Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C(N(CC)C(C)C)(C)C.C([O:23][C:24](=O)[CH:25]=[C:26]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=1[F:37])[CH2:27]Br)C>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([N:6]1[CH2:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=2[F:37])=[CH:25][C:24]1=[O:23])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: CCOC(=O)C=C(CBr)Oc1cccc(Cl)c1F
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC(C)C)N1CC(Oc2cccc(Cl)c2F)=CC1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 51.9 %

Procedure:
A mixture of (L)-leucine methyl ester hydrochloride (0.94 g, 5.17 mmol) in acetonitrile (11 mL) was treated with N,N-diisopropylethylamine (0.84 mL, 5.08 mmol). After addition was complete, the mixture was stirred at 60° C. for 1 h. At this time, the reaction was cooled to 25° C., treated with N,N-diisopropylethylamine (0.84 mL, 5.08 mmol) and acetonitrile (11 mL) and then heated to 80° C. Upon reaching 80° C., the reaction was treated with a solution of 4-bromo-3-(3-chloro-2-fluoro-phenoxy)-but-2-enoic acid ethyl ester (1.59 g, 4.71 mmol) in acetonitrile (11 mL). After the addition was complete the reaction mixture was heated to 100° C. and stirred overnight. At this time, the reaction mixture was cooled to 25° C. and concentrated in vacuo. The residue was diluted with dichloromethane (100 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL), a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, rinsed with dichloromethane and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 15-50% ethyl acetate/hexanes) afforded (S)-2-[4-(3-chloro-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (0.87 g, 52%) as a red/orange oil: HR-ES-MS m/z calculated for C17H19NO4FCl [M+H]+ 356.1060, observed 356.1060; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.6 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H), 1.36-1.54 (m, 1H), 1.62 (ddd, J=14.0, 9.6, 4.6 Hz, 1H), 1.81 (ddd, J=14.0, 11.4, 4.6 Hz, 1H), 3.66 (s, 3H), 4.22 (d, J=18.3 Hz, 1H), 4.28 (d, J=18.3 Hz, 1H), 4.74 (dd, J=11.4, 4.6 Hz, 1H), 5.07 (s, 1H), 7.33 (td, J=8.1, 1.4 Hz, 1H), 7.48-7.55 (m, 1H), 7.58 (ddd, J=8.1, 6.7, 1.4 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:6]=[C:7]([N+:9]([O-])=O)[CH:8]=1.[Cl-].[NH4+].CO>[Zn].O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[C:5]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:4]=1
Reactant: COc1cc(-c2ccsc2)cc([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: COc1cc(N)cc(-c2ccsc2)c1
Reaction time: 1 h
Yield: 93.4 %

Procedure:
To a mixture of 3-(3-methoxy-5-nitro-phenyl)-thiophene (3.78 g, 16.07 mmol), zinc dust (10.72 g, 160.7 mmol), and ammonium chloride (12.89 g, 241.1 mmol) were added methanol (50 mL) and water (25 mL) at room temperature. After addition of water, the reaction became exothermic. The suspension was stirred for 1 h and the reaction mixture was filtered through the Celite. The filter cake was washed with water and methanol. The filtrate was concentrated to remove methanol and the residue was extracted with ethyl acetate (2×100 mL). The combined extracts were washed with brine solution (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was then purified by using an ISCO 120 g column, eluting with 0-20% ethyl acetate in hexanes to afford 3-methoxy-5-thiophen-3-yl-phenylamine (3.08 g, 93%) as a light yellow solid: ES(+)-HRMS m/e calculated for C11H11NOS (M+H)+ 206.0634, found 206.0634.
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH2:4][CH2:3][C:2]1=[O:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22].Cl>CN(C)C=O>[C:21]([CH2:20][N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH2:4][CH2:3][C:2]1=[O:12])([O:23][CH3:24])=[O:22]
Reactant: COC(=O)CBr
Reactant: O=C1CCC2=C(CCCC2=O)N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)CCC2=C1CCCC2=O

