Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](O)[CH:2]=[CH2:3].[C:5]([O-:8])(=[O:7])[CH3:6].[Na+].C=C1O[C:13](=[O:14])[CH2:12]1>O1CCOCC1>[C:5]([O:8][CH2:1][CH:2]=[CH2:3])(=[O:7])[CH2:6][C:13]([CH3:12])=[O:14]
Reactant: CC(=O)[O-]
Reactant: C=C1CC(=O)O1
Reactant: C=CCO
Agent: [Na+]
Solvent: C1COCCO1
Product: C=CCOC(=O)CC(C)=O

Procedure:
A one liter reaction vessel equipped with a thermometer, a condenser and a dropping funnel was charged with 58 parts (1 mol) of allyl alcohol, 100 parts of dioxane and 0.41 parts of sodium acetate (catalyst) under nitrogen blanket and heated to 60° C., to which 84 parts (1mol) of diketene was added dropwise for one hour. After completion of the addition, it was allowed to react for 2 hours with heating and dioxane was removed at a reduced pressure. The reaction product was further distilled to obtain 2-propenyl acetoacetate. It was identified by absorption at 1,742, 1,721 and 1,684 cm-1 in IR spectrum.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8].[Cl:10][C:11]1[S:15][C:14]([C:16]2[O:20][N:19]=[C:18]([CH2:21][N:22]3[C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([C:31]([OH:33])=[O:32])[C:25]=4[CH:24]=[C:23]3[C:34](=[O:45])[NH:35][CH:36]3[CH2:41][CH2:40][N:39]([CH:42]([CH3:44])[CH3:43])[CH2:38][CH2:37]3)[CH:17]=2)=[CH:13][CH:12]=1.ClC1C=CC(NC(CN2C3C=CC=C(C(O)=O)C=3C=C2C(=O)NC2CCN(C(C)C)CC2)=O)=NC=1>>[CH3:8][C:7]1[O:6][C:5](=[O:9])[O:4][C:3]=1[CH2:2][O:33][C:31]([C:26]1[C:25]2[CH:24]=[C:23]([C:34](=[O:45])[NH:35][CH:36]3[CH2:41][CH2:40][N:39]([CH:42]([CH3:43])[CH3:44])[CH2:38][CH2:37]3)[N:22]([CH2:21][C:18]3[CH:17]=[C:16]([C:14]4[S:15][C:11]([Cl:10])=[CH:12][CH:13]=4)[O:20][N:19]=3)[C:30]=2[CH:29]=[CH:28][CH:27]=1)=[O:32]
Reactant: Cc1oc(=O)oc1CCl
Reactant: CC(C)N1CCC(NC(=O)c2cc3c(C(=O)O)cccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Agent: CC(C)N1CCC(NC(=O)c2cc3c(C(=O)O)cccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Product: Cc1oc(=O)oc1COC(=O)c1cccc2c1cc(C(=O)NC1CCN(C(C)C)CC1)n2Cc1cc(-c2ccc(Cl)s2)on1

Procedure:
The title compound was prepared analogously to example 5 with the difference that 4-Chloromethyl-5-methyl-[1,3]dioxol-2-one and 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-indole-4-carboxylic acid was used instead of Carbonic acid 1-chloro-ethyl ester 2-methoxy-ethyl ester and 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-indole-4-carboxylic acid. MS (ES+): m/e=639, chloro pattern.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1.[CH3:19][CH:20]([CH3:23])[CH:21]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClC(Cl)C.C(O)(=O)C>[CH3:19][CH:20]([CH3:23])[CH2:21][NH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1
Reactant: CC(C)C=O
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C(N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)CNC1CN(C(=O)OC(C)(C)C)Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a solution of tert-butyl 4-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (840 mg) and 2-methylpropanal (256 mg) in dichloroethane (10 ml) were added acetic acid (203 mg) and sodium triacetoxyborohydride (931 mg). The mixture was stirred at room temperature for 1 hr. The mixture was neutralized with 6% aqueous sodium hydrogen carbonate. After partitioning, the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object compound (940 mg) as an oil.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][C:21](O)=[O:22])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:31][N:32](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN>CN(C=O)C.O>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][C:21](=[O:22])[NH:32][CH3:31])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)[C@@H](CC(=O)O)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)C[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Reaction time: 0.05 h
Yield: 94.7 %

