Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[H-].[Na+].[C:14]([O:18][C:19](=[O:30])[NH:20][CH:21]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH:22]=O)([CH3:17])([CH3:16])[CH3:15].O>C1COCC1>[CH3:1][O:2][C:3](=[O:4])[CH:5]=[CH:22][CH:21]([NH:20][C:19]([O:18][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:30])[CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)NC(C=O)C1CCCCC1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C=CC(NC(=O)OC(C)(C)C)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice cooled solution of trimethyl phosphonoacetate (19 mL, 0.11 mol) in THF (200 mL) was added 60% NaH (3.1 g, 0.08 mol) in portions. The ice bath was removed and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was then cooled to 0° C. before a solution of (1-cyclohexyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (9 g, 37 mmol) in THF (200 mL) was added. The reaction mixture was stirred at room temperature for another 20 min. Water (100 mL) was added, and then most of the THF was evaporated. The product was extracted with EtOAc (400 mL), and the organic layer was washed with aqueous NaCl solution and then dried with MgSO4. Evaporation yielded a residue which was purified by column chromatography (1:1 heptane:EtOAc) to yield 4-tert-butoxycarbonylamino-4-cyclohexyl-but-2-enoic acid methyl ester as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:34])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[C:16]=2[O:32][CH3:33])[CH2:10][CH2:9]1)=O)(C)(C)C.C([O-])(O)=O.[Na+]>FC(F)(F)C(O)=O>[CH3:33][O:32][C:16]1[C:17]([O:21][Si:22]([CH:23]([CH3:25])[CH3:24])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:34]
Reactant: COc1c(O[Si](C(C)C)(C(C)C)C(C)C)cccc1C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1c(O[Si](C(C)C)(C(C)C)C(C)C)cccc1C(=O)C1CCNCC1
Reaction time: 2 h

Procedure:
Stir and cool in an ice bath under nitrogen, 4-(2-methoxy-3-triisopropylsilanyloxy-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester, Example 2B (5.71 g, 11.6 mmol) and add trifluoroacetic acid (30 mL). Remove the cold bath after 10 minutes. After 2 h, concentrate the reaction under vacuum at 40-45° C. and then pour into saturated aqueous NaHCO3. Extract the basic layer with CH2Cl2 (2×200 mL), dry (Na2SO4), and concentrate under vacuum to an oil, which eventually solidifies to afford 4-(2-methoxy-3-triisopropylsilanyloxy-benzoyl)-piperidine.
Reaction SMILES: ClC1C=CC(OC2C=CC(CCO[C:18]3[NH:19][CH:20]=[C:21]([CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[N:30][CH:31]=4)[C:22](=[O:24])[N:23]=3)=CC=2)=CC=1C(F)(F)F.[CH3:36]CN(C(C)C)C(C)C.CI>ClCCl>[CH3:36][N:19]1[CH:20]=[C:21]([CH2:25][C:26]2[CH:31]=[N:30][CH:29]=[N:28][CH:27]=2)[C:22](=[O:24])[N:23]=[CH:18]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=c1nc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1Cc1cncnc1
Solvent: ClCCl
Solvent: CI
Product: Cn1cnc(=O)c(Cc2cncnc2)c1
Yield: 43.8 %

Procedure:
To a solution of 2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-5-(5-pyrimidinylmethyl)-4(1H)-pyrimidinone (45 mg, 0.089 mmol) in dichloromethane (DCM) (2 mL) was added DIPEA (0.031 mL, 0.179 mmol) and MeI (8.39 μL, 0.134 mmol). The mixture was purified by reverse phase biotage affording 2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy})phenyl)ethyl]oxy}-1-methyl-5-(5-pyrimidinylmethyl)-4(1H)-pyrimidinone (20 mg, 0.039 mmol, 43.2% yield) LCMS: rt=3.37 min, [M+H+]=517
