Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[N:10][C:11]([C:17]2[CH:18]=[C:19]([S:23]([NH:26][P:27](=[O:30])([OH:29])[OH:28])(=[O:25])=[O:24])[CH:20]=[N:21][CH:22]=2)=[N:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Ca+2:40].[OH-]>C(O)C.O>[C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[N:10][C:11]([C:17]2[CH:18]=[C:19]([S:23]([NH:26][P:27](=[O:28])([O-:29])[O-:30])(=[O:24])=[O:25])[CH:20]=[N:21][CH:22]=2)=[N:12]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Ca+2:40]
Reactant: O=P(O)(O)NS(=O)(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=P([O-])([O-])NS(=O)(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
To a suspension of ((5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)quinazolin-2-yl)pyridin-3-yl)sulfonyl)phosphoramidic acid (2) (0.200 g, 0.365 mmol) in ethanol (5 mL) was added calcium hydroxide (0.041 g, 0.55 mmol) in 2 mL of water. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 2 h. The reaction mixture was concentrated to dryness and the residue was washed with ethyl acetate (2×10 mL), acetone (2×10 mL) and acetonitrile (2×15 mL) to afford calcium (5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)quinazolin-2-yl)pyridin-3-yl)sulfonylphosphoramidate (7) (0.195 g, 0.322 mmol, 88.6% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 4.77 (d, J=4.27 Hz, 2H), 6.92 (t, J=4.14 Hz, 1H), 7.26-7.35 (m, 2H), 7.39 (d, J=8.03 Hz, 1H), 7.50-7.60 (m, 5H), 7.79 (td, J=7.65, 1.76 Hz, 1H), 7.83-7.89 (m, 1H), 7.91-7.96 (m, 1H), 8.30 (d, J=4.27 Hz, 1H), 9.10 (s, 1H), 9.25 (t, J=2.13 Hz, 1H), 9.73 (d, J=2.01 Hz, 1H); LCMS Method I: retention time 1.66 min, [M−1]=547. HPLC Method B: Purity 94.3%, retention time 6.17 min, HPLC Method C: Purity 94.45%, retention time 5.97 min. Elemental analysis: Compound was hygroscopic, elemental analysis not obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:14](=[O:16])[CH3:15].[CH2:17](O)[CH2:18][OH:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]([C:14]2([CH3:15])[O:19][CH2:18][CH2:17][O:16]2)=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=1
Reactant: CC(=O)c1cccc(-c2ccncc2)c1F
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(c2cccc(-c3ccncc3)c2F)OCCO1
Yield: 64.8 %

Procedure:
A mixture of 1-(2-fluoro-3-pyridin-4-ylphenyl)ethanone (1.28 g, 5.95 mmol), ethylene glycol (1.66 ml, 29.75 mmol), molecular sieves (5 g, 3 Å) and p-toluenesulfonic acid monohydrate (0.11 g, 0.59 mmol) in toluene (20 ml) was heated at reflux for 2 h. The molecular sieves was filtered off and the residue was evaporated to dryness. Purification by flash column chromatography (ethyl acetate) gave the title compound (1.0 g). MS m/z (rel. intensity, 70 eV) 259 (M+, 1), 245 (15), 244 (bp), 200 (56), 87 (17).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5](=O)[CH2:4][CH2:3]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:33].[Na+]>CO.O>[CH3:1][C:2]1([CH3:26])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[CH:5]([NH2:33])[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(N)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.3 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoate (Compound 2 ) in 5 ml of MeOH was added 922 mg (12 mmol) of ammonium acetate and then 188 mg (3 mmol) of sodium cyanoborohydride. The reaction mixture was refluxed for 1 hour, stirred at ambient temperature for 12 hours and then diluted with water (10 ml) and extracted with Et20 (3×30 ml). The organic layer was washed with water (5 ml) and brine (5 ml), dried over MgSO4 and concentrated in vacuo to an oil. Recrystallization from EtOAc-hexane yielded the title compound as a white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:8]2[CH2:12][CH2:11][O:10][C:9]2=[O:13])C=CC=CC=1.[CH:26]([C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1)=O.C(Cl)(Cl)Cl>CS(C)=O>[O:13]=[C:9]1[C:8](=[CH:26][C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:12][CH2:11][O:10]1
