Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[CH2:14][O:15][S:17]([CH3:16])(=[O:19])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
(2S,4R)-4-Fluoro-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.87 g, 13.1 mmol) was dissolved in 45 mL of CH2Cl2. The mixture was cooled down to 0° C., and methanesulfonyl chloride (2.55 mL, 32.8 mmol) and triethylamine (4.56 mL, 32.8 mmol) were added. The mixture was allowed to warm to RT and stirred for 1.5 h. The mixture was quenched with a saturated aqueous solution of NaHCO3, extracted twice with CH2Cl2, dried over Na2SO4 and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAC 3:7) to afford the desired material. TLC, Rf (c-hexane/EtOAc 1:1)=0.4; MS: 320.0 [M+Na]+, 198.1 [MH−Boc]+, 617.2 [2M+Na]+.
Reaction SMILES: O[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1.O=P(Cl)(Cl)[Cl:23]>C(N(CC)CC)C>[Cl:23][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1
Reactant: CSc1ccc(-c2c(-c3ccccc3)noc2O)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CSc1ccc(-c2c(-c3ccccc3)noc2Cl)cc1
Temperature: 70 °C

Procedure:
To a mixture of 5-hydroxy-4(4-methylsulfanylphenyl)-3-phenyl isoxazole (Compound prepared in step 1) (0.6 g) and triethyamine (0.43 mL) was added POCl3 (10 mL) under stirring and the reaction mixture was heated to 70° C. for 4 h. Solvents were evaporated and the crude product was chromatographed over silicagel using petroleum ether as eluent to yield 310 mg of product as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH:12]([OH:14])[C@@H:11]([OH:15])[C@H:10]([OH:16])[C@H:9]2[OH:17])=[CH:4][C:3]=1[CH2:18][C:19]1[CH:28]=[CH:27][C:22]2[O:23][CH2:24][CH2:25][O:26][C:21]=2[CH:20]=1.C(O[C:33](=[O:35])[CH3:34])(=O)C>N1C=CC=CC=1>[C:12]([O:15][C@H:11]1[C@H:10]([O:16][C:10](=[O:16])[CH3:9])[C@@H:9]([O:17][C:22](=[O:23])[CH3:21])[C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([CH2:18][C:19]3[CH:28]=[CH:27][C:22]4[O:23][CH2:24][CH2:25][O:26][C:21]=4[CH:20]=3)[CH:4]=2)[O:13][CH:12]1[O:14][C:33](=[O:35])[CH3:34])(=[O:13])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: OC1O[C@@H](c2ccc(Br)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: c1ccncc1
Product: CC(=O)OC1O[C@@H](c2ccc(Br)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 113.8 %

Procedure:
To a cooled solution of (3S,4R,5R,6S)-6-[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2,3,4,5-tetraol (4.7 g, 9.9 mmol) in pyridine (20 ml) was added acetic anhydride (8.1 g, 79.5 mmol) at 0° C. After complete addition reaction mixture was stirred at room temperature for 2 h. Pyridine was evaporated under reduced pressure. The resulting residue was taken in ethyl acetate and washed with aqueous 1 N sodium bisulfate solution followed by brine, dried over sodium sulfate, concentrated to give 3.5 g of acetic acid (3S,4R,5S,6S)-3,4,5-triacetoxy-6-[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-yl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([O:14]/C=C/C)[C@@H:12]([O:18]/C=C/C)[C@H:11]([O:22]/C=C/C)[C@@H:10]([CH2:26][O:27]/C=C/C)[N:9]2[CH3:31])=[CH:4][C:3]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH3:41])=[CH:35][CH:34]=1>C1COCC1.CC(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:18])[C@H:11]([OH:22])[C@@H:10]([CH2:26][OH:27])[N:9]2[CH3:31])=[CH:4][C:3]=1[CH2:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH3:41])=[CH:37][CH:38]=1
Reactant: C/C=C/OC[C@@H]1[C@@H](O/C=C/C)[C@H](O/C=C/C)[C@@H](O/C=C/C)[C@H](c2ccc(Cl)c(Cc3ccc(OCC)cc3)c2)N1C
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOc1ccc(Cc2cc([C@H]3[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)N3C)ccc2Cl)cc1
Temperature: 70 °C
Yield: 55.9 %

