Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([C:19]([F:22])([F:21])[F:20])[CH:10]=1>[Cl-].[Na+].O>[OH:4][CH2:3][CH2:2][N:1]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([C:19]([F:22])([F:20])[F:21])[CH:10]=1)[CH2:5][CH2:6][OH:7]
Reactant: FC(F)(F)c1cc(Cl)c2ccccc2n1
Reactant: OCCNCCO
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: OCCN(CCO)c1cc(C(F)(F)F)nc2ccccc12
Temperature: 80 °C
Reaction time: 19 h

Procedure:
Diethanolamine (20 mL) was added to 4-chloro-2-trifluoromethylquinoline (5.04 g), and the mixture was stirred at 80° C. for 19 hr. Brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 4-[N,N-bis(2-hydroxyethyl)amino]-2-trifluoromethylquinoline (3.40 g) as a white powder.
Reaction SMILES: [O:1]1[CH2:6][CH:5](O)[CH2:4][O:3][CH2:2]1.[N+](=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N-]>ClCCl.CCCCCCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][CH:5]1[CH2:6][O:1][CH2:2][O:3][CH2:4]1)[CH3:15]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: OC1COCOC1
Agent: [Rh]
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)CC1COCOC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.3 %

Procedure:
To a solution of 1,3-dioxan-5-ol (1.04 g, 10.0 mmol) in dichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyl diazoacetate (0.95 mL, 9.03 mmol). The reaction mixture is stirred at rt for 4 h. The reaction mixture is diluted with heptane and filtered. The filtrate is evaporated, and the residue is purified by chromatography on silica gel; elution with EtOAc:heptane (1:4) gives 0.65 g of the product 454. 1H NMR (CDCl3) δ 5.04 (s, 1H), 4.89 (s, 1H), 4.25-4.20 (m, 5H), 3.98 (dd, 1H), 3.78 (dd, 1H), 3.65 (d, 1H), 1.29 (t, 3H)
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C([N:15]([CH2:18]C)CC)C.C(Cl)(Cl)=[S:21].[OH-].[NH4+]>C1COCC1>[NH:1]([CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1)[C:18]([NH2:15])=[S:21]
Reactant: CCN(CC)CC
Reactant: S=C(Cl)Cl
Reactant: CCOC(=O)N1CCC(N)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(NC(N)=S)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.3 %

Procedure:
A solution of ethyl 4-aminopiperidine-1-carboxylate (4.3 g, 0.025 mol) in dry THF was cooled to 0° C. and then treated with triethylamine (3.83 mL, 27.5 mol) and thiophosgene (2.1 mL, 27.5 mmol). The mixture was stirred for 1.5 hours at room temperature, cooled at 0° C. and then treated with ammonium hydroxide solution (7.7 mL, 28% in water). The mixture was stirred for approximately 12 hours and then concentrated by evaporation. The residue was taken up into ethyl acetate and the mixture was treated with a saturated solution of NaHCO3 and brine. The organic phase was separated, dried over sodium sulfate and then concentrated to dryness. The residue was taken up into diethyl ether and a resulting solid was collected by filtration and washed with diethyl ether to provide ethyl 4-thioureidopiperidine-1-carboxylate (4.18 g, 72% V). HNMR (dmso-d6): 7.57 (1H, d), 6.9 (1H, s), 4.05 (1H, bs), 4.02 (2H, q), 3.86 (2H, d), 2.89 (2H, bs), 1.82 (2H, bs), 1.20 (2H, m), 1.17 (3H, t).
Reaction SMILES: [CH2:1]([C:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:6][N:5]=1)[CH2:2][CH3:3].[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>>[CH2:12]([O:11][C:9]([C:7]1[CH:8]=[C:4]([CH2:1][CH2:2][CH3:3])[N:5]([CH2:19][C:18]2[CH:21]=[CH:22][C:15]([Br:14])=[CH:16][CH:17]=2)[N:6]=1)=[O:10])[CH3:13]
Reactant: BrCc1ccc(Br)cc1
Reactant: CCCc1cc(C(=O)OCC)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1cc(C(=O)OCC)nn1Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Ethyl 3-n-propylpyrazole-5-carboxylate (8.0 g, 43.0 mmol), 4-bromobenzyl bromide (11.0 g, 43.0 mmol) and potassium carbonate (5.9 g, 43.0 mmol) were dissolved in DMF (433 mL, 5590 mmol). The resulting suspension was stirred at room temperature over approximately 48 hours. The material was concentrated, then diluted with aqueous NaHCO3 and diethyl ether. The aqueous layer was further extracted with diethyl ether. The combined organics were dried over MgSO4, filtered and concentrated. The residue was purified using flash chromatography (1st 40:1 hexanes/EtOAc; 2nd 5:1 hexanes/EtOAc). The two isomers were separated and analyzed by NMR and NOE: 1-(4-bromobenzyl)-5-propyl-1H-pyrazole-3-carboxylic acid ethyl ester (5.7 g) and 2-(4-bromobenzyl)-5-propyl-2H-pyrazole-3-carboxylic acid ethyl ester.
Reaction SMILES: [C:1](=[NH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1.O>C1(C)C=CC=CC=1>[C:1](=[N:14][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Nc1cccc(O)c1
Solvent: O
Solvent: Cc1ccccc1
Product: Oc1cccc(N=C(c2ccccc2)c2ccccc2)c1

