Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6]C=C[CH:3]=1.C(Cl)(=[O:27])C1C=CC=CC=1>>[O:27]1[CH:6]=[CH:7][C:2]([C:1]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:8])=[CH:3]1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)CCCCCCC(=O)c1ccccc1
Product: CCOC(=O)CCCCCCC(=O)c1ccoc1
Yield: 24 %

Procedure:
Following a procedure analogous to that described above for 49a, but substituting 3-furanoyl chloride for benzoyl chloride, the title compound was obtained as a yellow oil in 24% yield: 1H NMR (300 MHz, CDCl3) δ 8.03 (m, 1H), 7.44 (m, 1H), 6.76 (m, 1H), 4.12 (q, J=6.9 Hz, 2H), 2.74 (t, J=7.5 Hz, 2H), 2.29 (t, J=7.5 Hz, 2H), 1.71 (m, 2H), 1.63 (m, 2H), 1.37 (m, 4H), 1.25 (t, J=6.9 Hz, 3H); 13C NMR (75.4 MHz, CDCl3) δ 14.18, 24.04, 24.69, 28.82(2), 34.18, 40.23, 60.13, 108.56, 127.69, 144.09, 146.98, 173.68, 195.10.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[Cl:11]N1C(=O)CCC1=O>C(Cl)Cl.O.C([O-])([O-])=O.[K+].[K+]>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[Cl:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Nc1ccc2[nH]nc(Cl)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-aminoindazole (1.373 g, 10.00 mmol) and N-chlorosuccinimide (1.381 g, 10.14 mmol) in methylene chloride (50 mL) was sonicated at rt for 30 min. The brown mixture was then stirred overnight at rt. The suspension was diluted with CH2Cl2 to ≈100 mL, water and aq. K2CO3 solution were added, and the insoluble brown material was filtered off and washed with CH2Cl2 and water. The layers of the filtrate were separated; the organic layer was washed with water (3×) and brine and dried over MgSO4. The dried solution was filtered through a pad of silica gel, washing with 5% MeOH in CH2Cl2 until no more product eluted as indicated by TLC. Concentrating and drying in vacuo gave the title compound as yellow solid. MS (ES+): m/z 168.2/170.2 (100/37) [MH+]. HPLC: tR=2.1 min (ZQ2000, polar—5 min). 1H NMR (CDCl3, 400 MHz): δ=5.06 (s, 2H), 6.96 (d, J=8.5 Hz, 1H), 7.27 (d, J=8.5 Hz, 1H), 7.78 (s, 1H), 12.95 (brs, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([O:33][CH2:34][CH:35]([OH:38])[CH2:36][OH:37])[C:23]=2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[C:18](O)=[O:19])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:39][C:40]1[NH:44][N:43]=[N:42][N:41]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([O:33][CH2:34][CH:35]([OH:38])[CH2:36][OH:37])[C:23]=2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[C:18]([NH:39][C:40]2[NH:44][N:43]=[N:42][N:41]=2)=[O:19])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc(C(=O)O)cc2OCC(O)CO)c1
Reactant: Nc1nnn[nH]1
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc(C(=O)Nc3nnn[nH]3)cc2OCC(O)CO)c1

Procedure:
In analogy to Example 121, by coupling 3-(4-tert-butyl-benzenesulphonylamino)-5-(2,3-dihydroxy-propoxy)-4-(3-methoxy-phenoxy)-benzoic acid with 5-aminotetrazole there was obtained 3-(4-tert-butybenzenesulphonylamino)-5-(2,3-dihydroxy-propoxy)-4-(3-methoxy-phenoxy)-N-(1H-tetrazol-5-yl)-benzamide as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([NH2:7])[O:4][N:3]=1.[CH:8]1[C:21]2[CH:20]([C:22](Cl)=[O:23])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[O:13][C:12]=2[CH:11]=[CH:10][CH:9]=1>>[CH3:1][C:2]1[N:6]=[C:5]([NH:7][C:22]([CH:20]2[C:21]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[O:13][C:14]3[C:19]2=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:23])[O:4][N:3]=1
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Reactant: Cc1noc(N)n1
Product: Cc1noc(NC(=O)C2c3ccccc3Oc3ccccc32)n1