Procedure:
Compound from Step B (54 mg, 0.093 mmol) was dissolved in a solution of THF/AcOH/1NHCl (0.5 ml:0.6 ml:0.30 ml) and heated to 70° C. for 30 minutes. The mixture was concentrated to give a pale yellow oil. Purification by preparative HPLC (sunfire C18, 30×100 mm, 5 μm, 10%-100% B over 15 minutes) afforded (2S,3S,4R,5R,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-1-methyl-piperidine-3,4,5-triol (22 mg, 0.052 mmol, 56%) as a white solid. MS (ES+) [M+H]+=422.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:25][CH2:26][OH:27]>CN(C=O)C.Cl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[O:17][CH2:25][CH2:26][OH:27]
Reactant: OCCCl
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Temperature: 70 °C
Reaction time: 3 h
Yield: 68.5 %

Procedure:
A mixture of 13 grams (0.048 mole) of 2,6-dichloro-4-phenylmethoxyphenol (known compound), 6.8 grams (0.048 mole) of potassium carbonate and 3.9 grams (0.048 mole) of 2-chloroethanol in 80 mL of DMF was heated to 70° C. where it stirred for three hours. After this time the reaction mixture was allowed to cool to ambient temperature. The reaction mixture was diluted with 100 mL of aqueous 10% hydrochloric acid then extracted with three 150 mL portions of ethyl acetate. The combined extracts were washed with an aqueous saturated sodium chloride solution, dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The crude residue was purified with column chromatography on silica gel using 6:4 heptane:ethyl acetate as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 10.3 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[Br:11]Br.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:11][C:6]1[CH:5]=[C:4]([CH3:9])[C:3]([OH:10])=[C:2]([CH3:1])[C:7]=1[CH3:8]
Reactant: Cc1ccc(C)c(O)c1C
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Br)c(C)c(C)c1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2,3,6-trimethylphenol (40 g; 0.294 mol) in DCM (600 ml) at ambient temperature was added a solution of bromine (16.6 ml; 0.294 mol) in DCM (300 ml) dropwise over 30 mins. Reaction stirred for a further 5 hrs at ambient temperature. A solution of 1M sodium sulfite (300 ml) was added. The layers were separated and the aq. layer extracted with DCM (150 ml). Organics combined, washed with half sat. brine (300 ml), dried (anh. MgSO4), filtered and the solvent evaporated to give a white solid (66.2 g; 105% Th.). 1H NMR (300 MHz, CDCl3), δ/ppm; 2.19 (3H, s, Ar—CH3), 2.22 (3H, s, Ar—CH3), 2.34 (3H, s, Ar—CH3), 7.18 (1H, s, Ar—H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([CH2:21]Cl)=[CH:9][N:8]=1.[C-:26]#[N:27].[Na+].[I-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([CH2:21][C:26]#[N:27])=[CH:9][N:8]=1
Reactant: [C-]#N
Reactant: COc1cccc(Cc2ncc(CCl)c3cc(OC)c(OC)cc23)c1
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(Cc2ncc(CC#N)c3cc(OC)c(OC)cc23)c1
Yield: 47.4 %

