Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[CH:11]1([C:16](Cl)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1.[N+](C)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH:11]1([C:16]([C:3]2[S:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]=2[CH3:1])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Cc1csc2ccccc12
Reactant: O=C(Cl)C1CCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Product: Cc1c(C(=O)C2CCCC2)sc2ccccc12
Reaction time: 1.5 h
Yield: 93 %

Procedure:
To a mixture of 3-methyl-1-benzothiophene (1.00 g), cyclopentanecarbonyl chloride (903 μL) and nitromethane (10 mL) was added aluminum chloride (1.35 g) at 0° C., and the mixture was stirred for 1.5 hr. Water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography (ethyl acetate) to give the title object compound (1.54 g, 93%) as a pale-brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2.[H-].[Na+].[CH2:15](Br)/[CH:16]=[C:17](/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])\[CH3:18]>CN(C=O)C>[CH3:18]/[C:17](/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:16]\[CH2:15][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2
Reactant: CC(C)=CCC/C(C)=C/CBr
Reactant: O=c1ccc2cc(O)ccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)=CCC/C(C)=C/COc1ccc2oc(=O)ccc2c1
Temperature: 0 °C

Procedure:
An oven-dried 50 mL round bottom flask was prepared with a magnetic stirring bar, a rubber septum cover, and a nitrogen inlet. 6-hydroxycoumarin (1) (114 mg, 0.7 mmol) and 4 mL of anhydrous DMF were added to the round bottom flask. The solution was stirred and cooled to 0° C. in a salt-ice bath. Sodium hydride (28 mg of 60% mineral oil suspension, 0.7 mmol) was added to the flask and the solution was kept stirring at 0° C. for 30 minutes. Geranyl bromide (329 μL, 1.66 mmol) in 1 mL of anhydrous DMF was cooled to 0° C. and added dropwise to the flask through the rubber septum using a syringe. The reaction mixture was left stirring under nitrogen at room temperature for 14 hours. The desired product was isolated by column chromatography using a solvent system of 100% Hexanes, 20:1 Hexanes:Ethyl acetate, 15:1 Hexanes:Ethyl acetate, 10:1 Hexanes:Ethyl acetate, 7:3 Hexanes:Ethyl acetate, and 2:1 Hexanes:Ethyl acetate. The purified product was characterized by NMR spectroscopy (1H-NMR, 13C-NMR) and high-resolution mass spectrometry (HRMS). 1H-NMR (300 MHz, CDCl3): ∂ 1.61-1.84 (9H), 2.13 (m, 4H), 4.57 (d, 2H, J=6 Hz), 5.1 (m, 1H), 5.48 (t, 1H), 6.43 (d, 1H, J=9 Hz), 6.93-7.67 (4H); 13C-NMR (75 MHz, CDCl3): ∂ 18.0, 18.2, 26.25, 26.38, 39.06, 65.20, 111.08, 117.01, 117.83, 118.89, 119.14, 119.70, 123.88, 131.94, 141.44, 143.27, 148.41, 155.33, 161.06. HRMS (CI) Calcd. for C19H23O3: 299.16473. found: 299.16377.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].I[CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: IC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCN(C2CCCC2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
This compound was synthesized from the commercially available piperidin-4-yl-carbamic acid tert-butyl ester (2) (5 g, 25 mmol, 1 equiv) which was dissolved in acetonitrile (150 mL), followed by the addition of iodo-cyclopentane (9.79 g, 50 mmol, 2 equiv) and K2CO3 (3.45 g, 25 mmol, 1 equiv). The solution was stirred at room temperature for 48 hours. Due to the incompleteness of the reaction, iodocyclo-pentane (1.70 g, 8.69 mmol, 0.35 equiv) and K2CO3 (1 g, 7.25 mmol, 0.29 equiv) were added to the solution. The solution was stirred at room temperature for several hours. The solution was filtered over a bed of dicalite and the filtrate was evaporated under reduced pressure to obtain 3 (6.70 g, 25 mmol, quantitative). LRMS (ES+): m/z 269.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][NH:20][C:21]3=[O:24])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.C(Cl)(Cl)Cl>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:23]([Cl:25])=[C:22]3[C:17]([CH2:18][CH2:19][NH:20][C:21]3=[O:24])=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)C(=O)NCC3)CC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2Cl)C(=O)NCC3)CC1
Temperature: 90 °C
Reaction time: 1 h
Yield: 12.2 %