Procedure:
The title compound, white solid, m.p. 208° C. and MS: m/e=307 (M+) was prepared in accordance with the general method of example 44a from 3-methyl-[1,2,4]oxadiazol-5-ylamine and 9H-xanthene-carboxylic acid chloride.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][O:22][CH3:23])[CH:17]=[CH:16][C:15]=1[CH:24]([CH2:39][CH:40]=[CH2:41])[C:25]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][O:37][CH3:38])=[CH:31][CH:30]=1)([CH3:28])[CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCOCC1>[CH3:23][O:22][CH2:21][O:20][C:18]1[CH:19]=[C:14]2[C:15]([CH:24]([CH2:39][CH:40]=[CH2:41])[C:25]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH2:36][O:37][CH3:38])=[CH:33][CH:34]=3)([CH3:26])[CH2:28][O:13]2)=[CH:16][CH:17]=1
Reactant: C=CCC(c1ccc(OCOC)cc1O)C(C)(CO)c1ccc(OCOC)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: C=CCC1c2ccc(OCOC)cc2OCC1(C)c1ccc(OCOC)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.6 %

Procedure:
Diethyl azodicarboxylate (5.94 ml) was added dropwise to an ice-cold solution of (2RS,3RS)-3-(2-hydroxy-4-methoxymethoxyphenyl)-2-(4-methoxymethoxyphenyl)-2-methyl-5-hexen-1-ol (6.9 g) and triphenylphosphine (11.24 g) in anhydrous 1,4-dioxane (120 ml) over 25 minutes under nitrogen atmosphere. The reaction mixture was stirred for 20 minutes at room temperature. Water was added to the reaction mixture, which was then extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated to give a crude product, which was then purified by flash column chromatography (silica gel: Merck Kieselgel 60, eluent: hexane/ethyl acetate=100/1→20/1→9/1) to give (3RS,4RS)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methyl-4-(2-propenyl)chroman (6.5 g, Yield 98.6%) as a colorless oil.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)(=[O:16])=[O:15])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][S:14]([CH2:13][C@@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)(=[O:15])=[O:16])=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CS(=O)(=O)Cc2ccc(F)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Cc1ccc(F)cc1)C[C@@H]1CCNC1

Procedure:
Using a similar method to that described in Example 93, step 2, (3R)-1-(tert-butoxycarbonyl)-3-[(4-fluorobenzylsulphonyl)-methyl]pyrrolidine (0.6465 g, 1.81 mmol) was reacted with trifluoroacetic acid (2ml) in dichloromethane (6 ml) to give, after work up, 0.4755 g of the title compound as a white solid, which was used without further purification. δH (360 MHz, CDCl3) 1.55 (1H, m), 2.15 (1H, m), 2.60-2.73 (2H, m), 2.90-3.00 (4H, m), 3.30 (1H, m), 4.21 (2H, s), 7.11 (2H, t, J=8.6 Hz), 7.37-7.41 (2H, m).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[CH2:49][S:50](Cl)(=[O:52])=[O:51]>C(#N)C>[Cl:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[CH2:49][S:50]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:52])=[O:51]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)Cc1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)Cc3ccccc3Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 37.7 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0313 g, 0.0678 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0570 mL, 0.407 mmol) and (2-chlorophenyl)methanesulfonyl chloride (0.0460 g, 0.203 mmol) to obtain 4-[(2-chlorophenyl)methanesulfonyloxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0166 g, yield 29%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[C:10]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)(=[O:12])[CH3:11]>C1(C)C(C)=CC=CC=1>[C:10]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:16]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)OCc1cccc(Br)c1
Reactant: Oc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CC(=O)OCc1cccc(Oc2ccccc2)c1
Yield: 77 %

