Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:16]3[N:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][C:17]=3B3OC(C)(C)C(C)(C)O3)[CH:12]=[CH:13][C:14]=2[Cl:15])=[CH:5][CH:4]=1.Br[C:38]1[C:43]([Cl:44])=[CH:42][C:41]([CH3:45])=[CH:40][N:39]=1>>[Cl:44][C:43]1[C:38]([C:17]2[C:16]([C:11]3[CH:12]=[CH:13][C:14]([Cl:15])=[C:9]([O:8][CH2:7][C:6]4[CH:35]=[CH:36][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH:10]=3)=[N:21][C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:18]=2)=[N:39][CH:40]=[C:41]([CH3:45])[CH:42]=1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc(Cl)c(OCc3ccc(OC)cc3)c2)n1
Reactant: Cc1cnc(Br)c(Cl)c1
Product: COC(=O)c1ccc(-c2ncc(C)cc2Cl)c(-c2ccc(Cl)c(OCc3ccc(OC)cc3)c2)n1
Yield: 63.8 %

Procedure:
The Suzuki-Myaura coupling performed between 1 g (1.96 mmol) of methyl 6-[3-[(4-methoxybenzyl)oxy]-4-chlorophenyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate and 526 mg (2.55 mmol) of 2-bromo-3-chloro-5-methylpyridine according to Example 1.6 gives 637 mg of methyl 3-chloro-2′-{4-chloro-3-[(4-methoxybenzyl)oxy]phenyl}-5-methyl-2,3′-bipyridine-6′-carboxylate in the form of an oil.
Reaction SMILES: C(O[CH2:4][CH3:5])C.O1[CH2:10][CH2:9]CC1.C(Cl)[Cl:12].[CH3:14][N:15]([CH3:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(N(CC)CC)C>[ClH:12].[CH2:16]([N:15]([CH2:4][CH3:5])[CH2:9][CH3:10])[CH3:17].[ClH:12].[CH3:14][N:15]([CH3:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCCl
Reactant: CCOCC
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)c1ccccc1
Product: Cl

