Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:14]([NH2:15])=[C:13]([NH:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]([CH3:26])=[C:11]([CH3:27])[N:10]=1.[C:28](Cl)(=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32]>C(#N)C>[Cl:8][C:9]1[C:14]([NH:15][C:28](=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32])=[C:13]([NH:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]([CH3:26])=[C:11]([CH3:27])[N:10]=1
Reactant: Cc1nc(Cl)c(N)c(NCCOc2ccccc2)c1C
Reactant: CCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCC(=O)Nc1c(Cl)nc(C)c(C)c1NCCOc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Triethylamine (1.39 ml), anhydrous acetonitrile (100 ml), and 2-chloro-5,6-dimethyl-N4-(2-phenoxyethyl)pyridine-3,4-diamine (2.92 g) from Part A of Example 2 were combined and cooled to 0° C. in an ice bath. Valeryl chloride (0.59 ml) was slowly added to the reaction mixture. After 2 hours, the reaction mixture was heated to 55° C. for 24 hours, at which point HPLC analysis indicated the reaction was complete. The reaction mixture was cooled and the solvent was removed under reduced pressure. The resulting oil was dissolved in dichloromethane and washed with water. The organic layer was dried with magnesium sulfate and the solvent was removed under reduced pressure. The product was then passed through a silica gel column using 50/50 ethyl acetate/hexane as the eluant. The resulting light brown solid was used in the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[B:9](OC)([O:12]C)[O:10]C.Cl>C1COCC1>[OH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:9]([OH:12])[OH:10]
Reactant: COB(OC)OC
Reactant: Oc1ccccc1Br
Agent: Cl
Solvent: C1CCOC1
Product: OB(O)c1ccccc1O
Temperature: 0 °C
Yield: 95.3 %

Procedure:
2-Bromophenol (10.0 g, 57.8 mmol) was dissolved in dry THF (100 ml) in a dry 250 ml flask flushed with nitrogen. The mixture was chilled in a dry ice/2-propanol bath, n-butyl lithium (51 ml of a 2.5M solution in hexanes, 127.2 mmol) was added, then the cooling bath was exchanged for an ice-water bath. The reaction was stirred for an hour at 0° C. then trimethyl borate (6.9 ml , 60.7 mmol) was added to the slurry which became homogeneous after a few minutes. The mixture was stirred at room temperature overnight, then treated with 2N aqueous HCl to pH 3, mixed well for 30 minutes and extracted with ether (3×25 ml). The organic materials were combined, dried (MgSO4), then concentrated under reduced pressure which gave 7.6 g (91%) of 2-hydroxybenzene boronic acid as a white solid, m.p. 156°-158° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.Br[CH2:11][C:12]([C:14]1[O:15][C:16]([Br:19])=[CH:17][CH:18]=1)=O>C(O)C>[Br:19][C:16]1[O:15][C:14]([C:12]2[N:1]=[C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]3[CH:11]=2)=[CH:18][CH:17]=1
Reactant: O=C(CBr)c1ccc(Br)o1
Reactant: N#Cc1ccc(N)nc1
Solvent: CCO
Product: N#Cc1ccc2nc(-c3ccc(Br)o3)cn2c1
Yield: 74 %