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([CH2:13][C@H:14]([NH:25][C:26]([O:28][CH3:29])=[O:27])[C:15]([O:17]CC2C=CC=CC=2)=[O:16])[N:10]=[N:9]1)C1C=CC=CC=1>CO.[Pd]>[CH3:29][O:28][C:26]([NH:25][C@@H:14]([CH2:13][C:11]1[N:10]=[N:9][NH:8][CH:12]=1)[C:15]([OH:17])=[O:16])=[O:27]
Reactant: COC(=O)N[C@@H](Cc1cn(Cc2ccccc2)nn1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)N[C@@H](Cc1c[nH]nn1)C(=O)O

Procedure:
(S)-benzyl 3-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-(methoxycarbonylamino)propanoate (502 mg, 1.11 mmol) was hydrogenated in the presence of Pd—C (82 mg) in MeOH (5 mL) at atmospheric pressure for 12 h. The mixture was filtered through diatomaceous earth (Celite®) and concentrated in vacuo. (S)-2-(methoxycarbonylamino)-3-(1H-1,2,3-triazol-4-yl)propanoic acid was obtained as a colorless gum (266 mg, 111%) which was contaminated with ca. 10% of the methyl ester. The material was used as in is without further purification.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:4]1.[Si]([O:24][CH2:25][CH2:26][C@@H:27]1[CH2:29][N:28]1[S:30]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)(=[O:32])=[O:31])(C(C)(C)C)(C)C.[CH3:40]I.Cl>CN(C=O)C.CCOC(C)=O.CC(OC)(C)C>[F:39][C:36]1[CH:37]=[CH:38][C:33]([S:30]([N:28]([CH3:40])[C@H:27]([CH2:26][CH2:25][OH:24])[CH2:29][N:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:4]2)(=[O:32])=[O:31])=[CH:34][CH:35]=1
Reactant: CI
Reactant: COC(=O)Cc1c[nH]c2ccccc12
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1CN1S(=O)(=O)c1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: COC(=O)Cc1cn(C[C@@H](CCO)N(C)S(=O)(=O)c2ccc(F)cc2)c2ccccc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 75 %

Procedure:
A three necked round bottom flask fitted with a magnetic stir bar, nitrogen inlet, temperature probe and addition funnel was charged with sodium hydride (2 equiv.) and DMF. The mixture was cooled to 0° C., and a solution of methyl 1H-indol-3-ylacetate (2 equiv.) from Step 5 in DMF (1 M) was added dropwise. After the addition, the reaction was stirred for 15 min, upon which a DMF (0.5 M) solution of (2R)-2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1-[(4-fluorophenyl)sulfonyl]aziridine (1 equiv.) from Step 4 was added dropwise. The reaction was allowed to stir 1.5 h. Methyl iodide (5 equiv.) was then added to the reaction and stirred an additional 1 h. Aqueous 2M HCl (7.2 equiv.) was then added carefully to the reaction followed by an equal volume of EtOAc and stirring continued for 2 h. The solution was diluted with EtOAc and layers separated. The organic phase was washed with ½ saturated brine (2×), dried over Na2SO4, filtered and concentrated to an orange syrup. The syrup was diluted with MTBE upon which solid started to form. The suspension was vigorously stirred while additional MTBE was added dropwise over 15 min. The suspension was cooled to 0° C. and Heptanes was added dropwise. The reaction was stirred for 1 h, and filtered. The solid cake was washed with MTBE/Heptanes (2:1) and dried on the fit under nitrogen for 16 h to provide the title compound (75%) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[CH3:18][O:17][C:15](=[O:16])[CH2:14][C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][CH:12]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: COC(=O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
