Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].[OH:4][C:5]([C:8]1[N:9]=[C:10]([CH2:18][CH2:19][CH3:20])[NH:11][C:12]=1[C:13]([O:15]CC)=[O:14])([CH3:7])[CH3:6].Cl>O.CO>[OH:4][C:5]([C:8]1[N:9]=[C:10]([CH2:18][CH2:19][CH3:20])[NH:11][C:12]=1[C:13]([OH:15])=[O:14])([CH3:7])[CH3:6]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCc1nc(C(C)(C)O)c(C(=O)O)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.2 %

Procedure:
A solution of 0.28 g of lithium hydroxide monohydrate in 5 ml of water was added to a solution of 0.48 g of ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (prepared as described in Preparation 9) in 5 ml of methanol, and the resulting mixture was stirred at room temperature for 18 hours. At the end of this time, the pH of the reaction mixture was adjusted to a value of 2.3 by adding 6.67 ml of 1N aqueous hydrochloric acid, and the mixture was concentrated by evaporation under reduced pressure to a volume of about 2 ml. The crystals which precipitated were collected by filtration to give 0.20 g of the title compound, melting at 232° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[N:15]4[N:16]=[C:17]([CH3:25])[CH:18]=[C:19]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[C:14]4=[N:13][C:12]=3[CH3:26])[NH:8]2)=[CH:4][CH:3]=1.[CH3:27]N(C=O)C.[H-].[Na+].CI>CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[N:15]4[N:16]=[C:17]([CH3:25])[CH:18]=[C:19]([CH:20]([CH2:21][CH3:22])[CH2:23][CH3:24])[C:14]4=[N:13][C:12]=3[CH3:26])[N:8]2[CH3:27])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CCC(CC)c1cc(C)nn2c(-c3cc4ccc(Cl)cc4[nH]3)c(C)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CCC(CC)c1cc(C)nn2c(-c3cc4ccc(Cl)cc4n3C)c(C)nc12
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a solution of 3-(6-chloro-1H-indol-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.050 g, 0.14 mmol) and DMF (2 mL) is added 60% NaH (0.013 g, 0.33 mmol). The solution is stirred for 30 minutes and MeI (0.010 mL, 0.16 mmol) is added. The solution is stirred for 1 hour, diluted with EtOAc (20 mL), washed with water (2×10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated. The residue is purified by silica gel chromatography (30%-50% EtOAc gradient) to furnish the title compound (0.021 g, 0.055 mmol, 40%). 1H NMR (CDCl3), δ 0.90 (t, J=7.4 Hz, 6H), 1.75-1.95 (m, 4H), 2.49 (s, 3H), 2.51 (s, 3H), 3.31-3.40 (m, 1H), 3.57 (s, 3H), 6.65 (d, J=0.9 Hz, 1H), 6.72 (s, 1H), 7.12 (dd, J=8.4, 1.8 Hz, 1H), 7.40-7.42 (m, 1H), 7.58 (8.4 Hz, 1H) ppm. LC/MS (m/z): calcd. for C22H25ClN4 (M+H)+: 380.2. found: 381.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:21][N:22]2[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]2)=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:7]=[CH:6]2.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>ClCCl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[CH3:1][O:2][C:3]1[C:4]([CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:13])=[O:14])[CH:7]=[CH:6]2
Reactant: COc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1CN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 4-{[5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-1-carboxylate (0.050 g, 0.102 mmol, Intermediate 76) was dissolved in dichloromethane (4 mL) and TFA (1 mL) was added. The mixture was stirred and rt for 2 h and evaporated. The crude product was purified by reversed phase preparative HPLC using ACE Prep UV C8 150×30 mm, flow 38 mL/min, gradient time 8.5 min using the eluent system: water/0.1% TFA and CH3CN (20-40% MeCN), fractions collected based on UV-signal (254 nm). The purest fractions were pooled and the acetonitrile was evaporated. Yield: 29 mg (46%). Brown liquid, off white solid after 1 h. Isolated as the TFA salt. MS (ESI+) for C20H23N3O3S m/z 386.4 (M+H)+.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][C@@H:7]([C@@H:9]([N:41]=[N+:42]=[N-:43])[CH2:10][C@@H:11]([CH:38]([CH3:40])[CH3:39])[CH:12]([OH:37])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:15]([O:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])[CH:14]=2)[O:6][C:5]1=[O:44])([CH3:3])[CH3:2].[C:45](OC(=O)C)(=[O:47])[CH3:46]>N1C=CC=CC=1>[CH:1]([C@@H:4]1[CH2:8][C@@H:7]([C@@H:9]([N:41]=[N+:42]=[N-:43])[CH2:10][C@@H:11]([CH:38]([CH3:39])[CH3:40])[CH:12]([O:37][C:45](=[O:47])[CH3:46])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[C:15]([O:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])[CH:14]=2)[O:6][C:5]1=[O:44])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: COCCCOc1cc(C(O)[C@@H](C[C@H](N=[N+]=[N-])[C@@H]2C[C@@H](C(C)C)C(=O)O2)C(C)C)ccc1OCCCOCc1ccccc1
Solvent: c1ccncc1
Product: COCCCOc1cc(C(OC(C)=O)[C@@H](C[C@H](N=[N+]=[N-])[C@@H]2C[C@@H](C(C)C)C(=O)O2)C(C)C)ccc1OCCCOCc1ccccc1