Procedure:
3.17 g (0.019 mol) of 3,4,7,8-tetrahydro-2,5(1H,6H)-quinolinedione are dissolved in 25 ml of dimethylformamide, mixed with 5.3 g (1.2×0.019 mol) of anhydrous. potassium carbonate and then with 3.52 g (2×0.019 mol) of methyl bromoacetate and the mixture is stirred for 16 hours at ambient temperature. The mixture is neutralised with methanolic hydrochloric acid and evaporated down in a rotary evaporator. The residue is purified by column chromatography (silica gel, eluant: cyclohexane/ethyl acetate (1:1)).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([N:33]5[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]5)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:40][CH2:41][CH3:42].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([N:33]5[CH2:38][CH2:37][N:36]([CH2:40][CH2:41][CH3:42])[CH2:35][CH2:34]5)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCI
Reactant: Nc1ncnn2c(-c3ccc(N4CCNCC4)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCN1CCN(c2ccc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)cc2)CC1
Temperature: 50 °C
Yield: 25.8 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(4-piperazin-1-ylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (75 mg, 0.15 mmol) and 1-iodopropane (31 mg, 0.18 mmol) in DMF (2 mL) was added potassium carbonate (37 mg, 0.27 mmol). The reaction was heated (50° C.) for 17 h. The reaction was cooled to rt and was partitioned between ethyl acetate (25 mL) and H2O (25 mL). The layers were separated and the organic was washed with brine, dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC using a gradient elution from 15% to 50% acetonitrile in water followed by trituration with Et2O to obtain 21 mg (25%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1 H), 7.97-7.91 (m, 3 H), 7.81 (d, 1 H), 7.65 (s, 1 H), 7.37-7.26 (m, 5H), 7.19 (d, 1 H), 7.04-6.96 (m, 3 H), 5.66 (s, 2 H), 325-3.15 (m, 4 H), 2.51-2.48 (m, 4 H), 2.32-2.24 (m, 2 H), 1.53-1.42 (m, 2 H), 0.88 (t, 3 H), 2.89 (s, 4 H); ES-MS m/z 543.4 [M+H]+, HPLC RT (min) 2.40.
Reaction SMILES: [CH3:1][C:2]1([CH3:51])[CH2:7][CH:6]([N:8]([CH2:45][CH2:46][CH2:47][CH3:48])[C:9]2[N:14]=[C:13]([N:15]([CH2:26][CH2:27][CH2:28][CH3:29])[CH:16]3[CH2:21][C:20]([CH3:23])([CH3:22])[NH:19][C:18]([CH3:25])([CH3:24])[CH2:17]3)[N:12]=[C:11]([N:30]([CH2:41][CH2:42][CH2:43][CH3:44])[CH:31]3[CH2:36][C:35]([CH3:38])([CH3:37])[NH:34][C:33]([CH3:40])([CH3:39])[CH2:32]3)[N:10]=2)[CH2:5][C:4]([CH3:50])([CH3:49])[NH:3]1.[C:52]([O:56]O)([CH3:55])([CH3:54])C>[Mo](=O)(=O)=O.C1CCCCC1>[CH:52]1([O:56][N:34]2[C:35]([CH3:38])([CH3:37])[CH2:36][CH:31]([N:30]([CH2:41][CH2:42][CH2:43][CH3:44])[C:11]3[N:10]=[C:9]([N:8]([CH2:45][CH2:46][CH2:47][CH3:48])[CH:6]4[CH2:5][C:4]([CH3:49])([CH3:50])[N:3]([O:56][CH:52]5[CH2:55][CH2:49][CH2:4][CH2:5][CH2:54]5)[C:2]([CH3:1])([CH3:51])[CH2:7]4)[N:14]=[C:13]([N:15]([CH2:26][CH2:27][CH2:28][CH3:29])[CH:16]4[CH2:21][C:20]([CH3:22])([CH3:23])[N:19]([O:56][CH:52]5[CH2:55][CH2:21][CH2:16][CH2:17][CH2:54]5)[C:18]([CH3:24])([CH3:25])[CH2:17]4)[N:12]=3)[CH2:32][C:33]2([CH3:40])[CH3:39])[CH2:55][CH2:7][CH2:2][CH2:1][CH2:54]1
Reactant: CCCCN(c1nc(N(CCCC)C2CC(C)(C)NC(C)(C)C2)nc(N(CCCC)C2CC(C)(C)NC(C)(C)C2)n1)C1CC(C)(C)NC(C)(C)C1
Reactant: CC(C)(C)OO
Agent: O=[Mo](=O)=O
Solvent: C1CCCCC1
Product: CCCCN(c1nc(N(CCCC)C2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)nc(N(CCCC)C2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)n1)C1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Temperature: 150 °C
Yield: 79.5 %

