Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])[C:10]([Cl:17])=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[N:12]=2)=[C:4]([Cl:26])[CH:3]=1.[CH3:27][S:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29].C([O-])([O-])=O.[K+].[K+].O>COCCOC>[Cl:17][C:10]1[N:9]([C:18]2[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:25])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([S:28]([CH3:27])(=[O:30])=[O:29])[CH:36]=3)=[CH:3][C:4]=2[Cl:26])=[N:12][C:11]=1[C:13]([OH:16])([CH3:15])[CH3:14]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CC(C)(O)c1nc(-c2ccc(Br)cc2Cl)n(-c2c(Cl)cccc2Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(O)c1nc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2Cl)n(-c2c(Cl)cccc2Cl)c1Cl
Temperature: 60 °C
Reaction time: 1.17 h
Yield: 78.2 %

Procedure:
A mixture of 2-[2-(4-bromo-2-chlorophenyl)-5-chloro-1-(2,6-dichlorophenyl)-1H-imidazol-4-yl]-propan-2-ol (184 mg, 0.37 mmol), 3-methanesulfonyl-phenylboronic acid (90 mg, 0.45 mmol), K2CO3 (0.15 g, 1.1 mmol), Cl2 Pd(dppf)-DCM (15 mg, 5 mol %) and H2O (0.2 mL) in DME (2 mL) was sparged with Argon for 5 min and then heated at 60° C. as a sealed flask. After 70 min the reaction mixture was allowed to cool to ambient temperature, filtered (Celite™) and the filter agent rinsed with EtOAc. The combined filtrates were concentrated under reduced pressure and purified by chromatography (silica, EtOAc/Hex, 20:80 to 60:40) to give the title compound (165 mg, 78%) as a white solid. 1H-NMR (DCM-d2): δ 8.08 (m, 1H), 7.93 (m, 1H), 7.84 (m, 1H), 7.73 (d, 1H), 7.67 (m, 1H), 7.33-7.47 (m, 5H), 3.42 (br s, 1H), 3.06 (s, 3H), 1.68 (s, 6H); MS (ES): 591, 593, 595 [M+Na]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si:15](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CN=C1>CN(C=O)C.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
To a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (400 mg, 1.98 mmol) in DMF (2 mL) was added TBDPS chloride (0.52 mL, 1.98 mmol) and imidazole (297 mg, 4.47 mmol) and the reaction stirred at RT for 16 h afterwhich time the reaction mixture was diluted with brine (10 mL), washed with CH2Cl2 (3×25 mL) and the organics combined and dried through a phase separation cartridge and concentrated in vacuo. The crude material was purified by silica gel column chromatography, eluting with EtOAc and increasing the polarity to 30% EtOAc/isohexane to obtain 4-(tert-butyl-diphenyl-silanyloxy)-piperidine-1-carboxylic acid tert-butyl ester as a colourless oil (545 mg, 62%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](Br)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][N:28]1[C:32]([Sn](CCCC)(CCCC)CCCC)=[CH:31][N:30]=[CH:29]1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:32]4[N:28]([CH3:27])[CH:29]=[N:30][CH:31]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cn1cncc1-c1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Yield: 89.8 %

Procedure:
The (4-benzyloxy-phenyl)-(6-bromoquinazolin-4-yl)-amine (1.0 g, 2.46 mmol), 1-methyl-5-(tributylstannyl)imidazole (prepared according to Gaare, K., et al. Acta Chem. Scand. (1993), 47(1), 57-62) (1.25 g, 3.37 mmol) and bis(triphenylphosphine)palladium (II) chloride (catalytic amount) were reacted according to Procedure B in dioxane (50 ml) for 3 hours. The solvent was removed in vacuo, and the solid was washed with i-hexane. The resulting dark solid was suspended in IMS, and undissolved material removed by filtration. The resulting filtrate was concentrated in vacuo to give the product as a pale baige solid (0.90 g, 2.21 mmol, 90%); δH [2H6]-DMSO 9.69 (1H, b, NH), 8.60 (1H, s, 5-H), 8.55 (1H, s, 2-H), 8.00 (1H, d, 7-H), 7.83 (2H, m, 8-H, imidazole-H), 7.69 (2H, d, 2′-H, 6′-H), 7.52-7.33 (5H, m, 5×Ph-H), 7.22 (1H, s, imidazole-H), 7.09 (2H, d, 3′-H, 5′-H), 5.14 (2H, s, CH2), 3.80 (3H, s, CH3); m/z 408 (M+1)+.
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:2]12.[Li+].[Br-]>>[C:2]1(=[O:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C1CCCCCC2OC2CCCC1
Agent: [Br-]
Agent: [Li+]
Product: O=C1CCCCCCCCCCC1
Yield: 100 %

