Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]([NH:22][NH2:23])=[O:21])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.CCN(CC)CC.Cl[C:32](=[O:38])[C:33]([O:35][CH2:36][CH3:37])=[O:34]>C1COCC1>[NH2:1][C:2]1[C:3]([C:20]([NH:22][NH:23][C:32](=[O:38])[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:21])=[N:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:15])=[O:16])=[CH:12][CH:13]=2)=[CH:6][N:7]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C(=O)NN)n2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)NNC(=O)c1nc(-c2ccc(S(=O)(=O)C(C)C)cc2)cnc1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58.5 %

Procedure:
3-amino-6-(4-isopropylsulfonylphenyl)pyrazine-2-carbohydrazide (2 g, 5.963 mmol) and Et3N (1.810 g, 2.493 mL, 17.89 mmol) were dissolved in THF (128.0 mL) and treated dropwise with ethyl 2-chloro-2-oxo-acetate (814.2 mg, 666.3 μL, 5.963 mmol) at 0° C. The reaction mixture was warmed slowly to room temperature and stirred for 1.5 h. The reaction mixture was filtered and grey solid washed with THF. The filtrate was evaporated to dryness azeotroping with acetonitrile. Then residue was then triturated with acetonitrile to give the product as a yellow solid (1.52 g, 58%); 1H NMR (400 MHZ, DMSO) d 1.19 (m, 6H), 1.32 (m, 3H), 3.34 (m, 1H), 4.32 (m, 2H), 7.88 (m, 2H), 8.56 (m, 2H), 9.07 (s, 1H), 10.95 (s, 1H) and 11.05 (s, 1H) ppm; MS (ES+) 436.32
Reaction SMILES: [CH2:1]([C:3](=[CH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:17][O:18][C:12]=2[CH:11]=1)[CH2:4][CH2:5]I)[CH3:2].[Li].[CH3:20][C:21](=[O:27])[CH2:22][C:23](=[O:26])[CH2:24][CH3:25]>CN(C)C=O>[CH2:1]([C:3](=[CH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:17][O:18][C:12]=2[CH:11]=1)[CH2:4][CH2:5][CH:22]([C:23](=[O:26])[CH2:24][CH3:25])[C:21](=[O:27])[CH3:20])[CH3:2]
Reactant: CCC(=O)CC(C)=O
Reactant: CCC(=CCCc1ccc2c(c1)OCO2)CCI
Agent: [Li]
Solvent: CN(C)C=O
Product: CCC(=O)C(CCC(=CCCc1ccc2c(c1)OCO2)CC)C(C)=O

Procedure:
[I; Ar is 3,4-methylenedioxyphenyl, R0 is H, R' is CH3CO, R" is CH3CH2CO, Y is C(C2H5)=CHCH2CH2 ] was prepared from 23.2 g. of 3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl iodide (Preparation D1) and 22.3 g. of the lithium salt of 2,4-hexanedione (prepared by the procedure described in Example 8 below) in 300 ml. of dimethylformamide according to the procedure described above in Example 2. There was thus obtained 21 g. of crude product which was chromatographed on 600 g. of silica gel in pentane solution containing 20% benzene. The column was eluted with the pentane-benzene-ether solvent series. Benzene containing 3% ether brought out the desired product, 14.5 g. of 3-[3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]-2,4-hexanedione as a yellow oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][CH2:11][NH2:12])[C:4]=2[O:3][CH2:2]1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][CH2:11][NH:12][C:13](=[O:15])[CH3:14])[C:4]=2[O:3][CH2:2]1
Reactant: NCCc1cccc2c1OCO2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NCCc1cccc2c1OCO2

Procedure:
In close analogy to the procedure described above, 2-benzo[1,3]dioxol-4-yl-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: Cl.[CH2:2]([O:4][NH2:5])[CH3:3].[OH-].[Na+].[OH:8][C:9]1[CH2:14][CH:13]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[C:17]([O:23][CH3:24])[C:16]=2[CH3:25])[CH2:12][C:11](=[O:26])[C:10]=1[C:27](=O)[CH2:28][CH3:29]>C(O)C>[CH2:2]([O:4][N:5]=[C:27]([C:10]1[C:11](=[O:26])[CH2:12][CH:13]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[C:17]([O:23][CH3:24])[C:16]=2[CH3:25])[CH2:14][C:9]=1[OH:8])[CH2:28][CH3:29])[CH3:3]
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(OC)c2C)CC1=O
Reactant: CCON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCON=C(CC)C1=C(O)CC(c2c(C)cc(C)c(OC)c2C)CC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.3 %