Procedure:
Prepared using General Procedures 7: To (R)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(tert-butoxy)-4-oxobutanoic acid (205.7 mg, 0.5 mmol) in DMF (5 mL) at 0° C. was added HATU (380 mg, 1.0 mmol). After stirring for 3 min, DIEA (277 μL, 1.5 mmol) and methylamine (40 wt % in water, 116 μL, 1.5 mmol) were added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was added to water (75 mL) and the precipitate was filtered and dried to give 201 mg (95%) of tert-butyl N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N4-methyl-D-asparaginate as a colorless semi-solid. LCMS-ESI (m/z) calculated for C24H28N2O5: 424.2. found 425.2 [M+H]+, tR=3.22 min (Method 16).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-])=O.[H][H]>[Pd].C(O)C>[NH:8]1[C:9]2[C:5](=[C:4]([NH2:1])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[N:7]1
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc2[nH]ncc12

Procedure:
A mixture of 4-nitro-1H-indazole C (760 mg, 4.68 mmol), palladium on charcoal (10%, cat.) and ethanol (30 mL) was stirred under a balloon of hydrogen for 4 h. The reaction mixture was then filtered through celite, and the solvent removed in vacuo to yield 1H-indazol-4-ylamine D (631 mg, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][O:13][C@H:12]([CH2:15][C:16](O)=[O:17])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[CH2:10][CH2:11][C@@H:12]([CH2:15][CH2:16][OH:17])[O:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](CC(=O)O)OC1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](CCO)OC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
A solution of borane dimethyl sulphide complex in tetrahydrofuran (2.0 M, 289 μL, 0.58 mmol, 3.0 eq) is added dropwise at 0° C. to a stirred solution of (2S,5R)-(5-tert-butoxycarbonylamino-tetrahydro-pyran-2-yl)-acetic acid (50 mg, 0.19 mmol, 1.0 eq) in tetrahydrofuran (2 mL). The reaction mixture is stirred at 0° C. for 30 minutes then at room temperature for 2 hours. Methanol (2 mL) is cautiously added to the reaction mixture that is then evaporated, repeatedly treated with methanol and concentrated to dryness to afford (3R,6S)-[6-(2-hydroxy-ethyl)-tetrahydro-pyran-3-yl]-carbamic acid tert-butyl ester as a white solid (47 mg, 99% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]([N:18]([CH2:22][C@@H:23]([NH:35][CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)C(=O)C)[S:7][C:8]=1[C:9]1[S:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[N:17]=1.C1COCC1.Cl.[OH-].[Na+]>C(Cl)Cl.CO>[CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]([NH:18][CH2:22][C@@H:23]([NH:35][CH2:36][CH2:37][N:38]2[CH2:39][CH2:40][O:41][CH2:42][CH2:43]2)[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:32])[F:34])=[CH:29][CH:30]=2)[S:7][C:8]=1[C:9]1[S:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[N:17]=1
Reactant: COCc1nc(N(C[C@H](Cc2ccc(C(F)(F)F)cc2)NCCN2CCOCC2)C(C)=O)sc1-c1nc2ccncc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: COCc1nc(NC[C@H](Cc2ccc(C(F)(F)F)cc2)NCCN2CCOCC2)sc1-c1nc2ccncc2s1
Temperature: 150 °C
Yield: 6.7 %