Cesium carbonate (5.35 g, 16.4 mmol, 3.00 equivalents) was added to a solution of methyl 4-hydroxyphenylacetate (1.00 g, 6.02 mmol, 1.10 equivalents) and benzyl bromide (0.65 mL, 5.47 mmol, 1.00 equivalents) in dichloromethane (40 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred vigorously overnight. The reaction was extracted with 1N hydrochloric acid (2×100 mL) and brine (100 mL). The organic portion was dried over sodium sulfate and the solvent removed in vacuo. The resulting oily solid was chromatographed on a 40S Biotage column (20% ethyl acetate/Hexanes) to give the title ester as a clear colorless oil (1.35 g, 96%). 1H NMR (400 MHz, CDCl3) δ 3.56 (s, 2H), 3.67 (s, 3H), 5.04 (s, 2H), 6.91-6.94 (d, 2H), 7.17-7.19 (d, 2H), 7.3-7.4 (m, 5H). F. 2-Acetylamino-3-[3-(1-tert-butoxycarbonylamino-3-methyl-butyl)-isoxazol-5-yl]-propionic acid ethyl ester
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([C:12]3[CH:21]=[C:20]4[C:15]([CH2:16][CH:17]([CH2:22][CH2:23][CH3:24])[CH2:18][O:19]4)=[CH:14][C:13]=3[F:25])[CH2:8][O:9]2)=[CH:4][C:3]=1[F:26].C([Li])CCC.C1(C)C=CC(S([C:41]#[N:42])(=O)=O)=CC=1>C1COCC1.CCCCCC.CCOCC>[F:26][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[C:41]#[N:42])[O:9][CH2:8][CH:7]([C:12]1[CH:21]=[C:20]3[C:15]([CH2:16][CH:17]([CH2:22][CH2:23][CH3:24])[CH2:18][O:19]3)=[CH:14][C:13]=1[F:25])[CH2:6]2
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: CCCC1COc2cc(C3COc4cc(Br)c(F)cc4C3)c(F)cc2C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCC1COc2cc(C3COc4cc(C#N)c(F)cc4C3)c(F)cc2C1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
1.4 g (3.31 mmol) of 7-bromo-6,6′-difluoro-3′-propyl-3,4,3′,4′-tetrahydro-2H,2′H-[3,7′]bichromenyl are dissolved in 20 ml of THF, and 3 ml (4.8 mmol) of a 15 percent solution of n-butyl-lithium in hexane are added at −50° C. The batch is left to stir for 2 h at −70° C., and a solution of 0.9 g (5.00 mmol) of p-toluenesulfonyl cyanide in 10 ml of THF is subsequently added at such a rate that the temperature does not exceed −65° C. After 30 min, the batch is allowed to thaw, diluted with ether and washed with dil. hydrochloric acid. The org. phase is dried over sodium sulfate and evaporated, and the crude product is chromatographed on silica gel with heptane/toluene (2:3), giving 6,6′-difluoro-3′-propyl-3,4,3′,4′-tetrahydro-2H,2′H-[3,7]bichromenyl-7-carbonitrile as colourless crystals of m.p. 122° C.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:28]2[N:37]=[CH:36][C:35]3[C:30](=[C:31]([F:42])[CH:32]=[C:33]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:34]=3)[C:29]2=[O:43])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[N:13]=[C:14]([NH:20][C:21]2[CH:22]=[N:23][N:24]([CH2:26][CH3:27])[CH:25]=2)[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[C:38]([C:33]1[CH:34]=[C:35]2[C:30](=[C:31]([F:42])[CH:32]=1)[C:29](=[O:43])[N:28]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[N:13]=[C:14]([NH:20][C:21]4[CH:22]=[N:23][N:24]([CH2:26][CH3:27])[CH:25]=4)[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=3)[CH:10]=[CH:9][N:8]=1)[N:37]=[CH:36]2)([CH3:41])([CH3:39])[CH3:40]
Reactant: CCn1cc(Nc2nc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3COC(C)=O)cn(C)c2=O)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: CCn1cc(Nc2nc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
