Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[C:5]2[O:10]C[N:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][C:6]=2[CH:15]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[N:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOCCOC.O>[C:11]([NH:8][CH2:7][C:6]1[CH:15]=[C:2]([C:29]2[CH:30]=[N:31][C:26]([C:25]([F:36])([F:35])[F:24])=[CH:27][CH:28]=2)[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[C:5]=1[OH:10])([CH3:14])([CH3:12])[CH3:13]
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Reactant: CC(C)(C)N1COc2c(cc(Br)cc2-c2ccc(Cl)c(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOCCOC
Product: CC(C)(C)NCc1cc(-c2ccc(C(F)(F)F)nc2)cc(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 68 °C
Yield: 15.2 %

Procedure:
A mixture of 6-bromo-3-(tert-butyl)-8-(3,4-dichlorophenyl)-3,4-dihydro-2H-benzo[e][1,3]oxazine (0.743 g, 1.80 mmol), (6-(trifluoromethyl)pyridin-3-yl)boronic acid (0.685 g, 2.0 equiv), and potassium carbonate (0.995 g, 4 equiv) in 2-methoxyethyl ether (32 mL) and water (6.5 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)Pd (0) (0.120 g, 5.8 mol %) was added and the resulting mixture was heated at 65-71° C. for 2 hours. The cooled reaction mixture was concentrated and the resulting residue was purified by column chromatograph to give 3-((tert-butylamino)methyl)-3′,4′-dichloro-5-(6-(trifluoromethyl)pyridine-3-yl)-[1,1′-biphenyl]2-ol (0.128 g). The free base was dissolved in methanol, and to the solution 37% HCl was added. The resulting solid was filtered and rinsed with ethyl acetate to give 3-((tert-butylamino)methyl)-3′,4′-dichloro-5-(6-(trifluoromethyl)pyridine-3-yl)-[1,1′-biphenyl]2-ol hydrochloride (0.126 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH:7]([CH2:14][CH2:15][CH3:16])[CH2:6]2.[Br:17]Br.C1CCN2C(=NCCC2)CC1>CC#N>[Br:17][C:8]1[C:7]([CH2:14][CH2:15][CH3:16])=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]=1[OH:13]
Reactant: CCCC1CC(=O)c2ccc(OC)cc2C1
Reactant: BrBr
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1cc2cc(OC)ccc2c(O)c1Br

Procedure:
Treatment of 6-(methyloxy)-3-propyl-3,4-dihydro-1(2H)-naphthalenone (93) (0.50 g, 2.29 mmol) with bromine followed by DBU in CH3CN gave 0.62 g of compound 94 as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 1.01 (t, J=7.4 Hz, 3H), 1.65-1.75 (m, 2H), 2.79 (t, J=7.7 Hz, 2H), 3.90 (s, 3H), 6.06 (s, 1H), 7.00 (d, J=2.4 Hz, 1H), 7.08 (dd, J1=9.1 Hz, J2=2.4 Hz, 1H), 7.17 (s, 1H), 8.07 (d, J=9.1 Hz, 1H). LCMS (ESI): m/z 295 (M+H)+, m/z 293 (M−H)−.
Reaction SMILES: Br[C:2]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10].[OH:17][CH2:18][CH:19]=[C:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(CC)CC)C>C(O)C>[C:11]1([C:2]2([N:23]3[CH2:24][CH2:25][C:20](=[CH:19][CH2:18][OH:17])[CH2:21][CH2:22]3)[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]2=[O:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1NC(=O)C(Br)(c2ccccc2)C(=O)N1
Reactant: OCC=C1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1NC(=O)C(c2ccccc2)(N2CCC(=CCO)CC2)C(=O)N1
Yield: 16.5 %