Procedure:
A glass microwave reaction vessel was charged with N-(4-(methoxymethyl)-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-yl)-N-((S)-2-(2-morpholinoethylamino)-3-(4-(trifluoromethyl)phenyl)propyl)acetamide (0.111 g, 0.2 mmol), THF (2.0 mL, 24 mmol), and HCl (2.0 mL, 10 mmol). The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 150° C. for 12 minutes. The mixture was then made basic with NaOH, extracted with EtOAc, and the organics were adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (4 g), eluting with a gradient of 1% to 10% 2 M NH3.MeOH in DCM, to provide the title compound, 4-(methoxymethyl)-N-((S)-2-(2-morpholinoethylamino)-3-(4-(trifluoromethyl)phenyl)propyl)-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-amine (0.008 g, 8% yield). LCMS (M+H) 593.2 calc. for C27H32F3N6O2S2 593.20. 1H NMR (400 MHz, CD3OD): δ ppm 9.13 (s, 1H), 8.50 (d, J=5.7 Hz, 1H), 7.83 (d, J=5.7 Hz, 1H), 7.62 (d, J=8.1 Hz, 1H), 7.48 (d, J=8.1 Hz, 1H), 4.69 (s, 2H), 3.50 (s, 3H), 3.47 (m, 6H), 3.14 (m, 1H), 2.95 (dd, J=6.0, 13.6 Hz, 1H), 2.84 (dd, J=7.9, 13.6 Hz, 1H), 2.77 (dd, J=5.8, 11.9 Hz, 1H), 2.68 (m, 1H), 2.40 (m, 2H), 2.29 (s, 4H).
Reaction SMILES: [CH2:1]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Al:26].C([Ti:30])(C)C>>[CH2:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[Al:26].[O-2:13].[O-2:13].[Ti+4:30]
Reactant: CC(C)[Ti]
Agent: CCCCCCCCCCCCOCCCCCCCCCCCC
Agent: [Al]
Product: [O-2]
Product: [Ti+4]

Procedure:
Aluminum dodecyloxide was prepared in the same manner as in Example 1. Then a part of the aluminum dodecyloxide was hydrolyzed in the same manner as in Example 1 to obtain an alumina slurry. A remained part of aluminum dodecyloxide was mixed with isopropyltitanium (produced by Kishida Kagaku K.K.) at a mixing ratio of 100:5 by weight. The mixture was hydrolysed in the same manner as in Example 1 employing the above alumina slurry as a crystal seed to obtain a titanium dioxide-containing alumina slurry. This alumina slurry was diluted with water to a solid alumina hydrate content 7.9%. The alumina slurry showed pH of 9.5. The pH was adjusted by adding a 3.9% nitric acid solution to a pH before aging as shown in Table 1. The alumina slurry was aged under the conditions shown in Table 1 to obtain a colloidal sol of alumina hydrate. This colloidal sol was spray-dried in the same manner as in Example 1 to obtain alumina hydrate, which had a boehmite structure, and was in a form of a plate-shaped particles as same as in Example 1. Properties of the alumna hydrate were measured as described above. The measured properties are shown in Table 1. The titanium dioxide was contained only at and near surface of the alumina hydrate particles.
Reaction SMILES: [CH2:1]([C:8]1([N:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1>CN(C)C=O>[CH2:1]([C:8]1([N:15]([CH3:16])[CH3:17])[CH2:13][CH2:12][CH:11]([O:14][CH2:29][C:28]2[CH:31]=[CH:32][C:25]([F:24])=[CH:26][CH:27]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: CN(C)C1(Cc2ccccc2)CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C1(Cc2ccccc2)CCC(OCc2ccc(F)cc2)CC1
Temperature: 0 °C
Yield: 54 %

Procedure:
2.00 g of 4-benzyl-4-dimethylaminocyclohexanol were dissolved in 20 ml of dimethylformamide; 1.06 g of potassium tert.-butoxide were added and stirring was carried out for 45 minutes, before 1.36 g of 4-fluorobenzyl chloride were added dropwise in the course of 30 minutes. After stirring overnight, the mixture was added to 25 ml of ice-water and extracted repeatedly with ethyl acetate. The combined extracts were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The resulting crude product (2.78 g) was separated on silica gel with hexane/ethyl acetate (V:V=1:1). 1.58 g of [1-benzyl-4-(4-fluorobenzyloxy)cyclohexyl]dimethylamine were obtained and, as described for Example 1, were converted into 890 mg of the corresponding hydrochloride using chlorotrimethylsilane and water in 2-butanone (white solid).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[C:10]12([C:20](=O)[CH2:21][C:22](OCC)=[O:23])[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2>>[C:10]12([C:20]3[S:9][C:6]4[C:7]([C:22](=[O:23])[CH:21]=3)=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH2:17][CH:16]3[CH2:15][CH:14]([CH2:13][CH:12]([CH2:18]3)[CH2:11]1)[CH2:19]2
Reactant: COc1ccc(S)cc1
Reactant: CCOC(=O)CC(=O)C12CC3CC(CC(C3)C1)C2
Product: COc1ccc2sc(C34CC5CC(CC(C5)C3)C4)cc(=O)c2c1
Reaction time: 1.5 h

