Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]=[CH:7][NH:6][N:5]=1.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[N:9]1([CH2:3][C:4]2[N:8]=[CH:7][NH:6][N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C1CCNCC1
Reactant: ClCc1nc[nH]n1
Agent: Cl
Product: c1nc(CN2CCCCC2)n[nH]1

Procedure:
3-Chloromethyl-1,2,4-triazole hydrochloride (0.5 g.) was added to piperidine (10 ml.) and the mixture was heated at 100° for 16 hours, then evaporated to dryness. The residue was dissolved in water (10 ml.) and basified with sodium bicarbonate. The resulting solution was evaporated to dryness and the residue was extracted twice with ethanol (50 ml.). The combined extracts were evaporated to dryness and the residual gum was subjected to MPLC on K60 silica gel using methanol/chloroform, 3/97 v/v, as solvent to give 3-(piperidinomethyl)-1,2,4-triazole with NMR data as follows: solvent--CDCl3 : 8.05 ppm (singlet, 1H), 3.75 ppm (singlet, 2H), 2.5 ppm (multiplet, 4H) and 1.6 ppm (multiplet, 6H).
Reaction SMILES: C([O:3][C:4](=[O:36])[C@H:5]([CH3:35])[CH2:6][C@H:7]([NH:21][C:22](=[O:34])[CH2:23][CH2:24][C:25]1[N:29](CCC#N)[N:28]=[N:27][N:26]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)C.C1CCN2C(=NCCC2)CC1>ClCCl>[C:12]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:14][C:9]([CH2:8][C@@H:7]([NH:21][C:22](=[O:34])[CH2:23][CH2:24][C:25]2[NH:29][N:28]=[N:27][N:26]=2)[CH2:6][C@@H:5]([CH3:35])[C:4]([OH:36])=[O:3])=[CH:10][CH:11]=1
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCc1nnnn1CCC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCc1nnn[nH]1)C(=O)O
Reaction time: 3 h
Yield: 52.9 %

Procedure:
To a solution of (2R,4S)-5-Biphenyl-4-yl-4-{3-[1-(2-cyano-ethyl)-1H-tetrazol-5-yl]-propionylamino}-2-methyl-pentanoic acid ethyl ester (32 mg, 0.065 mmol) in dichloromethane (1 mL) is added DBU (24 mg, 0.164 mmol). After stirring for 3 hours, additional DBU (24 mg, 0.146 mmol) is added. After stirring for 2 hours, the reaction mixture is diluted with dichloromethane and washed with saturated aqueous NH4Cl. The organic layer is dried over Na2SO4 and concentrated. The residue is dissolved in MeOH and treated with aqueous 2M NaOH. After stirring for 1 hours, the reaction mixture is diluted with ethyl acetate and acidified with aqueous 1M HCl. The mixture is extracted with ethyl acetate and washed with brine. The organic layer is dried over Na2SO4 and concentrated. The residue is purified by reverse phase HPLC (0.1% TFA-H2O/MeCN) to give (2R,4S)-5-biphenyl-4-yl-2-methyl-4-(3-1H-tetrazol-5-yl-propionylamino)-pentanoic acid (14 mg). HPLC Retention time 1.17 minutes (condition C); MS 408.0 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (d, J=7.07Hz, 3H), 1.34 (ddd, J=4.80, 10.11, 14.91Hz, 1H), 1.78 (ddd, J=4.04, 9.60, 13.64Hz, 1H), 2.31-2.42 (m, 1H), 2.52-2.59 (m, 2H), 2.68 (d, J=7.07Hz, 2H), 3.03 (dd, J=7.58, 7.58Hz, 2H), 3.90-4.01 (m, 1H), 7.20 (d, J=8.08Hz, 2H), 7.34 (t, J=9.09Hz, 1H), 7.45 (d, J=7.83Hz, 2H), 7.55 (d, J=8.34Hz, 2H), 7.64 (d, J=7.33Hz, 2H), 7.84 (d, J=8.34Hz, 1H), 11.99 (bs, 1H).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3].[NH:15]([C:19]1[S:20][CH:21]=[C:22]([CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]2[C:32](=O)[C:31](=[O:34])[C:30]=2[O:35]C)[N:23]=1)[C:16]([NH2:18])=[NH:17]>CO>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:32]2[C:31](=[O:34])[C:30](=[O:35])[C:29]=2[NH:28][CH2:27][CH2:26][CH2:25][CH2:24][C:22]2[N:23]=[C:19]([NH:15][C:16]([NH2:18])=[NH:17])[S:20][CH:21]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1nc(CCCCN)cs1
Reactant: COc1c(NCCCCc2csc(NC(=N)N)n2)c(=O)c1=O
Solvent: CO
Product: N=C(N)Nc1nc(CCCCNc2c(NCCCCc3csc(NC(=N)N)n3)c(=O)c2=O)cs1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-guanidino-4-(4-aminobutyl)thiazole (0.105 g) and 1-[4-(2-guanidinothiazol-4-yl)butylamino]-2-methoxycyclobutene-3,4-dione (0.16 g) in dry methanol (5 ml) was stirred for 18 hours at room temperature. The white solid was filtered off, washed with methanol and dried in vacuo to give 1,2-bis[4-(2-guanidinothiazol-4-yl)butylamino]cyclobutene-3,4-dione, 0.16 g., m.p. 228°-229° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[N:15]#[C:16]Br.C(N(CC)CC)C>CC(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:13][CH:14]=1)[C:8](=[O:9])[N:10]([C:16]#[N:15])[C:11]2=[O:12])([O-:3])=[O:2]
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: N#CBr
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: N#CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Reaction time: 0.33 h
Yield: 87.5 %

