Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=O)[CH2:2][CH3:3].[NH2:14][C:15]1[C:23]([C:24](=[O:26])[NH2:25])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH2:19])=[O:18].[OH-].[Na+].O>N1C=CC=CC=1.C(O)C>[C:17]([C:16]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:15]=1[N:14]=[C:7]([C:6]1[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=1[O:4][CH2:1][CH2:2][CH3:3])[NH:25][C:24]2=[O:26])(=[O:18])[NH2:19]
Reactant: CCCOc1ccccc1C(=O)Cl
Reactant: NC(=O)c1cccc(C(N)=O)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCO
Solvent: O
Product: CCCOc1ccccc1-c1nc2c(C(N)=O)cccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 21 %

Procedure:
2-n-Propoxybenzoyl chloride (7.27 g, 0.366 mol) was added dropwise to a stirred suspension of 2-amino-3-carbamoylbenzamide (Preparation 17; 2.63 g, 0.0147 mol) in pyridine (50 ml) at 0° C. The mixture was stirred at room temperature for 3 days, then the solvent evaporated under vacuum. The residue was treated with water (100 ml) and, on chilling the solution, colorless crystals formed. The product was collected by filtration and then suspended in a stirred mixture of sodium hydroxide (1.73 g, 0.043 mol), water (90 ml) and ethanol (20 ml). The mixture was heated under reflux for 3 hours, allowed to cool and filtered. The filtrate was acidified to pH 2 with concentrated hydrochloric acid and extracted with a methanoldichloromethane mixture (2:98, 3×100 ml). The organic extracts were combined, washed sequentially with saturated aqueous sodium carbonate solution (3×100 ml) and brine (3×50 ml), dried (Na2SO4) and evaporated under vacuum. Crystallization of the residue from ethyl acetate-methanol gave the title compound as a white solid (1 g, 40%), m.p. 226°-227° C. Found: C,67.00; H,5.40; N,12.90. C18H17N3O3 requires C,66.86; H,5.30; N,13.00%.
Reaction SMILES: [C:1](=[O:4])([OH:3])[O-:2].[Ca+2:5].[C:6](=[O:9])([OH:8])[O-:7].[Ca].[Mg:11].C(=O)(O)[O-].[Mg+2].C(=O)(O)[O-]>O>[C:1](=[O:2])([O-:4])[O-:3].[Ca+2:5].[C:6](=[O:7])([O-:9])[O-:8].[Mg+2:11]
Reactant: [Mg]
Reactant: O=C([O-])O
Agent: [Ca+2]
Agent: [Ca]
Agent: [Mg+2]
Solvent: O
Product: O=C([O-])[O-]