A mixture of 123d (152 mg, 0.26 mmol) and lithium hydroxide (61 mg, 2.56 mmol) in i-propanol/THF (1:1, 10 mL) and water (3 mL) was stirred at room temperature for 1 h. The mixture was evaporated under reduced pressure and the residue was extracted with ethyl acetate (2×10 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 123 (55 mg, 39%) as a yellow solid. MS-ESI: [M+H]+ 545.2. 1H NMR (500 MHz, DMSO-d6) δ 9.72 (s, 1H), 8.58 (d, J=5.0 Hz, 1H), 8.54 (d, J=2.5 Hz, 1H), 8.18 (s, 1H), 7.90 (d, J=2.0 Hz, 1H), 7.80-7.75 (m, 1H), 7.74 (s, 1H), 7.71 (d, J=5.0 Hz, 1H), 7.51 (s, 1H), 4.90 (t, J=5.0 Hz, 1H), 4.61-4.53 (m, 2H), 4.09 (q, J=7.5 Hz, 2H), 3.54 (s, 3H), 1.41 (s, 9H), 1.35 (t, J=6.0 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[F:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30]>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][CH2:9][C:10]([NH:30][C:29]1[CH:31]=[CH:32][CH:33]=[C:27]([F:26])[CH:28]=1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(F)c1
Reactant: O=C(O)COCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(COCc1ccccc1)Nc1cccc(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.8 %

Procedure:
To a solution of benzyloxyacetic acid (4.65 g, 28 mmol, 4.0 mL) in DCM (52 mL) was added oxalyl chloride (7.7 g, 61 mmol, 5.3 mL) and a drop of DMF. The reaction mixture was stirred at room temperature for 4 h. Excess of oxalyl chloride was removed in vacuo and the crude acyl chloride was diluted into DCM (100 mL) and triethylamine (5.3 mL, 41.6 mmol, 4.2 g) was added followed by 3-fluoroaniline (3.5 g, 32 mmol, 3.0 mL). The reaction mixture was stirred at RT overnight. The reaction was then quenched with 1 M aqueous HCl (100 mL), dried and concentrated in vacuo to afford 7.10 g (95%) of 2-benzyloxy-N-(3-fluoro-phenyl)-acetamide (39) as a yellow oil which was used in the next step without purification. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 69.2, 73.5, 106.9, 107.2, 111.0 (d, JCF=24 Hz), 114.9 (d, JCF=3 Hz), 127.8, 128.2, 128.5, 129.7 (d, JCF=9 Hz), 136.2, and 167.6.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([C@@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1)[N:9]1[CH2:16][CH2:15][C@H:14]([CH2:17][CH3:18])[C@H:10]1[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[Cl:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH2:42][NH2:43].CN1CCOCC1>CN(C=O)C>[Cl:38][C:39]1[CH:40]=[C:41]([CH2:42][NH:43][C:11](=[O:13])[C@@H:10]2[C@@H:14]([CH2:17][CH3:18])[CH2:15][CH2:16][N:9]2[CH:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C@@H:19]2[CH2:23][CH2:22][CH2:21][NH:20]2)[CH:44]=[CH:45][CH:46]=1
Reactant: CC[C@H]1CCN(C(C(=O)OC(C)(C)C)[C@@H]2CCCN2)[C@@H]1C(=O)O
Reactant: NCc1cccc(Cl)c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CC[C@H]1CCN(C(C(=O)OC(C)(C)C)[C@@H]2CCCN2)[C@@H]1C(=O)NCc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-[(t-Butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-proline (0.50 g, 1.53 mmol), EDC (0.293 g, 1.53 mmol), HOBT (0.243 g, 1.53 mmol) and 3-chlorobenzylamine(0.187 mL, 1.53 mmol) were dissolved in DMF (5 mL), the pH adjusted to 7 with N-methyl-morpholine (0.51 mL, 4.6 mmol), and the reaction mixture stirred for 18 hours at ambient temperature. After removing the solvent in vacuo the residue was partitioned between EtOAc and 5% aqueous NaHCO3. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated to give the title compound after chromatography (SiO2, EtOAc:hexane, 2:3).
