Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:29])[CH2:14][CH2:15][CH2:16]/[C:17](=[CH:18]\[CH:19]=[C:20]3\[CH2:21][C@@H:22]([OH:28])[CH2:23][C@H:24]([OH:27])[C:25]\3=[CH2:26])/[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].O[C@@H:31]1[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2[C@H](C)CCCC(C)C)C[C@@H](O)C1>>[CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:29])[CH2:14][CH2:15][CH2:16]/[C:17](=[CH:18]\[CH:19]=[C:20]3\[CH2:21][C@@H:22]([OH:28])[CH2:23][C@H:24]([OH:27])[C:25]\3=[CH2:26])/[C@@H:12]2[CH2:11][CH2:10]1)/[CH:3]=[CH:4]/[C@@H:5]([CH:6]([CH3:7])[CH3:8])[CH3:31]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reactant: C=C1/C(=C\C=C2/CCC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]23)C[C@@H](O)C[C@@H]1O
Product: C=C1/C(=C\C=C2/CCC[C@]3(C)[C@@H]([C@H](C)/C=C/[C@H](C)C(C)C)CC[C@@H]23)C[C@@H](O)C[C@@H]1O

Procedure:
A portion (58.3 mg) of the product from Example 1 is transferred to a 3-necked, 200 ml, round-bottomed flask equipped with a gas dispersion tube, gas exit bubbler and a thermometer. A charge of 150 mg of anthracene in 150 ml of benzene is added and the resulting solution irradiated at 10° C. (cold room) under a steady stream of nitrogen gas using 3-22 watt, circular fluorescent light bulbs. After 42 h of irradiation, TLC indicates the complete disappearance of a spot co-migrating with 5,6-trans-1α-hydroxyvitamin D3 and the appearance of a new spot co-migrating with 1α-hydroxyvitamin D3. After 45 h of irradiation the reaction is worked up by evaporation of the solvent. The residue is taken up in 15 ml of ether and filtered. The precipitate is washed with ether (3 ml, 3×). The combined filtrate and washings are evaporated and the residue applied in benzene to a 1×55 cm silica gel column. The column is eluted with benzene then with ethyl acetate/hexane mixtures, to yield 45 mg of a white powder shown to be identical with 1α-hydroxyvitamin D3 by comparison of nmr, uv, mass spectra and chromatographic properties with those of an authentic sample of this compound (prepared from 1α-hydroxycholesterol). Utilizing procedures essentially similar to that described above, but substituting other appropriate 5,6-trans-vitamin D compounds for 5,6-trans-1α-hydroxyvitamin D3, there is obtained 1α-hydroxyvitamin D2 from 5,6-trans-1α-hydroxyvitamin D2 ; 1α,25-dihydroxyvitamin D3 from 5,6-trans-1α,25-dihydroxyvitamin D3 ; 1α,24,25-trihydroxyvitamin D3 from 5,6-trans-1α,24,25-trihydroxyvitamin D3 ; 1α,25,26-trihydroxyvitamin D3 from 5,6-trans-1α,25,26-trihydroxyvitamin D3 ; 1α,24-dihydroxyvitamin D2 from 5,6-trans-1α,24-dihydroxyvitamin D2 ; 1α,25-dihydroxyvitamin D2 from 5,6-trans-1α,25-dihydroxyvitamin D2 ; 1α,24,25-trihydroxyvitamin D2 from 5,6-trans-1α,24,25-trihydroxyvitamin D2.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH:14][CH3:15])=[CH:9][CH:8]=2)([CH3:4])([CH3:3])[CH3:2].[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28]([OH:30])=O)[CH2:27][CH2:26]3)=[CH:24][C:19]=2[O:18][CH2:17]1.C(N(CC)CC)C>CN(C)C=O>[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28]([N:14]([C:10]4[CH:11]=[C:12]5[C:7](=[CH:8][CH:9]=4)[NH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:13]5)[CH3:15])=[O:30])[CH2:26][CH2:27]3)=[CH:24][C:19]=2[O:18][CH2:17]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: CNc1ccc2[nH]c(C(C)(C)C)cc2c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C(=O)C1(c2ccc3c(c2)OCO3)CC1)c1ccc2[nH]c(C(C)(C)C)cc2c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
2-tert-Butyl-N-methyl-1H-indol-5-amine (20.2 mg, 0.100 mmol) and 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (20.6 mg, 0.100 mmol) were dissolved in N,N-dimethylformamide (1 mL) containing triethylamine (42.1 μL, 0.300 mmol) and a magnetic stir bar. O-(7-Azabenzotriazol-1-yl)-N,N′,N′-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture and the resulting solution was allowed to stir for 16 h at 80° C. The crude product was then purified by preparative HPLC utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5-yl)-N-methylcyclopropanecarboxamide. ESI-MS m/z calc. 390.2, found 391.3 (M+1)+. Retention time of 3.41 minutes.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([NH:20][C:21]([N:11]2[CH2:12][CH2:13][CH:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]2)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C=Nc1ccccc1
Product: O=C(Nc1ccccc1)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound was prepared from 4-benzylpiperidine and phenyl isocyanate. 1H NMR (400 MHz, CDCl3): 7.35-7.10 (m, 9H), 7.02-6.97 (m, 1H), 6.50 (br s, 1H), 4.07-4.00 (m, 2H), 2.77 (td, J=13, 2.4 Hz, 2H), 2.54 (d, J=6.8 Hz, 2H), 1.76-1.64 (m, 3H), 1.28-1.15 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14](O)=[O:15])=[CH:10][C:9]=1[C:17]([O:19][CH3:20])=[O:18]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:17]([O:19][CH3:20])=[O:18])=[CH:10][C:11]([CH2:14][OH:15])=[CH:12][CH:13]=1
Reactant: COC(=O)c1cc(C(=O)O)ccc1-c1ccccc1F
Solvent: C1CCOC1
Product: COC(=O)c1cc(CO)ccc1-c1ccccc1F
Temperature: 23 °C
Reaction time: 7 h
Yield: 108.9 %