Procedure:
10.35 g. (0.11 mole) of phenol, 6.15 g. (0.11 mole) of potassium hydroxide and 35 cm3. of xylene are weighed together. The water is azeotropically distilled with stirring and boiling. 5 cm3. of pyridine and 0.5 g. of copper(I) chloride are added then 22.91 g. (0.1 mole) of 3-bromobenzyl acetate are dropped into the reaction mixture during 15 minutes with stirring and boiling. The reaction mixture is boiled with stirring for an additional three hours. After cooling the reaction mixture is filtered off and the filtrate washed with a mixture of 25 cm3. of 15% sodium chloride solution and 2 cm3. of 40% sodium hydroxide solution. The organic phase is evaporated in vacuo. The residue is distilled in vacuo and so 18.65 g. of 3-phenoxybenzyl acetate are obtained. Boiling point 142°-145° C./53.2 Pa, nD20 : 1.5621, yield 77%.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:16])[NH:7][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH3:17][CH:18]([CH3:23])[CH2:19][C:20](Cl)=[O:21]>>[CH:11]1([C:8]2[NH:7][C:6](=[O:16])[C:5]([CH:2]([NH:1][C:20](=[O:21])[CH2:19][CH:18]([CH3:23])[CH3:17])[CH2:3][CH3:4])=[N:10][N:9]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCC(N)c1nnc(C2CCCC2)[nH]c1=O
Reactant: CC(C)CC(=O)Cl
Product: CCC(NC(=O)CC(C)C)c1nnc(C2CCCC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 150 mg (0.67 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 90 mg (0.74 mmol) 3-methylbutanoyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:3]2[C:7]([CH:8]=[CH:9][CH:10]=1)=[N:6][N:5]1[CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]([Cl:15])=[N:14][C:4]=21.[C:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)#[N:23].C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[Cl:15][C:13]1[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][N:5]2[N:6]=[C:7]3[C:3]([C:2]([C:27]4[CH:28]=[CH:29][C:24]([C:22]#[N:23])=[CH:25][CH:26]=4)=[CH:10][CH:9]=[CH:8]3)=[C:4]2[N:14]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Clc1nc2c3c(Br)cccc3nn2cc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccc(-c2cccc3nn4cc(-c5ccccc5)c(Cl)nc4c23)cc1
Temperature: 105 °C
Yield: 26.7 %

Procedure:
400 mg (1.12 mmol) 10-Bromo-2-chloro-3-phenylpyrimido[1,2-b]indazole, intermediate example Int-1-3, 172.1 mg (1.17 mmol) 4-cyanophenylboronic acid, 91 mg (0.112 mmol) bis(diphenylphosphino)ferrocenedichloropalladium(II) and 354.6 mg (3.35 mmol) sodium carbonate in 12 mL degassed dioxane and 1.68 mL water were heated in the microwave for 45 min. at 105° C. The reaction mixture was poured on a mixture of water/saturated ammonium chloride/dichloromethane and stirred vigorously for 30′. The organic phase was separated, washed twice with brine and dried (sodium sulfate). After filtration and evaporation of the solvent the residue was purified by HPLC yielding 114 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.Cl[CH2:16][CH2:17][CH:18]([OH:27])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[O:20]([CH2:19][CH:18]([OH:27])[CH2:17][CH2:16][N:12]1[CH2:13][CH2:14][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:10][CH2:11]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OC(CCCl)COc1ccccc1
Reactant: COc1cccc(N2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: COc1cccc(N2CCN(CCC(O)COc3ccccc3)CC2)c1
Yield: 46.3 %