Procedure:
Mixing lime with the water will result in the lime preferentially reacting with carbon dioxide and bicarbonates to cause calcium carbonate to precipitate as calcium carbonate particles. This ordinarily occurs at a pH of approximately 10 to approximately 10.3. Once the carbon dioxide demand has been met, the lime is free to react with calcium bicarbonate, for example, which further results in the precipitation of calcium carbonate particles. Calcium bicarbonate is typically the most common calcium compound found in untreated water but other calcium-based hardness compounds have similar reactions. Magnesium compounds have a slightly different reaction. Generally, magnesium bicarbonate reacts with lime and produces calcium carbonate and magnesium carbonate. Then the magnesium carbonate reacts with lime and creates more calcium carbonate and magnesium hydroxide. Both of these compounds precipitate out of water.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:35][CH2:36][C:37]([NH:39][C@H:40]([C:44]([NH:46][CH2:47][C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])=[O:45])[CH:41]([CH3:43])[CH3:42])=[O:38].[Na+].[Cl-]>CN(C)C=O>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([NH:35][CH2:36][C:37]([NH:39][C@H:40]([C:44]([NH:46][CH2:47][C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])=[O:45])[CH:41]([CH3:43])[CH3:42])=[O:38])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)[C@H](NC(=O)CN)C(=O)NCC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
Boc-Phe-OH (9.16 g, 34.54 mmol) was dissolved in 100 ml of dimethylformamide (DMF), cooled to 0° C. and N-methylmorpholine (NMM) (3.83 ml) added. The solution was cooled to -15° C. and isobutyl chloroformate (IBCF) (3.96 ml, 30 mmol) was added slowly under stirring while maintaining the temperature at -15°±1° C. After stirring at this temperature for 15 minutes, a precooled solution of II (9.4 g, 21.59 mmol) and NMM (2.4 ml) in DMF (40 ml) was added and stirring continued for two hours at ice-bath temperature. A saturated solution of KHCO3 was added to bring the pH to 8.0 and stirred for an additional 30 minutes. The reaction mixture was poured into a cold 90% saturated NaCl solution (1000 ml) and the precipitate obtained was filtered, washed with satd. NaCl, H2O and dried. The peptide was crystallized from ethyl acetate to give 10 g of III (yield: 81.5%). Rf2 0.83 Anal. Calcd. for C30H40N4O7 : C 63.35, H 7.09, N 9.85%. Found: C 62.96, H 7.37, N 9.86%.
Reaction SMILES: [N:1]([CH:4]1[CH2:8][N:7]([C:9](=[O:24])[CH2:10][P:11]([OH:23])([CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:12])[C@H:6]([C:25]([OH:27])=[O:26])[CH2:5]1)=[N+]=[N-]>[Pd].O>[NH2:1][CH:4]1[CH2:8][N:7]([C:9](=[O:24])[CH2:10][P:11]([OH:23])([CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:12])[C@H:6]([C:25]([OH:27])=[O:26])[CH2:5]1
Reactant: [N-]=[N+]=NC1C[C@@H](C(=O)O)N(C(=O)CP(=O)(O)CCCCc2ccccc2)C1
Agent: [Pd]
Solvent: O
Product: NC1C[C@@H](C(=O)O)N(C(=O)CP(=O)(O)CCCCc2ccccc2)C1
Reaction time: 3 h
Yield: 40.1 %

Procedure:
A mixture of (S)-4-azido-1-[[hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-proline (0.8 g) acetic acid (about 20 ml) and 10% palladium on charcoal is hydrogenated on a Parr apparatus for 3 hours. The reaction mixture is filtered through Celite to remove the catalyst and the solvent is stripped leaving an oil. The oil is diluted with water and washed several times with ethyl acetate. The aqueous phase is lyophilized yielding 0.48 g of crude product as a solid. Crude product (400 mg) is run on a column of ion-exchange resin AG50X8 (about 30 ml), eluting first with water and then with a pyridine-acetic acid buffer (pH 6.5). The fractions containing the desired material are combined and evaporated leaving a glass, which is dissolved in water and lyophilized yielding 300 mg of the title compound having an optical rotation [α]D =-24.8° (c=10 mg/ml, methanol).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14].[CH3:15][NH:16][CH3:17]>>[CH3:15][N:16]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14])[CH3:17]
Reactant: CNC
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Product: COC(=O)c1ccc(CN(C)C)c(OC)c1
Yield: 77 %

Procedure:
The title compound was prepared in 77% yield by essentially following the procedure outlined in Example 37, Part A from methyl 4-bromomethyl-3-methoxybenzoate (see Example 37, Part A) and dimethylamine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][NH2:9])[N:3]=1.O=[C:11]1[CH2:18][CH:17]2[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:13]([CH2:14][CH2:15][CH2:16]2)[CH2:12]1>CCO>[Br:1][C:2]1[N:3]=[C:4]([NH:8][N:9]=[C:11]2[CH2:18][CH:17]3[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:13]([CH2:14][CH2:15][CH2:16]3)[CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C2CCCC1CC(=O)C2
Reactant: NNc1cccc(Br)n1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C2CCCC1CC(=NNc1cccc(Br)n1)C2
Yield: 99.9 %