Procedure:
To a stirred solution of 66.32B (0.90 g, 3 mmol) in THF (33 mL) at 0° C. was added borane-THF complex (7 mL, 7 mmol, 1.0M). The reaction was allowed to warm to 23° C. and stirred for 7 hours. The reaction mixture was then concentrated in vacuo. The reaction was diluted with 1N HCl and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-40% EtOAc in hexanes) to yield 66.32C as a colorless solid (0.850 g, 100% yield).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.OS(O)(=O)=O.[N+:17]([O-])([OH:19])=[O:18].[OH-].[Na+]>>[N+:17]([C:5]1[C:6]([NH2:9])=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=1)([O-:19])=[O:18]
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
To a 250-mL, round-bottomed flask was added 5-trifluoromethyl-pyridin-2-ylamine (8.3 g, 51.2 mmol, Matrix Scientific) and H2SO4 (49 mL). The resulting mixture was cooled to 0° C., and HNO3 (8.2 mL) was added dropwise. The mixture was heated to 80° C. for 48 h, cooled to room temperature and added dropwise into a vigorously stirred ice-water (500 mL). After the addition, the mixture was basified to pH 9 with ION NaOH and extracted with EtOAc (2×500 mL). The combined organic extracts were dried over MgSO4 and filtered. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography, eluting with EtOAc/hexane (1:2) to give the title compound as a yellow solid. MS (ESI, positive ion) m/z: 208 (M+1).
Reaction SMILES: [OH:1][CH:2]([CH2:32][OH:33])[CH2:3][O:4][C:5]1[N:6]=[N:7][C:8]([NH:11][NH:12][C:13](C2C=CC=CC=2)([C:20]2C=CC=CC=2)[C:14]2C=CC=CC=2)=[CH:9][CH:10]=1.[ClH:34]>O1CCCC1>[ClH:34].[OH:1][CH:2]([CH2:32][OH:33])[CH2:3][O:4][C:5]1[N:6]=[N:7][C:8]([NH:11][N:12]=[C:13]([CH3:14])[CH3:20])=[CH:9][CH:10]=1
Reactant: OCC(O)COc1ccc(NNC(c2ccccc2)(c2ccccc2)c2ccccc2)nn1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)=NNc1ccc(OCC(O)CO)nn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (RS)-3-(2,3-Dihydroxypropoxy)-6-(2-triphenylmethylhydrazino)pyridazine (3.2 g) in tetrahydrofuran (80 ml), conc. hydrochloric acid (2 ml) was added. After stirring at room temperature for 15 minutes the solution was concentrated under vacuum to small volume and diluted with acetone (50 ml). After stirring at room temperature for 30 minutes and then at 0° C. for 1 hour the precipitate was collected to yield 1.4 g of the title compound, identical to that obtained in Example 14.
Reaction SMILES: C([N:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:21])[CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:7][CH2:6]1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[C:15]1([CH2:14][CH2:13][CH2:12][C:11]([N:8]2[CH2:7][CH2:6][NH:5][CH2:10][CH2:9]2)=[O:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)N1CCN(C(=O)CCCc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CCCc1ccccc1)N1CCNCC1
Reaction time: 1 h