Procedure:
The compound (6.63 g) prepared in step (a) of Example 125 was dissolved in carbon tetrachloride (200 ml). N-Chlorosuccinimide (3.47 g) and AIBN (0.66 g) were added to the solution, and the mixture was heated at 90° C. with stirring for one hr. The temperature of the reaction solution was returned to room temperature. Chloroform was then added to the reaction solution, and the mixture was washed with water, followed by drying over anhydrous MgSO4 The solvent was then removed by distillation under the reduced pressure. The residue was crudely purified by column chromatography on silica gel (ethyl acetate). The solvent was removed by distillation under the reduced pressure. Chloroform was added to the residue, and the precipitated crystal was collected by filtration (and washed with diethyl ether) to give 7-(4-tert-butoxycarbonyl-piperazin-1-yl)-8-chloro-3,4-dihydro-2H-isoquinolin-1-one (0.89 g).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][C:14]2=[O:19])=[CH:7][CH:6]=1)([O-:4])=[O:3].Br[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.C(N(CC)CC)C>>[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=3)[CH2:15][C:14]2=[O:19])=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: O=C1CNCCN1CCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C1CN(CCc2ccc([N+](=O)[O-])cc2)CCN1CCc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 1-[2-(4-nitrophenyl)ethyl]piperazin-2-one hydrochloride (40 mg, 0.14 mmol) and 1-(2-bromoethyl)-4-nitrobenzene (39 mg, 0.17 mmol) was heated to 60° C. with triethylamine (0.078 mL, 0.56 mmol) for 16 hours. LC showed complete reaction at that point. The desired product was purified by reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 399 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]([NH2:10])[CH2:8][NH2:9])[CH:4]=[N:3]1.[F:11][C:12]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:13]=1[CH2:14][O:15][C:16]1[N:21]2[N:22]=[C:23]([CH3:28])[C:24]([C:25](Cl)=[O:26])=[C:20]2[CH:19]=[C:18]([CH3:29])[CH:17]=1.N1C=CC=CC=1>ClC(Cl)C>[NH2:10][CH:7]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)[CH2:8][NH:9][C:25]([C:24]1[C:23]([CH3:28])=[N:22][N:21]2[C:16]([O:15][CH2:14][C:13]3[C:30]([F:34])=[CH:31][CH:32]=[CH:33][C:12]=3[F:11])=[CH:17][C:18]([CH3:29])=[CH:19][C:20]=12)=[O:26]
Reactant: Cn1cc(C(N)CN)cn1
Reactant: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)Cl)c2c1
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)NCC(N)c3cnn(C)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
14.0 mg (0.10 mmol) of 1-(1-methyl-1H-pyrazol-4-yl)ethane-1,2-diamine were initially charged in a 96-well deep well multititre plate. A solution of 35.1 mg (0.10 mmol) of 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carbonyl chloride in 0.6 ml of dichloroethane and 0.032 ml (0.40 mmol) of pyridine were added successively and the mixture was stirred at RT overnight. Then the solvent was evaporated off completely, the residue was dissolved in 0.8 ml of DMF and filtered, and the target compound was isolated from the filtrate by preparative LC-MS (Method 9). The product-containing fractions were concentrated under reduced pressure using a centrifugal dryer. The residue of each product fraction was dissolved in 0.6 ml of DMSO. These were combined and finally freed of the solvent in a centrifugal dryer. 18 mg (37% of theory; 94% purity) of the title compound were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[N+:21]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F

Procedure:
The title compound was prepared from (5-dimethylamino-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example C1) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as an amorphous yellow substance (1.34 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3OC)[C:16]3[S:20][N:19]=[CH:18][N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([F:32])=[CH:4][N:3]=1.[C:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[C:37]([O:44][CH3:45])[CH:36]=1)#[N:34]>>[C:33]([C:35]1[CH:40]=[CH:39][C:38]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]4[S:20][N:19]=[CH:18][N:17]=4)(=[O:14])=[O:13])=[CH:9][CH:10]=3)[C:5]([F:32])=[CH:4][N:3]=2)=[C:37]([O:44][CH3:45])[CH:36]=1)#[N:34]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Cl)ncc(F)c3c2)c(OC)c1
Reactant: COc1cc(C#N)ccc1B(O)O
Product: COc1cc(C#N)ccc1-c1ncc(F)c2cc(S(=O)(=O)Nc3ncns3)ccc12