Procedure:
Ethoxyamine hydrochloride (0.43 g) and then aqueous sodium hydroxide (0.18 g in 10.0 ml of water) were added to a solution of 3-hydroxy-5-(3-methoxy-2,4,6-trimethylphenyl)-2-propionylcyclohex-2-en-1-one (1.35 g) in anhydrous absolute ethanol (200 ml). The mixture was stirred at room temperature for a period of 4 hours and then the ethanol was removed by evaporation under reduced pressure. The residue was treated with dichloromethane and the organic phase was washed twice with dilute aqueous hydrochloric acid and twice with water. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed by evaporation under reduced pressure to give 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-(3-methoxy-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (1.40 g), as a pale yellow oil which slowly solidified on standing. Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 1.20 (3H, t); 1.32 (3H, t); 2.23 (3H, s); 2.34 (6H, s); 2.35-4.00 (7H, m); 3.65 (3H, s); 4.12 (2H, q); 6.83 (1H, s); 14.95 (1H, s).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([O:15]CC)=[O:14])[N:12]=2)=[CH:4][CH:3]=1.C[O-].[Na+].ClC1N=CC(C2([C:33](O)=[O:34])NC=CS2)=CC=1.Cl>CO>[CH3:33][O:34][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)C1(c2ccc(Cl)nc2)NC=CS1
Reactant: CCOC(=O)c1csc(-c2ccc(Cl)nc2)n1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2nc(C(=O)O)cs2)cn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of the ethyl 2-(6-chloro-3-pyridyl)thiazole-4-carboxylate (0.61 g, 2.3 mmol) and MeOH (50 mL) was added solid NaOMe (135 mg, 2.5 mmol) and stirred at RT. After 3 h the ethyl ester transesterified to the methyl ester. NaOMe (1 eq, 135 mg) was added and the mixture was heated to reflux. After 15 h, the ester hydrolyzed to the 2-(6-chloro-3-pyridyl)thiazole carboxylic acid. NaOMe (2 eq) was added and the reaction was heated at reflux for 18 h. The mixture was acidified to pH 5 with concentrated HCl, extracted with EtOAc, washed with H2O and brine; dried (MgSO4) and concentrated in vacuo to give the desired carboxylic acid as a yellow solid. MS m/z: 237.1 (M+H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][CH2:11][C:10](=[O:13])[N:9]([CH3:14])[C:8]3[CH:15]=[N:16][C:17]([NH:19][C:20]4[CH:34]=[CH:33][C:23]([C:24]([NH:26][CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[O:25])=[CH:22][C:21]=4[O:35][CH3:36])=[N:18][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:51]1[CH2:56][CH2:55][C:54](=O)[CH2:53][CH2:52]1.C(O)(=O)C>C(Cl)Cl>[CH:1]1([N:6]2[CH2:12][CH2:11][C:10](=[O:13])[N:9]([CH3:14])[C:8]3[CH:15]=[N:16][C:17]([NH:19][C:20]4[CH:34]=[CH:33][C:23]([C:24]([NH:26][CH:27]5[CH2:32][CH2:31][N:30]([CH:54]6[CH2:55][CH2:56][O:51][CH2:52][CH2:53]6)[CH2:29][CH2:28]5)=[O:25])=[CH:22][C:21]=4[O:35][CH3:36])=[N:18][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1CCOCC1
Reactant: COc1cc(C(=O)NC2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(C(=O)NC2CCN(C3CCOCC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C
Yield: 24.7 %