Procedure:
A solution of 144 mg of 3(S)-isopropyl-5(S)-{1(S)-azido-3(S)-isopropyl-4(R,S)-hydroxy-4-[4-(3-benzyloxypropyloxy)-3-(3-methoxypropyloxy)-phenyl]-butyl}-tetrahydrofuran-2-one in 1.8 ml of acetic anhydride and 0.057 ml of pyridine is stirred for 30 hours at room temperature and is then concentrated to dryness by evaporation at room temperature and under reduced pressure. The residue is partitioned between dichloromethane (3x) and water/saturated sodium chloride solution (3x). The organic phases are combined, dried over magnesium sulfate and concentrated by evaporation, and the residue is purified by means of FC (hexane/ethyl acetate=4:1), yielding the title compound: Rf (hexane/ethyl acetate=2:1)=0.38 and 0.33; HPLC Rt =21.76 and 21.82 minutes (diastereoisomeric mixture); FAB-MS M+ =653, (M+Na)+ =676.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]3)=[C:12]([O:22][CH3:23])[CH:11]=2)[N:3]=1.[O-:24][CH2:25][CH3:26].[Na+]>C(O)C>[CH2:25]([O:24][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]3)=[C:12]([O:22][CH3:23])[CH:11]=2)[N:3]=1)[CH3:26]
Reactant: COc1cc(Nc2nc(C)cc(Cl)n2)ccc1-n1cnc(C)c1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc(C)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
A mixture of (4-chloro-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine (165 mg, 0.5 mmol) and sodium ethoxide (54 mg, 0.75 mmol) in ethanol (3 ml) was heated for 30 min to 160° C. in a microwave oven. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was stirred with diethyl ether for 30 min to yield the title compound as a brown solid (139 mg, 82%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28]OS(C)(=O)=O)[CH:22]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:28][CH2:27][C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCCc1cccnc1
Reactant: Cc1cccnc1[C@@H]1CCC[C@H](c2ncccc2C)N1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1[C@H]1CCC[C@@H](c2ncccc2C)N1CCc1cccnc1
Yield: 63.2 %

