Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][C:14](=[NH:17])OC)[N:9]=1)[C:2]([NH2:4])=[NH:3].[Cl-:18].[NH4+:19]>C(O)C>[ClH:18].[ClH:18].[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][C:14]([NH2:17])=[NH:19])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: COC(=N)CCSCc1csc(NC(=N)N)n1
Solvent: CCO
Product: Cl
Product: N=C(N)CCSCc1csc(NC(=N)N)n1
Yield: 65.8 %

Procedure:
Methyl 3-(2-guanidino-4-thiazolylmethylthio)propionimidate (4.09 g), ammonium chloride (0.8 g) and ethanol (25 ml) were stirred at room temperature for 5 hours. The methanol was evaporated at reduced pressure and the residue was chromatographed on silica gel using a chloroform/methanol gradient elution. Fractions containing the main product (as shown by T.L.C.) were combined and the solvent evaporated at reduced pressure. The residue was treated with ethanol containing hydrochloric acid. Excess of solvent was evaporated at reduced pressure and the residue was crystallised from isopropanol to give 3-(2-guanidino-4-thiazolylmethylthio)propionamidine dihydrochloride, (1.63 g) m.p. 174.5°-176.5° C.
Reaction SMILES: O.[NH2:2][NH2:3].C(O)C.Cl.[NH2:8][N:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14](=O)[CH3:15]>O>[NH2:8][N:9]1[CH:13]=[CH:12][CH:11]=[C:10]1/[C:14](=[N:2]/[NH2:3])/[CH3:15]
Reactant: CC(=O)c1cccn1N
Reactant: NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: C/C(=N\N)c1cccn1N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.6 %

Procedure:
Under a nitrogen atmosphere, hydrazine monohydrate (530 g) was added to ethanol (1.7 L) over 55 minutes. To the mixture was added 1-(1-amino-1H-pyrrol-2-yl)ethanone hydrochloride (170 g) over 20 minutes. The mixture was stirred for 10 minutes at room temperature and heated to refluxing temperature over 55 minutes, and refluxed for 15 minutes. After cooling the mixture under a water bath, water (1.7 L) was added to the mixture (30 to 31° C.). Ethanol was evaporated off, and the resulting mixture was extracted with chloroform (0.85×4 mL). The combined organic extract was washed with brine (1.3 L). The brine was extracted with chloroform (0.85 L). The combined organic extract was dried over anhydrous magnesium sulfate, and evaporated to give (1E)-1-(1-amino-1H-pyrrol-2-yl)ethanone hydrazone as a brown crystal (112 g).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:23][CH:22]4[C:24](O)=[O:25])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.P([N:52]=[N+:53]=[N-:54])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1>C1(C)C=CC=CC=1>[F:27][C:2]([F:28])([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:23][CH:22]4[C:24]([N:52]=[N+:53]=[N-:54])=[O:25])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: O=C(O)C1CC1c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)C1CC1c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To 2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)-cyclopropanecarboxylic acid (C20) (2.49 g, 6.40 mmol) in toluene (30 mL) was added triethylamine (2.20 mL, 16.0 mmol), followed by diphenyl phosphorazidate (1.70 mL, 8.00 mmol). The yellow solution was stirred overnight at room temperature. The reaction was quenched with water and saturated aqueous sodium bicarbonate, extracted with 1:1 ethyl acetate/hexanes (2×), dried over anhydrous sodium sulfate, and filtered. The crude compound was adsorbed onto silica gel and purified by flash column chromatography using 0-100% ethyl acetate/hexanes as eluent to afford the title compound as a yellow oil (1.94 g, 73%): 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.16-8.03 (m, 2H), 7.83-7.72 (m, 2H), 7.44-7.34 (m, 2H), 7.20 (d, J=8.2 Hz, 2H), 2.70 (ddd, J=9.3, 6.8, 4.1 Hz, 1H), 1.98 (ddd, J=8.4, 5.3, 4.1 Hz, 1H), 1.78 (dt, J=9.4, 5.0 Hz, 1H), 1.53 (ddd, J=8.3, 6.8, 4.7 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −58.03.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:10]2[C:14]([Cl:15])=[C:13]([O:16][CH:17]([F:19])[F:18])[N:12]([CH3:20])[N:11]=2)[CH:6]=[CH:7][C:8]=1[Cl:9].[C:21]([O-:24])(=[O:23])[CH3:22].[Na+].O>CN(C)C=O>[C:21]([O:24][CH2:2][C:3]1[CH:4]=[C:5]([C:10]2[C:14]([Cl:15])=[C:13]([O:16][CH:17]([F:19])[F:18])[N:12]([CH3:20])[N:11]=2)[CH:6]=[CH:7][C:8]=1[Cl:9])(=[O:23])[CH3:22]
Reactant: Cn1nc(-c2ccc(Cl)c(CBr)c2)c(Cl)c1OC(F)F
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCc1cc(-c2nn(C)c(OC(F)F)c2Cl)ccc1Cl