Procedure:
4-(9-Cyclopentyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperidin-4-yl)benzamide (Intermediate 12) (35 mg, 0.07 mmol, 1 eq) and sodium triacetoxyborohydride (18 mg, 0.084 mmol, 1.2 eq) in DCM (0.5 mL) were reacted with tetrahydropyran-4-one (6.5 μL, 0.07 mmol, 1 eq) at rt for 2 days. Further and sodium triacetoxyborohydride (18 mg, 1.2 eq), tetrahydropyran-4-one (6.5 μL, 1 eq) were added and acetic acid (4 μL, 1 eq). After two days the RM was diluted with DCM, washed with water and the organic layer concentrated in vacuo. The resulting residue was purified by preparative RP-HPLC-MS (Preparative 1) to provide 4-(9-cyclopentyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-[1-(tetrahydro-pyran-4-yl)-piperidin-4-yl]-benzamide (10 mg, 25%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9](O)[CH3:10])=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.P(Br)(Br)([Br:23])=O>BrCBr.C(OCC)(=O)C.O>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([Br:23])[CH3:10])=[CH:4][N:3]=1
Reactant: O=P(Br)(Br)Br
Reactant: CC(O)c1cnc(Cl)nc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(Br)c1cnc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of (±)-1-(2,4-dichloro-pyrimidin-5-yl)-ethanol (0.50 g; 2.60 mmol) (from Example 1a supra) and diisopropylethylamine (1.10 mL; 6.25 mmol) (Aldrich) in dibromomethane (0.35 mL) was cooled to 15° C. Phosphorus oxybromide (0.73 g; 2.83 mmol) was added in one portion. Cooling bath was removed and reaction mixture was stirred at room temperature. After 20 minutes, the reaction was diluted with ethyl acetate and water. The organic phase was washed with brine and then dried over anhydrous sodium sulfate, filtered and concentrated to give crude (±)-2,4-dichloro-5-(1-bromoethyl)-pyrimidine (0.61 g; 91.4%). Purification by flash chromatography (Biotage, 40M, 10:90 ethyl acetate-hexanes) gave pure (±)-2,4-dichloro-5-(1-bromoethyl)-pyrimidine as an oil which solidified when stored in refrigerator.
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][C:4]1[NH:5][N:6]=[C:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]=[C:8]2[NH2:17].C(=O)([O-])[O-].[K+].[K+].[Cl:25][CH2:26][CH2:27][CH2:28]I.CN(C=O)C>O>[Cl:25][CH2:26][CH2:27][CH2:28][N:5]1[C:4]([CH2:3][CH:2]([CH3:18])[CH3:1])=[C:16]2[C:7]([C:8]([NH2:17])=[N:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=32)=[N:6]1
Reactant: ClCCCI
Reactant: CC(C)Cc1[nH]nc2c(N)nc3ccccc3c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cc1c2c(nn1CCCCl)c(N)nc1ccccc12
Temperature: 40 °C

Procedure:
1-(2-Methylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (2.4 g, 9.99 mmol, prepared as described in Example 9), potassium carbonate (5.5 g, 39.9 mmol), 3-chloroiodopropane (1.2 mL, 11.0 mmol), and DMF (110 mL) were combined and heated at 40° C. overnight. The reaction mixture was diluted with water and then extracted with ethyl acetate. The combined extracts were washed with water and concentrated under reduced pressure. The residue was purified twice by chromatography on a HORIZON HPFC system (silica gel eluting with ethyl acetate) to provide 2-(3-chloropropyl)-1-(2-methylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH3:16][S:17][CH2:18][C:19](OCC)=[O:20].C(OCl)(C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[C:4]([C:3]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:2]=1[NH:1][C:19](=[O:20])[CH:18]2[S:17][CH3:16])(=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)CSC
Reactant: Nc1ccccc1C(=O)c1ccccc1
Agent: CC(C)(C)OCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSC1C(=O)Nc2c(C(=O)c3ccccc3)cccc21
Temperature: -65 °C
Reaction time: 2 h

Procedure:
A solution of 300 g. (1.52 mole) of 2-aminobenzophenone in 4 liters of methylene chloride was chilled to -40° C. and then treated with 204 g. (1.52 mole) of the ethyl α-(methylthio)acetate dissolved in 5 liters of methylene chloride. The reaction mixture was then cooled to -65° C. and treated dropwise with 500 ml. of a methylene chloride solution containing 164 g. (1.52 mole) of t-butylhypochlorite. After addition was complete, stirring was continued for 2 hr. at -70° C. treated with 182 g. (1.8 mole) of triethylamine and allowed to come to room temperature overnight. The methylene chloride solution was washed twice with 3 liters of ice water followed by drying over sodium sulfate and concentrating the dried solution to a yellow oil under reduced pressure. The oil was taken into 1.5 liters of methanol treated with 1 liter of 1N hydrochloric acid and refluxed for 2 hrs. After cooling in an ice bath 343 g. (79.9%) of crude produce was recovered after filtering and drying. Two recrystallizations from toluene gave creamy white flakes; m.p. 130° C.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]([OH:24])=O)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[NH2:26][C:27]([CH3:31])([CH3:30])[CH2:28][OH:29]>C1COCC1>[OH:29][CH2:28][C:27]([NH:26][C:22]([C:20]1[CH:19]=[CH:18][C:17]2[C:11]3[N:12]([CH:25]=[C:9]([C:8]4[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=4)[N:10]=3)[CH2:13][CH2:14][O:15][C:16]=2[CH:21]=1)=[O:24])([CH3:31])[CH3:30]
Reactant: CC(C)(N)CO
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C(=O)O)cc1OCC2
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C(=O)NC(C)(C)CO)cc1OCC2