Procedure:
1-tert-Butyl-4-(4-phenylbutanoyl)piperazine (A, 2.64 g) was dissolved in trifluoroacetic acid (10 mL)—dichloromethane (10 mL). After siring for 1 hr, the reaction mixture was evaporated in vacuo. Toluene and methanol were added to the residue, then evaporated in vacuo to give the titled compound (1.63 g) as a colorless solid.
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][CH:22]=[N:23]2>>[N:23]1[C:24]2[C:19](=[C:18]([N:17]=[C:4]3[N:8]4[CH2:9][C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=5[CH2:16][C@H:7]4[CH2:6][S:5]3)[CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Reactant: Nc1cccc2ncccc12
Agent: [I-]
Product: c1ccc2c(c1)C[C@H]1CSC(=Nc3cccc4ncccc34)N1C2
Yield: 90.3 %

Procedure:
By following the procedure of Example 2, but using (S)-3-methylthio-1,5,10,10a-tetrahydrothiazolo-[3,4-b]isoquinolinium iodide (18.2 g) and 5-aminoquinoline (14.4 g) as the starting materials, (S)-3-(quinol-5-yl-imino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (15.0 g) is obtained in the form of light beige crystals, m.p.=194° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([O:10][CH3:11])[CH2:7][CH2:6][CH:5]([O:8][CH3:9])[O:4]1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>O1CCCC1>[CH3:11][O:10][C:3]1([CH2:2][NH:1][C:19](=[O:21])[CH3:20])[CH2:7][CH2:6][CH:5]([O:8][CH3:9])[O:4]1
Reactant: COC1CCC(CN)(OC)O1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC1CCC(CNC(C)=O)(OC)O1
Reaction time: 1 h
Yield: 82.8 %

Procedure:
11.5 [lacuna] (71.3 mmol) of 2-aminomethyl-2,5-dimethoxytetrahydrofuran and 20 ml (143 mmol) of triethylamine were dissolved in 150 ml of anhydrous tetrahydrofuran. At 0° C., a solution of 5 ml (71.3 mmol) of acetyl chloride in 50 ml of tetrahydrofuran was added dropwise, and the mixture was stirred for 1 h. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. 12 g of crude product were obtained and were reacted further without purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]2[CH:12]=[CH:13][S:14][C:10]=2[CH:9]=1.Cl.[NH:18]1[CH2:21][CH:20]([OH:22])[CH2:19]1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.C(OCC)(=O)C.O>[S:14]1[C:10]2[CH:9]=[C:8]([CH2:7][CH2:6][O:5][CH2:4][CH2:3][CH2:2][N:18]3[CH2:21][CH:20]([OH:22])[CH2:19]3)[CH:16]=[CH:15][C:11]=2[CH:12]=[CH:13]1
Reactant: ClCCCOCCc1ccc2ccsc2c1
Reactant: OC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: OC1CN(CCCOCCc2ccc3ccsc3c2)C1
Temperature: 75 °C
Reaction time: 2.5 h
Yield: 24.5 %