Procedure:
A solution of 6.8 g (18 mmol) of 3-(3-bromomethyl-4-chlorophenyl)-4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazole and 1.5 g (18 mmol) of sodium acetate in 20 ml of dimethylformamide was stirred overnight and then stirred into 100 ml of cold water. The product was extracted from the aqueous phase using ethyl acetate. The ethyl acetate phase was dried over magneisum sulfate and concentrated. The crude product thus obtained was purified by silica gel chromatography (eluent: hexane/ethyl acetate=9:1). Yield: 4.7 g.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:19]=[C:18]([N+:20]([O-])=O)[C:17]([N+:23]([O-])=O)=[CH:16][C:15]=1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].O.NN>[Pd].C(O)C>[CH2:1]([O:13][C:14]1[CH:19]=[C:18]([NH2:20])[C:17]([NH2:23])=[CH:16][C:15]=1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1OCCCCCCCCCCCC
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCOc1cc(N)c(N)cc1OCCCCCCCCCCCC
Yield: 75 %

Procedure:
This compound was synthesized according to a literature procedure.24 In a Schlenk tube, 1,2-Bis-dodecyloxy-4,5-dinitro benzene BK2—13 (2.36 g, 4.39 mmol), hydrazine monohydrate (8.25 ml, 48.5 mmol), 131 mg of Pd/C, and 65 ml of absolute ethanol were placed. The reaction mixture was refluxed under argon for 22 hours. Hot filtration under argon was then performed. Upon cooling, a white solid formed. The solid was washed with O2-free methanol and was dried overnight under nitrogen to yield 1.57 g (75%) of white solid. 1H (300 MHz, CDCl3) δ 6.353 (s, 2H), 3.880-3.835 (t, J=6.6 Hz, 4H), 3.062 (br s, 4H, NH2), 1.767-1.673 (pentet, J=7.2 Hz, 4H), 1.43-1.36 (m, 4H), 1.358-1.080 (m, 32H), 0.878-0.833 (t, J=7.2 Hz, 6H).13C (CDCl3, 75 MHz) δ 143.20, 128.20, 106.69, 70.67, 32.00, 29.78, 29.73, 29.67, 29.55, 29.45, 26.17, 22.78, 14.22 ppm. HRMS-E1 (m/z): [M]+ calcd. for C30H56N2O2, 476.43418. found 476.43449.
Reaction SMILES: [CH2:1]([OH:9])[CH:2]([OH:8])[CH:3]([OH:7])[CH2:4][CH:5]=[CH2:6].N1C=CN=C1.[Si:15](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl.CN(C)C=O.C(OCC)C>[CH3:31][C:28]([Si:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[O:9][CH2:1][CH:2]([OH:8])[CH:3]([OH:7])[CH2:4][CH:5]=[CH2:6])([CH3:29])[CH3:30]
Reactant: C=CCC(O)C(O)CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCC(O)C(O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
A 0° C. solution of 7.33 g of product from Example 273 in 120 ml of 5:1 dry methylene chloride/N,N-dimethylformamide is treated with 5.29 g of imidazole and 16.77 g of t-butyl diphenylsilyl chloride. The reaction mixture is warmed to room temperature and stirred vigorously for 16 hours, diluted with diethyl ether and filtered. The filtrate is concentrated and purified by chromatography (Silica Gel: 0-50% ethyl acetate/hexane) to give 15 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][C@@H:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13][CH2:14]Cl)[CH:3]=1.[I-:22].[Na+]>CC(C)=O>[Cl:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][C@@H:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13][CH2:14][I:22])[CH:3]=1
Reactant: N#Cc1cc(F)c(Cl)cc1O[C@H](CCCl)c1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: N#Cc1cc(F)c(Cl)cc1O[C@H](CCI)c1ccccc1
Yield: 98.8 %