Procedure:
A mixture of 5-Bromo-5-phenylbarbituric Acid (2.45 g), 4-(hydroxyethylidene)piperidine (1.053 g) and triethylamine (1.15 ml) in 50 ml of ethanol is refluxed for 2 hours. The solvent is evaporated under reduced pressure and the residue is purified by silica gel chromatography (40 g; eluent: ethyl acetate/petroleum ether 8:2), to give 450 mg of the product.
Reaction SMILES: Br[C:2]1SC2C=C(OC)C=CC=2[N:6]=1.ClC1C=C(B(O)O)C=NC=1OC.Br[C:26]1[N:31]=[CH:30][C:29]([C:32]2[S:33][C:34]3[CH:40]=[C:39](OC)[CH:38]=[CH:37][C:35]=3[N:36]=2)=[CH:28][CH:27]=1>>[S:33]1[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=[C:32]1[C:29]1[CH:28]=[CH:27][C:26]([NH:6][CH3:2])=[N:31][CH:30]=1
Reactant: COc1ccc2nc(-c3ccc(Br)nc3)sc2c1
Reactant: COc1ccc2nc(Br)sc2c1
Agent: COc1ncc(B(O)O)cc1Cl
Product: CNc1ccc(-c2nc3ccccc3s2)cn1

Procedure:
2-Bromo-6-methoxy-1,3-benzothiazole (49 mg, 0.20 mmol) and (5-chloro-6-methoxypyridin-3-yl)boronic acid (45 mg, 0.24 mmol) were reacted according to the procedure used for the preparation of 2-(6-bromopyridin-3-yl)-6-methoxy-1,3-benzothiazole to give the title compound (0.2 mg). 1H NMR (CHLOROFORM-d: CD3OD) δ 8.51 (d, 1 H) 8.03 (dd, 1 H) 7.87 (d, 1 H) 7.43 (d, 1 H) 7.10 (dd, 1 H) 4.08 (s, 3 H) 3.88 (s, 3 H); MS m/z (M+H) 291.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH2:6][CH2:7][C:8]([CH2:14][CH2:15][CH2:16][CH:17]([CH2:19][CH2:20][CH2:21][CH:22]([CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH3:23])[CH3:18])([CH3:13])[O:9]2)=[C:4]([CH3:30])[C:3]=1[OH:31].[C:32](O)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[N:35][CH:34]=1.C(OC(=O)C1C=CC=NC=1)(=O)C1C=CC=NC=1.C(Cl)(=O)C1C=CC=NC=1.Cl>N1C=CC=CC=1>[CH3:12][C:11]1[C:2]([CH3:1])=[C:3]([O:31][C:32]([C:33]2[CH:38]=[CH:37][CH:36]=[N:35][CH:34]=2)=[O:39])[C:4]([CH3:30])=[C:5]2[CH2:6][CH2:7][C@:8]([CH2:14][CH2:15][CH2:16][C@@H:17]([CH2:19][CH2:20][CH2:21][C@@H:22]([CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH3:23])[CH3:18])([CH3:13])[O:9][C:10]=12
Reactant: O=C(O)c1cccnc1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Agent: Cl
Agent: O=C(Cl)c1cccnc1
Agent: O=C(OC(=O)c1cccnc1)c1cccnc1
Solvent: c1ccncc1
Product: Cc1c(C)c2c(c(C)c1OC(=O)c1cccnc1)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2

Procedure:
More specifically, dl-α-tocopherol is reacted with a reactive derivative of nicotinic acid such as nicotinic anhydride or nicotinic chloride in the presence of a hydrochloride and pyridine, and the resulting reaction product is post-treated and purified by column chromatography, whereby pure dl-α-tocopheryl nicotinate is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[CH:14]=[C:13]3[O:18][CH2:19][CH2:20][O:21][C:12]3=[CH:11][C:10]=2[NH:9][CH:8]=1)=[O:6].[H-].[Na+].Br.Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[CH:14]=[C:13]3[O:18][CH2:19][CH2:20][O:21][C:12]3=[CH:11][C:10]=2[N:9]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:8]=1)=[O:6]
Reactant: Cc1ccc(C(=O)c2c[nH]c3cc4c(cc3c2=O)OCCO4)cc1C
Reactant: BrCc1ccccn1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3ccccn3)c3cc4c(cc3c2=O)OCCO4)cc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 58 mg (0.17 mmol) of 8-(3,4-dimethyl-benzoyl)-2,3-dihydro-6H-[1,4]dioxino[2,3-g]quinolin-9-one, 18 mg of 60% sodium hydride, 57 mg of 2-bromomethylpyridine hydrobromide and 1.2 mL of N,N-dimethylformamide. Yield: 63 mg of a white solid: LC-MSD, m/z for C26H22N2O4 [M+H]+=427.5; HPLC retention time: 2.1 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18](F)[CH:17]=2)=[N:4][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:7]=1.[F:24][C:25]([F:39])([F:38])[C@H:26]([O:36][CH3:37])[CH2:27][NH:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH2:35])[CH2:31][CH2:30]1.N1C(C)=CC=CC=1C>CS(C)=O>[Cl:1][C:2]1[C:3]([C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([NH:35][C@H:32]3[CH2:31][CH2:30][C@H:29]([NH:28][CH2:27][C@@H:26]([O:36][CH3:37])[C:25]([F:38])([F:39])[F:24])[CH2:34][CH2:33]3)[CH:17]=2)=[N:4][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:7]=1
Reactant: Fc1cc(-c2nc(NCC3CCOCC3)ccc2Cl)c(Cl)cn1
Reactant: CO[C@H](CN[C@H]1CC[C@H](N)CC1)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: CS(C)=O
Product: CO[C@H](CN[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)ccc3Cl)c(Cl)cn2)CC1)C(F)(F)F
Temperature: 120 °C
Reaction time: 20 h