Procedure:
To a refluxing mixture of 13.5 g (19.0 mmol) of 2,4,6-tris[N-(2,2,6,6-tetramethylpiperidin-4-yl)-n-butylamino]-1,3,5-triazine, 0.2 g of molybdenum trioxide, and 175 ml of cyclohexane are added 36.6 g (284 mmol) of 70% aqueous t-butyl hydroperoxide over a 10 minute interval. The red reaction mixture is heated at reflux for one hour and then transferred to a Fischer-Porter pressure bottle using 25 ml of fresh cyclohexane. The reaction mixture is then heated for 3 hours at 150° C. to discharge the red color. Solids are removed by filtration and the filtrate is concentrated to a residue which is purified by flash chromatography on silica gel (19:1 heptane:ethyl acetate). The product is crystallized from isopropyl alcohol to afford 7.6 g (40% yield) of a white powder, m.p. 189°-94° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[N:5]2[CH:18]=[CH:19][N:20]=[C:4]2[C:3]=1[CH2:21][C:22]([O:24][CH3:25])=[O:23].O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+].CCOC(C)=O>CCO>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[N:5]2[CH:18]=[CH:19][N:20]=[C:4]2[C:3]=1[CH2:21][C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc([N+](=O)[O-])cc2)n2ccnc12
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)Cc1c(Cl)nc(Cc2ccc(N)cc2)n2ccnc12
Temperature: 25 °C
Yield: 91.8 %

Procedure:
A mixture of methyl [7-chloro-5-(4-nitrobenzyl)imidazo[1,2-c]pyrimidin-8-yl]acetate (0.383 g, 1.06 mmol) and SnCl2.2H2O (1.44 g, 6.37 mmol) in EtOH (5 mL) was heated at refluxing temperature for 1 hour. After cooling to room temperature, the reaction mixture was poured into sat. NaHCO3 aq. and EtOAc and the resulting white suspension was filtered through a pad of Celite. The aqueous layer was separated and extracted with EtOAc. The combined organic extracts was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give methyl [7-chloro-5-(4-aminobenzyl)imidazo[1,2-c]pyrimidin-8-yl]acetate (0.322 g, 92%).
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH:4]([CH2:6][CH3:7])O.[CH2:9]([O:12][CH2:13][CH:14]([SH:17])[CH2:15][SH:16])[CH2:10][CH3:11]>>[CH2:2]([C:3]1[S:16][CH2:15][CH:14]([CH2:13][O:12][CH2:9][CH2:10][CH3:11])[S:17][C:4]=1[CH2:6][CH3:7])[CH3:1]
Reactant: CCC(=O)C(O)CC
Reactant: CCCOCC(S)CS
Product: CCCOCC1CSC(CC)=C(CC)S1
Yield: 42 %