Procedure:
Following the same procedure as for 133, 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylic acid (20 mg, 0.06 mmol) was reacted with 2-amino-2-methyl-1-propanol (11 mg, 0.12 mmol) in THF to provide N-(1-hydroxy-2-methylpropan-2-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxamide 163. LC/MS (ESI+): m/z 411 (M+H). 1H NMR (400 MHz, DMSO) δ 8.45 (d, J=8.4, 1H), 7.95 (d, J=22.3, 2H), 7.64-7.45 (m, 3H), 5.86 (dt, J=13.1, 6.5, 1H), 4.88 (t, J=6.0, 1H), 4.63-4.44 (m, 4H), 3.58-3.45 (m, 3H), 1.49 (d, J=6.6, 6H), 1.32 (s, 6H)
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([O:19][C:20]1[C:21]([NH2:34])=[N:22][CH:23]=[C:24]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[C:1]([NH:9][C:10]([NH:34][C:21]1[C:20]([O:19][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:25][C:24]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])=[CH:23][N:22]=1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncc(Oc2ccccc2Cl)cc1OCc1ccccc1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: O=C(NC(=S)Nc1ncc(Oc2ccccc2Cl)cc1OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
Benzoyl isothiocyanate (0.330 g, 2.02 mmol) was added to a solution of 3-(benzyloxy)-5-(2-chlorophenoxy)pyridin-2-amine (0.660 g, 2.02 mmol) in THF (4 mL). The reaction mixture was stirred for 2 hours at room temperature, diluted with hexanes, filtered, and washed with hexanes to afford 1-benzoyl-3-(3-(benzyloxy)-5-(2-chlorophenoxy)pyridin-2-yl)thiourea (0.92 g, 93.0% yield) as a light yellow powder. 1H NMR (CDCl3) δ 5.16 (s, 2H), 6.95 (s, 1H), 7.00-8.04 (m, 17H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:61][CH:62]=[CH:63][C:64]1[CH:69]=[CH:68][C:67]([Cl:70])=[CH:66][CH:65]=1.FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:61][CH:62]=[CH:63][C:64]3[CH:69]=[CH:68][C:67]([Cl:70])=[CH:66][CH:65]=3)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: N=C(OCC=Cc1ccc(Cl)cc1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC=Cc4ccc(Cl)cc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (200 mg in 6 ml 33% methylene chloride in cyclohexane), p-chlorocinnamyl trichloroacetimidate (119 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (7 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 30 minutes the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×20 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (34 mg).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[Cl:13][CH2:14][CH2:15][CH2:16][CH:17](P(OCC)(OCC)=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH-].[Li+].O>O1CCCC1.C(O)C>[Cl:13][CH2:14][CH2:15][CH2:16][C:17](=[CH:5][C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[C:2]([F:12])([F:11])[F:1])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C(CCCCl)P(=O)(OCC)OCC
Reactant: O=Cc1ccccc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(=Cc1ccccc1C(F)(F)F)CCCCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(Trifluoromethyl)benzaldehyde (1 g) and ethyl 5-chloro-2-(diethoxyphosphoryl)pentanoate (CAS No. 870843-20-2, 2.1 g) were dissolved in a mixed solvent of tetrahydrofuran (30 mL) and ethanol (10 mL). Lithium hydroxide (412 mg) was added and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration, and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a geometric isomer mixture of the title compound (1.4 g).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([O:19][CH3:20])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17]Br)=[CH:9][CH:8]=1)C.[C:22]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:24])[CH3:23]>>[CH3:20][O:19][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][O:37][C:34]2[CH:33]=[CH:32][C:31]([C:22]([CH3:24])([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH3:23])=[CH:36][CH:35]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:21]
Reactant: CCOC(=O)C(Cc1ccc(C#CCCCBr)cc1)OC
Reactant: CC(C)(c1ccccc1)c1ccc(O)cc1
Product: CO[C@@H](Cc1ccc(C#CCCCOc2ccc(C(C)(C)c3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from 3-[4-(5-Bromo-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 24, Step A and 4-cumylphenol in a manner analogous to that described for Example 24, Step B. MS(ES) for C30H32O4 [M+NH4]+: 474.3
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:12][CH:13]=2)[C:8]([S:29]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[N:7]1.[NH:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][N:45]3[CH2:49][CH2:48][CH2:47][CH2:46]3)=[CH:12][CH:13]=2)[C:8]([S:29]([C:32]2[C:41]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:35]=[CH:34][CH:33]=2)(=[O:30])=[O:31])=[N:7]1
Reactant: C1CCNC1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3Cc2cccc(Cl)c2)cc1
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)c1nn(Cc2cccc(Cl)c2)c2ccc(OCCN3CCCC3)cc12
Temperature: 25 °C
Yield: 87.8 %