Procedure:
The title compound was prepared in an analogous manner to that of EXAMPLE 228, except that 1-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide and (4-cyano-2-methoxyphenyl)boronic acid were used as the coupling partners. The final compound was purified via column chromatography (RediSep Gold 12 g silica gel column, gradient elution 0-10% MeOH:DCM) to afford 1-(4-cyano-2-methoxyphenyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.76 (d, J=1.4 Hz, 1H), 8.50 (d, J=1.4 Hz, 1H), 8.48 (s, 1H), 8.00 (dd, J=1.7, 8.9 Hz, 1H), 7.79 (d, J=9.0 Hz, 1H), 7.76 (s, 1H), 7.62 (dd, J=1.1, 7.7 Hz, 1H), 7.57-7.52 (m, 1H), 3.72 (s, 3H). m/z (ESI) 442.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=O)[CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:7][C:6]=2[CH:18]=1.B.CSC.Cl.[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:7][C:6]=2[CH:18]=1
Reactant: Cc1ccc2c(c1)OC(c1ccccc1)C(=O)N2
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: CSC
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)OC(c1ccccc1)CN2
Temperature: 0 °C
Yield: 53.1 %

Procedure:
7-Methyl-2-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one (2.2 g) was dissolved in THF (40 mL), and the mixture was cooled to 0° C. Borane-DMS (2.7 g) was added dropwise under inert atmosphere. After addition, the reaction mixture was heated to 70° C. for 4 h. The reaction was monitored by TLC. After completion of reaction, the mixture was cooled, and to it was added 1N HCl (50 mL). The reaction mixture was basified to pH 12 with NaOH solution and then extracted with EtOAc (3×100 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography using silica (100-200 mesh size) using 8% EtOAc/Hexane as eluent, to provide 1.1 g of pure product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14](O)=[O:15])[CH:11]=[N:10][C:9]=2[N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:29][O:30][C:31](=[O:36])[C:32]([NH2:35])([CH3:34])[CH3:33].C(N(CC)C(C)C)(C)C.[N-]=C=O>ClCCl>[CH3:29][O:30][C:31](=[O:36])[C:32]([NH:35][C:14]([C:12]1[CH:11]=[N:10][C:9]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:13]=1)=[O:15])([CH3:34])[CH3:33]
Reactant: COC(=O)C(C)(C)N
Reactant: O=C(O)c1cnc(N2CCCCC2)c(-c2ccc(F)cc2)n1
Agent: O=C(Cl)C(=O)Cl
Agent: [N-]=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C(C)(C)NC(=O)c1cnc(N2CCCCC2)c(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a dichloromethane (1 ml) solution of 6-(4-Fluoro-phenyl)-5-piperidin-1-yl-pyrazine-2-carboxylic acid (0.107 g, 0.358 mmol, 1.0 eq) was added oxalyl chloride (0.136 g, 1.07 mmol, 3.0 eq). The reaction was stirred at room temperature for 3 hours after which time the solvent was removed in vacuo. The residue was re-dissolved in dichloromethane (3 ml) and added portion-wise to a dichloromethane (1 ml) solution of aminoisobutyric acid methyl ester (0.066 g, 0.429 mmol, 1.2 eq). PS-N,N-diisopropyl-ethylamine (0.31 g, 1.04 mmol, 3.0 eq) resin was added to the reaction and the mixture stirred overnight at room temperature. PS-isocyanate (0.15 g, 0.358 mmol, 1.0 eq) and PS-aminomethyl (0.15 g, 0.358 mmol, 1.0 eq) resin were added to the reaction and the mixture stirred for a further 12 hrs at room temperature. The reaction was filtered and resin washed successfully with dichloromethane (2×3 ml). The combined filtrates were concentrated in vacuo and the residue purified by chromatography on silica gel with heptane:ethyl acetate (1:1) to afford 2-{[6-(4-fluoro-phenyl)-5-piperidin-1-yl-pyrazine-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester. Yield=0.030 g (21%). HPLC-MS=100%; 2.52 min (MW=400; M+1=401.2).
Reaction SMILES: [F:1][C:2]1[C:24]([O:25]C)=[CH:23][C:5]2[NH:6][C:7]([C:9]3[C:21]4[C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14](=[O:22])[C:13]=4[CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.B(Br)(Br)Br.O>ClCCl>[F:1][C:2]1[C:24]([OH:25])=[CH:23][C:5]2[NH:6][C:7]([C:9]3[C:21]4[C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14](=[O:22])[C:13]=4[CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: COc1cc2[nH]c(-c3cccc4c3-c3ccccc3C4=O)nc2cc1F
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C1c2ccccc2-c2c1cccc2-c1nc2cc(F)c(O)cc2[nH]1
Temperature: 0 °C
Reaction time: 20 h
Yield: 89 %