Procedure:
The method of Example 4 was followed, using propioin (4-hydroxy-3-hexanone) (11.6 g) and 3-propoxypropane-1,2-dithiol (16.6 g) to give 5,6-diethyl-2,3-dihydro-2-propoxymethyl-1,4-dithiin as a greenish oil, b.p. 110°-111.5°/0.2 mm, yield 42%. N.M.R. (CDCl3) 0.8-1.25 δ triplets), 1.6-1.95 δ (complex overlapping signals), 2.75-3.65 δ (complex overlapping signals).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([Cl:26])[CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:23]=[C:24]([Cl:26])[CH:25]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4cc(Cl)cc(Cl)c4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, light grey solid (58 mg, 62%), MS (ISN) m/z=368.4 [(M−H)+], mp 347° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 3,5-dichloro-phenylboronic acid (62.0 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:33])[C:28]([CH3:32])([CH3:31])[CH:29]=[CH2:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].I[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:33])[C:28]([CH3:32])([CH3:31])/[CH:29]=[CH:30]/[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C=CC(C)(C)C(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1
Reactant: Ic1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C(C)(C)/C=C/c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 168, Step 1, using 1-{4′-[4-(1-hydroxy-2,2-dimethyl-but-3-enyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and iodobenzene.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]([CH:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][CH2:8][C:7]1=[O:13])=[O:5])[CH3:2].[Br:16]Br>C(OCC)C>[CH2:14]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][CH:8]([Br:16])[C:7]=1[OH:13])=[O:5])[CH3:15]
Reactant: CCN(CC)C(=O)C1CC(C)CCC1=O
Reactant: BrBr
Solvent: CCOCC
Product: CCN(CC)C(=O)C1=C(O)C(Br)CC(C)C1
Temperature: 0 °C
Yield: 100.1 %

Procedure:
5-methyl-2-oxo-cyclohexanecarboxylic acid diethylamide (46) (4.4 g, 21 mmol) was dissolved in diethyl ether (5 mL) and cooled to 0° C. under N2. Bromine (3.32 g, 21 mmol, 1.1 mL) was added dropwise over 15 min and the reaction mixture was allowed to warm to room temperature over 90 min. The mixture was slowly poured into ice-cold saturated aqueous sodium carbonate solution (40 mL) and extracted with ethyl acetate (3×40 mL). The combined organic layers were dried and concentrated in vacuo to afford 6.1 g (quantitative) of 3-bromo-2-hydroxy-5-methyl-cyclohex-1-enecarboxylic acid diethylamide (47) as an off-white solid. The structure was confirmed by 1H NMR (300 MHz, CDCl3) δH 0.8-1.20 (9H, m, CH3 and N(CH2CH3)2), 1.80-2.40 (5H, m, CH2CH(CH3)CH2), 3.15-3.55 (4H, m, N(CH2CH3)2), 4.65-4.74 (1H, m, CHBr), and 12.04 (1H, s, OH).
Reaction SMILES: [OH-].[Na+].C1COCC1.[CH:8]([O:11][C:12]1[CH:13]=[C:14]([CH:28]=[C:29]([CH2:31][S:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[F:41])(=[O:34])=[O:33])[CH:30]=1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26]C)=[O:25])=[CH:20][N:19]=1)=[O:16])([CH3:10])[CH3:9]>>[CH:8]([O:11][C:12]1[CH:13]=[C:14]([CH:28]=[C:29]([CH2:31][S:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[F:41])(=[O:33])=[O:34])[CH:30]=1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][N:19]=1)=[O:16])([CH3:10])[CH3:9]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(CS(=O)(=O)c3ccccc3F)cc(OC(C)C)c2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Oc1cc(CS(=O)(=O)c2ccccc2F)cc(C(=O)Nc2ccc(C(=O)O)cn2)c1

Procedure:
Standard ester hydrolysis (2M NaOH/THF), as described in Example A, of methyl 2-[3-isopropyloxy-5-(2-fluorophenylsulfonyl) methyl benzoyl]aminopyridine-5-carboxylate gave the title compound as a pale yellow solid, 1H NMR δ (300 MHz, d6-DMSO): 1.12 (d, 6H); 4.58–4.66 (m, 1H); 4.79 (s, 2H); 6.98 (s, 1H); 7.30–7.41 (m, 2H); 7.43 (s, 1H); 7.48–7.63 (m, 2H); 7.72–7.81 (m, 1H); 8.30 (s, 2H); 8.86 (S, 1H); 11.08 (br s, 1H); m/z 473 (M+H)+, 471
Reaction SMILES: C1(C2C=CC([P:17]([OH:20])(=[O:19])[OH:18])=CC=2)C=CC([P:7]([OH:10])(=[O:9])[OH:8])=CC=1.[P:21](O)([OH:23])[OH:22]>CS(C)=O.O>[PH:21]([O:20][PH:17]([OH:18])=[O:19])([OH:23])=[O:22].[P:7]([OH:10])([OH:9])[OH:8]
Reactant: O=P(O)(O)c1ccc(-c2ccc(P(=O)(O)O)cc2)cc1
Agent: OP(O)O
Solvent: CS(C)=O
Solvent: O
Product: O=[PH](O)O[PH](=O)O