Procedure:
3-(Benzhydrylidene-amino)-phenol was prepared as follows: A stirred solution of benzophenone imine (15.0 g, 82.8 mmol) and 3-aminophenol (9.03 g, 82.8 mmol) in 25 mL toluene was heated at reflux with removal of H2O with a Dean-Stark trap for 3.5 h. The crystals that formed from the cooled reaction mixture were collected by vacuum filtration, washed with hexanes and air dried. In this manner, 3-(benzhydrylidene-amino)-phenol was obtained as a light yellow solid (17.3 g, 76%): 1H NMR (CDCl3) δ 7.64 (d, 2H, J=7.1 Hz), 7.38 (d, 1H, J=7.1 Hz), 7.34-7.15 (m, 7H), 7.04 (d, 2H, J=7.2 Hz), 6.88 (t, 1H, J=8.1 Hz), 6.82 (d, 1H, J=8.2 Hz), 6.23 (s, 1H), 6.21 (d, 1H, J=7.8 Hz). Anal. Calc. for C19H15NO: C, 83.49; H, 5.53; N, 5.12. Found: C, 83.51; H, 5.65; N, 5.03.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16]C)=[CH:13][CH:14]=2)[N:9]([CH3:18])[C:8]=1[CH3:19])=[O:6])[CH2:2][CH3:3].B(Br)(Br)Br>>[CH2:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=2)[N:9]([CH3:18])[C:8]=1[CH3:19])=[O:6])[CH2:2][CH3:3]
Reactant: CCCNC(=O)c1c(C)n(C)c2cc(OC)ccc12
Agent: BrB(Br)Br
Product: CCCNC(=O)c1c(C)n(C)c2cc(O)ccc12

Procedure:
This material was prepared from 6-methoxy-1,2-dimethyl-1H-indol-3-carboxylic acid propylamide 58a by treatment with BBr3 in a manner as previously described for example 1d. 1H NMR (300 MHz, CD3OD) δ7.50 (1H, d, J=8.7 Hz), 6.74 (1H, d, J=1.9 Hz), 6.68 (1H, dd, J=1.9, 8.7 Hz), 3.61 (3H, s), 3.32 (2H, m), 2.58 (3H, s), 1.66 (2H, m), 1.01 (3H, t, J=7.4 Hz). LCMS (ESI+) [M+H]/z Calc'd 247, found 247.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([CH2:21][CH3:22])[C:19]([C:23](=[O:26])[CH2:24][CH3:25])=[CH:18][C:17]=2[CH3:27])=[CH:12][CH:11]=1.C(OCC)(=O)C>C1COCC1>[Br:1][C:18]1[C:17]([CH3:27])=[C:16]([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)[N:20]([CH2:21][CH3:22])[C:19]=1[C:23](=[O:26])[CH2:24][CH3:25]
Reactant: CCC(=O)c1cc(C)c(-c2ccc(Cl)cc2)n1CC
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(=O)c1c(Br)c(C)c(-c2ccc(Cl)cc2)n1CC
Temperature: -78 °C
Reaction time: 5 h
Yield: 77.9 %