Procedure:
The aminations of Equations 43a and 43e are most conveniently effected by adding the requisite sulfonyl chlorides to a solution of the aminopyrazoles LIIa and LIIa' in a suitable solvent such as diethyl ether, tetrahydrofuran, or methylene chloride containing at least two equivalents of an acid scavenger such as triethylamine or dimethylaniline at temperatures between 0° C. and 65° C. The desired sulfonamides of Formulas LIIb and LIIb' are isolated either by filtration, in which case the by-product triethylamine hydrochloride or dimethylaniline hydrochloride is removed by washing with water, or extraction into a suitable organic solvent such as methylene chloride or ethyl acetate. Drying and evaporation of the solvent then affords the products LIIb and LIIb', which are usually sufficiently pure to be carried directly onto the next step.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([O:7][C:8]([NH:10][C@H:11]([C:15]([OH:17])=[O:16])[CH2:12][CH2:13][OH:14])=[O:9])([CH3:6])[CH3:5].[CH2:18](Br)[CH:19]=[CH2:20]>CN(C=O)C>[CH2:20]([O:14][CH2:13][CH2:12][C@H:11]([NH:10][C:8]([O:7][C:4]([CH3:3])([CH3:5])[CH3:6])=[O:9])[C:15]([OH:17])=[O:16])[CH:19]=[CH2:18]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
To a mixture of sodium hydride (913 mg, 22.8 mmoL) in DMF at 0° C. was added N-t-Boc-L-homoserine (2 g, 9.13 mmoL). This reaction mixture was stirred at 0° C. for 15 min, and then allyl bromide (1.38 g, 11.4 mmoL) was added. The mixture was warmed up to rt, and stirred for 2 h. It was then concentrated in vacuo. The residue was diluted with water, and sequentially washed with hexane and ether. The organic layers were discarded, and the aqueous layer was carefully adjusted to pH 3 with 1 N HCl. This acidic aqueous solution was extracted with ethyl acetate. The organic phase was dried (MgSO4), and concentrated in vacuo to yield 2.2 g (93%) of (S)-4-allyloxy-2-(tert-butoxycarbonylamino)butyric acid as a colorless oil. 1H NMR (300 MHz, CD3OD) δ 1.42 (s, 9H), 1.80–1.90 (m, 1H), 2.04–2.16 (m, 1H), 3.50–3.54 (m, 2H), 3.97 (d, J=0.39 Hz, 2H), 4.23 (dd, J=8.78, 4.39 Hz, 1H), 5.15 (d, J=10.25 Hz, 1H), 5.26 (dd, J=17.38, 1.65 Hz, 1H), 5.84–5.97 (m, 1H). This starting material was employed in the synthesis of (1R,2S)-ethyl 1-((3R,5S)-1-((S)-4-(allyloxy)-2-(tert-butoxycarbonyl)butanoyl)-3-(6-methoxyisoquinolin-1-yloxy)pyrrolidine-5-carboxamido)-2-vinylcyclopropane-carboxylate as described in example 2.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][CH:13]=[C:9]3[N:8]=[C:7]([CH2:14][C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[CH:6]=2)[CH2:3][CH2:2]1.O=P(Cl)(Cl)Cl.CN([CH:31]=[O:32])C>>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:31]=[O:32])=[C:9]3[N:8]=[C:7]([CH2:14][C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[CH:6]=2)[CH2:3][CH2:2]1
Reactant: CN(C)C=O
Reactant: N#Cc1cccc(Cc2cc(NC3CC3)n3nccc3n2)c1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cccc(Cc2cc(NC3CC3)n3ncc(C=O)c3n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To 3-((7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)benzonitrile (69 mg, 0.24 mmol) in DMF (0.6 mL), POCl3 (130 μL, 1.4 mmol) was added at room temperature. After the addition was complete, the reaction was stirred for 1 hour at room temperature. Then, the reaction was quenched by addition to ice cold 6N NaOH. The mixture was diluted with water and the solid was collected by filtration. The solid was washed several more times with water then dried under vacuum overnight. The product, 3-((7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)methyl)benzonitrile, was collected as a solid in 37% yield. LCMS (M+1=318)
Reaction SMILES: [OH:1][C@@H:2]([CH2:30][C@@H:31]([NH:39][C:40](=[O:51])[C@@H:41]([NH:46][C:47]([O:49][CH3:50])=[O:48])[C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@@H:3]([NH:19]C(=O)OCC1C=CC=CC=1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[N:12]=2)=[CH:7][CH:6]=1.Cl>CO.[Pd]>[NH2:19][C@@H:3]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[N:12]=2)=[CH:9][CH:10]=1)[C@@H:2]([OH:1])[CH2:30][C@@H:31]([NH:39][C:40]([C@@H:41]([NH:46][C:47](=[O:48])[O:49][CH3:50])[C:42]([CH3:44])([CH3:45])[CH3:43])=[O:51])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccc(-c2cccc(OC)n2)cc1)NC(=O)OCc1ccccc1)C(C)(C)C
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccc(-c2cccc(OC)n2)cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution containing the product from Example 120A (0.028 g, 0.041 mmol) in methanol (1 mL) was treated with 10% Pd on carbon (0.003 g) and HCl solution (0.030 mL, 4 N in dioxane), and the reaction was stirred under a hydrogen atmosphere (balloon pressure) at 25° C. for 16 hours. The reaction was filtered through a bed of celite and rinsed with methanol. The solvent was concentrated to give the title compound as the hydrochloride salt, which was used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:7]=2[C:6]1=[O:18].[F:20][C:21]1[CH:22]=[C:23]([C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH2:29][C:30](=[O:36])[NH:31]3)[CH:24]=[CH:25][CH:26]=1>>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:12][C:13](/[CH:16]=[C:29]3\[C:30](=[O:36])[NH:31][C:32]4[C:28]\3=[C:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([F:20])[CH:22]=3)[CH:35]=[CH:34][CH:33]=4)=[C:14]([CH3:15])[C:7]=2[C:6]1=[O:18]
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Product: Cc1c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Yield: 38.9 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 23 with 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 23c obtained from step 3 of Example 23 and 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-5-(2-dimethylamino-ethyl)-2-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 41 (37 mg, yield 38.9%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[Sn](Cl)(Cl)(Cl)Cl.[CH3:20][O:21]C(Cl)Cl>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:12]([C:11]3[CH:10]=[CH:9][C:8]([CH:20]=[O:21])=[CH:7][C:6]=3[CH2:5]2)=[CH:13][CH:14]=1
Reactant: Brc1ccc2c(c1)Cc1ccccc1-2
Reactant: COC(Cl)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1ccc2c(c1)Cc1cc(Br)ccc1-2
Temperature: -2 °C
Reaction time: 0.33 h