Procedure:
Using General Procedure A: A solution of 3,3″-Dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-cis-[2,2′;6′,2″]terpyridine (0.219 g, 0.82 mmol), methanesulfonic acid 2-pyridin-3-yl-ethyl ester (approx. 3 mmol), KI (15 mg), and DIPEA (0.25 mL, 1.44 mmol) in DMF (3 mL was heated at 80° C. for 17 hours. Purification of the crude material by column chromatography on silica gel (CH2Cl2—CH3OH—NH4OH, 94:4:2) followed by radial chromatography on silica gel (1 mm plate, CH2Cl2—CH3OH—NH4OH, 50:1:1) provided 193 mg (63%) of COMPOUND 92 as a colorless oil. 1H NMR (CDCl3) δ 1.61-1.70 (m, 4H), 2.00-2.22 (m, 4H), 2.51 (s, 6H), 2.51-2.55 (m, 2H), 4.14-4.18 (m, 2H), 6.55-6.60 (m, 1H), 6.85 (dd, 1H, J=7.5, 4.8 Hz), 7.09-7.12 (m, 2H), 7.42 (d, 2H, J=6.9 Hz), 7.54-7.60 (m, 1H), 8.18 (dd, 1H, J=4.8, 1.5 Hz), 8.42-8.46 (m, 2H); 13C NMR (CDCl3) δ 17.59, 22.43, 24.32, 26.23, 28.85, 30.67, 47.26, 51.85, 63.52, 70.06, 121.05, 121.87, 131.24, 134.51, 137.16, 138.57, 145.34, 145.73, 148.78, 158.55; ES-MS m/z 373 (M+H). Anal. Calcd. for C24H28N4.0.3 H2O: C, 76.28; H, 7.63; N, 14.83. Found: C, 76.14; H, 7.78; N, 14.82.
Reaction SMILES: C([O:5][C:6](=[O:41])[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]([C:19](=[O:40])[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([C:27]2[C:36]([C:37]#[N:38])=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][C:33]=3[F:39])[N:28]=2)[CH:21]=1)[CH3:18])(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]([N:17]([CH3:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7][C:6]([OH:41])=[O:5])=[O:40])=[CH:21][C:22]=1[C:27]1[C:36]([C:37]#[N:38])=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][C:33]=2[F:39])[N:28]=1
Reactant: CN(C(=O)c1ccc(Cl)c(-c2nc3cccc(F)c3cc2C#N)c1)c1ccccc1OCCCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)c1ccc(Cl)c(-c2nc3cccc(F)c3cc2C#N)c1)c1ccccc1OCCCC(=O)O
Yield: 31.6 %

Procedure:
4-(2-{[4-Chloro-3-(3-cyano-5-fluoro-quinolin-2-yl)-benzoyl]-methyl-amino}-phenoxy)-butyric acid tert-butyl ester (80.2 mg) was stirred in 50% trifluoroacetic acid in dichloromethane (2 mL) for 2 hrs and purified via reverse phase preparative LCMS to afford 4-(2-{[4-chloro-3-(3-cyano-5-fluoro-quinolin-2-yl)-benzoyl]-methyl-amino}-phenoxy)-butyric acid 33-1 (22.9 mg). MS [M+H]+: 518.4; tR=3.47 min. (method 3)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[CH2:15][CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:25]1[C:34]2[C:29](=[CH:30][C:31]([C:35]([F:38])([F:37])[F:36])=[CH:32][CH:33]=2)[N:28]=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH:14]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:25]4[C:34]5[C:29](=[CH:30][C:31]([C:35]([F:38])([F:36])[F:37])=[CH:32][CH:33]=5)[N:28]=[CH:27][CH:26]=4)=[CH:21][CH:22]=3)[CH2:15][CH3:16])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Reactant: CCC(c1ccc(N)cc1)N1CCN(c2ccc(F)cc2)CC1
Product: CCC(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCN(c2ccc(F)cc2)CC1

Procedure:
In the manner given in Example 1C, 1-(p-fluorophenyl)-4-[1-(4-aminophenyl)propyl]piperazine and 4-chloro-7-(trifluoromethyl)quinoline are reacted together at reflux to give 4-[[4-[1-[4-(p-fluorophenyl)-1-piperazinyl]propyl]phenyl]amino]-7-(trifluoromethyl)quinoline.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14](/[CH:17]=[CH:18]/[C:19]#[C:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:28][OH:29]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH:18]([NH:28][OH:29])[C:19]#[C:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: NO
Reactant: O=S(=O)(/C=C/C#CCc1ccccc1)N1CCN(c2ccc(F)cc2)CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(CC(C#CCc1ccccc1)NO)N1CCN(c2ccc(F)cc2)CC1
Temperature: 60 °C
Yield: 29.9 %