Procedure:
Further, SU Patent 407,874 discloses an isomerization reaction of an epoxycyclododecane, in the presence of a catalyst consisting of anhydrous LiBr, in no solvent. In examples of the SU patent, it is reported that, when the reaction was carried out in an amount of LiBr of 4% by weight at a reaction temperature of 120 to 130° C. for a reaction time of 18 hours or in an amount of LiBr of 3.3% by weight at a reaction temperature of 200° C. for a reaction time of 3 hours, the target cyclododecanone was obtained at a yield of 100% or 83.3%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH2:23][CH3:24]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:22][CH2:23][CH3:24])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCCI
Reactant: OC1(c2cc(F)cc(F)c2)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCC(O)(c2cc(F)cc(F)c2)C1

Procedure:
Preparation according to Example 24: Enantiomer E1 of 3-(3,5-difluorophenyl)-pyrrolidin-3-ol (0.53 g, 2.66 mmol), acetonitrile (3 mL), potassium carbonate (0.55 g, 3.99 mmol) and iodopropane (260 μl, 2.66 mmol). Purification by HPLC on Waters OBD 018, 5 μm (MeOH/33 mM NH3, 40:60 to 60:40). Yield: 0.274 g. [α]D=+21.2° (methanol). The amine was converted to the oxalic acid salt and recrystallized from methanol/diethyl ether: M.p. 117-118° C.; MS m/z (relative intensity, 70 eV) 241 (M+, 8), 212, (bp), 182 (35), 127 (12), 84 (45).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[C@H:10]([CH:27]([CH3:29])[CH3:28])[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:40](Cl)(=[O:45])[CH2:41][CH2:42][CH2:43][CH3:44]>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:30])[C@H:10]([CH:27]([CH3:28])[CH3:29])[N:11]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[CH:17][CH:18]=1)[C:40](=[O:45])[CH2:41][CH2:42][CH2:43][CH3:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NCc1ccc(-c2ccccc2C#N)cc1)C(=O)OCc1ccccc1
Reactant: CCCCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)[C@H](C(=O)OCc1ccccc1)C(C)C

Procedure:
6.2 g (15.5 mmol) of N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester and 8.0 ml of Hunig base, dissolved in 50 ml of methylene chloride, are treated with 2.3 ml of valeryl chloride with stirring and further processed analogously to Example 29b. The title compound is thus obtained as a yellow oil which is further used in crude form (Rf 0.51, toluene-methanol 19:1)
Reaction SMILES: CC([O:4][C@@H:5]1[C@H:10]([O:11][C:12]([CH3:14])=[O:13])[C@@H:9]([O:15][C:16]([CH3:18])=[O:17])[C@@H:8]([O:19][C@:20]2([CH2:35][OH:36])[O:24][C@H:23]([CH2:25][OH:26])[C@@H:22]([O:27][C:28]([CH3:30])=[O:29])[C@@H:21]2[O:31][C:32]([CH3:34])=[O:33])[O:7][C@@H:6]1[CH2:37]O)=O.[C:39]([OH:42])(=[O:41])[CH3:40]>C1(C)C=CC=CC=1>[CH3:40][C:39]([O:42][CH2:37][C@H:6]1[O:7][C@H:8]([O:19][C@@:20]2([CH2:35][OH:36])[O:24][C@@H:23]([CH2:25][OH:26])[C@@H:22]([O:27][C:28]([CH3:30])=[O:29])[C@H:21]2[O:31][C:32]([CH3:34])=[O:33])[C@H:9]([O:15][C:16]([CH3:18])=[O:17])[C@@H:10]([O:11][C:12]([CH3:14])=[O:13])[C@@H:5]1[OH:4])=[O:41]
Reactant: CC(=O)O
Reactant: CC(=O)O[C@H]1[C@@H](OC(C)=O)[C@@H](CO)O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](OC(C)=O)[C@@H]2OC(C)=O)[C@@H]1OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)OC[C@H]1O[C@H](O[C@@]2(CO)O[C@@H](CO)[C@@H](OC(C)=O)[C@H]2OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1O
Temperature: 25 °C
Yield: 83.3 %