Procedure:
A solution of N-bromosuccinimide (0.35 g, 1.99 mmol) in THF (10 ml) was added dropwise to a stirred solution of 1-(5-(4-chlorophenyl)-1-ethyl-4-methyl-1H-pyrrol-2-yl)propan-1-one (compound 51b, 0.5 g, 1.81 mmol) in THF (25 ml) at about −78° C. The resulting reaction mixture was stirred at about −78° C. for 5 hr. The reaction mixture was then allowed to warm to 25° C. slowly during further 3 to 4 hr. The progress of the reaction was monitored by TLC. The solvent was evaporated from the reaction mixture under reduced pressure and to the residue so obtained was added ethyl acetate (50 ml). The mixture so obtained was washed with saturated sodium bicarbonate solution (1×30 ml) followed by washing with water (1×30 ml). The combined organic layer was then dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product, which was then purified by flash column chromatography 10% ethyl acetate in hexanes as an eluent to obtain the title compound (0.5 g, 78.0%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:27]=[CH:26][C:14]([O:15][CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[CH3:25][CH:16]([O:15][C:14]1[CH:26]=[CH:27][C:11]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][NH:2][C:35](=[O:37])[CH3:36])=[CH:10][CH:9]=2)=[CH:12][CH:13]=1)[CH2:17][NH:18][S:19]([CH:22]([CH3:23])[CH3:24])(=[O:21])=[O:20]
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(CCN)cc2)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCc1ccc(-c2ccc(OC(C)CNS(=O)(=O)C(C)C)cc2)cc1
Yield: 38.9 %

Procedure:
The title compound (108 mg, 39%, slow crystallizing foam) was prepared from (2-{4-[4-(2-aminoethyl)phenyl]phenoxy}propyl)[(methylethyl)sulfonyl]amine hydrochloride (250 mg, 0.664 mmol, prepared in example 39), methylene chloride (4.5 mL, anhydrous), triethylamine (0.09 mL, 0.664 mmol), and acetyl chloride (0.05 mL, 0.664 mmol) in a manner analogous to the procedure described in Example 40.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH:25][CH:26]([CH3:32])[CH2:27][CH2:28][CH2:29][C:30]#[CH:31]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[CH2:1]([O:11][C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:31]#[C:30][CH2:29][CH2:28][CH2:27][CH:26]([OH:25])[CH3:32])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(Br)cc2)nc1
Reactant: C#CCCCC(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCOc1cnc(-c2ccc(C#CCCCC(C)O)cc2)nc1
Temperature: 90 °C
Yield: 86.7 %

Procedure:
In a reactor equipped with a stirrer and a thermometer, 5-decyloxy-2-(4-bromophenyl)pyrimidine (25 g), optically active 6-hydroxy-1-heptyne (8.58 g), dichlorobis(triphenylphosphine)palladium (0.1 g), copper iodide (0.1 g), triphenylphosphine (0.52 g) and triethylamine (200 ml) are charged and heated up to 90° C. to carry out a reaction for 10 hours. After evaporating triethylamine off under reduced pressure, toluene and 10% hydrochloric acid are added to the residue for extraction, and the organic layer is washed with water and evaporated under reduced pressure. A resulting residue is purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain (-)-5-decyloxy-2-[4-(6-hydroxyheptynyl)phenyl]-pyrimidine (23.4 g). [α]D20 =-3.3° (c=1.035, CHCl3).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[N:9]=[CH:10][C:11]([C:26]2[CH:36]=[CH:35][C:29]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])=[CH:28][CH:27]=2)=[N:12][C:13]=1[C:14]1[O:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[OH:25])=[N:17][N:18]=1.Br[CH2:38][CH3:39].O>CN(C=O)C>[NH2:7][C:8]1[N:9]=[CH:10][C:11]([C:26]2[CH:36]=[CH:35][C:29]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])=[CH:28][CH:27]=2)=[N:12][C:13]=1[C:14]1[O:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH2:38][CH3:39])=[N:17][N:18]=1
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccccc4O)o3)n2)cc1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccccc1-c1nnc(-c2nc(-c3ccc(C(=O)N(C)C)cc3)cnc2N)o1
Temperature: 62.5 °C
Reaction time: 0.33 h
Yield: 72.5 %