Procedure:
A solution of toluene-4-sulfonic acid 2-[1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.359 g, 0.555 mmol) and pyrrolidine (1.0 mL, 12 mmol) in THF (8 mL) was stirred at 70° C. in a sealed tube for 2 hours. After cooling to ambient temperature, the reaction mixture was solvent evaporated. It was then partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered, concentrated and dried in vacuo at 80° C. for 20 minutes to give 1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-5-(2-pyrrolidin-1-yl-ethoxy)-1H-indazole as a yellow semi-solid (0.266 g, 87.8%). This was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried at 82° C. in vacuo for 14 hours to yield the hydrochloride as a light orange foam (0.205 g); Mass Spectrum (+EI, [M+H]+) m/z 546. 1HNMR (500 MHz, DMSO-d6): δ10.18-10.19 (s, 1H), 8.73-8.75 (m, 1H), 8.55-8.57 (m, 1H), 8.27 (d, 1H, J=8.30 Hz), 8.02-8.04 (m, 1H), 7.82 (d, 1H, J=9.15 Hz), 7.70-7.74 (m, 1H), 7.57-7.64 (m, 2H), 7.15-7.29 (m, 5H), 7.04 (d, 1H, J=7.69 Hz), 5.73 (s, 2H), 4.33-4.35 (m, 2H), 3.55 (br, s, 4H), 3.07-3.15 (s, br, 2H), 1.81-2.02 ppm (br, m, 4H). Elemental Analysis for C30H28ClN3O3S.1.00 HCl.0.70 mole H2O: Calcd: C, 60.54; H, 5.15; N, 7.06; Found: C, 60.16; H, 5.11; N, 6.74.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][CH3:10])=[C:6]([CH:8]=1)N.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:20].[K+]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][CH3:10])=[C:6]([I:20])[CH:8]=1
Reactant: CCc1ccc(Br)cc1N
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: CCc1ccc(Br)cc1I
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 5-bromo-2-ethylaniline (3.39 g, 200 mmol) in distilled water (110 ml) is added concentrated sulfuric acid (5.60 ml), followed by brief heating at reflux until dissolution. The mixture is allowed to cool to room temperature, producing a fine precipitate, then further cooled to approximately 0° C. in an ice/salt bath. To this slurry is added an aqueous solution of sodium nitrite (1.17 g, 16.94 mmol) in distilled water (10 ml) dropwise over 15 minutes, maintaining a temperature below 5° C., followed by additional stirring for 30 minutes. The reaction mixture is next filtered then added to a second solution of aqueous potassium iodide (8.44 g, 50.83 mmol) in distilled water (45 ml) dropwise at room temperature. After the addition is complete the solution is briefly heated to 80° C. then allowed to cool to room temperature again. The reaction mixture is extracted with ethyl acetate (3×50 ml), and the organic phase is washed with 1M aqueous hydrochloric acid (30 ml) and aqueous sodium thiosulfate (2×30 ml). After drying over anhydrous magnesium sulfate and concentration in vacuo 4-bromo-1-ethyl-2-iodobenzene (4.90 g) is furnished as an orange liquid.