Procedure:
2-Bromo-6-hydrazinylpyridine (393 mg, 2.09 mmol) and tert-butyl 3-oxo-9-azabicyclo[3.3.1]nonane-9-carboxylate (500 mg, 2.09 mmol) were heated at reflux in EtOH (5 mL) for 16 h and the mixture concentrated to provide the title compound (855 mg, 100%) as a yellow solid: ESI MS m/z 409 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:16][CH2:15]2)[C:3]=1[CH3:26].[O:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:34]=[C:35]([NH2:39])[CH:36]=[N:37][CH:38]=2)[CH2:29][CH2:28]1>C1(C)C=CC=CC=1>[CH:20]1([N:17]2[CH2:18][CH2:19][N:14]([C:4]3[C:3]([CH3:26])=[C:2]([NH:39][C:35]4[CH:36]=[N:37][CH:38]=[C:33]([N:30]5[CH2:31][CH2:32][O:27][CH2:28][CH2:29]5)[CH:34]=4)[C:11]4[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=4[F:12])[N:5]=3)[CH2:15][CH2:16]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Nc1cncc(N2CCOCC2)c1
Reactant: Cc1c(N2CCN(C3CCCCC3)CC2)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(N2CCN(C3CCCCC3)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Essentially prepared according to Procedure H using 4-chloro-2-(4-cyclohexylpiperazin-1-yl)-5,7-difluoro-3-methylquinoline (22.0 mg, 0.058 mmol) and 5-morpholinopyridin-3-amine in toluene to give 2-(4-cyclohexylpiperazin-1-yl)-5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (CDCl3) δ ppm 7.93 (1H, d, J=2.3 Hz), 7.70 (1H, d, J=1.8 Hz), 7.27-7.33 (1H, m), 6.86 (1H, d, J=12.9 Hz), 6.78 (1H, ddd, J=13.9, 8.6, 2.5 Hz), 6.57 (1H, t, J=2.3 Hz), 3.79-3.91 (4H, m), 3.35-3.61 (4H, m), 3.07-3.23 (4H, m), 2.70-2.98 (4H, m), 2.06 (3H, s), 1.91-2.03 (2H, m), 1.77-1.91 (2H, m), 1.67 (1H, d, J=12.9 Hz), 1.05-1.41 (6H, m). Mass Spectrum (ESI) m/e=524.3 (M+1).
Reaction SMILES: [C:1]1([C:101]2[CH:106]=[CH:105][CH:104]=[CH:103][CH:102]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]([CH3:100])[C:20](=[O:99])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([C:37]2[CH:42]=[CH:41][C:40]([N:43]([C:45](=[O:98])[CH2:46][CH2:47][N:48]([C:50](=[O:97])[CH2:51][O:52][C@@H:53]3[C:61]4([CH2:66][CH2:65][N:64]([CH2:67][CH2:68][C@:69]5([C:90]6[CH:95]=[CH:94][C:93]([F:96])=[CH:92][CH:91]=6)[O:73][CH2:72][N:71]([C:74](=[O:89])[C:75]6[CH:80]=[C:79]([C:81]([F:84])([F:83])[F:82])[CH:78]=[C:77]([C:85]([F:88])([F:87])[F:86])[CH:76]=6)[CH2:70]5)[CH2:63][CH2:62]4)[C:60]4[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=4)[CH2:54]3)[CH3:49])[CH3:44])=[CH:39][CH:38]=2)C(=O)OCC2C=CC=CC=2)[CH2:13][CH2:12]1)=[O:9]>C(O)C.C(OCC)(=O)C.[C].[Pd]>[C:1]1([C:101]2[CH:102]=[CH:103][CH:104]=[CH:105][CH:106]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:9])[O:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]([C:20](=[O:99])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:37]2[CH:38]=[CH:39][C:40]([N:43]([C:45](=[O:98])[CH2:46][CH2:47][N:48]([C:50](=[O:97])[CH2:51][O:52][C@@H:53]3[C:61]4([CH2:66][CH2:65][N:64]([CH2:67][CH2:68][C@:69]5([C:90]6[CH:95]=[CH:94][C:93]([F:96])=[CH:92][CH:91]=6)[O:73][CH2:72][N:71]([C:74](=[O:89])[C:75]6[CH:80]=[C:79]([C:81]([F:82])([F:83])[F:84])[CH:78]=[C:77]([C:85]([F:87])([F:88])[F:86])[CH:76]=6)[CH2:70]5)[CH2:63][CH2:62]4)[C:60]4[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=4)[CH2:54]3)[CH3:49])[CH3:44])=[CH:41][CH:42]=2)[CH3:100])[CH2:13][CH2:12]1
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCN(C(=O)OCc1ccccc1)c1ccc(N(C)C(=O)CCN(C)C(=O)CO[C@H]2Cc3ccccc3C23CCN(CC[C@@]2(c4ccc(F)cc4)CN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CO2)CC3)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ccc(N(C)C(=O)CCN(C)C(=O)CO[C@H]2Cc3ccccc3C23CCN(CC[C@@]2(c4ccc(F)cc4)CN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CO2)CC3)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.1 %