Procedure:
4-Chloro-2-{[(1R)-3-chloro-1-phenylpropyl]oxy}-5-fluorobenzonitrile (1.8 , 5.6 mmol) and sodium iodide (12.8 g, 100 mmol) were dissolved in acetone (50 ml) and heated under reflux for 24 h. The reaction mixture was cooled, filtered and evaporated. The semi-solid residue was dissolved in toluene, filtered and evaporated again to give 2.3 g of the crude product as a yellow oil. This was used without purification for the next step.
Reaction SMILES: S(Cl)([Cl:3])=O.C1C=CC=CC=1.[Cl:11][C:12]1[C:20]([Br:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[CH:17][C:13]=1[C:14](O)=[O:15]>CN(C=O)C>[Cl:11][C:12]1[C:20]([Br:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[CH:17][C:13]=1[C:14]([Cl:3])=[O:15]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(Br)c1Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc([N+](=O)[O-])cc(Br)c1Cl
Yield: 100.4 %

Procedure:
5.1 ml (69.9 mmol) of thionyl chloride and a solvent mixture comprising 50 ml of benzene and 0.2 ml of DMF were added to 14.07 g (50.2 mmol) of 2-chloro-3-bromo-5-nitrobenzoic acid. The obtained mixture was heated under reflux for 2 hours and distilled to remove the solvent. Benzene was added to the residue and the obtained mixture was distilled again to remove the solvent. Thus, 15.07 g of the title compound was obtained (yield: quantitative).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.ClC(OCC)=O.[C:36]1([NH:42][CH2:43][CH2:44][NH2:45])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([NH:45][CH2:44][CH2:43][NH:42][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:21])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNC(=O)CCCCC(=O)O)cc1OC
Reactant: NCCNc1ccccc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CCNC(=O)CCCCC(=O)NCCNc2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.2 %

Procedure:
6-[2-(3,4-Dimethoxyphenyl)ethylamino]-6-oxohexanoic acid (6.0 g, 0.19) was dissolved in dry dichloromethane (200 ml) and triethylamine (2.28 g, 0.021 mole), and ethyl chloroformate (1.86 ml, 0.019 mole) added at O°. After 1 hour at 0° N-phenyl-1,2-ethanediamine (2.64 g, 0.019 mole) was added and the mixture stirred at room temperature for 18 hr. After washing with water and drying (Na2SO4), the reaction mixture was evaporated and the residue recrystallised from ethyl acetate to give the sub title compound (5.3 g) mp 109°-11°.
Reaction SMILES: [NH:1]1[CH:7]([CH2:8][C:9]([OH:11])=O)[C:5](=[O:6])[NH:4][C:2]1=[O:3].C1C=CC2N(O)N=NC=2C=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([CH:35]([CH3:38])[CH2:36][NH2:37])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1>CN1C(=O)CCC1>[O:3]=[C:2]1[NH:1][CH:7]([CH2:8][C:9]([NH:37][CH2:36][CH:35]([C:32]2[CH:33]=[CH:34][C:29]([C:26]3[CH:25]=[CH:24][C:23]([F:22])=[CH:28][CH:27]=3)=[CH:30][CH:31]=2)[CH3:38])=[O:11])[C:5](=[O:6])[NH:4]1
Reactant: CC(CN)c1ccc(-c2ccc(F)cc2)cc1
Reactant: O=C(O)CC1NC(=O)NC1=O
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Product: CC(CNC(=O)CC1NC(=O)NC1=O)c1ccc(-c2ccc(F)cc2)cc1
Reaction time: 8 h