Procedure:
The above 1-(3-methoxybenzyl)-4-chloromethyl-6,7-dimethoxyisoquinoline (361 mg, 1.0 mmol) was suspended into 15 ml of 90% ethanol. Then sodium cyanide (392 mg, 8.0 mmol) and sodium iodide (83 mg, 0.5 mmol) was added. The mixture was refluxed for 4 hrs. solvents were evaporated and the residue was extracted with ethyl acetate. After the evaporation of solvents, the residue was purified by flash column chromatography using ethyl acetate and hexane (2/1) to give 1-(3-methoxybenzyl)-4-cyanomethyl-6,7-dimethoxyisoquinoline as a solid (165 mg, 47.4%). ES-MS calculated for C21H20O3N2 (m/e) 348.41, observed 349.5.5 (M+1). 1H-NMR is consistent with the desired structure.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][N:13]1[CH:21]=[N:20][C:19]2[C:14]1=[N:15][C:16]([NH:23]C=O)=[N:17][C:18]=2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:26][CH2:27][CH3:28].[Na+]>C(O)C>[NH2:23][C:16]1[N:15]=[C:14]2[C:19]([N:20]=[CH:21][N:13]2[O:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:18]([O:26][CH2:27][CH3:28])[N:17]=1
Reactant: CC[O-]
Reactant: O=CNc1nc(Cl)c2ncn(OCCCOCc3ccccc3)c2n1
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(N)nc2c1ncn2OCCCOCc1ccccc1
Yield: 8 %

Procedure:
A solution of 9-(3-benzyloxyprop-1-oxy)-6-chloro-2-formamidopurine (500 mg, 1.38 mmol) in 0.4M sodium ethoxide in ethanol (10 ml) was heated at 80° C. for 2.5 hours. The mixture was then cooled and evaporated under reduced pressure. The residue was dissolved in water (20 ml) and the solution was brought to pH 7 with dilute hydrochloric acid. The aqueous solution was extracted with chloroform (2×20 ml) and the combined extracts were washed with water (10 ml), dried (magnesium sulphate) and evaporated under reduced pressure. Column chromatography on silica gel (eluted with chloroform-ethanol, 50:1) yielded the title compound (390 mg, 8%). IR: υmax (KBr) 3353, 3217, 1652, 1611, 1579, 1506, 1461, 1445, 1407 cm-1. 1H NMR: δH [(CD3)2SO] 1.35 (3H, t, J=7.2 Hz, CH3CH2O), 1.95 (2H, quintet, J=6.3, 6.6 Hz, CH2CH2CH2), 3.60 (2H, t, 6.3 Hz), 4.37 (2H, t, J=6.6 Hz, CH2ON), 4.42 (2H, quartet, J=7.2 Hz, CH3CH2O), 4.48 (2H, s, CH2Ph), 6.55 (2H, br.s, D2O exchangeable, NH2), 7.33 (5H, m, Ph), 8.07 (1H, s, H-8).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[Br:12]N1C(=O)CCC1=O>>[Br:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]2[N:4]=[N:3][N:2]([CH3:1])[C:6]=2[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2nnn(C)c2c1
Product: Cn1nnc2ccc(CBr)cc21

Procedure:
The dimethyl compound (a) is reacted with N-bromosuccinimide, yielding the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=O)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[Cl:27][C:28]1[CH:37]=[CH:36][C:31]([C:32](=[NH:35])[NH:33]O)=[CH:30][CH:29]=1.[H-].[Na+]>C1COCC1>[Cl:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]2[N:35]=[C:19]([C:18]3[CH:23]=[CH:24][C:15]([N:11]4[C:12](=[O:14])[NH:13][C:9]([C:3]5[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=5[Cl:8])=[N:10]4)=[CH:16][C:17]=3[O:25][CH3:26])[O:21][N:33]=2)=[CH:30][CH:29]=1
Reactant: N=C(NO)c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)ccc1-c1nc(-c2ccc(Cl)cc2)no1
Yield: 11.7 %