Procedure:
To a solution of 3,5′-dichloro-2′-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridin-6-amine (36 mg, 0.10 mmol) in DMSO (0.4 mL) was added trans-N1-((R)-3,3,3-trifluoro-2-methoxypropyl)cyclohexane-1,4-diamine (48 mg, 0.20 mmol) and 2,6-lutidine (0.023 mL, 0.20 mmol). The mixture was stirred at 120° C. for 20 hr. The cooled reaction mixture was purified by reverse phase HPLC and lyophilized to give 11.4 mg of 3,5′-dichloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2′-(trans-4-((R)-3,3,3-trifluoro-2-methoxypropylamino)cyclohexyl)-2,4′-bipyridine-2′,6-diamine as its TFA salt. LCMS (m/z): 576.2 (MH+), retention time=0.68 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]#[C:18][CH2:19]OS(C)(=O)=O)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C[CH:26]=[CH:27][CH2:28][NH2:29].[OH-].[Na+].[CH3:32]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]#[C:18][CH2:19][N:29]([CH2:28][CH:27]=[CH2:26])[CH3:32])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: CC=CCN
Reactant: CS(=O)(=O)OCC#CC1CCN(C(=O)Oc2ccc(Cl)cc2)CC1
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: C=CCN(C)CC#CC1CCN(C(=O)Oc2ccc(Cl)cc2)CC1
Yield: 70 %

Procedure:
A solution of 320 mg (0.83 mmol) of 4-(3-Methanesulfonyloxy-prop-1-ynyl)-piperidine-1-carboxylic acid 4-chloro-phenyl ester and 0.79 ml (8.3mmol) of N-methylallylamine in 7 ml of methanol was stirred over night at RT. Then an aqueous solution of 1N NaOH was added and extracted with ether (3×). The organic phase was dried with Na2SO4, filtered and evaporated. The residue was purified by flash column chromatography on silica gel (CH2Cl2/MeOH 19:1 to 9:1) to yield 201 mg (70%) of pure 4-[3-(Allyl-methyl-amino)-prop 1 ynyl]-piperidine-1-carboxylic acid 4-chloro-phenyl ester, MS: 347 (MH+, 1Cl).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH:10]=[CH:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:7]2[CH:21]=[CH:22][CH:23]=[CH:24][C:6]=2[S:5]1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[Cl:35])[C:29](Cl)=[O:30].C1(C2C=CC=CC=2C(Cl)=O)C=CC=CC=1>>[OH:1][CH2:2][CH2:3][CH:4]1[CH:10]=[CH:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:34]([Cl:35])=[C:26]([Cl:25])[CH:27]=3)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:7]2[CH:21]=[CH:22][CH:23]=[CH:24][C:6]=2[S:5]1
Reactant: Nc1ccc(S(=O)(=O)N2C=CC(CCO)Sc3ccccc32)cc1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)c1ccccc1-c1ccccc1
Product: O=C(Nc1ccc(S(=O)(=O)N2C=CC(CCO)Sc3ccccc32)cc1)c1ccc(Cl)c(Cl)c1

Procedure:
Compound 4 as prepared in Example 25 was treated as described in Example 26 with 3,4-dichlorobenzoyl chloride (0.085 g, 0.41 mM) substituted for 2-phenylbenzoyl chloride to give the product. m/z (MH+)537
Reaction SMILES: [N:1]1([CH2:7][C:8]([O:10]CC)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>Cl>[N:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CN1CCCCC1
Agent: Cl
Product: O=C(O)CN1CCCCC1
Yield: 95 %