Procedure:
600μL of a 0.15M solution in NMP of 5-hydantoin acetic acid was mixed with 98 mg of polystyrene-bound caibodiimide resin (loading 1.28 mmol/g). 340 μL of a 0.3M solution of HOBT in NMP was added to the mixture and vortexed for 10 minutes before 200 μL of a 0.3M solution in NMP of 2-(4′-fluoro-biphenyl-4-yl)-propylamine was added. The reaction mixture was vortexed overnight at room temperature in a sealed vessel. Resin was removed by filtration and the solution was evaporated to dryness. The product was purified on semi prep-HPLC C18-column (H2O:CH3CN, 0.1% TFA buffer, gradient 10% to 95% CH3CN, 10 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([F:26])[C:13]([F:25])=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:27][Si:28](C#N)([CH3:30])[CH3:29].[CH2:33]([N:35](CC)CC)C>[I-].[Zn+2].[I-]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)([O:18][Si:28]([CH3:30])([CH3:29])[CH3:27])[C:33]#[N:35])=[C:15]3[C:10]([CH:11]=[C:12]([F:26])[C:13]([F:25])=[CH:14]3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: O=C(c1c2cc(F)c(F)cc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Product: C[Si](C)(C)OC(C#N)(c1c2cc(F)c(F)cc2nn1-c1ccc(Cl)cc1)C1CCCCC1

Procedure:
In analogy to the procedure described in example 10.3, [2-(4-chloro-phenyl)-5,6-difluoro-2H-indazol-3-yl]-cyclohexyl-methanone was treated with trimethylsilyl cyanide and zinc(II) iodide in triethylamine to give the title compound as yellow solid. MS: m/e=474.2 [M+H+].
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](OCC(OC)=O)=[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].Cl.[CH2:42]([S:49][CH2:50][CH2:51][NH2:52])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH2:42]([S:49][CH2:50][CH2:51][NH:52][C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:6]([O:5][CH3:1])=[O:7])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: NCCSCc1ccccc1
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Agent: Cl
Product: COC(=O)c1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)NCCSCc2ccccc2)cc1C(=O)O
Yield: 25.1 %

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 2-(benzylsulfanyl)-1-ethanamine hydrochloride (44 mg, 0.22 mmol) according to Method C with HPLC purification to give the title compound (15 mg). 1H-NMR (400 MHz, CD3OD) d 7.76 (s, 1H), 6.97 (d, J=8.6 Hz, 1H), 4.77 (s, 2H), 4.51 (m, 1H), 4.24 (dd, J=5.1 Hz, J=9.3 Hz, 1H), 3.71 (s, 2H), 3.19 (m, 1H), 2.74 (m, 1H), 2.41 (m, 2H), 1.35 (s, 9H); HRMS m/z 679.2542 (calc. of monoisotopic mass for C34H41N3O9S gives 679.2564).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([I:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.IC1C=C2C(C(N)=CC=N2)=CC=1.[O:25]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)CCC>[O:25]([C:32]1[CH:33]=[CH:34][C:35]([NH:36][C:2]2[C:11]3[C:6](=[CH:7][C:8]([I:12])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:37][CH:38]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Clc1ccnc2cc(I)ccc12
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: Nc1ccnc2cc(I)ccc12
Solvent: CCCCO
Product: Ic1ccc2c(Nc3ccc(Oc4ccccc4)cc3)ccnc2c1
Temperature: 120 °C