Procedure:
The title compound was prepared by following the procedure as described for Example-40 by using methyl 4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (Intermediate-21, 0.100 g, 0.25 mmol), 4-chloro-N-hydroxybenzimidamide (Intermediate-19, 0.064 g, 0.38 mmol), sodium hydride (0.020 g, 0.50 mmol) and dry THF (5.0 mL) at RT to afford 0.015 g of desired product. 1HNMR (DMSO-d6): δ 4.00 (s, 3H), 7.66-7.72 (m, 5H), 7.81 (d, J=8.7 Hz, 1H), 7.89 (s, 1H), 8.10 (d, J=8.4 Hz, 2H), 8.22 (d, J=9.0 Hz, 1H), 12.82 (br s, 1H); MS (m/z): 515.84 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[C:5]2[CH:6]=[C:7]([CH3:28])[C:8]([NH:16][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=3)=[CH:9][C:10]=2[C:11]([CH3:15])([CH3:14])[CH2:12][CH:13]=1)([CH3:3])[CH3:2].[CH:29](=O)[CH2:30][CH3:31]>>[CH2:29]([N:16]([C:8]1[C:7]([CH3:28])=[CH:6][C:5]2[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:13][CH2:12][C:11]([CH3:14])([CH3:15])[C:10]=2[CH:9]=1)[C:17]1[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=1)[CH2:30][CH3:31]
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C(C)C)=CCC3(C)C)cc1
Reactant: CCC=O
Product: CCCN(c1ccc(C(=O)OCC)cc1)c1cc2c(cc1C)C(C(C)C)=CCC2(C)C
Yield: 64.2 %

Procedure:
Following General Procedure D, ethyl 4-(5-isopropyl-3,8,8-trimethyl-7,8-dihydronaphthalen-2-ylamino)benzoate (Compound 48, 0.10 g, 0.26 mmol) was reacted with propionaldehyde (0.20 mL, 2.6 mmol) to give 0.070 g (68%) of the title compound as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])[CH:5]=[C:4]([CH3:14])[C:3]=1[OH:15].[H][H]>[Pt]=O.C(O)(=O)C>[CH3:1][CH:2]1[CH:7]([CH3:8])[CH:6]([CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:5][CH:4]([CH3:14])[CH:3]1[OH:15]
Reactant: CC(C)=CCc1cc(C)c(O)c(C)c1C
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC(C)CCC1CC(C)C(O)C(C)C1C
Yield: 53.4 %

Procedure:
A mixture of 2,3,6-trimethyl-4-(3-methyl-2-butenyl)phenol (30 g, 0.15 mol), platinum oxide (3 g), and acetic acid (150 mL) was hydrogenated at 50° C. and 200-300 psig until hydrogen uptake ceased. The mixture was filtered to remove the catalyst and the filtrate poured into water. The product was extracted with ethyl acetate and the extract washed successively with water, 5% sodium bicarbonate solution, and brine. The organic layer was dried, the solvent removed, and the residue fractionated to afford 17 g of the desired alcohol, bp 105°-110° C. (1 mm). NMR (CDCl3) δ0.7-2.2 (27H, complex pattern), 3.6 (1H, bs). IR (film) 3700, 1500, 1020, 970 cm-1. MS (m/e) 212 (M+), 123, 35, 69, 95.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][CH:28]=[CH:27]2>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][CH:28]=[CH:27]2
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: Oc1ccc2ncccc2c1
Product: COc1cc2c(Oc3ccc4ncccc4c3)ncnc2cc1OCC1CCN(C)CC1
Yield: 89.9 %