Procedure:
Potassium carbonate (25.46 mg, 0.1842 mmol) was added to a mixture of 4-[5-amino-6-[5-(2-hydroxyphenyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-N,N-dimethyl-benzamide (50 mg, 0.1228 mmol) in DMF (1 mL) at room temperature. Colour change observed from yellow to orange. The resulting suspension was heated at 60-65° C. and bromoethane (14.72 mg, 10.01 μL, 0.1351 mmol) was added slowly. After the addition is complete the reaction heated at 60-65° C. for 30 min. The reaction mixture was cooled to room temperature. Water (2 mL) was added slowly at and the mixture stirred at room temperature for 20 min. A precipitate formed and was filtered and washed with water. The solid was re-dissolved in DCM and dried over MgSO4, filtered and evaporated to dryness. The solid was triturated with acetonitrile to give the product as a yellow solid (38.3 mg, 73% yield); 1H NMR (400.0 MHz, DMSO) d 1.49 (t, 3H), 2.97-3.02 (m, 6H), 4.24-4.29 (m, 2H), 7.17-7.18 (m, 1H), 7.20 (d, 1H), 7.32-7.35 (m, 2H), 7.53 (d, 1H), 7.65 (br s, 2H), 8.05 (d, 1H), 8.17 (d, 2H) and 8.99 (s, 1H) ppm; MS (ES+) 431.24
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([CH3:14])[C:8]=1[C:9]([O:11][CH2:12]C)=[O:10].ClC(OC(Cl)(Cl)Cl)=[O:17]>O>[CH3:14][C:7]1[C:8]2[C:9](=[O:10])[O:11][C:12](=[O:17])[NH:3][C:4]=2[S:5][CH:6]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(C)csc1N
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1csc2[nH]c(=O)oc(=O)c12
Temperature: 100 °C
Reaction time: 5 h
Yield: 67.2 %

Procedure:
Potassium hydroxide (14.77 g, 0.26 mol) was dissolved in 500 mL water. To this solution was added ethyl 2-amino-4-methyl-thiophene-3-carboxylate (24.38 g, 0.13 mol). The solution was heated at 100° C. for 16 hours. The solution was then cooled to 0° C. and trichloromethyl chloroformate (23.8 mL, 0.20 mol) was added slowly. The solution was allowed to come to room temperature and further stirred for 5 hours. The precipitated solid was collected by vacuum filtration to yield 16.0 g (66%) of 5-methyl-1H-thieno[2,3-d][1,3]oxazine-2,4-dione. MP 220° C. 1H-NMR (DMSO-d6) δ 2.30 (d, J=1.2 Hz, 3H), 6.78 (d, J=1.2 Hz, 1H), 12.55 (b, 1H) ppm; EIMS m/z 184 (M+1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].CN(C=[O:27])C>CCOCC>[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH:6][O:27][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Product: COC(=O)[C@H](CO)NO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Serine methyl ester hydrochloride [HOCH2CH(NH2)CO2CH3. HCl] (18.7 g; 0.120 mol) and imidazole (30 g; 0.44 mol) are dissolved in DMF (100 ml) and cooled to 0° C. t-Butyldimethylsilyl chloride (19.5 g; 0.13 mol) is added and the reaction allowed to stir 15 hours at 25° C. The reaction is then diluted with ether (2 L), washed with water (4x 500 ml), dried (MgSO4) and concentrated to yield t-butyldimethylsilyloxyserine methyl ester as an oil which is used directly in Step B.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[O:7][CH2:8][C@@H:9]([NH:31][C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])=[O:33])[CH2:10][C@H:11]([C:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=1)[CH:12]([CH3:14])[CH3:13])([CH3:4])([CH3:3])[CH3:2]>C(O)C.C(O)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:38])[O:7][CH2:8][C@@H:9]([NH:31][C:32]([C:34]([CH3:35])([CH3:37])[CH3:36])=[O:33])[CH2:10][C@H:11]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=1)[CH:12]([CH3:13])[CH3:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: COCCCOc1cc(C(=O)[C@@H](C[C@@H](COC(=O)OC(C)(C)C)NC(=O)C(C)(C)C)C(C)C)ccc1OC
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: COCCCOc1cc(C[C@@H](C[C@@H](COC(=O)OC(C)(C)C)NC(=O)C(C)(C)C)C(C)C)ccc1OC