Procedure:
4-Chloro-7-iodoquinoline (10 g, 34 mmol) [Semenov, V. P.; Studenikov, A. N. Synthesis of 7-iodo-4-aminoquinoline derivatives. Khim. Geterotsikl. Soedin. (1980), Issue 7, 972-5] and 4-phenoxyaniline (6.38 g, 34 mmol) in butanol (75 ml) were heated at gentle reflux (120° C.) overnight (18 hrs). On cooling the resultant precipitate was collected by filtration and washed with acetonitrile (2×50 ml). The resultant solid was suspended in chloroform (500 ml) and 2N sodium carbonate solution (300 ml) and heated at 75° C. for 45 mins. On cooling the resultant precipitate was collected by filtration, washed with water (2×50 ml) and dried to yield the product as a pale brown solid. (9.95 g, 66%) δH [2H6] DMSO 8.35 (3H, m), 8.20 (1H, s), 8.10 (1H, d), 7.85 (1H, s), 7.35 (4H, m), 7.15 (4H, d), 6.75 (1H, d).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][CH2:12][C:11](O[Si](C)(C)C)=[C:10](O[Si](C)(C)C)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br.Br.[NH2:26][CH2:27][C:28]([NH2:30])=[NH:29]>>[NH2:30][C:28]1[CH:27]=[N:26][C:11]2[CH2:12][CH2:13][N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:8][CH2:9][C:10]=2[N:29]=1
Reactant: N=C(N)CN
Reactant: C[Si](C)(C)OC1=C(O[Si](C)(C)C)CCN(C2CCCCC2)CC1
Agent: Br
Product: Nc1cnc2c(n1)CCN(C1CCCCC1)CC2

Procedure:
This compound was prepared analogous to Example 1 from 1-cyclohexyl-2,3,6,7-tetrahydro-4,5-bis(trimethylsilyloxy)azepine and 2-amino-acetamidine dihydrobromide.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=[O:4].[CH3:13][N:14]1[CH2:19][CH2:18][C@H:17]([OH:20])[C@H:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[OH:53].[C:54]([OH:61])(=[O:60])/[CH:55]=[CH:56]/[C:57]([OH:59])=[O:58]>C1C=CC=CC=1.CCOCC.C(O)C>[OH2:4].[C:54]([OH:61])(=[O:60])/[CH:55]=[CH:56]/[C:57]([OH:59])=[O:58].[F:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[O:20][C@@H:17]1[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][C@H:16]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[F:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[O:53][C@@H:17]1[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][C@H:16]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:54]([OH:61])(=[O:60])/[CH:55]=[CH:56]/[C:57]([OH:59])=[O:58]
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: CN1CC[C@H](O)[C@H](c2ccccc2)C1
Reactant: Oc1ccccc1F
Agent: O=C(O)/C=C/C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCO
Solvent: c1ccccc1
Product: CN1CC[C@@H](Oc2ccccc2F)[C@H](c2ccccc2)C1
Product: O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4.79 g of diethyl azodicarboxylate in 125 ml of benzene is added dropwise under a nitrogen atmosphere at 5°-10° C. over a 90 minute period to a mixture of 4.78 g of cis-1-methyl-3-phenyl-4-piperidinol, 7.21 g of triphenylphosphine, 3.08 g of 2-fluorophenol and 125 ml of dry benzene. After the addition, the mixture is stirred for 18 hours at room temperature, then filtered, and the solid waste is washed well with hexane. The filtrate is concentrated in vacuo to an oil which is stirred 18 hours with hexane. A gummy solid is filtered off, washed with hexane, and the filtrate concentrated in vacuo to an oil. This material is taken up in ether and extracted with 2 N HCl solution. The acid extracts are extracted with dichloromethane. The dichloromethane extracts are washed with 10% by weight of aqueous NaOH solution, then with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, and concentrated in vacuo to afford an oil. The oil is chromatographed on silica gel, using acetone as solvent. A purified free base is obtained as an oil. This material is dissolved in 75 ml of ether and treated dropwise with a solution of 1.44 g of fumaric acid in a mixture of 25 ml of absolute ethanol and 50 ml of ether. Scratching of the resulting solution causes crystallization to occur. The solid is filtered, washed with ether, and dried to afford a colorless solid of trans-4-(2-fluorophenoxy)-1-methyl-3-phenylpiperidine fumarate hemihydrate, m.p. partially melts 149°, 161°-167° C. Recrystallization from ethyl acetate affords the product having mp s 154, 156° C., dec.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:3]1.[BH4-].[Na+]>CO.O>[OH:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])[CH2:3]1
Reactant: CC(C)(C)OC(=O)NC1CCCCC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCCCC(O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.2 %