Procedure:
2,3,4,3',4'-Penta-O-acetylsucrose (2 g; purity 83.63%) and glacial acetic acid (0.2 liter) were added to toluene (10.0 liter) and the mixture was heated to reflux and maintained at reflux for 6 hours or until the acetyl migration was completed. The solution was cooled to ambient temperature and the precipitate filtered off, washed with fresh toluene and dried in a vacuum oven at 40° C. to give 2,3,6,3',4'-penta-O-acetylsucrose (15.90 g; purity 87.65%) in an overall yield of 83.3%
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=O.[C:7]([NH2:15])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[Cl:1][CH2:2][C:3]1[N:15]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:14][CH:5]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1ccccc1
Product: ClCc1coc(-c2ccccc2)n1
Yield: 68 %

Procedure:
This compound was synthesized from 1,3-dichloroacetone and benzamide as described in example 71 step 1 (65 g, yield 68%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.06-8.04 (m, 2H), 7.72 (m, 1H), 7.49-7.46 (m, 3H), 4.59 (d, J=1.1 Hz, 2H). MS (ESI) m/z: Calculated for C10H8ClNO: 193.03. found: 194.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:15])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:16][N:17]1[C:21](=[O:22])[CH2:20][CH:19]([C:23](O)=[O:24])[C:18]1([CH3:27])[CH3:26].C([O-])(=O)C.[NH4+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:23]([CH:19]3[CH2:20][C:21](=[O:22])[N:17]([CH3:16])[C:18]3([CH3:27])[CH3:26])=[O:24])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: Nc1cc(Cl)cc2c1[nH]c1cnccc12
Reactant: CN1C(=O)CC(C(=O)O)C1(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CN1C(=O)CC(C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)C1(C)C
Yield: 68 %

Procedure:
The desired compound was prepared according to Method B from 6-chloro-9H-β-carboline-8-ylamine and 1,2,2-trimethyl-5-oxo-pyrrolidine-3-carboxylic acid in 68% yield. 1H-NMR (DMSO-d6, 300 MHz) δ 1.23 (s, 3H), 1.45 (s, 3H), 2.59 (dd, 1H), 2.66(s, 3H), 2.70 (dd, 1H), 3.17 (t, 1H), 7.91 (m, 1H), 8.18 (d, 1H), 8.24 (d, 1H), 8.40 (d, 1H), 9.07 (s, 1H), 10.16 (s, 1H), 11.32 (s, 1H). Retention Time (LC, method: ammonium acetate standard): 1.17 min. MS (M+H+): 371.3.
Reaction SMILES: [C:1](O)(=O)/C=C\C(O)=O.[C:9]([O:16][CH3:17])(=[O:15])/[CH:10]=[CH:11]\[C:12]([O-:14])=[O:13]>CO>[C:12]([O:14][CH3:1])(=[O:13])/[CH:11]=[CH:10]\[C:9]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)/C=C\C(=O)[O-]
Reactant: O=C(O)/C=C\C(=O)O
Solvent: CO
Product: COC(=O)/C=C\C(=O)OC