Procedure:
The solution of ethyl 2-(piperidin-1-yl)acetate (1 g, 5.84 mmol, 1.0 eq) in 8 N HCl was stirred at 95° C. for 16 h. The mixture was concentrated and quenched and extracted as in Intermediate Example 15(b). The solvent was distilled off to afford the product in 95% yield (0.8 g). LC-MS (ESI): Calculated mass: 143.1; Observed mass 144.4 [M+H]+ (rt: 0.21 min).
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[OH:22])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].CN(C)C1C=CC=CC=1.[Br:32][CH2:33][C:34](Br)=[O:35].C(OCC)(=O)C>ClCCl>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:34](=[O:35])[CH2:33][Br:32])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: O=C(Br)CBr
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1O
Solvent: CN(C)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Temperature: 25 °C
Yield: 74.6 %

Procedure:
In 40 ml of dichloromethane are dissolved 4.5 g of 16β-ethyl-17β-hydroxy-4-estren-3-one and 1.8 g of N,N-dimethylaniline and, with ice-cooling and stirring, a solution of 3.5 g of bromoacetyl bromide in 5 ml of dichloromethane is added dropwise to the above solution. The mixture is stirred with ice-cooling for 30 minutes and at room temperature (15°-25° C.) for 5 hours, and 200 ml of ethyl acetate is added. The mixture is washed with 10% cold sulfuric acid (three times), water and saturated aqueous sodium chloride solution in that order and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure. The residue is recrystallized from diisopropyl ether-petroleum ether (1:1) to give 4.7 g of the above-identified compound as colorless crystals.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[F:6][C:7](=[C:17]([F:19])[F:18])[CH2:8][CH2:9][S:10][CH:11]1[NH:15][C:14](=O)[CH2:13][O:12]1.N1C=CC=CC=1>ClCCl>[Cl:3][C:14]1[N:15]=[C:11]([S:10][CH2:9][CH2:8][C:7]([F:6])=[C:17]([F:19])[F:18])[O:12][CH:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1COC(SCCC(F)=C(F)F)N1
Solvent: ClCCl
Solvent: c1ccncc1
Product: FC(F)=C(F)CCSc1nc(Cl)co1
Temperature: 75 °C
Reaction time: 3 h
Yield: 65.3 %

Procedure:
2 g of phosphorus oxychloride were added dropwise to a mixture of 1 g of 2-(3,4,4-trifluoro-3-butenylthio)oxazolidin-4-one and 0.35 g of pyridine under ice cooling and stirred at 70-80° C. for 3 hours. After addition of ice water to the reaction mixture and stirring for 30 minutes, the mixture was extractred with dichloromethane. The extracted layer was washed with water, dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane) to obtain 0.7 g of 4-chloro-2-(3,4,4-trifluoro-3-butenylthio)oxazole (yield 65%). n20D=1.4813.
Reaction SMILES: Br[CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:15])[F:14])(=[O:6])=[O:5].C(N(CC)CC)C>ClCCl>[CH:3]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:15])([F:14])[F:16])(=[O:5])=[O:6])=[CH2:2]
Reactant: O=S(=O)(CCBr)c1ccccc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CS(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 50 °C
Yield: 84.2 %

Procedure:
To a stirred solution of 1-(2-bromo-ethylsulfonyl)-2-trifluoromethyl-benzene (5.4 g, 19 mmol) in dichloromethane (50 ml) was added triethylamine (4.66 ml, 34 mmol). The reaction mixture was heated under reflux conditions to 50° C. for 12 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, EtOAc/heptane) to yield the title compound (3.68 g, 16 mmol; 69%) as off-white semi-solid. MS (ESI): m/z=254.1 [M+NH4]+.
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:10])([CH3:9])[S:4]1)[OH:2].[CH:11]1([N:14]=[C:15]=[O:16])[CH2:13][CH2:12]1>>[CH:11]1([NH:14][C:15]([O:2][N:1]=[C:3]2[N:7]=[C:6]([CH3:8])[C:5]([CH3:10])([CH3:9])[S:4]2)=[O:16])[CH2:13][CH2:12]1
Reactant: O=C=NC1CC1
Reactant: CC1=NC(=NO)SC1(C)C
Product: CC1=NC(=NOC(=O)NC2CC2)SC1(C)C