Procedure:
A 25 mL round-bottomed flask was charged with 4-nitrophthalimide (0.96 g, 5.0 mmol), cyanogen bromide (0.64 g, 6.0 mmol), and 10 mL of reagent grade acetone. The resulting suspension was cooled using an ice/salt bath, and triethylamine (1.0 mL, 7.1 mmol) was added dropwise over a 4 minute period. The mixture was allowed to stir for 20 minutes before being partitioned between ethyl acetate and water. The organic phase was washed with water, saturated brine, dried (MgSO4), and concentrated to give 0.95 g of a yellow solid. This material was recrystallized from ethyl acetate to afford 0.65 g (60%) of yellow crystals, mp 209.5°-210.5° C. (reported in Zh. Org. Khim. 1977, 13, 968 as 215° C.): IR (nujol) 2261 (nitrile), 1811 (carbonyl), 1769 (carbonyl), 1533 (nitro), 1343 (nitro) cm-1 ; 1H NMR (200 MHz, DMSO) δ 8.34 (d, 1, J=8.9 Hz), 8.70-8.78 (m, 2); 13C NMR (50 MHz, DMSO) δ 161.15, 160.92, 152.34, 135.19, 132.10, 131.16, 126.48, 119.76, 102.26; GC/MS (relative intensity) 217 (77.8), 149 (71.7), 103 (64.4), 75 (100), 74 (52.7).
Reaction SMILES: [NH2:1][C@H:2]([C:13](O)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.S(C)C>C1COCC1>[NH2:1][C@@H:2]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)[CH2:13][OH:14]
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Solvent: CSC
Solvent: C1CCOC1
Product: N[C@H](CO)Cc1c[nH]c2ccccc12
Temperature: 70 °C
Yield: 92 %

Procedure:
To a stirred solution of (S)-tryptophan (4.0 g, 20.0 mmol) in THF (100 mL) at 0° C. was slowly added BH3.Me2S complex (5.9 mL, 10M solution in THF, 59.0 mmol). The reaction mixture was heated to 70° C. for 16 h and, after cooling, the excess borane was quenched by the addition of MeOH (10 mL) at 0° C. The reaction mixture was then concentrated in vacuo and the resultant white solid was dissolved in EtOAc (100 mL) and washed with aqueous 20% NaOH solution (2×70 mL). The organic layer was then extracted into aqueous 2M HCl (2×100 mL). The combined acidic aqueous layers were basified to pH 14 (addition of solid NaOH) and were re-extracted with EtOAc (2×150 mL). The combined organic fractions were washed with brine (70 mL), dried over MgSO4, filtered and concentrated in vacuo to give the title compound (3.5 g, 92%) as a white solid that required no further purification. δH (CD3OD) 7.46 (1H, d, J 7.9 Hz), 7.21 (1H, d, J 8.0 Hz), 6.96 (3H, m), 3.79 (1H, dd, J 11.3 and 3.6 Hz), 3.54 (1H, dd, J 11.2 and 6.2 Hz), 3.05 (1H, m), 2.80 (1H, m), 2.61 (1H, m). Exchangeable protons were not observed.
Reaction SMILES: [OH:1][C@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[Br:24][C:25]1[CH:26]=[C:27]([F:35])[CH:28]=[C:29]2[C:33]=1[NH:32][C:31](=[O:34])[CH2:30]2>>[Br:24][C:25]1[CH:26]=[C:27]([F:35])[CH:28]=[C:29]2[C:33]=1[NH:32][C:31](=[O:34])/[C:30]/2=[CH:14]\[C:11]1[NH:10][C:7]2[CH2:8][CH2:9][N:4]([CH2:3][C@H:2]([OH:1])[CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:5](=[O:16])[C:6]=2[C:12]=1[CH3:13]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CC2
Reactant: O=C1Cc2cc(F)cc(Br)c2N1
Product: Cc1c(/C=C2\C(=O)Nc3c(Br)cc(F)cc32)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CC2
Yield: 40 %