Procedure:
1.4 g 4-methoxythiophenol is added to 10 g of polyphosphoric acid preheated to about 90°. Then 2.5 g ethyl 3-(1-adamantyl)-3-oxopropionate is added slowly, and the mixture is stirred for altogether 1.5 hours at 90°. The mixture is poured onto ice/water, vigorously stirred and extracted with ethyl acetate. The combined organic layers are dried over magnesium sulfate and evaporated in vacuo. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 6/1). 2-(1-adamantyl)-6-methoxy-4H-thiochromen-4-one is obtained (colourless crystals; mp 140°). b) Under argon 14 ml of 1M boron tribromide solution in dichloromethane are added at room temperature to a solution of 1.12 g 2-(1-adamantyl)-6-methoxy-4H-thiochromen-4-one in dry dichloromethane. After stirring for 1 hour the mixture is poured onto ice/water and extracted with dichloromethane. The combined organic layers are washed with aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo. The title compound is obtained (colourless crystals; mp 257° after chromatography on silica gel using cyclohexane/ethyl acetate 4/1 as an eluant).
Reaction SMILES: CCO.[CH2:4]([O:6][C:7](=[O:21])[CH2:8][S:9]/[C:10](=[C:12]1/[C@H:13]2[C@@H:15]([CH2:16][C:17]/1=O)[C:14]2([CH3:20])[CH3:19])/[CH3:11])[CH3:5]>[OH-].[Na+]>[CH2:4]([O:6][C:7]([C:8]1[S:9][C:10]([CH3:11])=[C:12]2[C:17]=1[CH2:16][C@H:15]1[C:14]([CH3:20])([CH3:19])[C@H:13]12)=[O:21])[CH3:5]
Reactant: CCOC(=O)CS/C(C)=C1\C(=O)C[C@@H]2[C@H]1C2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Temperature: 75 °C
Reaction time: 0.33 h
Yield: 61.7 %

Procedure:
A solution of Na (1.70 g, 74.8 mmol) in abs. EtOH (75 mL) is heated at 60° C. before it is treated with a solution of crude {1-[(1S,5R)-6,6-dimethyl-3-oxo-bicyclo[3.1.0]hex-(2Z)-ylidene]-ethylsulfanyl}-acetic acid ethyl ester (18.2 g, 68.0 mmol) in abs. EtOH (200 mL). The mixture is stirred at 75° C. for 20 min, then cooled to rt, diluted with 0.5 M aq. NaOH (500 mL) and extracted with DCM (450+200 mL). The combined extracts are dried over Na2SO4, filtered and the solvent is removed in vacuo. This yields crude (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (10.5 g) as a yellow oil of 87% puritiy (LC-MS, UV 280 nm). LC-MS: tR=1.11 min, [M+1]+=251.14; 1H NMR (CDCl3): δ 4.26 (q, J=7.0 Hz, 2H), 2.95 (dp, Jd=18.8 Hz, Jp=3.5 Hz, 1H), 2.79 (d, J=19.3, 1H), 2.37 (s, 3H), 1.89-1.84 (m, 2H), 1.34 (t, J=7.0 Hz, 3H), 1.12 (s, 3H), 0.72 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH:13]([CH3:14])[CH2:12][N:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=3)[CH:17]=2)[CH2:10][CH:9]1[CH3:29])=O)(C)(C)C.[NH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>>[CH3:29][CH:9]1[NH:8][CH:13]([CH3:14])[CH2:12][N:11]([CH2:15][C:16]2[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:30][CH2:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=4)[N:23]=3)[CH:19]=[CH:20][CH:21]=2)[CH2:10]1
Reactant: NCCc1ccc(O)cc1
Reactant: CC1CN(Cc2cccc(-c3ccnc(Cl)n3)c2)CC(C)N1C(=O)OC(C)(C)C
Product: CC1CN(Cc2cccc(-c3ccnc(NCCc4ccc(O)cc4)n3)c2)CC(C)N1