Procedure:
0.19 g of 4,4'-(biphenyl) diphosphonic acid and 0.77 g of phosphorous acid are dissolved in 18 ml of DMSO in a plastic container kept at a temperature of 80° C. 0.80 g of ZrOCl2.8H2O dissolved in 1.5 ml of concentrated HF and 1 ml of water, are added to the clear solution. The solid obtained after 24 hours, separated, washed, dried and analysed as described in Example 1, gave a diphosphonic acid/phosphorous acid molar ratio of 0.8:1 and a distance between layers of 14 Å. Measurement of the surface area gives a value of 300 m2 /g with a pore distribution concentrated at a maximum at 22 Å.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[C:35]([CH3:40])[C:34]=1[S:41](Cl)(=[O:43])=[O:42]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:41]([C:34]4[C:35]([CH3:40])=[CH:36][C:37]([CH3:39])=[CH:38][C:33]=4[CH3:32])(=[O:43])=[O:42])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4c(C)cc(C)cc4C)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2,4,6-trimethyl-benzenesulfonyl chloride. Purity (ELSD, based on MW=603.7)=60%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([OH:10])=[O:9])[CH:7]=1.OS(O)(=O)=O.[CH3:16][CH2:17]O>>[CH2:16]([O:9][C:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[N:4][CH:5]=1)=[O:10])[CH3:17]
Reactant: CCO
Reactant: O=C(O)c1cncc(Br)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cncc(Br)c1

Procedure:
A stirred mixture of 3-bromo-5-pyridine-carboxylic acid (10.1 g, 50 mmol) and H2SO4 (1.5 ml) in EtOH (150 ml) was refluxed for 6 hrs. After cooling, the solvent was removed by evaporation in vacuo. The residue was diluted with H2O (100 ml), basified with 5% NaHCO3 (aq) solution and extracted with ether (4×100 ml). The combined organic extracts were washed with saturated NaCl and dried over Na2SO4. Filtration and concentration in vacuo of the filtrate yielded 3-bromo-5-pyridine-carboxylic acid ethyl ester as an oil that solidified on standing: (9.8 g, 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1.[F:19][C:20]([F:46])([F:45])[CH:21]([CH3:44])[CH:22]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][C:39]=3[F:42])[C:34]2=[O:43])=[CH:28][CH:27]=1)[C:23](O)=[O:24].O.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:46][C:20]([F:19])([F:45])[CH:21]([CH3:44])[CH:22]([C:26]1[CH:27]=[CH:28][C:29]([CH2:32][N:33]2[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][C:39]=3[F:42])[C:34]2=[O:43])=[CH:30][CH:31]=1)[C:23]([NH:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])[CH2:8][CH2:7]1)=[O:24]
Reactant: CC(C)(C)OC(=O)C1(Cc2cccc(N)c2)CC1
Reactant: CC(C(C(=O)O)c1ccc(CN2Cc3c(F)cccc3C2=O)cc1)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(C(=O)Nc1cccc(CC2(C(=O)OC(C)(C)C)CC2)c1)c1ccc(CN2Cc3c(F)cccc3C2=O)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
110.8 mg (0.41 mmol) of tert-butyl 1-(3-aminobenzyl)cyclopropanecarboxylate were added to a solution of 129.0 mg (0.33 mmol) of 4,4,4-trifluoro-2-{4-[(4-fluoro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-3-methylbutanoic acid and 52.9 mg (0.39 mmol) of 1-hydroxy-1H-benzotriazole hydrate in 1 ml of DMF. At 0° C., 142 μl (0.82 mmol) of DIEA and then, a little at a time, 136.5 mg (0.36 mmol) of HATU were added to the resulting mixture. The reaction mixture was then slowly warmed to RT and stirred at RT for 2.5 h. The mixture was added to water and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (mobile phase: acetonitrile/water gradient). This gave 97.4 mg (47.6% of theory) of the title compound.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[Na].C1COCC1.Cl[C:15]1[N:19]([C:20]([CH3:22])=[CH2:21])[C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=2[N:16]=1>O>[OH:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:7][C:15]1[N:19]([C:20]([CH3:22])=[CH2:21])[C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=2[N:16]=1
Reactant: OCCCCCO
Reactant: C=C(C)n1c(Cl)nc2ccccc21
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)n1c(OCCCCCO)nc2ccccc21
Temperature: 25 °C
Yield: 51 %