Procedure:
1.00 g of 6-(2-(3-chloropropoxy)ethyl)-1-benzothiophene was dissolved in 5 ml of dimethyl sulfoxide. Thereafter, 0.86 g of 3-azetidinol hydrochloride and 1.63 g of potassium carbonate were added to the obtained solution, and the obtained mixture was stirred at 75° C. for 2.5 hours, and then at 95° C. for 1.5 hours. Thereafter, the reaction solution was cooled, and thereafter, water and ethyl acetate were added to the reaction mixture. The pH of the obtained mixture was adjusted to pH 1 by addition of 6 mol/l hydrochloric acid, and a water layer was then separated. Ethyl acetate was added to the water layer, and the pH of the obtained mixture was adjusted to pH 10 by addition of a 2 mol/l aqueous sodium hydroxide solution, followed by separation of an organic layer. The organic layer was successively washed with water and a saturated saline solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was distilled away under a reduced pressure. The residue was purified by column chromatography (eluent; chloroform:methanol=30:1 to 5:1), so as to obtain 0.28 g of an achromatic oil product, 1-(3-(2-(1-benzothiophene-6-yl)ethoxy)propyl)-3-azetidinol.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:9]=[C:10]([O:14][CH2:15][C@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](OC(C)(C)C)=O)[CH:11]=[N:12][CH:13]=1.ClC1C=C(OC[C@@H]2CCCN2C)C=NC=1>CO.C(Cl)(Cl)Cl>[Cl:7][C:8]1[CH:9]=[C:10]([O:14][CH2:15][C@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[CH3:21])[CH:11]=[N:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cncc(Cl)c1
Agent: CN1CCC[C@H]1COc1cncc(Cl)c1
Solvent: CO
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CN1CCC[C@@H]1COc1cncc(Cl)c1

Procedure:
Following the procedure of Example 16a, replacing the 5-chloro-3-(N-t-butoxycarbonyl-2-S)-pyrrolidinylmethoxy)pyridine thereof with 5-chloro-3-(N-t-butoxycarbonyl-2-(R)-pyrrolidinylmethoxy)pyridine (prepared from the (R)-isomer of the starting material following the procedure of Example 15a), the tide compound was prepared. TLC Rf =0.23 (10% MeOH/CHCl3). MS and 1H NMR (CDCl3, 300 MHz) are similar to 16a.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1>C(O)C>[NH2:1][CH2:2][C@@H:3]1[O:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1
Reactant: NCC1CN(Cc2ccccc2)CCO1
Solvent: CCO
Product: NC[C@H]1CN(Cc2ccccc2)CCO1
Reaction time: 16 h
Yield: 42.4 %

Procedure:
(RS)-2-Aminomethyl-4-benzylmorpholine (326.1 g) was dissolved in ethanol (3 L) and dibenzoyl-D-tartaric monohydrate (535 g) was added. The mixture was refluxed for dissolution and then left standing at room temperature for 16 hours. The precipitated crystals were collected by filtration and recrystallized from a mixed solvent of ethanol:water=25:1. The obtained crystals were suspended in water (1.2 L) and aqueous sodium hydroxide solution was added with stirring to make the suspension basic, which was followed by extraction with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off to give 138.4 g of (S)-2-aminomethyl-4-benzylmorpholine as a colorless oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[O:13][CH2:14][CH:15]([OH:17])[CH3:16])([CH3:3])[CH3:2].C(C1C=CC=CC=1OCC(O)CC)(C)(C)C>[Pd]>[CH:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]([CH:10]([CH3:11])[CH3:12])[CH:5]1[O:13][CH2:14][CH:15]([OH:17])[CH3:16])([CH3:2])[CH3:3]
Reactant: CC(O)COc1c(C(C)C)cccc1C(C)C
Agent: [Pd]
Agent: CCC(O)COc1ccccc1C(C)(C)C
Product: CC(O)COC1C(C(C)C)CCCC1C(C)C
Reaction time: 5 h
Yield: 66.6 %