Procedure:
The procedure used in stage 1 of Example 230 is followed. In a 50 ml round-bottomed flask under argon, dissolve 1.07 g of 4-(5-fluoro-6-methoxy-1H-benzimidazol-2-yl)-9H-fluoren-9-one, obtained in stage 3 of Example 268, in 20 ml of dichloromethane, cooled to 0° C. and add 7.8 ml of a molar solution of boron tribromide in dichloromethane. After stirring for 20 hours, the reaction mixture is poured into water, and the insoluble material is drained, washed with water and then dried. After purification by formation of a paste with diisopropyl ether, in this way we obtain 914 mg of 4-(5-fluoro-6-hydroxy-1H-benzimidazol-2-yl)-9H-fluoren-9-one, in the form of a brown powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:20]2[CH:25]=[CH:24][C:23]([C:26]([O:28]C)=[O:27])=[CH:22][N:21]=2)=[CH:4][CH:3]=1.[OH-].[K+].CO.Cl>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:20]2[CH:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22][N:21]=2)=[CH:30][CH:31]=1
Reactant: COC(=O)c1ccc(-c2cc3cc(S(C)(=O)=O)ccc3n2Cc2ccc(F)cc2)nc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc2c(c1)cc(-c1ccc(C(=O)O)cn1)n2Cc1ccc(F)cc1
Yield: 97.7 %

Procedure:
A mixture of 1-(4-fluorobenzyl)-5-methanesulfonyl-2-(5-methoxycarbonylpyridin-2-yl)indole (0.37 g), potassium hydroxide (0.12 g) and methanol (40 ml) was heated under reflux for 3 hours under nitrogen atmosphere. To the reaction solution was added water and the mixture was neutralized with hydrochloric acid. The precipitated crystal was filtered off. The resulting crude crystal was recrystallized (ethanol) to obtain 0.35 g of the desired product.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]1[O:12][C:10](=[O:11])[C@@H:8]([OH:9])[C@H:6]1[OH:7])[OH:4].[CH3:13]O.[OH-].[K+]>CS(O)(=O)=O>[O:11]([CH3:13])[C@@H:10]1[O:12][C@@H:5]2[C@@H:3]([C:2]([O:7][C@@H:6]2[C@H:8]1[OH:9])=[O:1])[OH:4]
Reactant: CO
Reactant: O=C[C@H](O)[C@H]1OC(=O)[C@@H](O)[C@H]1O
Agent: CS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Product: CO[C@@H]1O[C@H]2[C@H](OC(=O)[C@H]2O)[C@H]1O
Yield: 19.3 %

Procedure:
D-Glucurono-6,3-lactone (100.0 g, 0.57 mole), anhydrous methanol (200.0 g, 6.24 moles), and methanesulfonic acid (3 drops) were placed in an oven dried three-necked round bottom flask equipped with mechanical stirrer, thermometer and condenser. The mixture was heated for 24 hours at reflux, cooled and neutralized with 0.1N methanolic KOH. The mixture was filtered and washed with cold methanol (20 ml) yielding 20.9 g of methyl b-D-glucofuranosidurono-6,3-lactone (MbGlucl). By further concentration of the filtrate an additional 28.2 g of MbGlucl was isolated giving a total yield of 49.1 g (45.3%), MP=139° C., purity=99.1% (GC).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[C:10]1([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)CCC>[CH3:9][NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:19]2[CH2:20][CH2:21][CH:16]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:17][CH2:18]2)[N:7]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CNc1ccnc(Cl)n1
Solvent: CCCCO
Product: CNc1ccnc(N2CCC(c3ccccc3)CC2)n1
Temperature: 130 °C
Yield: 74.5 %