Procedure:
The title compound was prepared under the same conditions as described in step 6 of Example 1 with (R)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 1f obtained from step 5 of Example 1 and 7-bromo-5-fluoro-1,3-dihydro-indol-2-one 12b as starting materials to give (R,Z)-2-(7-bromo-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 14 (20 mg, yield 40%) as a yellow solid.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([O:17][C:18]2[N:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]3[O:26][C@:27]4([CH2:35][N:36]=3)[CH:32]3[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]3)[CH2:28]4)[CH:19]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1>C1COCC1>[CH:12]1([O:17][C:18]2[N:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]3[O:26][C@:27]4([CH2:35][N:36]=3)[CH:32]3[CH2:31][CH2:30][N+:29]([O-:9])([CH2:34][CH2:33]3)[CH2:28]4)[CH:19]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: c1nc(NC2=NC[C@@]3(CN4CCC3CC4)O2)cc(OC2CCCC2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: [O-][N+]12CCC(CC1)[C@]1(CN=C(Nc3cc(OC4CCCC4)ncn3)O1)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
mCPBA (0.114 g, 0.510 mmol) was added to a solution of (R)—N-(6-(cyclopentyloxy)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.175 g, 0.510 mmol) in THF (15 ml). The mixture was stirred at room temperature for 18 h and concentrated. The residue was purified by silica gel chromatography (5-25% 9:1 methanol:ammonium hydroxide-ethyl acetate) to afford (S)-2-(6-(cyclopentyloxy)pyrimidin-4-ylamino)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]1′-oxide an off-white solid (0.076 g, 0.207 mmol, 41%). 1H NMR (400 MHz, MeOD) δ ppm 8.38 (1H, s), 6.34 (1H, br. s.), 5.18-5.37 (1H, m), 4.01 (1H, d, J=11.08 Hz), 3.85 (1H, d, J=10.83 Hz), 3.58-3.75 (2H, m), 3.34-3.53 (3H, m), 3.20-3.27 (1H, m), 2.32-2.46 (1H, m), 2.23-2.31 (1H, m), 1.98-2.19 (3H, m), 1.93-1.99 (2H, m), 1.68-1.84 (4H, m), 1.55-1.70 (2H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[N+:16]([O-])([OH:18])=[O:17]>C(O)(=O)C>[Br:15][C:10]1[CH:9]=[C:8]([N+:16]([O-:18])=[O:17])[C:7]2[NH:6][C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=3
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Br)cc2c1[nH]c1ccc(Br)cc12
Temperature: 0 °C

Procedure:
Acetic acid (600 ml) and 3,6-dibromocarbazole (45 g) was placed into a one liter three-necked RB flask equipped with a reflux condenser, mechanical stirrer, and heating mantle. The stirred solution was heated to reflux at which time a solution of nitric acid (10 ml, density 1.4 g/cc, 0.156 mole in 100 ml of acetic acid) was added over a period of 30 minutes. After 2/3 of the nitrating mixture was added, a flocculent yellow precipitate deposited. The remainder of the nitrating mixture was added and the whole refluxed gently for one hour, cooled to 0° C. in an ice bath and filtered. The crude yellow precipitate softens at 232° C. and melts at 243°-246° C. The crude product was recrystallized from boiling acetonitrile to give yellow crystals with m.p. 252°-256° C. (uncovered), 256°-260° C. (covered). [H. Lindemann & F. Muhlhaus, Ber., 58, 2371 (1925) report a m.p. of 260° C. for the product].
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[C:6]([O:13][CH3:14])[CH:5]=1)(=[O:3])[CH3:2].Br[CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20]>>[C:1]([C:4]1[CH:5]=[C:6]([O:13][CH3:14])[C:7]([O:12][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[C:8]([O:10][CH3:11])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCBr
Reactant: COc1cc(C(C)=O)cc(OC)c1O
Product: COc1cc(C(C)=O)cc(OC)c1OCCCC(=O)O