Reactant: O=C1OCCC1=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(C=C2CCOC2=O)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of 40.00 g (0.12 mol) of 3-(triphenylphosphoranylidene)dihydro-2(3H)-furanone and 20.85 g (0.13 mol) of methyl 4-formylbenzoate in 240 ml of dimethyl sulfoxide is stirred at 80° C. for 18 hours. After cooling, 400 ml of chloroform are added, and the mixture is extracted five times with 200 ml of water. The organic phase is dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is stirred with diethyl ether and dried under reduced pressure at 40° C.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[CH:7]=[C:8]([CH3:10])[O:9][C:4]=2[CH:3]=1.Cl[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.[OH-].[K+].CN(C)C=O>C1(C)C=CC=CC=1>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([O:1][C:2]2[CH:14]=[CH:13][C:5]3[C:6]([CH3:11])([CH3:12])[CH:7]=[C:8]([CH3:10])[O:9][C:4]=3[CH:3]=2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: CC1=CC(C)(C)c2ccc(O)cc2O1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC1=CC(C)(C)c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
One hundred grams of 7-hydroxy-2,4,4-trimethyl-4H-1-benzopyran (synthesized by the method of Japanese Laid-Open Patent Publication No. 5475/1981), 79 g of p-chloronitrobenzene, 42 g of potassium hydroxide, 500 ml of N,N-dimethylformamide and 500 ml of toluene were introduced into a flask equipped with the Dean-Stark condenser, and heated at 110° to 116° C. While removing the distilled water as an azeotrope with toluene, the mixture was stirred for 2 hours. The reaction mixture was cooled to room temperature, and 1 liter of water, 500 ml of ethyl acetate and 120 ml of 2N-HCl were added. The insoluble materials were separated by filtration. The filtrate was subjected to oil-water separation. The oil layer was washed with 500 ml of brine, and dried over magnesium sulfate. The solvent was evaporated. Methanol (650 ml) was added to the residue, and crystals that precipitated were collected, washed with 650 ml of hexane, and dried to give 106 g (yield 67%) of the desired product as a brown powder (melting point 80° C.).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[CH:20]=[C:19]([CH2:21][OH:22])[CH:18]=[N:17]3)[C@@H:13]([OH:23])[C@H:12]2[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1.FC(F)(F)C(O)=O.C1(C(C2C=CC=CC=2)CNC2N=C(NCCN3CCCCC3)N=C3C=2N=CN3[C@@H]2C[C@H](N3C=C(CO)C=N3)[C@@H](O)[C@H]2O)C=CC=CC=1.[C:94]([O:98][C:99](=[O:106])[NH:100][C@@H:101]1[CH2:105][CH2:104][NH:103][CH2:102]1)([CH3:97])([CH3:96])[CH3:95]>>[C:94]([O:98][C:99](=[O:106])[NH:100][C@@H:101]1[CH2:105][CH2:104][N:103]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[C@@H:11]3[CH2:15][C@H:14]([N:16]4[CH:20]=[C:19]([CH2:21][OH:22])[CH:18]=[N:17]4)[C@@H:13]([OH:23])[C@H:12]3[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:3]=2)[CH2:102]1)([CH3:97])([CH3:95])[CH3:96]
Reactant: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](n5cc(CO)cn5)[C@@H](O)[C@H]4O)c3n2)C1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol (Intermediate BA7) using a procedure analogous to that of (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoro-acetate (Example 46) by replacing trans-1,4-diaminocyclohexane with (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=O>[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[N:7]=[N:6][C:5]([NH:8][C:9]3[CH:18]=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[N:16]4)=[CH:11][CH:10]=3)=[CH:4][C:3]=2[C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:33][CH:32]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Nc3ccc4cccnc4c3)nnc2Cl)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nnc(Nc3ccc4cccnc4c3)cc2-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of [6-chloro-5-(4-trifluoromethylphenyl)pyridazin-3-yl]-[quinolin-7-yl]amine, Example 88, (100 mg, 0.3 mmol) in dioxane (2 mL) was added 4-methoxyphenylboronic acid (46 mg, 0.3 mmol, Aldrich), followed by the addition of 2M aq Na2CO3 (0.2 mL, 0.4 mmol) and Pd[PPh3]4 (35 mg, 0.03 mmol, Aldrich). The mixture was flushed with N2 and heated under at 100° C. under N2 atmosphere for 24 h. The reaction mixture was cooled to room temperature, additional amounts of 2M aq Na2CO3 (0.2 mL, 0.4 mmol), 4-methoxyphenyl-boronic acid (46 mg, 0.3 mmol) and Pd[PPh3]4 (35 mg, 0.03 mmol) were added and the mixture was heated at 100° C. with stirring under N2 atmosphere for 4 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL) and washed with 5% Na2CO3. The organic layer was dried over Na2SO4, filtered and the solvent evaporated in vacuo. The residue was purified by column chromatography, eluting with MeOH:CH2Cl2 (1:19), to give the title compound as a tan crystalline solid. MS (ESI, pos. ion) m/z: 473 (M+1). MP: 215-217° C.
