH3:38]>C(Cl)Cl>[C:35]([O:15][C@@H:13]([CH3:14])[C@@H:12]([NH:11][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=1[CH3:10])[C:16]1[O:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=2)=[N:19][N:20]=1)(=[O:39])[CH2:36][CH2:37][CH3:38]
Reactant: CCCC(=O)Cl
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)O[C@@H](C)[C@@H](Nc1ccc(C#N)c(Cl)c1C)c1nnc(-c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
To a 50 mL round bottomed flask was added 2-chloro-4-((1R,2S)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-3-methylbenzonitrile (200 mg, 0.508 mmol, pyridine (1 mL, 12.41 mmol) and methylene chloride (15 mL). Butyryl chloride (0.26 mL, 2.54 mmol) was then added dropwise and the mixture was stirred at room temperature for 18 h. The reaction mixture was then quenched with 10% aq HCl (15 mL) and methylene chloride (30 mL) was added. The phases were partitioned and the aqueous phase extracted with methylene chloride (30 mL) (×2). The combined organics were washed with a saturated solution of sodium hydrogen carbonate, dried (Na2SO4) and concentrated to furnish a yellow oil (0.139 g, 60%). 1H NMR (Acetone d6, 400 MHz) δ 8.23 (d, J=9 Hz, 2 H), 8.02 (d, J=9 Hz, 1 H), 7.54 (d, J=9 Hz, 1 H), 7.02 (d, J=9 Hz, 1 H), 5.74 (d, J=9 Hz, 1 H), 5.72-5.64 (m, 1H), 5.48 (dd, J=5 and 8 Hz, 1H), 2.37 (s, 3 H), 2.33-2.25 (m, 2H), 1.64-1.50 (m, 2 H), 1.47 (d, J=6 Hz, 3 H) and 0.92 (t, J=8 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[N:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH3:10][NH:11][CH3:12]>C(O)C>[NH2:1][C:2]1[C:7]([N:11]([CH3:12])[CH3:10])=[N:6][C:5]([Br:9])=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: CNC
Solvent: CCO
Product: CN(C)c1nc(Br)cnc1N

Procedure:
2-Amino-3,5-dibromopyrazine (1.0 g) was dissolved in a solution of dimethylamine in ethanol (33% w/v; 20 ml) and the solution was heated under reflux for 18 hours. Volatile material was removed by evaporation and the residue was purified by elution with dichloromethane through a silica gel Mega Bond Elut column to give 2-amino-5-bromo-3-dimethylaminopyrazine (0.67 g); 1H NMR (d6 -DMSO): 2.75 (s, 6H), 6.1-6.2 (br s, 2H), 7.6 (s, 1H); mass spectrum (+ve CI): 217 (M+H)+.