Procedure:
Utilizing the procedure of Preparation 3, 2.61 g (13.32 mmol) of 4-acetyl-2,6-dimethoxyphenol is treated with ethyl 4-bromobutyrate. This gives the desired product after drying at -70° C., under high vacuum, as a brown oil. This is chromatographed on a column of silica gel, and eluted with a 1:1 mixture of ether/hexane leaving 0.40 g (10%) of 4-(4-acetyl-2,6-dimethoxyphenoxy)butanoic acid, ethyl ester as a colorless oil: IR (neat) 1735, 1675 cm-1 ; 1H-NMR (CDCl3) is consistent with the desired product; MS (FAB) m/e 311.1489 Δ=+0.6 mmμ (M+ +H). Analysis calculated for C16H22O6 : C, 61.92; H, 7.14; O, 30.94. Found: C, 61.48; H, 7.04; O, 31.48.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][N:10]=[C:11]2[C:15](=O)[O:14][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:12]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH4+:23].[OH-].Cl.O>CC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:12][C:11]([C:15]([NH2:23])=[O:14])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: [NH4+]
Reactant: Cc1cc(NN=C2N=C(c3ccccc3)OC2=O)ccc1F
Agent: Cl
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(-n2nc(C(N)=O)nc2-c2ccccc2)ccc1F
Yield: 55.2 %

Procedure:
3.0 g (0.01 mole) of 4-(3-methyl-4-fluorophenylhydrazono)-2-phenyl-oxazoline-5-one (R1 =3--CH3, R2 =4--F and R3 =H in the formula II) was suspended in 16 ml of acetone. To the suspension, 1.57 ml of 29% solution of NH4OH (0.013 mole) was added dropwise at room temperature. After refluxing the reaction mixture for 25 minutes, heating was stopped and 1.57 ml of concentrated hydrochloric acid was added dropwise. After the addition was over, the reaction mixture was refluxed again for 5 minutes. Then 40 ml of water was added to the reaction mixture, and the resulting crystal was filtered out, washed with acetone containing water and dried. The obtained crystal was recrystallized from a mixture of 20 ml of ethanol and 5 ml of water to obtain 1.7 g of almost colorless crystal, m.p. 123°-126° C., with a yield of 55.2%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.Cl.[N:20]1[CH:25]=[CH:24][C:23]([C:26](Cl)=[O:27])=[CH:22][CH:21]=1>>[N:20]1[CH:25]=[CH:24][C:23]([C:26]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:27])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: CCN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Agent: Cl
Product: CCN1CCC(c2c[nH]c3ccc(NC(=O)c4ccncc4)nc23)CC1

Procedure:
Beginning with 0.015 gm (0.061 mMol) 5-amino-3-(1-ethylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.014 gm (0.080 mMol) 4-pyridinecarbonyl chloride hydrochloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10]([NH:12][C@H:13]([C@H:28]([OH:47])[CH2:29][N:30]([S:35]([C:38]2[CH:46]=[CH:45][C:41]3[O:42][CH2:43][O:44][C:40]=3[CH:39]=2)(=[O:37])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:14][C:15]2[CH:27]=[CH:26][C:18]([O:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=O)=[CH:17][CH:16]=2)=[O:11])[CH2:2]1.[CH:48]([N:51](CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN>CN(C=O)C.CCO>[O:42]1[C:41]2[CH:45]=[CH:46][C:38]([S:35]([N:30]([CH2:31][CH:32]([CH3:33])[CH3:34])[CH2:29][C@@H:28]([OH:47])[C@@H:13]([NH:12][C:10](=[O:11])[O:9][C@@H:3]3[C@H:4]4[C@H:5]([O:6][CH2:7][CH2:8]4)[O:1][CH2:2]3)[CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:19][CH2:20][CH2:21][CH2:22][C:23]([NH:51][CH3:48])=[O:25])=[CH:26][CH:27]=3)(=[O:36])=[O:37])=[CH:39][C:40]=2[O:44][CH2:43]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCC(=O)O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCO
Product: CNC(=O)CCCOc1ccc(C[C@H](NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)[C@H](O)CN(CC(C)C)S(=O)(=O)c2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61.2 %