Procedure:
Two hundred milliliters of n-butanol was added to 3.0 g (0.02 mole) of 2-chloro-4-methylaminopyrimidine and 8.4 g (0.05 mole) of 4-phenylpiperidine, and the mixture was heated at 130° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and extracted with dichloromethane. The dichloromethane layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4.0 g (yield 71%) of the desired compound as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C@H:16]([OH:25])[CH2:17][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.O.C(N(CC)CC)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>ClCCl>[C:34]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C@H:16]([OH:25])[CH2:17][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1cccc(-c2ccc(OC[C@H](O)CCc3cccnc3)cc2)c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cccc(-c2ccc(OC[C@H](O)CCc3cccnc3)cc2)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
(2R)-1-(3'-Hydroxybiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol (0.34 g, Example 99) was dissolved in dichloromethane (10 ml) and cooled to 0° C. using ice and water. Triethylamine (0.14 ml) and acetic anhydride (0.09 ml) were added and the reaction mixture allowed to room temperature with stirring for 18 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with dichloromethane:methanol (97:3) to give the title compound as an oil (0.20 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([NH2:29])(=O)C.B(F)(F)F.CCOCC>C1(C)C(C)=CC=CC=1>[CH2:19]([O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[N:29]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:8][CH:9]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(N)=O
Reactant: O=C(COCc1ccccc1)c1ccccc1OCc1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: c1ccc(COc2ccccc2-c2coc(-c3ccccc3)n2)cc1
Yield: 29.3 %

Procedure:
3.46 g of 2-benzyloxy-1-(2-benzyloxy-phenyl)-ethanone according to step (c) are refluxed with 2.95 g of acetamide and 0.9 ml of boron trifluoride etherate in 100 ml of anhydrous xylene over 20 hours. After the solution obtained has been cooled and washed with water it is dried over sodium sulphate, the solvent is distilled off in vacuo and the residue remaining is chromatographed on silica gel (toluene). In addition to re-isolated educt, 1 g (31%) of the target compound is isolated.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1(Cl)[N+:14]([O-])=O)[C:6]#[N:7])[CH3:2].CCCCCC.C(Cl)(Cl)[Cl:26]>C(O)(=O)C.[Zn]>[CH2:1]([O:3][C:4]([C:5]1[C:8]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[Cl:26])[NH:14][C:6]=1[NH2:7])=[O:18])[CH3:2]
Reactant: CCOC(=O)C(C#N)C1C=CC=CC1(Cl)[N+](=O)[O-]
Reactant: ClC(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CCOC(=O)c1c(N)[nH]c2cccc(Cl)c12
Temperature: 55 °C

Procedure:
4 (18 g, 67 mmol) in 250 mL glacial acetic acid, was treated with a single charge of 18 g of zinc dust. The mixture was heated at 55° C. for 45 minutes. Later 6 g more zinc dust was added. After heating for another 105 minutes, the yellow mixture was filtered through a pad of celite. The pad was washed with acetic acid and the filtrate was concentrated to a residue that was distributed between chloroform and water. The organic phase was washed with NaHCO3 (5%) to provide a pink precipitate which was filtered, dried over P2O5, dissolved in methanol, added silica gel and converted to a silica gel plug by removing the solvent under reduced pressure. The plug was transferred on top of a column packed with silica gel, ten times the weight of plug, eluted with hexane, chloroform, 5% ethylacetate in chloroform and 10% ethylacetate in chloroform. Fractions containing the product 5 (TLC) were pooled and evaporated to give a pink solid. The overall yield from 3 to 5 was 63%. TLC Rf 0.187 (hexane-chloroform 1:1); mp 140-142° C.; 1H NMR (DMSO-d6) δ 1.25-1.28 (t, 3H, CH3); 4.18-4.20 (q, 2H, CH2); 6.85 (bs, 2H, 2-NH2, exch); 6.92-7.09 (m, 3H, phenyl); 10.93 (bs, 1H, 9-NH, exch). Anal. Calculated (C11HnClN2O2): C, 55.36; H, 4.65; N, 11.74; Cl, 14.85. Found: C, 55.39; H, 4.60; N, 11.65; Cl, 14.96.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[Cl:21])[NH:10][C:9]=2[C:8]([OH:22])=[CH:7][CH:6]=1)=[O:4].O[Li].O>C1COCC1.CO.O>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:11]1[NH:10][C:9]2[C:8]([OH:22])=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=2[N:12]=1
Reactant: COC(=O)c1ccc(O)c2[nH]c(-c3ccc(F)cc3Cl)nc12
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(O)c2[nH]c(-c3ccc(F)cc3Cl)nc12
Temperature: 25 °C
Yield: 89.4 %

Procedure:
Wang resin-supported 2-(2-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methyl ester (570 mg, 0.47 mmol) obtained in step 5 was dissolved in THF, LiOH.H2O (99 mg, 2.35 mmol) in MeOH—H2O was added thereto and the resulting mixture was refluxed for 5 hours. The resulting solution was cooled to room temperature and filtered. The filtrate was washed with MeOH and CH2Cl2, and dried to obtain the title compound (551 mg, 0.42 mmol) in a yield of 90%.