Procedure:
This example relates particularly to FIG. 3 and illustrates use of a side heater in the reaction column. In this example a 95 wt % solution of aqueous maleic acid is provided as described in Example 1. The aqueous maleic acid feed is mixed with recycle methanol from the refining section (line 38/16a′) and fed to a plug flow, mono-ester reactor (36), where more than 80% of the maleic acid is converted to mono-methyl maleate. The product from this is fed to reaction column (19′) to react to the mono-methyl maleate with methanol to produce di-methyl maleate. This reaction column includes a heater near the feed point. The heater helps to drive off water from the column. 350 moles per hour of methanol (lines 42 and 41) are fed to the bottom of the reaction column (19′). Essentially water free, fully converted di-methyl maleate (line 26′) is fed to hydrogenation (20). Recycle methanol from the refining section is fed to the top of the reaction column as wash (line 16b′) to minimize the di-methyl maleate and maleic acid in the overhead of the column. Methanol or water from the overhead (line 31′) of the reaction column is fed to the methanol column (25′) where the methanol is separated and recycled to the reaction column (line 39). Water and a small amount of recovered maleic acid and di-methyl maleate from the bottom of the methanol column are recycled to the absorber (2) in line 3′.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[Br:12]N1C(=O)CCC1=O>CC#N>[NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][C:5]([Br:12])=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1nccnc1N
Solvent: CC#N
Product: COC(=O)c1nc(Br)cnc1N
Yield: 92.3 %

Procedure:
A mixture of methyl 3-aminopyrazine-2-carboxylate (8.35 g, 54.53 mmol) and N-bromo-succinimide (9.705 g, 54.53 mmol) was stirred in MeCN (100 mL) at room temp overnight. The resultant precipitate was filtered, washed with MeCN and dried to give the desired product as a yellow solid (11.68 g, 92% Yield)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.F[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:14][O:13][C:11]([C:10]1[CH:15]=[CH:16][C:7]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:8][CH:9]=1)=[O:12]
Reactant: c1c[nH]cn1
Reactant: COC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(-n2ccnc2)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
A mixture of imidazole (132 g, 1.9 mol), methyl 4-fluorobenzoate (170 ml, 1.3 mol) and potassium carbonate (357 g, 2.6 mol) in DMSO (200 ml) is stirred at 120° C. for 3 h. After cooling to room temperature, the mixture is added to ice-water. Precipitated product is filtered off and washed with water. Yield: 59%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=2[N+:16]([O-])=O)=[CH:4][CH:3]=1.[Cl-].[NH4+]>CCO.[Fe]>[NH2:16][C:10]1[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(O)ccc1Sc1ccc(O)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1cc(O)ccc1Sc1ccc(O)cc1
Yield: 98.4 %

Procedure:
The product from Example 16A (1.34 g, 5.09 mmol) was reacted with iron (1.42 g, 25.48 mmol) and ammonium chloride (409 mg, 1.5 mmol) in 20 mL EtOH/20 mL THF/6 mL water following the procedure from Example 10E to provide the title compound (1.168 g, 97%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl>[CH2:1]([O:14][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:17]([Br:19])=[CH:18][C:10]=1[F:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)c1ccc(Br)cc1F
Yield: 102.4 %

Procedure:
Benzyl bromide (2.80 mL, 23.6 mmol) was added to a solution of 2-fluoro-4-bromobenzoic acid (4.34 g, 19.8 mmol) and Cs2CO3 (9.79 g, 30.0 mmol) in CH2Cl2 (50 mL). The mixture was heated to reflux for 4 hr. The reaction was quenched with H2O (150 mL) and extracted with CH2Cl2 (150 mL). The organic layer was dried over MgSO4 and concentrated. The residue was purified by flash column chromatograph eluting with 10% EtOAc in hexanes to give a colorless oil (6.27 g, 100% yield). 1H NMR (400 MHz, CDCl3) δ 7.82-7.88 (m, 1 H) 7.44-7.47 (m, 2 H) 7.34-7.42 (m, 5 H) 5.38 (s, 2 H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:5]2=[N:6][CH:7]=1.[Cl:13]C1C=CC=CC=1>>[Cl:13][CH2:1][C:2]1[CH:3]=[C:4]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1cnc2c(c1)C(=O)OC2=O
Reactant: Clc1ccccc1
Product: O=C1OC(=O)c2ncc(CCl)cc21
Temperature: 85 °C
Reaction time: 1.5 h