Procedure:
Using a procedure analogous to that described for Example 10, 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (74 mg, 0.23 mmol), (prepared as described for the starting material in Example 10), was reacted with 6-hydroxyquinoline (41 mg, 0.28 mol) to give 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(quinolin-6-yloxy)quinazoline (89 mg, 94%).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([N:10]([CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:11]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20](=[NH:22])[NH2:21])[CH2:16][CH2:15]2)=[O:12])[CH:7]=[CH:8][CH:9]=1)#[N:3].C(=O)([O-])[O-].[NH4+:34].[NH4+]>C(O)C>[C:2]([C:4]1[CH:5]=[C:6]([N:10]([CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:11]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20](=[NH:21])[NH2:22])[CH2:16][CH2:15]2)=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[NH:34])[NH2:3]
Reactant: [NH4+]
Reactant: N#Cc1cccc(N(C(=O)NC2CCN(C(=N)N)CC2)C2CCCCCC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: N=C(N)c1cccc(N(C(=O)NC2CCN(C(=N)N)CC2)C2CCCCCC2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dry hydrogen chloride gas was bubbled through an ice cooled solution of N-(3-cyanophenyl)-N′-(1-amidinopiperidin-4-yl)cycloheptylurea (0.03 g, 0.075 mmol) in anhydrous ethanol (5 ml) for 15 min. The reaction was stoppered, allowed to warm to ambient temperature and stirred for 24 h. The reaction was concentrated to give a viscous residue which was dissolved in anhydrous ethanol and ammonium carbonate (0.06 g, 0.63 mmol) was added. The reaction was stirred over night at ambient temperature and then concentrated in vacuo. The crude product appeared to be about 1:2 ratio of the desired product to starting material. Pure N-(3-amidinophenyl)-N′-(1-amidinopiperidin-4-yl)cycloheptylurea was isolated by HPLC on a Vydec® C-18 column eluting with solvent mixture A (acetonitrile:water:TFA 80:20:0.3) and solvent mixture B (water:TFA 99.7:0.3) using a gradient starting with A:B at 3:97 and changing to A:B at 70:30 over 20 min, to give two major fractions: N-(3-amidinophenyl)-N′-(1-amidinopiperidin-4-yl)cycloheptylurea, the desired product eluted at 13.3 minutes, (8.2 mg); LRMS (M+2H)+2 m/z 179.8; HRMS calc. 358.2355, found 358.2349; 1H NMR (DMSO-d6): 9.25(s, 2H), 9.0(s, 2H), 7.55-7.4(m, 4H), 7.32(s, 4H), 3.95(m, 3H), 3.65(m, 2H), 3.25(m, 2H), 3.07(m, 2H), 1.8-1.6(m, 8H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19][C:20]#[N:21]>>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]1[C:20]([NH2:21])=[N:1][C:2]2[C:7]([CH:8]=1)=[CH:6][N:5]=[CH:4][CH:3]=2
Reactant: COc1ccccc1CCC#N
Reactant: Nc1ccncc1C=O
Product: COc1ccccc1Cc1cc2cnccc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 4-aminonicotinaldehyde and 3-(2-methoxyphenyl)propionitrile.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([F:10])([F:9])[CH:4]([OH:8])[CH2:5][CH2:6]I.[N-:13]=[N+:14]=[N-:15].[Na+].O>CS(C)=O>[N:13]([CH2:6][CH2:5][CH:4]([OH:8])[C:3]([F:10])([F:9])[C:2]([F:12])([F:11])[F:1])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: OC(CCI)C(F)(F)C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCCC(O)C(F)(F)C(F)(F)F
Temperature: 50 °C
Reaction time: 8 h
Yield: 103.7 %

Procedure:
A solution of 1,1,1,2,2-pentafluoro-5-iodo-3-pentanol (1.99 g, 7.48 mmol) in dimethylsulfoxide (20 ml) was treated with sodium azide (585 mg, 8.98 mmol) and the reaction was heated to 50° C. After stirring overnight, the reaction was cooled to room temperature. It was then added to water (30 ml) and extracted with diethyl ether (3×30 ml). The combined organics were washed with brine (40 ml) and dried over anhydrous sodium sulphate. Removal of the solvents yielded an orange liquid. Purification by silica gel chromatography using 1:1 hexanes/ethyl acetate gave the title compound as an orange liquid (1.7 g, 100%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].[C:30]([C:35]1[N:36]=[CH:37][N:38]2[CH:42]=[CH:41][S:40][C:39]=12)(=[O:34])[CH:31]([CH3:33])[CH3:32].C(OCC)(=O)C>C1COCC1>[C:30]([C:35]1[N:36]=[CH:37][N:38]2[CH:42]=[C:41]([Sn:20]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:17][CH2:18][CH3:19])[S:40][C:39]=12)(=[O:34])[CH:31]([CH3:33])[CH3:32]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)C(=O)c1ncn2ccsc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)C(C)C)c2s1
Reaction time: 1 h