Procedure:
To a mechanically stirred solution of commercially available 2-bromofluorene (79.1 g 90% pure, 71.19 g at 100% purity, 0.29 mol) in 350 mL dichloromethane, in a 1-liter 3-neck round-bottomed flask, cooled in a ice-salt bath, tin(IV)chloride (60 mL, 133.56 g, 0.513 mol) was added. Maintaining the temperature at −2° C., over a period of 20 minutes, dichloromethyl methyl ether (33 mL, 41.94 g, 0.365 mol) was added dropwise, stirred near 0 to −1° C. for 1.5 hours, and then allowed to warm to room temperature over a period of 3 hours. The mixture was poured into crushed ice, and methylene chloride was allowed to evaporate. The product slurry was then filtered and washed with water. The dry crude product (mixture of two aldehydes) weighed 87.9 g, m.p. 138-144° C. This was stirred with 750 mL of 10% toluene-heptane at reflux for 2 hours, cooled and filtered at room temperature, 73.5 g, m.p. 161-170° C. This was dissolved in 400 mL hot toluene (hazy solution; tin salts might be still present) diluted with 300 mL heptanes, and the slurry was kept at reflux for 3 hours, cooled and collected at room temperature, 59.0 g, m.p. 176-179° C. A recrystallization by dissolution in toluene (600 mL), clarification while hot, and dilution with heptanes (300 mL) delivered 50 g of pure 7-bromo-9H-fluorene-2-carbaldehyde, m.p. 177-180° C. The yield is 57 or 63% based on assumed purity of 100% or 90% for the sample of 2-bromofluorene used. Mass spec: m/z 272, 274 (M+). Anal Calcd for C14H9BrO: C, 61.57%; H, 3.32%; Br, 29.26%. Found: C, 61.53%; H, 3.44%; Br, 29.22%. 1H NMR (CDCl3), δ ppm: 3.94 (s, 2H), 7.53-7.56 (dd, 1H), 7.68-7.72 (m, 2H), 7.85-7.91 (m, 2H), 8.03 (s, 1H), and 10.04 (s, 1H). 13C NMR: 36.57 (1 sp3C), 120.19, 122.23, 122.46, 125.82, 128.55, 129.81, 130.40, 135.32, 139.21, 143.28, 146.45, 146.72, and 191.90 (13 sp2C).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][C:7]=1[CH:15]=[O:16].[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1I>>[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:17])[CH3:1])=[C:7]([CH:15]=[O:16])[CH:8]=1
Reactant: CN(C)CCOc1ccc(B(O)O)cc1C=O
Reactant: Brc1ccccc1I
Product: CN(C)CCOc1ccc(-c2ccccc2Br)cc1C=O
Yield: 68 %

Procedure:
General procedure G, using 4-(2-dimethylamino-ethoxy)-3-formyl-benzeneboronic acid and 1-bromo-2-iodo-benzene gave the title product as yellow oil in 68% yield. 1H-NMR (CDCl3) δ 10.51 (s, 1H), 7.90 (d, 1H), 7.70-7.65 (m, 2H), 7.41-7.20 (m, 3H), 7.09 (d, 1H), 4.40 (t, 2H), 3.04 (bs, 2H), 2.56 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH:15]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH3:16])[C:4]2[C:9]([C:10]=1[C:11]([O:13]C)=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.C(O)C.[OH-].[Na+]>>[CH3:1][C:2]1[N:3]([CH:15]([CH:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[CH3:16])[C:4]2[C:9]([C:10]=1[C:11]([OH:13])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: COC(=O)c1c(C)n(C(C)C2CCOCC2)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(=O)O)c2ccccc2n1C(C)C1CCOCC1
Temperature: 25 °C
Yield: 93.2 %