Procedure:
Intermediate 142 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 418. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.67 (s, 1H) 8.56 (d, 1H)) 8.52 (d, 1H) 8.00 (d, 1H) 7.75 (t, 1H) 7.65 (d, 1H) 7.15 (d, 2H) 6.67 (d, 2H) 4.70 (s, 2H) 3.75 (d, 2H) 3.70 (d, 2H) 3.60-3.66 (m, 2H) 3.40 (t, 2H) 2.96 (t, 2H) 1.44 (d, 6H).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18](Cl)=[N:17][N:16]=[C:15]3Cl)=[O:11])[CH:6]=[CH:7][CH:8]=1.[Na+].[I-:27].[IH:28]>CC(C)=O>[F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([I:27])=[N:17][N:16]=[C:15]3[I:28])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: I
Reactant: [I-]
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc2c(Cl)nnc(Cl)c2c1
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc2c(I)nnc(I)c2c1
Yield: 82.5 %

Procedure:
To a solution of 1,4-dichloro-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (3.3 g, 8.55 mmol) in acetone (100 mL) were added NaI (6.44 g, 42.96 mmol) and HI (few drops). The solution was refluxed for 1 hour then concentrated under vacuum and purified by chromatography (hexanes/EtOAc) to provide 1,4-di-iodo-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (4.01 g, 82.5%) as a colored solid.
Reaction SMILES: Br[O-:2].[Na+].C([C:7]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]=2[CH:8]=1)(=O)C.[O:21]1[CH2:26]COCC1>>[C:26]([C:7]1[CH:20]=[CH:19][C:18]2[C:13]3[C:12](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=[CH:10][C:9]=2[CH:8]=1)([OH:21])=[O:2]
Reactant: C1COCCO1
Reactant: [O-]Br
Reactant: CC(=O)c1ccc2c(ccc3ccccc32)c1
Agent: [Na+]
Product: O=C(O)c1ccc2c(ccc3ccccc32)c1
Yield: 99.2 %

Procedure:
Bromine (4.7 ml, 0.091 mol) was added to an ice-cold solution of sodium hydroxide (12.7 g, 0.318 mol) in water (70 ml) to form a basic solution of sodium hypobromite. The sodium hypobromite solution was added to a stirred solution of 2-acetylphenanthrene in dioxane (70 ml) at 60-65 ° C. for 15 min. Excess sodium hypobromite was removed by the addition of 10% solution of sodium metabisulphite (20 ml). Water (300 ml) was added and approximately 100 ml of solvent was removed under reduced pressure. The reaction mixture was acidified with concentrated HCl. The precipitate formed was filtered and washed with water to give the title compound as a solid (4.01 g, 99.2%).
Reaction SMILES: Cl[CH2:2][Si:3]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].[Na].[NH:14]1[CH:18]=[N:17][CH:16]=[N:15]1>CN(C)C=O.O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([Si:3]([CH3:5])([CH3:4])[CH2:2][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)=[CH:7][CH:8]=1
Reactant: C[Si](C)(CCl)c1ccc(Cl)cc1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(Cn1cncn1)c1ccc(Cl)cc1
Yield: 39.7 %