Procedure:
A mixture of 6-Amino-nicotinonitrile (1.19 g, 10 mmol) and 2-Bromo-1-(5-bromofuran-2-yl)-ethanone (2.66 g, 10 mmol) in ethanol (50 mL) was refluxed for 24 h. The precipitate was filtered and neutralized with aqueous NaHCO3 solution. The precipitate was filtered and dried to furnish 3a in 74% yield, mp 212-214° C. (EtOH). 1H NMR (DMSO-d6); δ 6.75 (d, J=3.6 Hz, 1H), 6.98 (d, J=3.6 Hz, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 8.29 (s, 1H), 9.30 (s, 1H). 13C NMR; δ 150.5, 144.2, 137.3, 134.3, 125.4, 121.9, 117.2, 116.9, 113.9, 110.4, 109.8, 97.2. MS (m/z, rel.int.); 288 (M+, 100), 161 (8). Anal. Calcd. for 3a (C12H6BrN3O): C % 50.03, H % 2.10. Found: C % 49.97, H % 2.17.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19]CC)=[O:18])=[C:15]([O:22][CH3:23])[C:14]([C:24]3[CH:28]=[CH:27][O:26][N:25]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].O1CCOCC1.Cl>C(O)(C)C>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[C:15]([O:22][CH3:23])[C:14]([C:24]3[CH:28]=[CH:27][O:26][N:25]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccon2)c1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1COCCO1
Product: COc1c(-c2ccon2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
A mixture of ethyl 6-(benzenesulphonylmethyl)-3-(isoxazol-3-yl)-2-methoxybenzoate (Intermediate 47, 0.03 g), lithium hydroxide (1M aqueous solution, 0.4 ml) and dioxane (1 ml) was stirred at room temperature overnight then heated at 40° C. for 8 hours. It was left to stand at room temperature overnight then heated at 60° C. for 6 hours. The resultant mixture was acidified by addition of concentrated hydrochloric acid followed by addition of isopropanol (˜0.5 ml). The mixture was purified by preparative HPLC (C18), eluting with a mixture of methanol and water containing 0.1% formic acid with a gradient of 40-98% to give 6-(benzenesulphonylmethyl)-3-(isoxazol-3-yl)-2-methoxybenzoic acid (0.02 g) as a clear glass.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].O1CCCC1.[Cl:9][C:10]1[N:11]=[C:12]([C:17]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][C:21]2=O)=[O:18])[NH:13][C:14]=1[CH2:15][CH3:16].C([BH3-])#N.[Na+].C(O)(=O)C>>[Cl:9][C:10]1[N:11]=[C:12]([C:17]([NH:19][C@@H:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][C@H:21]2[NH:3][CH2:1][CH3:2])=[O:18])[NH:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1[nH]c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2=O)nc1Cl
Reactant: CCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCN[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Temperature: 70 °C
Reaction time: 15 h
Yield: 46 %

Procedure:
A 2 N ethylamine/tetrahydrofuran solution (5 mL) was added to tert-butyl 4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-oxopiperidine-1-carboxylate obtained in Example (201c) (102 mg, 0.275 mmol), and the mixture was heated under reflux at 70° C. for four hours. The reaction solution was concentrated under reduced pressure, and then tetrahydrofuran (2 mL) and methanol (2 mL) were added. A 2 N ethylamine-tetrahydrofuran solution (138 μL), sodium cyanoborohydride (86.4 mg, 1.38 mmol) and acetic acid (110 μL, 1.93 mmol) were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and aqueous saturated sodium bicarbonate solution was added to the residue, followed by extraction with chloroform. The resulting organic layer was dried over anhydrous sodium sulfate, and then the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform:methanol=10:1 v/v) to obtain 46 mg of the cis isomer of the title compound (42%) as a pale yellow oily substance and 51 mg of the trans isomer of the title compound (46%) as a pale yellow oily substance.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:15]=4[N:14]=[CH:13]3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:25]([O:27][C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH2:30])[CH3:26].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:22][O:21][C:19]1[C:18]([O:23][CH3:24])=[CH:17][C:16]2[N:12]([CH2:11][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([NH:30][C:29]5[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=5[O:27][CH2:25][CH3:26])[S:3][C:4]=4[CH:10]=3)[CH:13]=[N:14][C:15]=2[CH:20]=1
Reactant: COc1cc2ncn(Cc3ccc4nc(Br)sc4c3)c2cc1OC
Reactant: CCOc1ccccc1N
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccccc1Nc1nc2ccc(Cn3cnc4cc(OC)c(OC)cc43)cc2s1
Temperature: 110 °C
Yield: 22 %