Procedure:
The compound (180 mg, 0.12 mmol) obtained in Example 97f was dissolved in a mixed solvent of ethanol (3 mL) and ethyl acetate (3 mL), 10% palladium-carbon (36 mg, 20% by weight) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 18 hours. After the reaction was completed, the reaction mixture was filtered through celite, the filtrate was washed with methanol, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol, 30:1, v/v) to give the title compound (141 mg; yield, 86%) as a white solid.
Reaction SMILES: FC(F)(F)C([O-])=O.[CH3:8][O:9][P:10]([CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(=[O:13])[O:11][CH3:12].C(N(C(C)C)CC)(C)C.[CH:31]([O:44][C:45]1[C:54]2[N:53]=[CH:52][CH:51]=[CH:50][C:49]=2[C:48]([C:55](O)=[O:56])=[C:47]2[CH2:58][N:59]([CH2:62][C:63]3[CH:68]=[CH:67][C:66]([F:69])=[CH:65][CH:64]=3)[C:60](=[O:61])[C:46]=12)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH3:12][O:11][P:10]([CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][N:19]([C:55]([C:48]2[C:49]3[CH:50]=[CH:51][CH:52]=[N:53][C:54]=3[C:45]([O:44][CH:31]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[C:46]3[C:60](=[O:61])[N:59]([CH2:62][C:63]4[CH:64]=[CH:65][C:66]([F:69])=[CH:67][CH:68]=4)[CH2:58][C:47]=23)=[O:56])[CH2:20][CH2:21]1)(=[O:13])[O:9][CH3:8]
Reactant: O=C(O)c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Reactant: COP(=O)(CCN1CCNCC1)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COP(=O)(CCN1CCN(C(=O)c2c3c(c(OC(c4ccccc4)c4ccccc4)c4ncccc24)C(=O)N(Cc2ccc(F)cc2)C3)CC1)OC
Yield: 72.8 %

Procedure:
To a solution of the trifluoroacetate salt of (2-piperazin-1-yl-ethyl)-phosphonic acid dimethyl ester 187 (0.023 g, 0.077 mmol) in 1 ml DMF was added diisopropylethylamine (33 μL, 0.192 mmol). This mixture was added to a solution of 9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid 213 (0.020 g, 0.038 mmol) that had been mixed with HATU (0.0293 g, 0.077 mmol) in 1 ml of DMF. The reaction was stirred at rt under inert atmosphere for 3 h, at which time TLC in 100% EtOAc showed complete consumption of starting material. The reaction mixture was introduced directly onto silica gel (99/1 EtOH/Et3N) to give 20 mg of (2-{4-[9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carbonyl]-piperazin-1-yl}-ethyl)-phosphonic acid dimethyl ester 291 after flash chromatography.
Reaction SMILES: C([O:3][C:4](=[O:43])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[C:29]([OH:36])[C:28]=2[CH2:37][CH2:38][CH3:39])[C:10]=1[CH2:40][CH2:41][CH3:42])C.[OH-].[Na+]>CO>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:43])=[O:3])=[C:10]([CH2:40][CH2:41][CH3:42])[C:11]=1[O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[C:29]([OH:36])[C:28]=1[CH2:37][CH2:38][CH3:39])(=[O:17])[CH3:16]
Reactant: CCCc1c(OCCCOCCCOc2c(C(C)=O)ccc(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCCOCCCOc2c(C(C)=O)ccc(OCCCC(=O)O)c2CCC)ccc(C(C)=O)c1O
Yield: 93 %

Procedure:
A solution of 2.06 g (0.0034 mole) of 4-[4-acetyl-3-[3-[3(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]butanoic acid ethyl ester in 50 ml of methanol and 17 ml (0.017 mole) of 1.0N sodium hydroxide was stirred at reflux for 2 hours. Most of the solvent was removed and the pH of the residue was adjusted to 2.0. The product was extracted with methylene chloride. The extract was washed with water, dried (magnesium sulfate) and concentrated in vacuo to give 1.81 g (92% yield) of 4-[4-acetyl-3-[3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]butanoic acid as an oil.
Reaction SMILES: [Mg].Cl[CH2:3][Si:4]([CH3:7])([CH3:6])[CH3:5].[CH3:8][C:9]1[C:16]([CH3:17])=[C:15]([OH:18])[C:14]([CH3:19])=[CH:13][C:10]=1[CH:11]=[O:12].[Cl-].[NH4+]>C(OCC)C>[OH:18][C:15]1[C:14]([CH3:19])=[CH:13][C:10]([CH:11]([CH2:3][Si:4]([CH3:7])([CH3:6])[CH3:5])[OH:12])=[C:9]([CH3:8])[C:16]=1[CH3:17]
Reactant: C[Si](C)(C)CCl
Reactant: Cc1cc(C=O)c(C)c(C)c1O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: Cc1cc(C(O)C[Si](C)(C)C)c(C)c(C)c1O
Temperature: 0 °C