Reaction SMILES: [CH2:1]([C:5]([CH2:10][CH:11]([CH3:13])[CH3:12])([CH2:8][OH:9])[CH2:6][OH:7])[CH:2]([CH3:4])[CH3:3].ClCCl.[CH3:17][Si:18](Cl)([CH3:20])[CH3:19]>C(N(CC)CC)C>[CH2:1]([C:5]([CH2:10][CH:11]([CH3:13])[CH3:12])([CH2:6][O:7][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH2:8][O:9][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CC(CO)(CO)CC(C)C
Reactant: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC(CO[Si](C)(C)C)(CO[Si](C)(C)C)CC(C)C
Temperature: 0 °C

Procedure:
0.9 g of 2,2-diisobutyl-1,3-propandiol was admixed with 20 ml of dichloromethane. The mixture was cooled in ice-water bath, thereto was added 2.0 ml of triethyl amine, followed by the addition of 1.58 ml of trimethylsilyl chloride. The mixture was stirred in ice-water bath for further 2 hours. The reaction mixture was washed with water, and the organic layer separated was dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to give 1.45 g of concentrate. The crude product was purified by column chromatography using petroleum ether as eluent, to give colorless pure compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12](=[O:14])[O-:13])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH:15]([O-:17])=O.[Na+].[C]=O>CN(C)C=O.C(OCC)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:15]([C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12](=[O:14])[O:13][C:4]([CH3:10])([CH3:5])[CH3:3])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1)=[O:17]
Reactant: COc1ncc(Br)cc1CNC(=O)[O-]
Reactant: O=C[O-]
Agent: [C]=O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ncc(C=O)cc1CNC(=O)OC(C)(C)C
Yield: 77.6 %

Procedure:
1.009 g of N-[(5-bromo-2-methoxy-3-pyridyl)methyl]carbamate, 45 mg of dichlorobistriphenylphosphine palladium, 325 mg of sodium formate and 17 mg of triphenylphosphine were dissolved in 3 ml anhydrous N,N-dimethylformamide, followed by stirring at 110° C. for 2.5 hours in a carbon monoxide atmosphere. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 401 mg of tertiary butyl N-[(5-formyl-2-methoxy-3-pyridyl)methyl]carbamate was obtained from fractions eluted with hexane-ethyl acetate (3.5:1).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[CH:4]=1)[NH2:2].[CH3:10][C:11](=O)[CH2:12][CH3:13]>C(O)C>[C:11](=[N:2][NH:1][C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[CH:4]=1)([CH2:12][CH3:13])[CH3:10]
Reactant: NNc1cc[nH]c(=O)c1
Reactant: CCC(C)=O
Solvent: CCO
Product: CCC(C)=NNc1cc[nH]c(=O)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
4-hydrazino-1H-pyridin-2-one (20.1 g, 161.0 mmol) prepared in Step 1 and 2-butanone (21.6 ml, 241.0 mmol) were added to ethanol (400 ml). The reaction mixture was refluxed under stirring for 4 hours and cooled to 0° C. The resulting precipitate was filtered and then washed with cooled ethanol to give the titled compound as a white solid. (Yield: 75.0%)
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[CH2:11](Br)[CH:12]=[CH2:13].O1CCOCC1.[OH-].[Na+]>C(OCC)(=O)C>[CH2:13]([N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[Br:1])[CH:12]=[CH2:11]
Reactant: C=CCBr
Reactant: Brc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=CCn1c(Br)nc2ccccc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
A mixture of 2-bromo-1H-benzo[d]imidazole (0.400 g, 2.04 mmol), allyl bromide (0.35 mL, 4.08 mmol), 1,4-dioxane (15 mL), and 2 M aqueous sodium hydroxide solution (15 mL, 3.00 mmol) stirred for 2 h at 100° C. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (50 mL). The organic phase was separated and washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via preparative thin layer chromatography (eluting with 20% ethyl acetate/petroleum ether) to afford 1-allyl-2-bromo-1H-benzo[d]imidazole (0.251 g, 52%) as a yellow oil. MS (ESI, pos. ion) m/z 237, 239 [M+H]+.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].Cl/[C:6](=[N:12]/[OH:13])/[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.[Cl-].[Na+]>O1CCCC1>[OH:4][CH2:1][C:2]1[O:13][N:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=1