Procedure:
To a solution of 1-(4-fluorophenyl)-4-{[(1E)-5-phenyl-1-penten-3-ynyl]sulfonyl}piperazine (155 mg; 0.40 mmol) in THF (8 mL) was added hydroxylamine (0.71 mL; 12.1 mmol). The reaction mixture was heated at 60° C. for 1 h. It was then diluted with EtOAc, washed with brine, dried over magnesium sulfate, filtrated and concentrated. Purification of the crude (135 mg) by flash chromatography on silica gave the title compound (50 mg, 30% yield). HPLC, Rt: 3.84 min (purity: 94.5%). LC/MS, M+(ESI): 418.3, M−(ESI): 416.2. 1H NMR (CDCl3) δ: 7.22-7.31 (m, 5H), 7.01 (m, 4H), 4.33 (m, 1H), 3.62 (d, J=1.9 Hz, 2H), 3.53-3.60 (m, 5H), 3.20-3.27 (m, 5H). 1H NMR (CDCl3) δ: 7.30 (m, 5H), 6.95 (m, 4H), 6.32 (d, J=15.6 Hz, 1H), 6.07 (dt, J=16.1, 7.4 Hz, 1H), 3.90 (s, 2H), 3.78 (d, J=6.6 Hz, 2H), 3.22 (m, 4H), 2.91 (m, 4H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[N:18]=[CH:17][C:16]([I:19])=[CH:15][N:14]=1>C(#N)C>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:12]=[C:13]3[N:18]=[CH:17][C:16]([I:19])=[CH:15][N:14]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(O)cc1
Reactant: Nc1ncc(I)cn1
Solvent: CC#N
Product: Oc1ccc(-c2cn3cc(I)cnc3n2)cc1
Temperature: 110 °C
Yield: 73 %

Procedure:
646 mg (corresponding to 3.0 mmol) of 2-bromo-4′-hydroxyacetophenone and 668 mg (corresponding to 3.0 mmol) of 2-amino-5-iodopyrimidine were dissolved in 20 mL of acetonitrile. The resulting solution was refluxed in an oil bath at 110° C. for 8 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered and recovered. The precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 10 mL of water and 10 mL of methanol. Then, about 15 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 3 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 737 mg (corresponding to 2.19 mmol) of 2-(4′-hydroxyphenyl)-6-iodoimidazo[1,2-a]pyrimidine (FIG. 1-8, Step 2).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:18][C:19](=[O:21])[CH3:20]>O.CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:18][C:19](=[O:21])[CH3:20]
Reactant: Sc1ccccc1Br
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)CSc1ccccc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
20 g (105.7 mmol) of 2-bromothiophenol, 19 g (137.5 mmol) of potassium carbonate, 27.8 g (165.5 mmol) of potassium iodide, 200 ml of dimethylformamide and 14.68 g (158.6 mmol) of chloroacetone are introduced into a 500 ml three-necked flask. The mixture is stirred for 2 hours at room temperature and is then poured into 800 ml of water. Extraction is carried out with ethyl acetate (3×400 ml). The organic phases are combined, washed with a molar sodium hydroxide solution (2×400 ml), dried over magnesium sulphate and concentrated. The residue is purified by chromatography on a silica column (elution solution: 10% ethyl acetate in cyclohexane). 24.1 g (Yield: 93%) of (2-bromothiophenoxy)acetone are obtained (yellow oil).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[CH2:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[N+:19](=[CH:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23])=[N-:20]>CCOCC>[CH2:16]([O:15][P:11]([C:9]1([P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[CH2:10][C:21]([C:22](=[O:23])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:19][NH:20]1)(=[O:18])[O:12][CH2:13][CH3:14])[CH3:17]
Reactant: C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Reactant: [N-]=[N+]=CC(=O)c1ccccc1
Solvent: CCOCC
Product: CCOP(=O)(OCC)C1(P(=O)(OCC)OCC)CC(C(=O)c2ccccc2)=NN1
Reaction time: 20 h