Procedure:
Mix magnesium turnings (240 mg, 10 mmol) and anhydrous ethyl ether under an inert atmosphere. Add a solution of chloromethyltrimethylsilane (1.9 g, 10 mmol) in anhydrous ethyl ether. Stir until the magnesium metal dissolves. Add a solution of 2,3,5-trimethyl-4-hydroxybenzaldehyde (1.7 g, 10 mmol) in anhydrous ethyl ether. Stir until reaction is complete. Cool the reaction mixture to 0° C. and add saturated ammonium chloride solution. Separate the ether layer, wash with water and dry (MgSO4). Evaporate to give 4-hydroxy-2,3,5-trimethyl-α-[(trimethylsilyl)methyl]benzenemethanol and purify by silica gel chromatrography.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]1[CH2:13][CH2:12][CH:11]([CH2:14]Br)[O:10]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:22][C:23]1[N:31]=[C:30]2[C:26]([NH:27][CH:28]=[N:29]2)=[C:25]([Cl:32])[N:24]=1>CN(C=O)C>[CH2:1]([O:3][P:4]([CH:9]1[CH2:13][CH2:12][CH:11]([CH2:14][N:27]2[C:26]3[C:30](=[N:31][C:23]([NH2:22])=[N:24][C:25]=3[Cl:32])[N:29]=[CH:28]2)[O:10]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: CCOP(=O)(OCC)C1CCC(CBr)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)C1CCC(Cn2cnc3nc(N)nc(Cl)c32)O1
Temperature: 100 °C
Reaction time: 3 h
Yield: 6 %

Procedure:
A solution of (5-Bromomethyl-tetrahydro-furan-2-yl)-phosphonic acid diethyl ester (1.0, 3.32 mmol) in DMF (7mL) was transferred via cannula to a solution of cesium carbonate (1.31 g, 4.98 mmol) and 2-amino-6-chloropurine (845 mg, 4.98 mmol) in DMF (7 mL) which had been previously heated at 100° C. for 0.5 hour . The reaction mixture was stirred at 100° C. for 3 hrs. The reaction mixture was then concentrated and chromatographed, eluting with 8% methanol/dichloromethane to give [5-(2-Amino-6-chloro-purin-7-ylmethyl)-tetrahydro-furan-2-yl]-phosphonic acid diethyl ester (78 mg, 6%):
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([C:28]2([C:35]3[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=3[F:42])[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(OC(C)C)(=O)C>O1CCCC1.O>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([S:25]([C:28]2([C:35]3[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=3[F:42])[CH2:29][CH2:30][C:31](=[CH:9][C:7]#[N:8])[CH2:32][CH2:33]2)(=[O:26])=[O:27])=[CH:23][CH:24]=1
Reactant: O=C1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)C
Product: N#CC=C1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Reaction time: 2 h
Yield: 87.2 %