Reactant: C=CCO
Reactant: CCOC(=O)/C(Cl)=N\O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(CO)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
24.03 g of 2-propene-1-ol and 16.24 g of ethyl (2E)-chloro(hydroxyimino)acetate were dissolved in 100 ml of tetrahydrofuran, and 12.12 ml of triethylamine dissolved in 50 ml of tetrahydrofuran was then added dropwise at 0° C. over 30 minutes. The mixture was stirred at room temperature overnight. After aqueous saturated sodium chloride was added, the reaction mixture was separated into layers. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over aqueous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 14.22 g of ethyl 5-(hydroxymethyl)-isoxazole-3-carboxylate.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([Cl:23])C(C(F)(F)F)=CN=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])C.O=P1(CC2C=CC(N)=CC=2)OCCCO1.ClC1N=C(Cl)[C:47]([C:51]([F:54])([F:53])[F:52])=[CH:46][N:45]=1>>[Cl:23][C:21]1[N:22]=[C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([CH2:9][P:4]3(=[O:8])[O:3][CH2:1][CH2:7][CH2:6][O:5]3)=[CH:15][CH:14]=2)[C:47]([C:51]([F:54])([F:53])[F:52])=[CH:46][N:45]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Agent: Nc1ccc(CP2(=O)OCCCO2)cc1
Product: O=P1(Cc2ccc(Nc3nc(Cl)ncc3C(F)(F)F)cc2)OCCCO1

Procedure:
The title compound was prepared according to the procedure for diethyl(4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate using 4-[(2-oxido-1,3,2-dioxaphosphinan-2-yl)methyl]aniline (Compound 230C) and 2,4-dichloro-5-trifluoromethylpyrimidine.
Reaction SMILES: [C:1]([NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([N:19]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[CH:16]=[CH:15][C:14]=1[O:36][CH3:37])=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrBr>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][N:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[C:17]2[C:18]3[S:11][C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:12][C:13]=3[C:14]([O:36][CH3:37])=[CH:15][CH:16]=2)=[CH:34][CH:33]=1
Reactant: COc1ccc(N(Cc2ccc(C)cc2)Cc2ccc(C)cc2)cc1NC(=S)NC(=O)c1ccccc1
Agent: BrBr
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(N(Cc2ccc(C)cc2)Cc2ccc(C)cc2)c2sc(NC(=O)c3ccccc3)nc12
Yield: 58.3 %

Procedure:
To a stirred solution of 500 mg (0.98 mmol) 1-benzoyl-3-{5-[bis-(4-methyl-benzyl)-amino]-2-methoxy-phenyl}-thiourea in 7 ml chloroform was added dropwise 0.050 ml (0.98 mmol) bromine and the reaction mixture heated at reflux for 18 hours. The mixture was then diluted with ethyl acetate and washed with water and then with brine. The organic phase was dried over sodium sulfate and concentrated in vacuo. Flash chromatography (ethyl acetate/hexane) afforded 290 mg (58%) N-{7-[bis-(4-methyl-benzyl)-amino]-4-methoxy-benzothiazol-2-yl}-benzamide as a yellow solid. ES-MS m/e (%): 394 (M+Na+, 14), 508 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:15][CH2:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1oc2ccccc2c1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1oc2ccccc2c1CBr
Temperature: 25 °C
Yield: 108.7 %

Procedure:
A solution of methyl 3-methylbenzofuran-2-carboxylate (1.0 g, 5.3 mmol), N-bromosuccinimide (0.95 g, 5.3 mmol) and 2,2′-azobisisobutyronitrile (87 mg, 0.53 mmol) was heated to reflux in CCl4 (40 ml) for 3 h, then cooled to room temperature and concentrated. The residue was dissolved in ethyl acetate (100 ml) and washed with water (100 ml). The organic layer was dried over magnesium sulfate and concentrated to provide crude methyl 3-bromomethylbenzofuran-2-carboxylate (1.55 g) as a yellowish solid, which was used in the next step without further purification.