Procedure:
Carbonic acid (2S,4S)-2-tert-butylcarbonylamino-4-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-5-methyl-hexylester tert-butyl ester (2.67 g) is dissolved in 25 mL of a mixture of ethanol/acetic acid, 2/1 at room temperature. Palladium metal, 10% on charcoal (0.3 g) is added and the suspension placed under an atmosphere of hydrogen at a pressure of 5 bar. Hydrogenation is continued for 3 days at 50° C. with periodic addition of more catalyst. The reaction mixture is filtered and the solvent removed to give an oil. The oil is purified by chromatography on silica-gel eluting with hexane/ethyl acetate mixtures. The product fractions are combined and the solvent is removed to give the title compound as an oil.
Reaction SMILES: [SH2:1].[Na].Cl[C:4]1[C:8]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:7][S:6][N:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](I)[CH3:22]>CN(C=O)C.O>[CH2:21]([S:1][C:4]1[C:8]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:7][S:6][N:5]=1)[CH3:22]
Reactant: CCI
Reactant: S
Reactant: Clc1nsnc1-c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1nsnc1-c1cccnc1
Reaction time: 0.5 h

Procedure:
Sodium hydrogen sulfide (0.25 g, 3.3 mmol) was added to a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (0.59 g, 3 mmol) in DMF (20 ml) at room temperature and the reaction mixture was stirred for 30 min. Potassium carbonate (1.24 g, 9 mmol) and ethyl iodide (0.36 ml, 4.5 mmol) were added and the reaction mixture was stirred for additionally 10 min. Water (50 ml) was added and extracted with ether. The combined ether phases were dried and evaporated to give the title compound.
Reaction SMILES: O1CCCCC1OC1CCCCO1.[Li]CCCC.[S:19]([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)([OH:22])(=[O:21])=[O:20].[S:30]([C:34]1[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=1)([OH:33])(=[O:32])=[O:31].[C:41]1(=[O:47])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>>[S:19]([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)([OH:22])(=[O:21])=[O:20].[S:30]([C:34]1[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=1)([OH:33])(=[O:32])=[O:31].[CH:41]1([OH:47])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: O=C1CCCCC1
Agent: C1CCC(OC2CCCCO2)OC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Li]CCCC
Product: OC1CCCCC1

Procedure:
Scheme 5 shows the synthesis of more highly substituted aryl analogs 19. A suitably protected hydroxy aryl bromide (e.g., as an acid-labile tetrahydropyranyl ether that can be deprotected selectively in the presence of an ester) is lithiated (e.g., n-BuLi) and reacted with cyclohexanone bis-tosylate 1 to give the corresponding cyclohexanol bis-tosylate 14. Base-mediated intramolecular reaction of the alcohol with a tosylate of 26 provides the oxabicyclo[2.2.2]tosylate 15 (same 2 steps as in Scheme 1). The tosylate 15 is then converted in the same 3 step sequence as described in Scheme 4 to give the 2-oxy-substituted ester 16. Selective deprotection of the phenol is then achieved under mild acid conditions to give phenol ester 17. The phenol intermediate 17 is then subjected to an O-arylation reaction (e.g., Chan-Lam coupling reaction with aryl boronic acids; examples in Qiao, J. et al., Synthesis, 829 (2011)) to give the aryl ethers 18, followed by ester deprotection to give the corresponding 2-oxy-substituted carboxylic acid analogs 19.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:9]=[C:10]([CH3:15])[C:11]([OH:14])=[N:12][CH:13]=1.Br[CH2:17][CH:18]1[CH2:20][CH2:19]1.CC(=O)OCC>CN(C=O)C>[Br:7][C:8]1[CH:9]=[C:10]([CH3:15])[C:11](=[O:14])[N:12]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[CH:13]=1
Reactant: BrCC1CC1
Reactant: Cc1cc(Br)cnc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Br)cn(CC2CC2)c1=O
Temperature: 70 °C
Yield: 66 %