Procedure:
This compound was prepared according to the procedure of Example 78. A mixture of 3.8 g (0.02 mole) of 1-(3-methoxyphenyl)piperazine, 4.0 g (0.02 mole) of 4-chloro-1-phenoxy-2-butanol and 8.0 g (0.075 mole) of anhydrous sodium carbonate in 150 ml of 1-butanol gave 3.3 g (45%) of off-white powder, m.p. 58°-60° C. Recrystallizing solvent used was diethyl ether-petroleum ether.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].[H-].[Na+].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]Cl)=[CH:28][N:27]=1.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:32][C:29]2[CH:28]=[N:27][C:26]([Cl:25])=[CH:31][CH:30]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: ClCc1ccc(Cl)nc1
Reactant: COC(=O)c1[nH]c(=O)c2ccc(Br)cc2c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.6 %

Procedure:
To a solution of 6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (290 mg) in DMF (3 ml) was added sodium hydride (60% in oil, 36 mg) under ice-cooling, and the mixture was allowed to warm to room temperature and stirred for 1 hr. To the reaction mixture was added 2-chloro-5-chloromethylpyridine (160 mg) at room temperature, and the mixture was stirred for 2 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from ethyl acetate to give the title compound (120 mg).
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])[CH2:18][CH2:17]1.S(=O)(=O)(O)O.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[O:8][CH:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N+:32]([O-:34])=[O:33])[CH2:20][CH2:21]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(c1ccccc1)c1ccccn1
Reactant: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccccc1OCCCN1CCC(OC(c2ccccc2)c2ccccn2)CC1
Temperature: 120 °C
Reaction time: 4 h
Yield: 29.3 %

Procedure:
There was stirred at 120° C. for 4 hours a mixture of 6.74 g of phenyl-2-pyridylmethanol, 7.85 g of 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine, 11.0 g of concentrated sulfuric acid and 15 ml of toluene. After cooling, the reaction solution was poured into ice water, made alkaline with an aqueous sodium hydroxide, and extracted with toluene. The extract was washed with water, and toluene was removed under reduced pressure. The residue was eluted with ethyl acetate-ethanol-dichloromethane (1:1:1) by silica gel column chromatography to give 3.67 g of oily 4-(phenyl-2-pyridylmethoxy)-1-[3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)[CH2:4][CH3:5].C(=O)([O-])[O-].[Cs+].[Cs+].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CN(C=O)C>[F:22][C:23]([F:32])([F:33])[C:24]1[CH:31]=[CH:30][C:27]([CH2:28][O:1][N:2]=[C:3]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=2)[CH2:4][CH3:5])=[CH:26][CH:25]=1
Reactant: CCC(=NO)c1ccc(NC(C)=O)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCC(=NOCc1ccc(C(F)(F)F)cc1)c1ccc(NC(C)=O)cc1
Reaction time: 3 h
Yield: 94.3 %

Procedure:
To a solution of N-(4-(1-(hydroxyimino)propyl)phenyl)acetamide (6 gm, 0.0291 moles) in DMF (60 mL), cesium carbonate (18.9 gm, 0.0582 moles) and 4-(trifluoromethyl)benzyl bromide (6.96 gm, 0.0291 moles) were added and the reaction mixture was srirred at 25° C. for 3 hours. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evaporated under reduced pressure to yield 10 gm (94%) of product as solid.
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:25][CH3:26])[C:12]2[CH:13]=[C:14]([CH2:23][CH3:24])[C:15]3[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=3[CH:22]=2)=[CH:7][CH:6]=1)C.[OH-].[Na+]>C(O)C>[CH2:25]([N:11]([C:12]1[CH:13]=[C:14]([CH2:23][CH3:24])[C:15]2[O:19][CH2:18][C:17]([CH3:20])([CH3:21])[C:16]=2[CH:22]=1)[C:8]1[CH:7]=[CH:6][C:5]([C:4]([OH:27])=[O:3])=[CH:10][CH:9]=1)[CH3:26]
Reactant: CCOC(=O)c1ccc(N(CC)c2cc(CC)c3c(c2)C(C)(C)CO3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc(N(CC)c2ccc(C(=O)O)cc2)cc2c1OCC2(C)C
Yield: 58.1 %