Reaction SMILES: [C:1]1([CH:7]2[S:12][CH2:11][CH2:10][CH2:9][S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:18]([O:22][C:23](=[O:32])[NH:24][CH:25]([CH:30]=[O:31])[CH2:26][CH2:27][CH2:28][CH3:29])([CH3:21])([CH3:20])[CH3:19].C(O)(=O)C>C1COCC1>[C:18]([O:22][C:23](=[O:32])[NH:24][CH:25]([CH:30]([OH:31])[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[S:8][CH2:9][CH2:10][CH2:11][S:12]1)[CH2:26][CH2:27][CH2:28][CH3:29])([CH3:19])([CH3:20])[CH3:21]
Reactant: CCCCC(C=O)NC(=O)OC(C)(C)C
Reactant: c1ccc(C2SCCCS2)cc1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCC(NC(=O)OC(C)(C)C)C(O)C1(c2ccccc2)SCCCS1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
2-Phenyl-1,3-dithiane (Aldrich) (3.79 g; 19.3 mmol) was mixed with dry distilled THF (20 mL) under a nitrogen atmosphere. The solution was cooled to −60° C. and n-butyl lithium (1.6M in pentane, 1.56 mmol, 9.74 mL) was added slowly by syringe. The reaction mixture was warmed to −20° C. and held at that temperature for 30 min., and then held at −10° C. for 15 min. The yellow solution was cooled to −78° C. and (1-formyl-pentyl)-carbamic acid tert-butyl ester (1.6 g, 1.4 mmol, in 5 mL THF) was added rapidly (over 20 seconds) and 60 seconds later a mixture of 2 mL acetic acid and 5 mL THF was added rapidly. After warming to 23° C. the solution was concentrated at reduced pressure. Excess 2-phenyl-1,3-dithiane was removed by its crystallization away from the desired product using a minimum of ethyl acetate in hexane. The mother liquors were concentrated and chromatographed using a hexane-ethyl acetate gradient to afford {1-[hydroxy-(2-phenyl-[1,3]dithian-2-yl)-methyl]-pentyl}-carbamic acid tert-butyl ester. (1.7 g, 56% yield).
Reaction SMILES: [H-].[Na+].[C:3]([N:6]1[CH2:11][CH2:10][C:9]([OH:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4].[F:19][C:20]1[C:25](F)=[C:24]([F:27])[C:23]([F:28])=[C:22]([F:29])[C:21]=1[F:30]>CN(C)C=O>[C:3]([N:6]1[CH2:11][CH2:10][C:9]([O:18][C:25]2[C:24]([F:27])=[C:23]([F:28])[C:22]([F:29])=[C:21]([F:30])[C:20]=2[F:19])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: Fc1c(F)c(F)c(F)c(F)c1F
Reactant: CC(=O)N1CCC(O)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(Oc2c(F)c(F)c(F)c(F)c2F)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 73.7 %

Procedure:
A stirred suspension of sodium hydride (60% in oil, 1.6 g) in 50 ml of dimethylformamide was treated with 7.0 g of 1-acetyl-4-hydroxy-4-phenylpiperidine in 100 ml of dimethylformamide. After the evolution of gas had ceased, the mixture was cooled to ice bath temperature and a solution of 6.88 g of hexafluorobenzene in 50 ml of dimethylformamide was added, dropwise. After stirring for 20 hours at ambient temperature the mixture was poured into ice water and then extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated. The concentrate was purified by means of high pressure liquid chromatography (silica gel; elution with 50% ethyl acetate/dichloromethane to yield 9.06 g (73.5%) of 1-acetyl-4-(2,3,4,5,6-pentafluorophenoxy)-4-phenylpiperidine, m.p. 115°-120° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([P:33]([CH3:36])([CH3:35])=[O:34])=[CH:29][C:28]=2[S:37]([CH:40]([CH3:42])[CH3:41])(=[O:39])=[O:38])=[N:4][C:5]([NH:8][C:9]2OC(N3CCN(C4C=CC=CN=4)CC3)=NN=2)=[N:6][CH:7]=1.[N:43]1([C:49]2[S:50][CH:51]=[C:52](CN)[N:53]=2)[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>>[Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([P:33]([CH3:35])([CH3:36])=[O:34])=[CH:29][C:28]=2[S:37]([CH:40]([CH3:41])[CH3:42])(=[O:38])=[O:39])=[N:4][C:5]([NH:8][CH2:9][C:52]2[N:53]=[C:49]([N:43]3[CH2:44][CH2:45][O:46][CH2:47][CH2:48]3)[S:50][CH:51]=2)=[N:6][CH:7]=1
Reactant: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1Nc1nc(Nc2nnc(N3CCN(c4ccccn4)CC3)o2)ncc1Cl
Reactant: NCc1csc(N2CCOCC2)n1
Product: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1Nc1nc(NCc2csc(N3CCOCC3)n2)ncc1Cl

Procedure:
This compound can be prepared as in Example 32 by reacting 2,5-dichloro-N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (as described in Example 53) with 1-[2-(morpholin-4-yl)-1,3-thiazol-4-yl]methanamine.