Procedure:
The synthesis was carried out in the same manner as described in Example 3b, except that 30 g (0.13 mol) of 1-(2,6-diisopropylphenyloxy)-2-propanol were used instead of 50 g (0.23 mol) of 1-(2-tert-butylphenyloxy)-2-butanol and the amount of the same palladium catalyst was increased to 1.5 g. The reaction was carried out for 5 hours and 21 g of 1-(2,6-diisopropylcyclohexyloxy)-2-propanol were obtained in a 67% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]([F:30])([F:29])[F:28])=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([C:17](O)=[O:18])[CH2:13][CH2:12]2)=[O:10])[C:6]=1[CH3:7].[NH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([C:27]([F:28])([F:29])[F:30])=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)([C:17]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[O:18])[CH2:13][CH2:12]2)=[O:10])[C:6]=1[CH3:7]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCC(C(=O)O)(c2ccc(Cl)cc2)CC1
Reactant: C1CNCCN1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCC(C(=O)N2CCNCC2)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 4 mL vial was added 50 mg of 1-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-4-(4-chloro-phenyl)-piperidine-4-carboxylic acid (0.11 mmol, 1.0 equiv), 11 mg of piperazine (0.13 mmol, 1.2 equiv), 60 μL TEA (0.43 mmol, 4.00 equiv), 71 mg BOP (0.16 mmol, 1.5 equiv), and 500 μL NMP. The mixture was stirred overnight at room temperature and the crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-phenyl)-4-(piperazine-1-carbonyl)-piperidin-1-yl]-ethanone:MS (ES) M+H expected=532.4, found=532.1.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[CH2:16]([NH2:22])[C:17]1[O:21][CH:20]=[CH:19][CH:18]=1>>[O:21]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH2:16][NH:22][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:9]
Reactant: NCc1ccco1
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Product: OC(c1ccccc1)C(NCc1ccco1)c1ccccc1
Temperature: 140 °C
Reaction time: 14 h
Yield: 78.4 %

Procedure:
A mixture of trans-stilbene oxide (1.96 g, 0.010 mol) and furfurylamine (3.00 g, 0.030 mol) was heated at 140° C. for 6 hours, and then allowed to stand at ambient temperature for 14 hours. The solidified reaction mixture was triturated with petroleum ether and the crude solid collected by filtration. Recrystallization from toluene-isooctane gave 2.3 g (78%) of the product; mp 141°-144° C.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.[CH3:10]O>>[CH3:10][O:6][C:5](=[O:7])[CH:4]1[CH2:8][CH2:9][NH:1][CH2:2][CH2:3]1
Reactant: O=C(O)C1CCNCC1
Reactant: CO
Product: COC(=O)C1CCNCC1
Reaction time: 0.17 h