Procedure:
106.8 g (0.65 mol) of 5-methyl-2,3-pyridine dicarboxylic acid anhydride were dissolved in 427 g chlorobenzene and heated up to 85° C. A solution of 0.64 g (0.004 mol) AlBN in 99.0 g (0.66 mol) SO2Cl2 was added during 45 min. The mixture was stirred for additional 90 min at 85° C. Chlorobenzene was partly distilled off and the solution was cooled to 10° C. via 10 h ramp. The precipitate was filtered off and washed with chlorobenzene/hexane.
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.[NH2:12][C@@:13]1([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:42]=2[F:48])[CH2:17][O:16][C@H:15]([CH2:18][O:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:14]1[CH2:39][OH:40].CCOC(C)=O>C(Cl)Cl>[F:48][C:42]1[C:43]([F:47])=[CH:44][CH:45]=[CH:46][C:41]=1[C@@:13]1([NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:11])[C@H:14]([CH2:39][OH:40])[C@@H:15]([CH2:18][O:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:16][CH2:17]1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: N[C@@]1(c2cccc(F)c2F)CO[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(NC(=S)N[C@@]1(c2cccc(F)c2F)CO[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1CO)c1ccccc1

Procedure:
Benzoyl isothiocyanate (6 g) was added dropwise to a solution containing ((2S,3R,4S)-4-amino-4-(2,3-difluorophenyl)-2-((trityloxy)methyl)tetrahydrofuran-3-yl)methanol, obtained in Preparation Example 1-(3), (15.42 g) in CH2Cl2 (80 mL), and the mixture was stirred at RT for 18 h. EtOAc was added and the mixture was extracted with NaHCO3 (3×100 mL), dried over MgSO4, evaporated, and the residue was purified by silica gel column chromatography (0% to 30% EtOAc in hexanes) to obtain the title compound (19.06 g). 1H-NMR (400 MHz, CDCl3) δ (ppm): 3.00 (t, J=6.2 Hz, 1H), 3.08-3.17 (m, 1H), 3.26 (dd, J=10.2, 4.2 Hz, 1H), 3.38 (dd, J=10.2, 3.9 Hz, 1H), 3.73-3.95 (m, 2H), 4.04-4.12 (m, 1H), 4.54 (d, J=9.6 Hz, 1H), 4.69 (d, J=9.9 Hz, 1H), 7.05-7.68 (m, 21H) 7.88 (d, J=7.1 Hz, 2H), 8.88 (s, 1H), 11.83 (s, 1H)
Reaction SMILES: [CH3:1][O:2]/[C:3](=[CH:7]\[C:8]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[C:11]([O:17][CH2:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:10][CH:9]=1)/[C:4]([OH:6])=[O:5].[H][H]>>[CH3:1][O:2][C@@H:3]([CH2:7][C:8]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[C:11]([O:17][CH2:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: CO/C(=C\c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Reactant: [H][H]
Product: CO[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O

Procedure:
In an analogous manner to Example 10, 2.5 g (5.74 mmol) of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid were asymmetrically hydrogenated in the presence of 3.22 mg of [Ru(OAc)2((S)-6-MeO-2-naphthyl)-MeOBIPHEP)] (S/C molar ratio 2000) at 40° C. under 15 bar of hydrogen for 24 h to reach 99.6% conversion. Rotary evaporation of the reaction mixture afforded quantitatively (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid of 75.8% ee with 98.5% purity (HPLC area). To a solution of 6.50 g (15.8 mmol) of crude product in 33 ml of tetrahydrofuran was added dropwise at reflux (63-65%° C.) under stirring a solution of 1.91 g (15.6 mmol) of (S)-phenyl ethylamine (commercially available from Fluka) in 3 ml of tetrahydrofuran. Addition of seed crystals and turning off the bath heating brought about the start of the crystallization. The crystallization was completed over night at room temperature, the white crystals were filtered off, washed with 20 ml of cold (−20° C.) tetrahydrofuran and dried to constant weight (50° C./10 mbar/6h) to afford 6.57 g (79.2%) of (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid as (S)-phenyl ethylamine salt of 96.3% ee with 99.9% purity (HPLC area), with a mp. of 157-159.5° C.
Reaction SMILES: S(=O)(=O)(O)O.O.[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13](=O)[C:14]3[C:19]([C:20]=2[CH:21]=1)=[CH:18][CH:17]=[CH:16][N:15]=3>[Pd].CO>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[C@@H:19]([C:20]=2[CH:21]=1)[CH2:18][CH2:17][CH2:16][NH:15]3
Reactant: COc1ccc2c(c1)-c1cccnc1C2=O
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)[C@H]1CCCN[C@H]1C2
Temperature: 60 °C