Procedure:
Following general procedure I and using 4-[ethyl-(3,3-dimethyl-7-ethyl-2,3-dihydro-benzofuran-5-yl)-amino]-benzoic acid ethyl ester (Compound 22, 0.134 g, 0.36 mmol) and 2 mL of 5M sodium hydroxide solution in 2 mL of ethanol, the title compound (0.071 g, 58%) was obtained as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.88 (d, 2H, J=9.0 Hz), 6.80 (d, 1H, J=2.0 Hz), 6.76 (d, 1H, J=2.0 Hz), 6.58 (d, 2H, J=9.0 Hz), 4.29 (s, 2H), 3.73 (q, 2H, J=7.1 Hz), 2.60 (q, 2H J=7.5 Hz), 1.34 (s, 6H), 1.27-1.12 (m, 6H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][SH:12])=[CH:9][C:4]=2[O:3][CH2:2]1.Cl[CH2:14][C:15](=[O:17])[CH3:16].[OH-].[Na+]>C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][S:12][CH2:14][C:15](=[O:17])[CH3:16])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: SCCc1ccc2c(c1)OCO2
Reactant: CC(=O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)CSCCc1ccc2c(c1)OCO2
Yield: 84.9 %

Procedure:
10 g of 2-(1,3-benzodioxol-5-yl)ethanethiol and 5.1 g of 1-chloro-2-propanone were dissolved in 200 ml of 90% ethanol. 2.2 g of sodium hydroxide was added to the solution and the mixture was heated under reflux for 10 min to conduct the reaction. The reaction mixture was concentrated under reduced pressure. 200 ml of ethyl acetate was added thereto to obtain a solution, which was washed with water three times. After drying over anhydrous sodium sulfate, the solvent was distilled off and the residue was purified according to silica gel column chromatography (benzene/ethyl acetate=30:1) to obtain 11.1 g of the intended compound in the form of a colorless oil.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([C:7]1[N:11]=[CH:10][NH:9][N:8]=1)=[O:6])[CH3:3].C(O[C@@H:16]1[CH2:48][C@:20]23[C:24]4[C@H:33]([CH2:34][CH2:35][C@H:19]2[C@@:18]([CH3:49])([CH2:23][O:22][CH2:21]3)[C@H:17]1[O:50][CH2:51][C@:52]([CH3:58])([NH:56][CH3:57])[CH:53]([CH3:55])[CH3:54])[C@:32]1([CH3:36])[C@:27]([CH3:46])([C@H:28]([C:43]([OH:45])=[O:44])[C@:29]([C@H:38]([CH3:42])[CH:39]([CH3:41])[CH3:40])([CH3:37])[CH2:30][CH2:31]1)[C:26](=[O:47])[CH:25]=4)(=O)C>ClCCCl>[CH3:58][C@@:52]([NH:56][CH3:57])([CH:53]([CH3:55])[CH3:54])[CH2:51][O:50][C@@H:17]1[C@@:18]2([CH3:49])[C@@H:19]3[CH2:35][CH2:34][C@H:33]4[C:24]([C@@:20]3([CH2:21][O:22][CH2:23]2)[CH2:48][C@H:16]1[N:8]1[C:7]([C:5]([NH:4][CH:2]([CH3:1])[CH3:3])=[O:6])=[N:11][CH:10]=[N:9]1)=[CH:25][C:26](=[O:47])[C@:27]1([CH3:46])[C@:32]4([CH3:36])[CH2:31][CH2:30][C@@:29]([C@H:38]([CH3:42])[CH:39]([CH3:40])[CH3:41])([CH3:37])[C@H:28]1[C:43]([OH:45])=[O:44]
Reactant: CN[C@@](C)(CO[C@H]1[C@H](OC(C)=O)C[C@@]23COC[C@]1(C)[C@@H]2CC[C@H]1C3=CC(=O)[C@@]2(C)[C@H](C(=O)O)[C@@](C)([C@H](C)C(C)C)CC[C@]12C)C(C)C
Reactant: CC(C)NC(=O)c1nc[nH]n1
Solvent: ClCCCl
Product: CN[C@@](C)(CO[C@H]1[C@H](n2ncnc2C(=O)NC(C)C)C[C@@]23COC[C@]1(C)[C@@H]2CC[C@H]1C3=CC(=O)[C@@]2(C)[C@H](C(=O)O)[C@@](C)([C@H](C)C(C)C)CC[C@]12C)C(C)C
Temperature: 50 °C
Reaction time: 50 h