Procedure:
2-oxo-4,5,5-trimethyl-3-thiazoline-oxime was reacted with cyclopropyl isocyanate as described in Example 4 to yield 2-oxo-4,5,5-trimethyl-3-thiazoline-O-(cyclopropylcarbamoyl)-oxime, m.p. 86°-89° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3]C=1.[C:12]([OH:20])(=[O:19])[CH:13]([CH2:15][C:16]([OH:18])=[O:17])[OH:14].[CH2:21](O)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>O1CCOCC1>[CH2:21]([O:19][C:12](=[O:20])[CH:13]([CH2:15][C:16]([O:18][CH2:3][CH2:4][CH2:5][CH2:6][CH2:1][CH3:11])=[O:17])[OH:14])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C(O)CC(O)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCCCCO
Solvent: C1COCCO1
Product: CCCCCCOC(=O)CC(O)C(=O)OCCCCCC
Temperature: 110 °C

Procedure:
Dihexyl-DL-malate was prepared using a procedure similar to that in Example 4 with p-toluenesulfonic acid as the catalyst. Unlike Examples 3-7, the reaction was not performed in neat alcohol. In this case, 1,4-dioxane was added to dissolve the starting acid. To the reaction flask, DL-malic acid (80.91 g), hexyl alcohol (307 mL), 1,4-dioxane (200 mL) and p-toluenesulfonic acid (12.3 g) were added. The mixture was placed under nitrogen and heated to reflux. At 103° C., one phase started to collect in the Dean-Stark trap. The reaction temperature was increased to 110° C. and after 2 hr 40 min very little liquid had collected in the trap. The reaction temperature was increased to 115° C. and held until no more liquid collected in the trap. The product was neutralized with saturated sodium bicarbonate, diluted with diethyl ether, washed three times with saturated sodium bicarbonate, once with water and dried over magnesium sulfate. The diethyl ether was removed via rotary evaporation. Dihexyl-DL-malate was obtained as a low viscosity, clear, colorless liquid with a slight pleasant odor (127.7 g, 70% yield) after removing residual hexyl alcohol via vacuum distillation.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.CCN(CC)CC.[C:40](Cl)(=[O:42])[CH3:41]>C(Cl)Cl>[C:40]([NH:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)(=[O:42])[CH3:41]
Reactant: CC(=O)Cl
Reactant: Cc1cccc(-c2c(F)cccc2[C@H](OCCN)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCO[C@@H](c1cccc(F)c1-c1cccc(C)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
To a solution of (3R)-tert-butyl 3-((R)-(2-aminoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)piperidine-1-carboxylate (86 mg, 0.2 mmol) in anhydrous CH2Cl2 (8 mL) was added Et3N (0.5 ml, 20 mmol). The mixture was cooled with an ice bath and acetyl chloride (15 mg, 0.2 mmol) in CH2Cl2 (4 mL) was added. The reaction mixture was stirred at rt for 0.5 h, then washed with water, dried over MgSO4, filtered and concentrated to give (3R)-tert-butyl 3-((R)-(2-acetamidoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)piperidine-1-carboxylate (80 mg, 85%), which was used in the next step without purification.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:21][NH:22][CH2:23][CH3:24]>>[CH2:23]([N:22]([CH3:21])[CH:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[CH:13][C:8]([CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:9][CH:10]=2)[CH2:15][CH2:16]1)[CH3:24]
Reactant: O=C1CCN(c2ccc(CN3CCOCC3)cc2)CC1
Reactant: CCNC
Product: CCN(C)C1CCN(c2ccc(CN3CCOCC3)cc2)CC1

Procedure:
Prepared from the product of Example 19 and N-methylethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH:11]([NH2:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:14]([N:16]1[C:20](=[O:21])[C:19]([O:22]C)=[C:18]([C:24](O)=[O:25])[CH2:17]1)[CH3:15]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH:11]([NH:13][C:24]([C:18]2[CH2:17][N:16]([CH2:14][CH3:15])[C:20](=[O:21])[C:19]=2[OH:22])=[O:25])[CH3:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCN1CC(C(=O)O)=C(OC)C1=O
Reactant: CC(N)CCc1ccc(Cl)c(Cl)c1
Product: CCN1CC(C(=O)NC(C)CCc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Yield: 15 %