Procedure:
Isonipecotic acid 2-3a (25 g, 0.19 mol; Aldrich) was suspended in MeOH (300 mL) at room temperature and HCl gas was bubbled through until saturated and a clear solution was obtained. After a further 10 minutes, the solvent was removed in vacuo to provide 2-3b as a solid (HCl salt).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:41][CH2:42][CH2:43][N:44]1[CH2:48][CH2:47][CH2:46][C:45]1=O>>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@H:13]([C:14](=[O:15])[NH:41][CH2:42][CH2:43][N:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: NCCN1CCCC1=O
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCCN1CCCC1
Yield: 8.9 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (100 mg, 0.18 mmol) and N-(2-aminoethyl)-pyrrolidinone (33 mg, 0.29 mmol) according to Method C with HPLC purification to give the title compound (10 mg). 1H-NMR (400 MHz, CD3OD) δ 1.36 (s, 9H) 2.05 (s, 4H) 2.68-3.20 (m, 8H) 3.39 (m, 4H) 4.28 (m, 1H) 4.39 (m, 1H) 4.69 (s, 2H) 7.05-7.40 (m, 7H) 7.52 (s, 1H); HRMS m/z 626.2929 (calc. of monoisotopic mass for C32H42N4O9 gives 626.2952).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:14])[C:6]([Cl:13])=[CH:7][C:8]=2[Cl:12])[N:3]=1.[CH3:15][NH2:16]>C(O)C>[Cl:12][C:8]1[CH:7]=[C:6]([Cl:13])[C:5]([OH:14])=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([NH:16][CH3:15])=[N:3]2
Reactant: Oc1c(Cl)cc(Cl)c2ccc(Cl)nc12
Reactant: CN
Solvent: CCO
Product: CNc1ccc2c(Cl)cc(Cl)c(O)c2n1

Procedure:
2,5,7-Trichloro-8-hydroxyquinoline 10 (200 mg, 0.805 mmol) and a solution of methylamine in ethanol (12 mL of a 33% solution) were heated in a sealed vessel at 90° C. for 26 h, and cooled. The precipitate was then isolated via filtration and washed with diethyl ether. This provided pure 5,7-dichloro-2-methylamino-8-hydroxyquinoline (PBT 1047) as a pale yellow solid (186 mg, 95%). 1H NMR (DMSO-d6, 400 MHz): δ 8.80 (br, 1 H), 7.98 (d, J=9.1, 1 H), 7.48 (br, 1 H), 7.25 (s, 1 H), 6.90 (d, J=9.1, 1H), 2.98 (d, J=4.8, 3 H); mass spectrum: m/z 243, 245 (M++1, 100 and 66%, respectively).
Reaction SMILES: [C:1]([C:3]1[C:4]([F:15])=[CH:5][C:6]([O:11][CH2:12][O:13][CH3:14])=[C:7]([CH:10]=1)[CH2:8][OH:9])#[N:2]>ClCCl.[O-2].[O-2].[Mn+4]>[C:1]([C:3]1[C:4]([F:15])=[CH:5][C:6]([O:11][CH2:12][O:13][CH3:14])=[C:7]([CH:10]=1)[CH:8]=[O:9])#[N:2]
Reactant: COCOc1cc(F)c(C#N)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COCOc1cc(F)c(C#N)cc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
To a solution of 5-cyano-4-fluoro-2-methoxymethoxybenzyl alcohol (10.0 g) in dichloromethane (500 ml) was added activated manganese dioxide (31.4 g). The mixture was stirred overnight at room temperature, and filtered through celite to remove manganese dioxide. The filtrate was condensed under reduced pressure to give a solid, which was washed with hexane to yield 5-cyano-4-fluoro-2-methoxymethoxybenzaldehyde (8.01 g) (Compound B-50). The physical properties was shown in Table 8.
Reaction SMILES: [NH2:1][C:2]1[C:12]([OH:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5]>Cl>[NH2:1][C:2]1[C:12]([OH:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1cc(Cl)cc(O)c1N
Agent: Cl
Product: Nc1c(O)cc(Cl)cc1C(=O)O
Temperature: 80 °C
Reaction time: 120 h
Yield: 55.2 %

Procedure:
Ethyl 2-amino-5-chloro-3-hydroxybenzoate (3.23 g) was dissolved in 160 ml of a 3N aqueous solution of hydrochloric acid and stirred at 85° C. for 3 hours and at 80° C. for 5 days. The reaction solution was cooled to room temperature, insoluble matters were filtered off, 320 ml of a 1N aqueous solution of sodium hydroxide was added to the filtrate and the mixture was stirred at room temperature for 1 hour. The resulting precipitate was filtered, washed with pure water and dried in vacuo to give 1.55 g of 2-amino-5-chloro-3-hydroxybenzoic acid.