Procedure:
A 1 L round bottom flask was charged with a magnetic stir bar, (R or S)-methyl 2-methyl-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-indole-3-carboxylate (11.60 g, 38.5 mmol), ethanol (96 ml, 38.5 mmol), and 6 N aqueous NaOH (64.1 ml, 385 mmol). The flask was fitted with a reflux condenser and heated to reflux for 6 h before being allowed to cool to rt. The volatiles were removed in vacuo and the resulting mixture was poured into 10% HCl (˜300 mL). A precipitate formed which was collected via vacuum filtration using a Buchner funnel. The filter cake was rinsed with an additional portion of water (˜200 mL), collected, and dried under vacuum to afford the title compound (10.87 g, 35.9 mmol, 93% yield) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:8][N:9]([CH:11](N(C)C)OC(C)(C)C)[CH3:10]>CN(C=O)C>[CH3:8][N:9]([CH3:11])[CH:10]=[CH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: Cc1ccncc1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Cc1ccncc1
Yield: 84.3 %

Procedure:
A solution of 4-methylpyridine (3.7 g, 40 mmol) and bis(dimethylamino)-tert-butoxymethane (8.44 g, 48 mmol) in DMF (10 mL) was heated at reflux for 12 hours under a nitrogen atmosphere and then concentrated under vacuum to give a tan solid. The product was re-crystallized from cyclohexane to give compound 4-(2-dimethylaminovinyl)pyridine (5.0 g, yield 85%) as light yellow crystals. A solution of 4-(2-dimethylaminovinyl)pyridine (5.0 g, 33.8 mmol), ethyl cyanoacetate (3.8 g, 33.8 mmol), sulfur (8.6 g, 270.2 mmol) and morpholine (1 mL) in EtOH (50 mL) was heated at 80° C. under a nitrogen atmosphere for 3 hours and chilled in ice. The resulting crystals were collected by filtration, washed with hexane, and dried to give the title compound (5.5 g, 66% yield) as an orange solid:
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([NH:20][C@H:21]1[CH2:27][S:26][CH2:25][C@@H:24]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)[N:23]([CH2:33][C:34]([O:36]C(C)(C)C)=[O:35])[C:22]1=[O:41])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[CH2:1]([O:8][C:9]([C@@H:11]([NH:20][C@H:21]1[CH2:27][S:26][CH2:25][C@@H:24]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)[N:23]([CH2:33][C:34]([OH:36])=[O:35])[C:22]1=[O:41])[CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](NC(CCc2ccccc2)C(=O)OCc2ccccc2)CSC[C@H]1c1cccs1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1C(=O)[C@@H](N[C@@H](CCc2ccccc2)C(=O)OCc2ccccc2)CSC[C@H]1c1cccs1

Procedure:
158 mg of isomer B of t-butyl α-[6(R)-(1-benzyloxycarbonyl-3-phenylpropylamino)-5-oxo-3(S)-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetate (prepared as described in Example 25) were treated with trifluoroacetic acid to remove its t-butyl group in the same manner as described in Example 3. The title compound was obtained as an amorphous solid in a yield of 109 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]=[N:13][S:14][CH:15]=2)=[O:10])=[CH:4][CH:3]=1.[N:16]([C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=1)=[C:17]=[S:18]>C(#N)C>[F:26][C:25]([F:27])([F:28])[C:23]1[CH:24]=[C:19]([NH:16][C:17](=[S:18])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]3[N:12]=[N:13][S:14][CH:15]=3)=[O:10])=[CH:6][CH:7]=2)[CH:20]=[C:21]([C:29]([F:31])([F:32])[F:30])[CH:22]=1
Reactant: Nc1ccc(NC(=O)c2csnn2)cc1
Reactant: FC(F)(F)c1cc(N=C=S)cc(C(F)(F)F)c1
Solvent: CC#N
Product: O=C(Nc1ccc(NC(=S)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1)c1csnn1
Temperature: 25 °C