Procedure:
By appropriate application of method described in Example 180, 4-(3,4-dichlorophenyl)butan-2-amine (racemic) (50 mg, 0.23 mmol) and 1-ethyl-4-methoxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (85 mg, 0.46 mmol) were converted to Example 225 (racemate) (12 mg, 0.032 mmol, 15% yield for two steps). HPLC/MS (Method D) RT=0.97 min, [M+1]+ 371.1; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.16-1.39 (m, 6H) 1.74-1.95 (m, 2H) 2.67 (t, J=7.78 Hz, 2H) 3.62 (q, J=7.03 Hz, 2H) 4.12 (s, 1H) 4.14-4.28 (m, 1H) 6.98-7.10 (m, 1H) 7.30 (d, J=1.25 Hz, 1H) 7.34 (d, J=8.28 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][O:11][CH3:12])=[CH:7][C:6]([O:13][CH3:14])=[C:5]([O:15][CH2:16][O:17][CH3:18])[C:4]=1[CH2:19][CH2:20][C:21]([OH:23])=O.C(OCC)(=O)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl.C(N(CC)CC)C>[CH3:30][S:31]([O:23][CH2:21][CH2:20][CH2:19][C:4]1[C:5]([O:15][CH2:16][O:17][CH3:18])=[C:6]([O:13][CH3:14])[CH:7]=[C:8]([O:9][CH2:10][O:11][CH3:12])[C:3]=1[O:2][CH3:1])(=[O:33])=[O:32]
Reactant: COCOc1cc(OC)c(OCOC)c(CCC(=O)O)c1OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COCOc1cc(OC)c(OCOC)c(CCCOS(C)(=O)=O)c1OC
Reaction time: 12 h

Procedure:
700 Milligrams of 3-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]propionyl alcohol was dissolved in 20 ml of anhydrous methylene chloride, under argon gas stream condition, 0.21 ml of methanesulfonyl chloride, 0.3 ml of triethylamine were added thereto under ice-cooled condition. The temperature of the reaction mixture was elevated to room temperature, then the reaction mixture was stirred continuously for 12 hours. 100 Milliliters of ethyl acetate was added to the reaction mixture, and the organic layer was washed with water, a saturated sodium chloride aqueous solution, then concentrated to yield 700 mg of 3-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]propyl methanesulfonate was obtained as a mesylate. Colorless oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:18])=[O:5])[CH3:2].[C:19]1(=O)[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[N:18]1[C:22](=[O:23])[C:21]2[C:20](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]1=[O:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(Br)cc2)csc1N
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccc(Br)cc2)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 2-amino-4-(4-bromophenyl)thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 21, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) is heated at reflux overnight. After cooling to room temperature, the acetic acid is removed in vacuo and the residue triturated with petroleum ether. The crude product is collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue is dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization affords the desired product.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[C:7]([O:17]CC)(=O)[CH:8]([CH2:10][C:11]([O:13]CC)=O)[OH:9]>>[CH2:1]([NH:6][C:7](=[O:17])[CH:8]([CH2:10][C:11]([NH:6][CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])=[O:13])[OH:9])[CH2:2][CH:3]([CH3:5])[CH3:4].[CH3:7][CH2:8][CH2:1][CH2:2][CH2:3][CH3:5]
Reactant: CC(C)CCN
Reactant: CCOC(=O)CC(O)C(=O)OCC
Product: CC(C)CCNC(=O)CC(O)C(=O)NCCC(C)C
Product: CCCCCC
Temperature: 25 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
N,N′-Di-iso-pentyl DL-malamide was prepared by the reaction of iso-pentylamine with diethyl DL-malate. To a round-bottomed flask were added diethyl DL-malate (20.013 g, 0.1052 mole, 1 eq) and iso-pentylamine (27.778 g, 3.03 eq). The clear light yellow solution was stirred for 20 hours at room temperature prior to the removal of the excess amine under vacuum with heating. A white waxy solid was obtained. The solid was triturated with hexane (4×100 mL); and the product was filtered through a glass frit after each trituration. Finally, the material was transferred to a round-bottomed flask and the white solid was dried under vacuum for one hour while heating (<100° C.) to remove any residual amine and hexane (28.99 g, ˜100% yield). The product was ˜100% pure as determined by NMR analyses.