Procedure:
3.3 g of 1,5-pentanediol and 0.4 g of sodium were stirred under nitrogen atmosphere for 30 minutes with heating. After the sodium disappeared, the reaction mixture was added dropwise with 30 ml of anhydrous THF containing 2.9 g of 2-chloro-1-isopropenylbenzimidazole and then refluxed for 8 hours. After cooling to room temperature, the mixture was added with water and extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography (ethyl acetate) to obtain 2 g of the title compounds (yield: 51%).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH2:10]O)=[CH:6][C:5]=12.C1C=CC(OP(OC2C=CC=CC=2)([N:21]=[N+:22]=[N-:23])=O)=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1.C(Cl)Cl.O>[N:21]([CH2:10][C:7]1[CH:8]=[CH:9][N:4]2[CH:3]=[CH:2][N:1]=[C:5]2[CH:6]=1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: OCc1ccn2ccnc2c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Solvent: O
Product: [N-]=[N+]=NCc1ccn2ccnc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a stirred solution of imidazo[1,2-a]pyridin-7-ylmethanol (80% purity, 1.68 g, 9.07 mmol) in toluene (40 mL) and CH2Cl2 (40 mL) at 0° C. was added diphenylphosphonic azide (3.5 mL, 16 mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (2.5 mL, 17 mmol). The mixture was stirred at 0° C. for 2 h and then at rt for 16 h. The reaction mixture was diluted with water (200 mL) and CH2Cl2 (200 mL). The organic layer was separated and washed with brine, dried (Mg2SO4), filtered, and concentrated. The residue was purified by silica gel column to afford the title compound as a colorless oil (1.5 g, 75% yield for two steps).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[NH:12][C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9]1.[C:16]([S:24][CH2:25][CH2:26][C:27](Cl)=[O:28])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>CC(C)=O.CCOCC>[C:16]([S:24][CH2:25][CH2:26][C:27]([N:12]1[C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9][CH:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])=[O:28])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)CCSC(=O)c1ccccc1
Reactant: O=C(O)[C@@H]1CSC(c2ccccc2O)N1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOCC
Product: O=C(SCCC(=O)N1C(c2ccccc2O)SC[C@H]1C(=O)O)c1ccccc1

Procedure:
11.3 g of (4R)-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid and 13.2 g of thriethylamine are dissolved in 200 ml of dehydrated acetone and 11.7 g of S-benzoyl-3-mercaptopropanoyl chloride is added dropwise while stirring under ice-cooling. After the addition, the mixture is stirred under ice-cooling for 1 hour. 4 N Hydrochloric acid in ether is added to this mixture and the precipitate is filtered. The filtrate is concentrated in vacuo and the obtained oil is dissolved in ethyl acetate, washed with 2 N hydrochloric acid and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to dryness in vacuo to give the titled compound, yield 12 g (58%), mp. 100.5°-101° C. (dec.) (ethyl acetatebenzene), [α]D26 +130.8° (c=1.0, methanol).