Procedure:
To solution of [1,2,3]-thiadiazole-4-carboxylic acid (4-amino-phenyl) amide (2.0 g) in acetonitrile (50 mL) is added 1-isothiocyanato-3,5-bis-trifluoromethyl-benzene 2.5 g) in acetonitrile (50 mL) dropwise but rapidly and the reaction is stirred at room temperature. After ninety minutes, the solvent is removed under reduced pressure and the resulting brown solid is recrystallized from ethyl acetate/hexanes to give the pure product. [M+H] 492.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:25]=[CH:24][C:23](F)=[C:22]([Cl:27])[CH:21]=3)(=[O:19])=[O:18])[CH3:16])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[H-].[Na+].[Cl:31][C:32]1C=C[C:35](O)=[CH:34][CH:33]=1.[C:39]([OH:42])(=O)[CH3:40]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([O:42][C:39]4[CH:40]=[CH:35][CH:34]=[CH:33][C:32]=4[Cl:31])=[C:22]([Cl:27])[CH:21]=3)(=[O:19])=[O:18])[CH3:16])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CC(=O)O
Reactant: Oc1ccc(Cl)cc1
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1ccc(Oc2ccccc2Cl)c(Cl)c1
Temperature: 100 °C
Yield: 77 %

Procedure:
{(R)-4-[(3-Chloro-4-fluoro-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (24 mg, 0.058 mmol), sodium hydride (60% dispersed in mineral oil, 11.6 mg) and 4-chlorophenol (0.52 mg, 0.40 mmol) were dissolved in N,N-dimethylformamide (2 mL). After being heated in a microwave oven at 100° C. for 15 minutes, the resulting mixture was acidified with acetic acid to pH 5, and filtered through a glass funnel. The precipitate was purified by preparative HPLC to afford ((R)-4-{[3-chloro-4-(2-chloro-phenoxy)-benzenesulfonyl]-methyl-amino}-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (24 mg, 77%) as a white powder. MS cald. for C24H25Cl2N3O5S 537, obsd. (ESI+) [(M+H)+]: 538.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19]C)[CH:15]=2)[C:10]=1[O:21][C:22]1[CH:36]=[CH:35][C:25]([O:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+].C(Cl)(Cl)[Cl:47].C(O)(C)C>C(Cl)Cl>[ClH:47].[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:10]([O:21][C:22]2[CH:36]=[CH:35][C:25]([O:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)=[CH:24][CH:23]=2)=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]2
Reactant: ClC(Cl)Cl
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3c(F)cccc3F)ccc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: Cl
Product: Oc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3c(F)cccc3F)ccc2c1
Temperature: 25 °C
Yield: 48 %

Procedure:
Dissolve 1-(2-{4-[2-(2,6-difluoro-phenyl)-6-methoxy-naphthalen-1-yloxy]-phenoxy}-ethyl)-piperidine (300 mg., 0.61 mmoles) in 20 ml methylene chloride and chill in ice. To this add 2.0 ml of boron tribromide with swirling and allow to warm to room temperature. Pour this mixture into a two-phase mixture consisting of saturated sodium bicarbonate and a 3/1 mixture of chloroform/isopropanol. Wash the organic layer with brine and dry over 3A molecular sieves. Purify further using reverse phase chromatography to give 138 mg of the title compound (48%). Convert to hydrochloride salt and lyophilize. 1H-NMR (CDCl3, 300 MHz) δ7.92 (d, J=9.0 Hz, 1H); 7.59 (d, J=8.4 Hz, 1H); 7.35 (d, J=8.4 Hz, 1H); 7.20-7.17 (m, 2H); 7.03 (dd, J=9.0, 2.1 Hz, 1H); 6.85-6.80 (m, 2H); 6.52 (s, 4H); 3.95 (t, J=5.7 Hz, 2H); 2.73 (t, J=6.0 Hz, 2H); 2.52-2.52 (m, 4H); 1.64-1.59 (m, 4H); 1.46-1.44 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=1)=[O:12]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:10][C:11]([C:13]2[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[CH:18]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: COc1cc(C(=O)CBr)cc(OC)c1OC
Reactant: Fc1ccc(S)cc1
Product: COc1cc(C(=O)CSc2ccc(F)cc2)cc(OC)c1OC
Yield: 125 %