Procedure:
Potassium carbonate (1.32 g, 9.57 mmol) was added to 5-bromo-3-methyl-2-hydroxypyridine (600 mg, 3.19 mmol) and bromomethylcyclopropane (861 mg, 6.38 mmol) in DMF (6 mL). After heating at 70° C. for 3 h, EA extractive work up and silica gel chromatography (PE: EA=30:110:1), the title compound (510 mg, yield: 66.0%) was obtained as a white solid. 1H NMR: (CDCl3, 400 MHz) δ: 7.39 (d, J=2.0 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 3.77 (d, J=6.8 Hz, 2H), 2.15 (s, 3H), 0.65-0.60 (m, 2H), 0.40-0.37 (m, 2H). LCMS: 242.1; 244.1 (M+H)+
Reaction SMILES: [CH2:1]([N:3]([CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)[C:4]1[C:5]([CH3:17])=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7](O)=[O:8])[CH3:2].Cl.[NH2:26][CH2:27][C:28]1[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=1[CH3:34].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:34][C:33]1[CH:32]=[C:31]([CH3:35])[NH:30][C:29](=[O:36])[C:28]=1[CH2:27][NH:26][C:7](=[O:8])[C:6]1[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=[C:4]([N:3]([CH2:1][CH3:2])[CH:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[C:5]=1[CH3:17]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CCN(c1cc(C(F)(F)F)cc(C(=O)O)c1C)C1CCN(C)CC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCN(c1cc(C(F)(F)F)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCN(C)CC1
Temperature: 23 °C
Reaction time: 20 h
Yield: 48 %

Procedure:
To a stirred solution of 3-[ethyl(1-methylpiperidin-4-yl)amino]-2-methyl-5-(trifluoromethyl)benzoic acid (crude material, 580 mg, 1.68 mmol) and 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one HCl salt (477 mg, 2.53 mmol) in DMSO (6 mL) was added PyBOP (1.57 g, 3.02 mmol) and hunig base (650 mg, 5.04 mmol). The reaction mixture was stirred at 23° C. for 20 hours. The reaction mixture was quenched with water and resulting precipitate was collected. The solid was purified by silica gel column chromatography (NH—SiO2 ethylacetate/MeOH=25/1) to give the titled compound as a white amorphous (386 mg, 48% yield). 1HNMR (400 MHz, CDCl3) δppm; 7.31 (s, 1H), 7.27 (s, 1H), 7.18 (t, J=5.7 Hz, 1H), 5.95 (s, 1H), 4.55 (d, J=5.9 Hz, 2H), 3.17 (dq, J=6.4, 3.3 Hz, 2H), 3.08 (q, J=7.0 Hz, 2H), 2.81 (m, 2H), 2.70 (m, 1H), 2.40 (s, 3H), 2.33 (s, 3H), 2.23 (s, 3H), 2.21 (s, 3H), 1.78-1.93 (m, 2H), 1.70 (m, 2H), 0.84 (t, J=7.0 Hz, 3H); MS (ES) [M+H] 479.2, [M+Na] 501.3; HPLC 96.8% purity.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:22]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)(=[NH:24])[NH2:23].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:20])[CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([NH:29][C:28]1[CH:30]=[CH:31][C:25]([C:22](=[NH:23])[NH2:24])=[CH:26][CH:27]=1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N=C(N)c1ccc(N)cc1
Reactant: O=C(O)C(C(=O)OCc1ccccc1)c1ccccc1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N=C(N)c1ccc(NC(=O)C(C(=O)OCc2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
10 g (37 mmol) phenyl malonic acid monobenzyl ester and 7.7 g (37 mmol) 4-amidino aniline hydrochloride were dissolved in 60 ml DMF and cooled to 0° C. 12.2 g (37 mmol) TOTU and 19 ml (111 mmol) DIPEA were added and the mixture stirred at rt overnight. The solvent was removed, the residue taken up in ethyl acetate, and extracted with 10% sodium carbonate solution and brine. After drying over sodium sulfate, the solution was evaporated to dryness and extracted with diethyl ether twice. The remaining solid product was sufficiently pure.