Procedure:
Ethenylidene bisphosphonic acid tetraethyl ester (II, PREPARATION 1, 6.00 g) in ether (20 ml) is treated with solid 2-diazo-1-phenylethanone (2.92 g) and stirred at 22° for 20 hrs. The precipitate is collected and washed with ether to give the title compound. An analytical sample is obtained by recrystallization from methylene chloride/hexane, mp 133.5°-134°; MS (m/e) 446, 327, 309, 281, 271, 253, 243, 215, 175; IR (mineral oil mull) 3183, 1631, 1600, 1578, 1548, 1433, 1260, 1242, 1161, 1067, 1043, 1020, 1001, 995, 976 and 962 cm-1 ; NMR (CDCl3) 8.10, 7.50, 6.90, 4.27, 3.69 and 1.34 δ.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21]OS(C)(=O)=O)=[CH:16][CH:15]=1)C1C=CC=CC=1>>[N:1]1([CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([OH:13])=[CH:15][CH:16]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CS(=O)(=O)OCCc1ccc(OCc2ccccc2)cc1
Reactant: c1nc[nH]n1
Product: Oc1ccc(CCn2cncn2)cc1

Procedure:
In a manner analogous to that described in Example 10(b), from 1H-1,2,4-triazole and 1-benzyloxy-4-(2-methane-sulfonyloxyethyl)benzene, 4-[2-(1H-1,2,4,-triazol-1-yl)ethyl]phenol was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:37](Cl)(=[O:40])[CH:38]=[CH2:39]>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:37](=[O:40])[CH:38]=[CH2:39])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(=O)(=O)NC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1ccc(S(=O)(=O)NC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 8.4 %

Procedure:
4-(4-Amino-benzenesulfonylamino)-piperidine-1-carboxylic acid benzyl ester (1 g, 2.4 mmol) was dissolved in THF (10 ml). To this was added diisopropylethylamine (1.27 ml, 7.2 mmol) in one portion followed by the drop wise addition of acryloyl chloride (0.2 ml, 2.6 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The THF was removed under vacuum and the resulting crude material was purified by column chromatography (elution: 40% heptane, 60% ethyl acetate) to give the title compound (89 mg, 8% yield) as a white powder.
Reaction SMILES: [CH2:1]([C:3](=[CH:7][CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:17][O:18][C:12]=2[CH:11]=1)[CH2:4][CH2:5]Br)[CH3:2].[I-:19].[Na+]>CC(C)=O>[CH2:1]([C:3](=[CH:7][CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:17][O:18][C:12]=2[CH:11]=1)[CH2:4][CH2:5][I:19])[CH3:2]
Reactant: [I-]
Reactant: CCC(=CC=Cc1ccc2c(c1)OCO2)CCBr
Agent: [Na+]
Solvent: CC(C)=O
Product: CCC(=CC=Cc1ccc2c(c1)OCO2)CCI

Procedure:
3-Ethyl-6-(3,4-methylenedioxyphenyl)-3,5-hexadienyl iodide [IX; Ar is 3,4-methylenedioxyphenyl, R is C2H5 ] was prepared from 10 g. of 3-ethyl-6-(3,4-methylenedioxyphenyl)-3,5-hexadienyl bromide (Preparation C9) and 6 g. of sodium iodide in 120 ml. of acetone, to give 10.5 g. of product as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:13])[CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].I[CH2:15][CH3:16]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:13])[CH2:12][N:11]([CH2:15][CH3:16])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCI
Reactant: OC1(c2ccc(F)c(F)c2)CNC1
Solvent: C1CCOC1
Product: CCN1CC(O)(c2ccc(F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 57.9 %