Procedure:
N-(1-methylethyl)-1H-1,2,4-triazole-3-carboxamide (82.3 mg, 0.534 mmol) and BF3OEt2 (200 μl, 1.578 mmol) were added to a stirred solution of (1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-14-(acetyloxy)-15-[[(2R)-2,3-dimethyl-2-(methylamino)butyl]oxy]-8-[(1R)-1,2-dimethylpropyl]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-6-oxo-4H-1,4a-propano-2H-phenanthro[1,2-c]pyran-7-carboxylic acid (free base form of Example 152 in WO2007127012, herein incorporated by reference in its entirety, 70.2 mg, 0.107 mmol) in 1,2-dichloroethane (1.5 ml). The reaction mixture was a light amber solution that was heated to 50° C. After 50 hours, the reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, and the resulting residue was placed under high vacuum. The residue was dissolved in methanol and purified using two HPLC runs (˜35 mg/run) on a 19×150 mm Sunfire Prep C18 OBD 10 μm column by eluting with acetonitrile/water+0.1% TFA. The total flow rate was 15 ml/min and the HPLC method employed a 12 minute 20%-100% acetonitrile/water gradient followed by a 7 minute acetonitrile flush. The product HPLC fractions were combined, the solvent was evaporated under reduced pressure, and the residue was lyophilized from ethanol and benzene to give the title compound (24.2 mg, 0.028 mmol) as a white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([O:18]CC=C)=[CH:17][C:12]=3[O:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:23]1[CH:28]=CC=C[C:24]=1Cl>>[C:1]1([CH2:7][CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([OH:18])=[C:17]([CH2:28][CH:23]=[CH2:24])[C:12]=3[O:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ccccc1Cl
Reactant: C=CCOc1ccc2c(CCc3ccccc3)coc2c1
Product: C=CCc1c(O)ccc2c(CCc3ccccc3)coc12
Temperature: 50 °C

Procedure:
The product from Step D (1.245 grams), dissolved in 1,2-dichlorobenzene (20 mL) was refluxed under nitrogen for 11 hours. The solution was cooled to approx. 50° C. High vacuum was applied and the solvent removed until the residue solidified. The solid was dissolved in CH2Cl2 (100 mL), recovered, re-evaporated and chromatographed over silica gel (5:1 hex/ethyl acetate). Evaporation of the appropriate fractions gave the title compound as a pale yellow solid.
Reaction SMILES: Cl[C:2]([C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]=1[S:13]([Cl:16])(=[O:15])=[O:14])=[O:3].[CH3:17][OH:18]>C(Cl)(Cl)Cl>[CH3:17][O:18][C:2]([C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]=1[S:13]([Cl:16])(=[O:14])=[O:15])=[O:3]
Reactant: O=C(Cl)c1sc2ccccc2c1S(=O)(=O)Cl
Reactant: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1sc2ccccc2c1S(=O)(=O)Cl
Yield: 53.5 %

Procedure:
168.0 gm (0.569 mol) of 2-chlorocarbonyl-benzo[b]thiophene-3-sulfonic acid chloride were dissolved in 1 liter of anhydrous chloroform, and the solution was admixed with 27.5 gm (0.858 mol) of dry methanol and refluxed for 3 hours. The reaction mixture was evaporated in vacuo, and the residue was recrystallized twice from a little methanol, yielding 88.5 gm (53.5% of theory) of colorless 2-methoxycarbonyl-benzo[b]-thiophene-3-sulfonic acid chloride. M.p.: 100°-101° C.