Procedure:
A mixture of 2.2 g (0.010 mol) of chloromethyl(4-chlorophenyl)dimethylsilane and 1.1 g (0.012 mol) of 1,2,4-triazole sodium salt in 5 ml of dimethylformamide was warmed to 80°-90° for 2 hours, diluted with water, and extracted with ether. The ether solution was washed with water and brine, dried over magnesium sulfate, and evaporated to leave 2:1 g (83%) of the title compound as a yellow liquid: nD21 1.5428; ir (neat) 1555, 1470, 1245, 1130, 1080, 1010, 835, 805, 795, 735 cm-1 ; nmr (CDCl3) 0.4 (6H, s), 3.8 (2H, s), 7.4 (4H, broad s), 7.8 (1H, s), 7.9 (1H, s).
Reaction SMILES: CS([O:5][CH:6]([CH2:9][CH3:10])[C:7]#[N:8])(=O)=O.[Cl:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][C:13]=1O.C(=O)([O-])[O-].[K+].[K+].C(OC)(C)(C)C>C(#N)C.O>[Cl:11][C:12]1[C:17]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:15]=[CH:14][C:13]=1[O:5][CH:6]([CH2:9][CH3:10])[C:7]#[N:8]
Reactant: Oc1cccc(C(F)(F)F)c1Cl
Reactant: CCC(C#N)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: COC(C)(C)C
Solvent: O
Product: CCC(C#N)Oc1cccc(C(F)(F)F)c1Cl
Temperature: 95 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(methanesulfonyloxy)-butyronitrile (204 mg, 1.25 mmol) (prepared following Marco et. al., Tetrahedron, 2000, 56, 2525-31) 2-chloro-3-trifluoromethylphenol (196 mg, 1.0 mmol) and potassium carbonate (172 mg, 1.25 mmol) in acetonitrile (5 ml) was stirred for 1 hour at 95° C. The mixture was shaken between tBuOMe and water and the ethereal phase dried with Na2SO4, filtered over a silicagel pad and evaporated to give as yellowish oil 2-(2-chloro-3-trifluoromethyl-phenoxy)-butyronitrile; 1H-NMR (CDCl3): 1.27 t, 3H, 2.20 m, 2H, 2.40 s, 3H, 4.78 t, 1H, 7.34, d, 1H; 7.39, t, 1H, 7.48 d, 1H.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7]O.[CH:9]1([C:12](=[O:31])[C:13](=[CH:27]OCC)[C:14]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][C:17]=2[F:26])=[O:15])[CH2:11][CH2:10]1>C(O)C>[CH:9]1([C:12]([C:13]2[CH:27]=[N:7][O:15][C:14]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][C:17]=2[F:26])=[O:31])[CH2:11][CH2:10]1
Reactant: CCOC=C(C(=O)c1ccc(S(C)(=O)=O)cc1F)C(=O)C1CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2oncc2C(=O)C2CC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium acetate (7.4 g) was added to a mixture of hydroxylamine hydrochloride (6.3g) and 3-cyclopropyl-2-ethoxymethylene-1-(2-fluoro-4-methylsulphonylphenyl)-propan-1,3-dione (29.0g) in ethanol. The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water, dried (anhydrous magnesium sulphate) filtered and evaporated to dryness. The residue was triturated with ether and filtered. The resultant solid was recrystallized from methanol. The mother liquors from the recrystallization were combined and evaporated to dryness. The residue was purified by column chromatography on silica gel to give 4-cyclopropylcarbonyl-5-(2-fluoro-4-methylsulphonylphenyl)-isoxazole (compound 1) as a white solid, m.p. 129.5°-130.5° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([N:26]([CH2:35][C:36]2[CH:41]=[C:40]([O:42][CH2:43][CH3:44])[CH:39]=[C:38]([O:45][CH:46]([CH3:48])[CH3:47])[C:37]=2[F:49])[C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)[N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.[OH2:50].[NH2:51]O>CS(C)=O>[Br:1][C:2]1[N:3]=[C:4]([N:26]([CH2:35][C:36]2[CH:41]=[C:40]([O:42][CH2:43][CH3:44])[CH:39]=[C:38]([O:45][CH:46]([CH3:48])[CH3:47])[C:37]=2[F:49])[C:27]2[CH:28]=[CH:29][C:30]([C:31]([NH2:51])=[N:32][OH:50])=[CH:33][CH:34]=2)[N:5]([C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=1
Reactant: CCOc1cc(CN(c2ccc(C#N)cc2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(OC(C)C)c1
Reactant: O
Reactant: NO
Solvent: CS(C)=O
Product: CCOc1cc(CN(c2ccc(C(N)=NO)cc2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(OC(C)C)c1

Procedure:
To a solution of Intermediate 28.1 (2.00 g, 2.8 mmol) in 3M NH2OH in DMSO (6 mL) (prepared according to example 1) was heated at 60° C. for 3 h. The reaction mixture was poured into water and the resultant precipitate was collected by filtration and dried in vacuo to afford Intermediate 66.1, which was used in the following step without purification.