Procedure:
To a suspension of 2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole (60 mg, 0.15 mmol) from Example 2 and 2-ethoxyaniline (61 mg, 0.46 mmol) in anhydrous DMA (600 μL) at rt was added DIEA (155 μL, 0.90 mmol). The mixture was heated in a sealed tube at 110° C. for 72 h. After cooling to rt, the resulting reaction solution was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford 6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-(2-ethoxyphenyl)benzo[d]thiazol-2-amine (15.2 mg, 22%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.31-8.44 (m, 1H), 8.18 (s, 1H), 7.76 (d, J=1.1 Hz, 1H), 7.51 (d, J=8.1 Hz, 1H), 7.29 (dd, J=1.5, 8.3 Hz, 1H), 7.19 (d, J=2.4 Hz, 2H), 6.91-7.07 (m, 3H), 5.47 (s, 2H), 4.12 (q, J=6.8 Hz, 2H), 3.76 (s, 6H), 1.37 (t, J=7.0 Hz, 3H). LCMS (ESI) m/z 461 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:13]([C:16]([F:20])=[C:17]([F:19])[F:18])[CH2:14]Br>C(#N)C>[F:20][C:16](=[C:17]([F:19])[F:18])[CH2:13][CH2:14][S:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1
Reactant: Sc1nccs1
Reactant: FC(F)=C(F)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC(F)=C(F)CCSc1nccs1
Yield: 86.4 %

Procedure:
2-Mercaptothiazole (5.18 g), potassium carbonate (6.72 g) and 4-bromo-1,1,2-trifluorobutene-1 (9.21 g) are refluxed in acetonitrile (60 ml) in the presence of argon gas for 6 hours by heating. After the reaction mixture has reached room temperature, it is filtered and the solvent is distilled off. The residue is dissolved in dichloromethane and washed with 5% aqueous solution of sodium hydroxide and water in this order. It is dried over unhydrous sodium sulfate and purified by column chromatography (eluent: dichloromethane) to obtain 2-(3,4,4-trifluoro-3-butenyl-thio)thiazole (8.6 g) as pale yellow liquid (n20D 1.5200).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21]CCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(O)=O)[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1.[F:47][C:48]([F:76])([C:66]([F:75])([F:74])[C:67]([F:73])([F:72])[C:68]([F:71])([F:70])[F:69])[CH2:49][CH2:50][CH2:51][CH:52]([CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH:64]=C)[C:53]([O:55]CC)=[O:54]>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][CH2:58][CH:52]([CH2:51][CH2:50][CH2:49][C:48]([F:47])([F:76])[C:66]([F:74])([F:75])[C:67]([F:72])([F:73])[C:68]([F:70])([F:69])[F:71])[C:53]([OH:55])=[O:54])[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1
Reactant: C=CCCCCCCC(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Reactant: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O
Product: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCCC(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 8 and the ethyl 2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-9-decenoate prepared in Example 7, a procedure analogous to that as shown in Example 8 was repeated to give 11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)undecanoic acid.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35](O)=[O:36])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][OH:47]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][C:35]([NH:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][OH:47])=[O:36])=[CH:31][CH:32]=2)=[CH:38][CH:39]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCC(=O)O)cc2)cc1
Reactant: NCCCCCCO
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCC(=O)NCCCCCCO)cc2)cc1

Procedure:
The product from Example 104A and 6-amino-1-hexanol processed as described in Example 147 to provide the title compound. 1H NMR (500 MHz, DMSO-D) δ8.95 (s, 1 H), 7.73 (t, 1 H), 7.26 (m, 6 H), 7.19 (m, 3 H), 7.04 (t, 1 H), 6.96 (m, 2 H), 6.87 (m, 4 H), 4.03 (d, 4 H), 3.35 (m, 2 H), 3.00 (dd, 2 H), 2.91 (s, 3 H), 2.78 (t, 2 H), 2.39 (s, 3 H), 2.33 (t, 2 H), 1.37 (m, 4 H), 1.23 (m, 4 H); MS (APCI+) m/z 645 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]=[C:8]=[O:9])[CH:2]=1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH2:15][CH2:14]2>>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:8](=[O:9])[NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:15][CH2:14]2
Reactant: O=C=Nc1cccnc1
Reactant: Clc1ccc2c(c1)CCN2
Product: O=C(Nc1cccnc1)N1CCc2cc(Cl)ccc21