Procedure:
A 1.0 N lithiumbis(trimethylsilyl)amide/THF solution (12 ml) was added to 60 ml of THF. Tri-n-butylstannyl chloride (2.36 ml) and a solution of 1.18 g of 7-isobutyrylimidazo[5,1-b]thiazole in 1.18 ml of THF were added dropwise thereto in an argon atmosphere at −68° C. The mixture was stirred at the same temperature for one hr. Ethyl acetate (450 ml) was added to the reaction solution, and the mixture was washed with 200 ml of brine. The organic layer was dried over anhydrous magnesium sulfate, and then filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:2) to give 1.55 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10](C)[C:11]1[N:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=2)[NH:22][CH:21]=[C:20]3[CH:29]2[CH2:34][CH2:33][N:32]([S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[CH2:31][CH2:30]2)=[CH:13][CH:12]=1)[CH3:9].[CH3:41]NC>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:38]([S:35]([N:32]1[CH2:31][CH2:30][CH:29]([C:20]2[C:19]3[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=[C:17]([C:14]4[CH:15]=[N:16][C:11]([NH:10][CH:8]([CH3:41])[CH3:9])=[CH:12][CH:13]=4)[CH:18]=3)[NH:22][CH:21]=2)[CH2:34][CH2:33]1)(=[O:36])=[O:37])[CH3:39]
Reactant: CCN(C)c1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cn1
Reactant: CNC
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(NC(C)C)nc4)cc23)CC1
Yield: 14.5 %

Procedure:
The title compound was prepared according to the general procedure of 5-{6-[ethyl(methyl)amino]-3-pyridinyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 2-propanamine (64.3 mg, 1 mmol) for dimethylamine to afford 9.8 mg of the title compound (14.5%).
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12](O)=[O:13].C(OC(=O)C)(=O)C>>[CH:12]([N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][C:9]([OH:11])=[O:10])=[O:13]
Reactant: O=C(O)CNc1ccccc1
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Product: O=CN(CC(=O)O)c1ccccc1
Yield: 3503.5 %

Procedure:
7.56 g (50 mmole) of N-phenyl glycine and 54.87 g (1.19 mmole) of formic acid were transferred into a reaction vessel and 16.23 g (159 mol) of acetic anhydride was added dropwise over about 10 minutes while cooling and stirring. The reaction mixture was stirred for one hour at 0° C. and for two hours at room temperature. The resulting reaction mixture was concentrated under vacuum to obtain crude crystals. The crystals were recrystallized from ethanol-isopropyl ether to obtain 7.47 g of the title compound (yield 83.4%).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][N:7]([CH3:28])[C:8]([C:10]1[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:12][C:13](COS(C)(=O)=O)=[N:14][CH:15]=1)=[O:9].C(Cl)Cl.[OH2:41]>>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][N:7]([CH3:28])[C:8]([C:10]1[C:11]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[N:12][C:13]([CH2:28][N:7]2[CH2:8][CH2:10][O:41][CH2:5][CH2:6]2)=[N:14][CH:15]=1)=[O:9]
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1cnc(COS(C)(=O)=O)nc1-c1ccccc1
Reactant: O
Solvent: ClCCl
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1cnc(CN2CCOCC2)nc1-c1ccccc1
Reaction time: 16 h
Yield: 88 %

Procedure:
To a solution of 0.40 g (0.73 mmol) methanesulfonic acid 5-[(3,5-bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4-phenyl-pyrimidin-2-ylmethyl ester in 5 ml CH2Cl2 0.095 ml (1.10 mmol) morpholine were added. The reaction mixture was stirred for 16 hrs. at RT. The reaction mixture was poured into H2O and extracted three times with 50 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH 10:1) to give 0.33 g (88%) 2-morpholin-4-ylmethyl-4-phenyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a pale yellow waxy solid, MS (ISP): 539.3 (M+H+).