Procedure:
A solution of 35 mg (0.052 mmol) of 4-(4-{(2S,3R)-2-({[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl}amino)-4-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-3-hydroxybutyl}phenoxy)butanoic acid and 27 μL (0.16 mmol) of N,N-diisopropylethylamine in 1 mL of anhydrous DMF was treated with 49 mg (0.13 mmol) of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU). The resulting solution was stirred at RT for 15 minutes and was then treated with 0.5 mL of 8M MeNH2 in EtOH. After 18 hours TLC indicated the reaction to be complete. The solution was concentrated to dryness at reduced pressure and the residue subjected to flash chromatography (SiO2, 95:5 CH2Cl2/MeOH) to afford 22 mg (61%) of the desired compound as a white powder. 1H NMR (CDCl3): 7.37 (d, 1H), 7.22 (s, 1H), 7.13 (d, 2H), 6.92 (d, 1H), 6.82 (d, 2H), 6.13 (s 2H), 5.67 (m, 2H), 5.05 (m, 2H), 4.00 (m, 3H), 3.88 (m, 3H), 3.72 (m, 2H), 3.24-2.71 (m, 11H), 2.40 (t, 2H), 2.16 (m, 2H), 1.88 (m, 1H), 1.67 (m, 1H), 1.53 (m, 1H), 0.94 (m, 6H). MS(ESI): 692(M+H).
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:32])=[O:3])=[CH:14][CH:13]=3)[N:19]=2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(OC)cc3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2nc(CCOc3ccc(OC(C)(C)C(=O)O)cc3)c(C)o2)cc1
Yield: 100.9 %

Procedure:
A solution of 2-(4-{2-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester (0.036 g, 0.0819 mmol) in ethanol (5 mL) was treated with 5 N NaOH (0.1 mL) and the reaction heated to reflux for 1 h. The reaction mixture was cooled and the solvent removed in vacuo. The resultant oil was acidified with 1 N HCl and extracted with EtOAc and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford 0.034 g (100%) of 2-(4-{2-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid. 1H NMR (500 MHz, CDCl3) δ 7.93 (d, 2H, J=8.60 Hz), 6.94 (d, 2H, J=8.60 Hz), 6.90-6.87 (m, 2H), 6.79-6.77 (m, 2H), 4.17 (t, 2H, J=6.45 Hz), 3.85 (s, 3H), 2.98 (t, 2H, J=6.45 Hz), 2.36 (s, 3H), 1.52 (s, 6H); HRMS (ES+) m/z exact mass calcd for C23H26NO6 412.1760, found 412.1783 The following compounds were prepared following the same procedure using ethyl iodide, 2-iodopropane, 1-iodopropane, and 1-iodohexane, respectively:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[C:5]([CH2:9][CH2:10][CH2:11][CH3:12])=[C:4]([CH3:13])[N:3]=1.P(Cl)(Cl)([Cl:16])=O>>[CH2:9]([C:5]1[C:6]([Cl:16])=[N:7][C:2]([NH2:1])=[N:3][C:4]=1[CH3:13])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCc1c(C)nc(N)nc1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCCCc1c(C)nc(N)nc1Cl
Yield: 29 %

Procedure:
2-Amino-5-butyl-6-methylpyrimidine-4-ol (1.0 g, 5.52 mmol) and phosphorus oxychloride (12 ml) were refluxed for 3 hours. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography(n-hexane: ethyl acetate=2:1) to give the object compound (325 mg, 29%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17](CC#N)=[CH:16][CH:15]=2)=[C:4]([CH3:23])[N:3]=1.[C:24]([OH:27])(=[O:26])[CH3:25]>CO.[OH-].[K+].O>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:25][C:24]([OH:27])=[O:26])=[CH:18][CH:19]=2)=[C:4]([CH3:23])[N:3]=1
Reactant: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC#N)cc1
Reactant: CC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1

Procedure:
The product from step (v) in MeOH (10 ml) and 5M KOH in water (3 ml) was heated under reflux for 18 h. The mixture was neutralised with acetic acid then purified by RPHPLC to afford the subtitle compound, 0.168 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].C(O)(=O)C1C=CC=CC=1.[Cl:22][S:23](O)(=[O:25])=[O:24]>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([Br:12])[C:9]([S:23]([Cl:22])(=[O:25])=[O:24])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: O=S(=O)(O)Cl
Reactant: COc1cc(Br)ccc1C(=O)O
Agent: O=C(O)c1ccccc1
Product: COc1cc(Br)c(S(=O)(=O)Cl)cc1C(=O)O
Temperature: 80 °C