Procedure:
To a solution of potassium tert butoxide (1.0M in THF, 3.20 Kg, 3.55 mol) in tetrahydrofuran (2.1L) was added diethyl (cyanomethyl)phosphonate (642 g, 3.62 mol), maintaining the temperature below 5° C. The resulting solution was aged for 2 h and a solution of 4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexanone (1.07 Kg, 2.78 mol) (Preparation 2) in tetrahydrofuran (3.9 L) was added. After the reaction was completed, isopropyl acetate (13.1 L) and water (26.3 L) were added. The organic layer was washed with brine and then concentrated to 1 L. Heptane (10.5 L) was added. The resulting solid was filtered, washed with heptane, dried in vacuo at 37° C. and then slurried in diethyl ether (5 L). Filtration and drying in vacuo afforded 989 g (87% yield) of [4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexylidene]acetonitrile. 1H NMR (CDCl3) 7.41-7.34 (4H, m), 7.25-7.06 (2H, m), 6.94-6.87 (1H, m), 5.12 (1H, s), 3.05-3.03 (1H, m), 2.92-2.86 (2H, m), 2.54-2.50 (1H, m), and 2.30-2.03 (4H, m).
Reaction SMILES: C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:41]=1[S:47](Cl)(=[O:49])=[O:48]>O1CCCC1>[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][N:34]([S:47]([C:41]3[CH:42]=[C:43]([Cl:46])[CH:44]=[CH:45][C:40]=3[Cl:39])(=[O:49])=[O:48])[CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1
Reactant: COC(=O)Cc1cc(C2CCNCC2)c2cc(F)ccc2c1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3cc(Cl)ccc3Cl)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
Diisopropylethylamine (0.6 mL, 3.4 mmol) was added at 0° C. to a solution of (6-fluoro-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 150 mg, 0.36 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 30 min. 2,5-Dichlorobenzenesulfonyl chloride (available from Sigma-Aldrich; 133 mg, 0.54 mmol) was added and the mixture was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure. Ethyl acetate was added and the mixture was washed with aqueous NaHCO3 (5 mL) and water (5 mL). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using a Biotage purification system, eluting with 10% ethyl acetate/hexanes, to give {4-[1-(2,5-dichloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid methyl ester (126 mg, 68%) as a sticky off-white solid. MS cald. for C24H23Cl2FNO4S [(M+H)+]: 510, obsd. 510.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([C:22]2[C:31]([OH:32])=[C:30]3[C:25]([CH:26]=[CH:27][CH:28]=[N:29]3)=[C:24]([Cl:33])[CH:23]=2)[NH:11][C:12](=[O:21])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>C1COCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]([C:22]2[C:31]([OH:32])=[C:30]3[C:25]([CH:26]=[CH:27][CH:28]=[N:29]3)=[C:24]([Cl:33])[CH:23]=2)[NH:11][C:12](=[O:21])[CH2:13][O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(COc1ccccc1)NC(c1cccc([N+](=O)[O-])c1)c1cc(Cl)c2cccnc2c1O
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cccc(C(NC(=O)COc2ccccc2)c2cc(Cl)c3cccnc3c2O)c1
Reaction time: 20 h
Yield: 58.8 %

Procedure:
A mixture of N-[(3-nitrophenyl)(5-chloro-8-hydroxyquinolin-7-yl)methyl]-2-phenoxyacetamide (2 g, 4.31 mmol) and 10% Pd/C (250 mg, Lancaster) in THF was hydrogenated for 20 h at 40 psi. The catalyst was filtered off, and solvent was removed under vacuum. The residue was triturated with ether, filtered and the cake was washed with ether to give 1.1 g of N-[(3-aminophenyl)(5-chloro-8-hydroxyquinolin-7-yl)methyl]-2-phenoxyacetamide as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]2[C:5]([N:6]3[C:11](=[CH:12]2)[C:10](=[O:15])[NH:9][CH2:8][CH2:7]3)=[N:4][CH:3]=1.[CH:16]([N:19]1[CH2:24][CH2:23][CH:22](O)[CH2:21][CH2:20]1)([CH3:18])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>>[CH:16]([N:19]1[CH2:24][CH2:23][CH:22]([O:1][C:2]2[CH:14]=[C:13]3[C:5]([N:6]4[C:11](=[CH:12]3)[C:10](=[O:15])[NH:9][CH2:8][CH2:7]4)=[N:4][CH:3]=2)[CH2:21][CH2:20]1)([CH3:18])[CH3:17]
Reactant: CC(C)N1CCC(O)CC1
Reactant: O=C1NCCn2c1cc1cc(O)cnc12
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)N1CCC(Oc2cnc3c(c2)cc2n3CCNC2=O)CC1
Yield: 42 %

Procedure:
The title compound was synthesized in analogy to example 1, from 7-hydroxy-3,4-dihydro-2H-2,4a,5-triaza-fluoren-1-one, 1-isopropyl-piperidin-4-ol (commercially available), triphenylphosphine and di-tert-butylazodicarboxylate, to give the desired product as a white solid (42%).