Procedure:
To a solution of tert-butyl 3-oxocycloheptylcarbamate (31.09 g, 137 mmol) in methanol (454 mL) was added sodium borohydride (15.52 g, 410 mmol) portion-wise over ˜10 minutes with mixing. The resulting solution was stirred for 2 h at room temperature and then diluted with water (200 mL). The methanol was removed in-vacuo and the resulting aqueous mixture was diluted further with 500 mL ethyl acetate and 100 mL saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer back-extracted with 2×1000 mL ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated to an oil that was purified by silica gel chromatography (0-50% ethyl acetate in hexanes). Product containing fractions were concentrated to afford tert-butyl 3-hydroxycycloheptylcarbamate (21.1 g, 92 mmol, 67.3% yield). MS (ESI) m/z 230.3 [M+H]+. The above two reactions were repeated starting with 9.52 g cyclohept-2-enone and yielding 9.27 g of tert-butyl 3-hydroxycycloheptylcarbamate. The two batches of tert-butyl 3-hydroxycycloheptylcarbamate were then combined. 29.2 g of the combined material was separated into the 4 constituent stereoisomers (two diastereomers and their corresponding enantiomers) by preparative chiral SFC utilizing multiple injections over a series of 3 separate columns. First column: ChiralPak IC-H, 250×30 mm I.D., isocratic 15% ethanol in CO2, 38° C. Second column: ChiralCel OJ-H, 250×30 mm I.D., isocratic 10% isopropanol in CO2, 38° C. Third column: ChiralPak AD-H, 250×50 mm I.D., isocratic 20% isopropanol in CO2, 38° C. The separated isomers were characterized on an analytical scale Phenomenex Lux Amylose-2 column, 250×4.6 mm I.D., isocratic 15% ethanol in CO, (10 min run time) and labeled as Intermediate 1 to Intermediate 4.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([OH:23])[CH:19]=3)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:24]1([CH:30]2[CH2:35][CH2:34][CH:33](O)[CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[C:24]1([C@@H:30]2[CH2:35][CH2:34][C@H:33]([O:23][C:18]3[CH:19]=[C:20]4[C:15](=[CH:16][CH:17]=3)[CH:14]=[C:13]([CH2:12][N:9]3[CH2:10][CH2:11][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]3)[CH:22]=[CH:21]4)[CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)C1CCN(Cc2ccc3cc(O)ccc3c2)CC1
Reactant: OC1CCC(c2ccccc2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(Cc2ccc3cc(O[C@H]4CC[C@@H](c5ccccc5)CC4)ccc3c2)CC1
Reaction time: 0.33 h
Yield: 49.7 %

Procedure:
A mixture of 1-(6-hydroxy-naphthalen-2-ylmethyl)-piperidine-4-carboxylic acid ethyl ester (0.400 g, 1.28 mmol), 4-phenyl-cyclohexanol (0.2479 g, 1.406 mmol) and triphenylphosphine (0.6695 g, 2.553 mmol) in toluene (5 mL, 40 mmol) was stirred for 20 min, then diisopropyl azodicarboxylate (0.32 mL, 1.5 mmol) was added dropwise at 0° C. The solution was stirred at reflux overnight. The reaction was added silica gel and the solvent was concentrated. The residue was purified with silica gel eluted with EtOAc in hexanes from 0 to 20% to give product as an oil (0.3 g, 50%). LCMS: Rt=1.75 min, m/z=472.45 [M+H].