Procedure:
A mixture of 3-(3,4-difluorophenyl)azetidin-3-ol (0.3 g, 1.62 mmol) triethylamine (0.68 ml, 4.87 mmol) and iodoethane (0.19 ml, 2.44 mmol) in tetrahydrofuran (15 ml) was stirred at ambient temperature for 15 h. The solvent was evaporated and aqueous hydrochloric acid (50 mL. 10%) was added and the mixture was washed with tert-butyl methyl ether (2×50 ml). The aqueous phase was made basic by addition of aqueous sodium hydroxide (5 M) and extracted with tert-butyl methyl ether (2×50 ml). The combined organic phase was dried (Na2SO4) and evaporated under reduced pressure to give the crude product (0.26 g). Purification by flash column chromatography on silica gel (ethyl acetate/methanol 1:1) gave 0.2 g (58%) of the title compound. The amine was converted to the fumaric acid salt and recrystallized from methanol/diethyl ether: M.p. 177-179° C. MS m/z (relative intensity, 70 eV) 213 (M+, 1), 141 (86), 127 (45), 114 (58), 58 (bp).
Reaction SMILES: O.NN.[C:4]1([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CCO>[C:4]1([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCc1ccccc1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCCCc1ccccc1
Temperature: 25 °C
Yield: 74.6 %

Procedure:
Hydrazine monohydrate (0.36 g, 7.2 mmol) was added to a solution of 2-(5-phenylpentyl)isoindoline-1,3-dione (0.68 g, 2.3 mmol) in 25 mL of EtOH. The solution was stirred under reflux for 5 hrs and then cooled to room temperature. The white precipitate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in a 1N solution of NaOH (80 mL) and extracted with chloroform (3×70 mL). The combined organic layers were washed with brine, dried over Na2SO4 and the solvent was removed under reduced pressure. The crude was purified by column chromatography using a Teledyne ISCO apparatus (solid deposition with TEA, eluent: 20% MeOH in dichloromethane with 1% of TEA) to afford the title compound (0.28 g, 73%) as a white solid. 1H NMR (400 MHz, CDCl3): 1.37-1.48 (m, 2H), 1.58-1.72 (m, 4H), 2.57-2.69 (m, 2H), 3.29 (t, J=6.70 Hz, 2H), 7.13-7.24 (m, 3H), 7.26-7.34 (m, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[CH:5][C:4]=1[O:11][CH2:12][C:13]1[C:14]([C:19]2[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][C:26]([O:28]C)=[O:27])[N:20]=2)=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:2].[OH-].[Na+]>CO.C1COCC1>[CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[CH:5][C:4]=1[O:11][CH2:12][C:13]1[C:14]([C:19]2[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[N:20]=2)=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:2]
Reactant: COC(=O)CCn1ccc(-c2ncccc2COc2cnc(OC)cc2C=O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C=O)c(OCc2cccnc2-c2ccn(CCC(=O)O)n2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To methyl 3-(3-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoate (72 mg, 0.18 mmol, 1 eq.) in a mixture of MeOH/THF (1/6, 6.0 mL) was added NaOH (3 N, 0.6 mL, 1.8 mmol, 10 eq.). The mixture was stirred at rt for 2 h, acidified to pH 3, extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated to give 3-(3-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoic acid (53.4 mg, 78%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.42 (s, 1H), 8.57 (d, J=4.6 Hz, 1H), 8.08 (s, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.46 (d, J=2.3 Hz, 1H), 7.23 (dd, J=7.9, 4.6 Hz, 1H), 7.03 (s, 1H), 6.85 (d, J=2.3 Hz, 1H), 5.64 (s, 2H), 4.42 (t, J=6.1 Hz, 2H), 3.83 (s, 3H), 2.86 (t, J=6.1 Hz, 2H). LRMS (M+H+) m/z 383.1.