Procedure:
A mixture of sulfuric acid (98%, 6 kg), water (6 L), and methanol (6 L) is added to an autoclave charged with 6-methoxy-indeno[2,1-b]pyridin-9-one (1.2 kg) and wet 10% palladium on carbon (50%, 0.48 kg). The autoclave is purged with nitrogen and filled then with hydrogen (100 psi). The mixture is heated to 60° C. and maintained at this temperature and hydrogen pressure until the starting material is completely consumed (2-12 h). The mixture is cooled to 50-55° C. and filtered over Celite. The Celite is washed with a warm 1:1 mixture of water and methanol several times (total 20 L). The combined filtrate is added to an autoclave charged with wet 10% palladium on carbon (50%, 0.96 kg). The autoclave is purged with nitrogen and filled then with hydrogen (100 psi). The mixture is heated to 60° C. and maintained at this temperature and hydrogen pressure until the intermediate is completely consumed (12-24 h). The mixture is cooled to ambient temperature and filtered over Celite. The Celite is washed with a mixture of methanol and water (5 L/5 L). The combined filtrate is cooled to 0-10° C. and the pH value is adjusted to 10-11 using 30% aqueous NaOH solution while maintaining the solution temperature below 40° C. Water (10 L) is added and the resulting mixture is extracted with dichloromethane (2×5 L). The combined extract is washed with 10% aqueous NaCl solution and concentrated. The residue is taken up twice in methyl ethyl ketone and concentrated again to give the crude title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:15]=[C:14]([CH2:16][OH:17])[CH:13]=[C:7]([C:8]([O:10]CC)=[O:9])[CH:6]=1)[CH3:2].[OH-].[Na+]>CC(C)=O.C(O)C>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:15]=[C:14]([CH2:16][OH:17])[CH:13]=[C:7]([C:8]([OH:10])=[O:9])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(CO)cc(C(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(CO)cc(C(=O)O)c1
Yield: 42.8 %

Procedure:
Add a solution of diethyl-5-(hydroxymethyl)-isophthalate (5 g, 19.8 mmol) in acetone (88 mL) to a solution of NaOH (792 mg, 19.8 mmol) in ethanol (12 mL). After 4 h collect precipitate. Dissolve the precipitate in water (200 mL), add 5 N HCl to about pH=1 and collect the precipitate. Extract the aqueous with dichloromethane, combine the extracts with the precipitate and concentrate to give to give the title compound (1.9 g, 43%)
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[OH-:14].[Na+]>>[OH:14][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: [OH-]
Agent: [Na+]
Product: O=C(O)c1cc(O)ccc1[N+](=O)[O-]

Procedure:
124.6 g (0.618 mol) of 5-chloro-2-nitro-benzoic acid (Fluka Buchs, Switzerland) are heated under reflux in an aqueous sodium hydroxide solution [197.8 g (4.94 mol) of NaOH in 1.23 l water] for 18 h. The cold reaction mixture is extracted several times with ether-ethyl acetate, washed with brine and dried over sodium sulfate. The raw material is crystallized from isopropyl ether-hexane. The crystals are filtered off and dried at 50° C. (high-vacuum). mp: 167-171° C.; MS: 182 (M+−1); HPLC: W-=6.315 min (Grad 1).