Procedure:
300 ml of chlorosulphonic acid of density 1.766 (4.55 mole) is placed in a 1 liter flask fitted with an agitator, a thermometer and a condenser, and 69.3 g of 2-methoxy-4-bromobenzoic acid (0.30 mole) is added in stages. The reaction is slightly exothermic and the temperature reaches 40° C. by the time all the benzoic acid has been added. The reaction medium is heated to 80° C. then returned to room temperature. The solution, which is brown, is poured slowly over 2 kg of crushed ice.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][OH:5].C(=O)([O-])[O-].[K+].[K+].[CH3:12][CH:13]1[O:18][CH:17]([CH3:19])[CH2:16][NH:15][CH2:14]1>C(#N)C>[CH3:19][C@H:17]1[CH2:16][N:15]([CH2:2][CH2:3][CH2:4][OH:5])[CH2:14][C@@H:13]([CH3:12])[O:18]1
Reactant: CC1CNCC(C)O1
Reactant: OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CN(CCCO)C[C@H](C)O1
Yield: 28.9 %

Procedure:
3-Chloro-1-propanol (1.04 g, 11 mmol) followed by potassium carbonate (2.07 g, 15 mmol) was added to a solution of 2,6-dimethylmorpholine (1.15 g, 10 mmol), (supplied by Aldrich Chemical Company Limited as a mixture of isomers), in acetonitrile (15 ml). The mixture was heated at reflux overnight and allowed to cool, the insolubles were removed by filtration and the volatiles were removed from the filtrate by evaporation. The residue was purified by column chromatography on silica eluting with methylene chloride/acetonitrile/methanol (60/35/5 followed by 60/30/10) to give cis-3-(2,6-dimethylmorpholino)-1-propanol (500 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)(O)[CH:10]([C:22](C2C=CC=CC=2)(C2C=CC=CC=2)[O:23][SiH2]C(C)(C)C)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([C:15]2[CH:16]=[CH:17][C:18]([Br:21])=[CH:19][CH:20]=2)[CH:10]([CH2:22][OH:23])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)C1CN(Cc2ccccc2)CCC1(O)c1ccc(Br)cc1
Solvent: O=C(O)C(F)(F)F
Product: OCC1CN(Cc2ccccc2)CC=C1c1ccc(Br)cc1

Procedure:
In an analogous manner to that described in Example 62(c), from (3RS,4RS)- and/or (3RS,4SR)-1-benzyl-4-(4-bromo-phenyl)-3-(tert-butyl-diphenyl-silanyloxymethyl)-piperidin-4-ol by eliminating the tert. alcohol and simultaneous cleavage of the silyl group using trifluoroacetic acid there was obtained (3RS)-[1-benzyl-4-(4-bromo-phenyl)-1,2,3,6-tetrahydro-pyridin-3-yl]-methanol as a colourless solid; MS: 360 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]1[C:9](=[O:15])[NH:10][N:11]=[C:12]([CH3:14])[CH:13]=1.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25](Br)[C:26]([NH:28][S:29]([C:32]3[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=3)(=[O:31])=[O:30])=[O:27])=[CH:24][C:19]=2[O:18][CH2:17]1>CN(C=O)C>[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25]([N:10]3[C:9](=[O:15])[C:8]([CH3:7])=[CH:13][C:12]([CH3:14])=[N:11]3)[C:26]([NH:28][S:29]([C:32]3[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=3)(=[O:30])=[O:31])=[O:27])=[CH:24][C:19]=2[O:18][CH2:17]1
Reactant: Cc1cc(C)c(=O)[nH]n1
Reactant: CC(C)c1ccc(S(=O)(=O)NC(=O)C(Br)c2ccc3c(c2)OCO3)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(=O)n(C(C(=O)NS(=O)(=O)c2ccc(C(C)C)cc2)c2ccc3c(c2)OCO3)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.3 g of caesium carbonate are added to a solution of 1.55 g of 2,3-dihydro-4,6-dimethylpyridazin-3-one (prepared according to F. H. McMillan et al., J. Am.Chem. Soc. 78, 407 (1956)) and 4.52 g of 2-(1,3-benzodioxol-5-yl)-2-bromo-N-(4-isopropylphenylsulfonyl)acetamide in 100 ml of DMF. The mixture is stirred at room temperature for 2 hours and worked up in the customary manner and 2-(1,3-benzodioxol-5-yl)-2-(2,3-dihydro-4,6-dimethylpyridazin-3-on-2-yl)N-(4-isopropylphenylsulfonyl)acetamide is obtained, m.p. 105°.