Procedure:
Substantially the same procedure as in Reference Example 13 was repeated using 4-fluorothiophenol (0.82 g) and 2-bromo-3',4',5'-trimethoxyacetophenone (Compound XIa, 1.54 g) obtained in Reference Example 1 to give 2-(4-fluorophenylthio)-3',4',5'-trimethoxyacetophenone (Compound IX-11, 2.24 g).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:16]([O:25][CH2:26][CH3:27])(=[O:24])/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20].F[C:29](F)(F)C(O)=O.Cl>C1COCC1.CCCCCCC>[CH2:26]([O:25][C:16]([C@H:17]1[C@H:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:29]1)=[O:24])[CH3:27]
Reactant: C[Si](C)(C)CNCc1ccccc1
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)/C=C/C(=O)OCC
Agent: C=O
Agent: Cl
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1C(=O)OCC
Reaction time: 0.25 h

Procedure:
900 g of N-Benzyl-N-trimethylsilylmethyl-amine (4654 mmol) were dissolved in 5.6 l THF at 20-25° C. 450 ml of 36% aqueous formaldehyde (5880 mmol, 1.26 equiv.) were added over 15 min, keeping the temperature between 20-25° C. After 15 min, a mixture of 760 ml diethyl fumarate (1 equiv.), 2.25 l THF and 11.2 ml trifluoroacetic acid (0.03 equiv.) was added over 15 min. The reaction mixture was stirred overnight keeping the temperature between 20-30° C. (in process control by GC). 3.5 l of 1N HCl were added, followed by 2.3 l heptane. The aqueous phase was separated and washed with 3.4 l heptane. The heptane phases were washed sequentially with 3.5 l 1N HCl. 4.5 l MTBE were added to the combined aqueous phases. 720 ml of 32% NaOHaq were added (pH 13) under vigorous stirring. The aqueous phase was separated and re-extracted with 4.5 l MTBE. The MTBE phases were washed sequentially with 2.2 l water, combined and concentrated to dryness at 45° C. to give 1.295 kg of crude (rac)-trans-N-benzyl-pyrrolidine-3,4-dicarboxylic acid diethyl ester. If required, the crude cycloadduct can be distilled.
Reaction SMILES: [C:1]1([OH:10])[O:2]C=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.[Br-].C(CCCCC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(O)=O>>[C:1]([OH:10])(=[O:2])/[CH:9]=[CH:8]\[CH2:7][CH2:6][CH2:5][CH3:4]
Reactant: Oc1occ2ccccc12
Agent: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CCCC/C=C\C(=O)O

Procedure:
These reactions are carried out using readily available starting materials and give good yields of the end product. Thus, as shown above for the 1,4 di-substituted benzenes, dicyanohydroquinone is sequentially treated with the appropriate alkyl halide, sodium hydroxide, and acetic anhydride, to yield the corresponding phthalic anhydride, which is then reduced to the isobenzofuranol derivative. The latter is treated with the ylide derived from 5-carboxypentyltriphenylphosphonium bromide to give the cis-heptenoic acid. This derivative is esterified and hydrogenated to produce the corresponding saturated hydroxy ester. The ester is then oxidized and treated with the sodium salt of dimethyl(2-oxoheptyl)phosphonate to yield the enone. The enone compound is then reduced to the corresponding alcohol by reacting it with a suitable reducing agent such as potassium borohydride in a suitable organic solvent. The ester is converted to the acid by reacting it with an aqueous alcoholic potassium carbonate solution.