Reaction SMILES: Cl[C:2](=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:3](=[O:5])[CH3:4].[CH3:16][S:17][C:18]1[CH:23]=[CH:22][C:21]([SH:24])=[CH:20][CH:19]=1.C(N(CC)CC)C>C(O)C>[CH3:16][S:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][C:2](=[N:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:3](=[O:5])[CH3:4])=[CH:20][CH:19]=1
Reactant: COc1ccc(NN=C(Cl)C(C)=O)cc1
Reactant: CSc1ccc(S)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(NN=C(Sc2ccc(SC)cc2)C(C)=O)cc1

Procedure:
A suspension of 31.7 g (0.139 mol)of 1-chloro-1-[(4-methoxyphenyl)hydrazono]-2-propanone in 400 ml of ethanol was treated with 23.4 g of 4-methylthiothiophenol and 23.4 of triethylamine. The suspension was heated at reflux for 2 hours and cooled. The resultant suspension was filtered and the precipitate was washed with 1 portion of cold ethanol. The solids were dried in vacuo to yield 1-[(4-methylthiophenyl)thio]-1-[(4-methoxyphenyl)hydrazono]-2-propanone, mp 124-127° C. 1H NMR(400 MHz, CDCl3): 2.41 (s, 3 H), 2.54 (s, 3 H), 3.78 (s, 3 H), 6.87 (d, J=8.8 Hz, 2 H), 7.12 (m, 6 H), 9.20 (broad s, 1 H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[P:6]([O:11][CH2:12][CH3:13])(=[O:10])[O:7][CH2:8][CH3:9].C([N-]C1CCCCC1)(C)C.[Li+].[I:25]I>C1COCC1>[I:25][C:5]1[O:1][C:2]([P:6]([O:7][CH2:8][CH3:9])(=[O:10])[O:11][CH2:12][CH3:13])=[CH:3][CH:4]=1
Reactant: CCOP(=O)(OCC)c1ccco1
Reactant: II
Agent: CC(C)[N-]C1CCCCC1
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1ccc(I)o1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of diethyl 2-furanphosphonate (prepared as described in Step A, Example 1) (1 mmol) in 2 mL THF was cooled to −78° C. and added to a solution of lithium isopropylcyclohexylamide (LICA) (1 mmol) in 2 mL THF at −78° C. over 20 min. The resulting mixture was stirred −78° C. for 20 min and added into a solution of iodine (1 mmole) in 1 mL THF at −78° C. over 20 min. The mixture was then stirred at −78° C. for 20 min. Extraction and chromatography provided diethyl 5-iodo-2-furanphosphonate as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][C:13](OC(C)(C)C)=[O:14])[C:5]=2[CH2:4][O:3]1.[Li+].[BH4-].CO>C1COCC1>[CH3:1][C:2]1([CH3:20])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][CH2:13][OH:14])[C:5]=2[CH2:4][O:3]1
Reactant: CC(C)(C)OC(=O)Cc1cccc2c1COC(C)(C)O2
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)OCc2c(CCO)cccc2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
To a solution of tert-butyl 2-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-5-yl)acetate (2.6 g, 80% pure, 9.34 mmol, 1 eq.) in THF (20 mL) were added LiBH4 (7.0 mL, 14.01 mmol, 1.5 eq.) and MeOH (1.0 mL) at rt. The mixture was stirred at rt for 30 min, added MeOH (20 mL), concentrated to dryness, added MeOH (20 mL) and silica gel, and concentrated to dryness again. The mixture was loaded directly on silica gel for purification using a mixture of EtOAc and hexanes as eluent to give 2-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-5-yl)ethanol (1.1 g, 71%) as a pale brown oil. 1H NMR (400 MHz, CDCl3) δ 7.28 (t, J=7.9 Hz, 1H), 6.92 (d, J=7.4 Hz, 1H), 6.86 (d, J=8.2 Hz, 1H), 5.02 (s, 2H), 3.99 (q, J=6.4 Hz, 2H), 2.86 (t, J=6.6 Hz, 2H), 1.68 (s, 6H), 1.57 (t, J=5.5 Hz, 1H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH:5]([N:7]1[C:20]2[CH:19]=[C:18]([C:21]#[N:22])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].I[CH2:30][CH3:31]>CN(C)C=O>[CH2:1]([N:3]([CH2:30][CH3:31])[CH2:4][CH:5]([N:7]1[C:20]2[CH:19]=[C:18]([C:21]#[N:22])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6])[CH3:2]
Reactant: CCI
Reactant: CCNCC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Temperature: 150 °C

Procedure:
A mixture of 10-(1-ethylamino-2-propyl)-2-phenothiazinecarbonitrile acid fumarate, D series (4 g), sodium carbonate (1.32 g) and iodoethane (1 cc) in dimethylformamide (50 cc) is heated to a temperature in the region of 150° C. for 6 hours. After being cooled, the reaction mixture is concentrated to dryness (30 mm Hg; 4 kPa) at 50° C. and the residue is taken up with ethyl acetate (100 cc) and washed successively with distilled water (50 cc) and with saturated aqueous sodium chloride solution (50 cc). The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 10-(1-Diethylamino-2-propyl)-2-phenothiazinecarbonitrile, D series (3.4 g) is thereby obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[NH2:43][C:44]1[S:45][C:46]([C:49]([CH3:52])([CH3:51])[CH3:50])=[N:47][N:48]=1>C(Cl)(Cl)Cl.O>[C:49]([C:46]1[S:45][C:44]([NH:43][C:35]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][C:18]=2[F:23])=[O:41])=[N:48][N:47]=1)([CH3:52])([CH3:51])[CH3:50]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: CC(C)(C)c1nnc(N)s1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4nnc(C(C)(C)C)s4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (100 mg) was dissolved in chloroform (5 ml) and triethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 15 min. Next, 2-amino-5-tert-butyl-1,3,4-thiadiazole (65 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Distilled water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine and was dried over sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by HPLC using chloroform/acetone for development to give 49 mg of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)(=[O:16])=[O:15])[CH:6]=[CH:5][C:4]1=2.Cl.[O-:25][C:26]#[N:27].[K+]>O>[F:23][C:19]1[CH:18]=[C:17]([S:14]([NH:13][C:7]2[CH:6]=[CH:5][C:4]3[CH:3]([CH2:2][NH:1][C:26]([NH2:27])=[O:25])[CH2:12][CH2:11][CH2:10][C:9]=3[CH:8]=2)(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=1
Reactant: N#C[O-]
Reactant: NCC1CCCc2cc(NS(=O)(=O)c3cccc(F)c3)ccc21
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)NCC1CCCc2cc(NS(=O)(=O)c3cccc(F)c3)ccc21

Procedure:
A mixture of 0.23 grams (0.688 mmoles) N-(5-aminomethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-3-fluoro-benzenesulfonamide, 0.15 mL 6M hydrochloric acid, and 0.112 grams (1.38 mmole) potassium cyanate in 25 mL water was heated under reflux for 1.5 hours. The solid precipitate was collected by filtration and dried in vacuo to provide 3-fluoro-N-(5-ureidomethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzenesulfonamide as a white solid, 0.21 gram (81%), m.p. 162-163° C., M+H=378.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:16][N:17]1[C:22]([NH:23][CH2:24][CH2:25]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][C:20](=[O:37])[N:19]([CH3:38])[C:18]1=[O:39].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:16][N:17]1[C:22]([NH:23][CH2:24][CH2:25][N:13]2[CH2:12][CH2:11][N:10]([C:7]3[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:9][CH:8]=3)[CH2:15][CH2:14]2)=[CH:21][C:20](=[O:37])[N:19]([CH3:38])[C:18]1=[O:39]
Reactant: Cc1ccc(S(=O)(=O)OCCNc2cc(=O)n(C)c(=O)n2C)cc1
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)c1ccc(N2CCN(CCNc3cc(=O)n(C)c(=O)n3C)CC2)cc1
Temperature: 80 °C
Yield: 41.7 %

Procedure:
A mixture of 1.6 g of 1-(4-acetylphenyl)piperazine and 1.1 g of 1,3-dimethyl-6-[2-(p-toluenesulfonyloxy)-ethylamino]-2,4(1H,3H)-pyrimidinedione was heated at 80° C. for 6 hours, and after standing for cooling, the reaction solution was poured into a 5% aqueous sodium carbonate solution, stirred and then extracted with chloroform. The chloroform solution was washed with water and then concentrated, and the resultant residue was purified through a silica gel column chromatograph (chloroform/methanol=50/1 in volume ratio), thereby obtaining 0.5 g of 1,3-dimethyl-6-[2-(4-[4-acetylphenyl]piperazin-1-yl)ethylamino]-2,4(1H,3H)-pyrimidinedione.