Procedure:
The title compound was prepared as in the method of (Example 2) from 3-pyridylisocyanate and 5-chloroindoline (D35) to give (E18) (1.4 g, 82%) m.p. 204°-5° C.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1>C1COCC1>[N:8]1([CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C=CC(=O)OCC
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: CCOC(=O)CCN1CCCC1
Reaction time: 3.5 h

Procedure:
Ethyl acrylate (110.0 g; 1.1 mol) was dissolved in THF (250 ml). To this a solution of pyrrolidine (71.5 g; 1.0 mol) in THF (100 ml) was added dropwise in 75 minutes, after which stirring was continued for 3.5 hours at room temperature. The reaction mixture was evaporated by means of a rotary evaporator. The yield was 161.8 g (94%).
Reaction SMILES: O.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][N:12]=[C:11]([C:14](O)=[O:15])[C:10]=2[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[K+]>C1COCC1.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[NH:13][N:12]=[C:11]([CH2:14][OH:15])[C:10]=2[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)=[CH:7][CH:8]=1
Reactant: O=C(O)c1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Yield: 56.5 %

Procedure:
To a suspension of 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-carboxylic acid, monohydrate prepared in accordance with Example A-200 (0.526 g, 2.0 mmol) in dry THF (15 ml) at reflux under nitrogen, a solution of 1N lithium aluminum hydride in THF (4.0 ml, 4.0 mmol) was added dropwise over 15 minutes. A precipitate formed. The mixture was boiled for an additional hour. Excess lithium aluminum hydride was then decomposed by cautiously adding a solution of 4N potassium hydroxide in water (0.5 ml). Upon hydrolysis, a white salt precipitated. After the addition was complete, the mixture was heated at reflux for 15 minutes. The hot solution was filtered by suction through a Buchner funnel, and remaining product was extracted from the precipitate by refluxing with THF (15 ml) for 1 hour, followed again by suction filtration. The combined filtrates were concentrated under reduced pressure. The resulting residue was taken into ethyl acetate, washed with water and brine, dried over MgSO4 to give a crude product (0.45 g). Recrystallization of the crude product from methanol gave 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-methanol (0.2808 g, 56.5%). DSC: 260.26° C.; Anal. Calc'd for C15H12N3FO (269): C, 66.91; H, 4.49; N, 15.60; Found: C, 66.07; H, 4.63; N, 15.20. MS (MH+): 270 (base peak).
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:41][C:42]3[CH:47]=[C:46]([CH3:48])[C:45]([OH:49])=[C:44]([CH3:50])[CH:43]=3)[C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH:29]4[CH2:34][CH2:33][N:32]([CH2:35][C:36]([O:38]CC)=[O:37])[CH2:31][CH2:30]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:51]=[CH:52][CH:53]=[CH:54][C:6]=2[NH:5]1>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C@H:20]([CH2:41][C:42]3[CH:47]=[C:46]([CH3:48])[C:45]([OH:49])=[C:44]([CH3:50])[CH:43]=3)[C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH:29]4[CH2:30][CH2:31][N:32]([CH2:35][C:36]([OH:38])=[O:37])[CH2:33][CH2:34]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:15][CH2:16]2)[CH2:9][CH2:8][C:7]2[CH:51]=[CH:52][CH:53]=[CH:54][C:6]=2[NH:5]1
Reactant: CCOC(=O)CN1CCC(N2CCN(C(=O)[C@@H](Cc3cc(C)c(O)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(CC(=O)O)CC3)CC2)cc(C)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 96 mg (4.00 mmol) LiOH in 5 mL water was added at RT to a solution of 1.77 g (2.46 mmol) of (R)-2-[4-(1-ethoxycarbonylmethyl-piperidin-4-yl)-piperazin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 20 mL THF and the reaction solution was stirred overnight at RT. The mixture was evaporated down i.vac., the residue was taken up in 10 mL water and the aqueous phase was washed with 10 mL EtOAc. The aqueous phase was combined with 4 mL of 1 M HCl and this was again washed with 10 mL EtOAc. The aqueous phase was concentrated by evaporation i. vac. and dried. The product which contained LiCl was further reacted without purification.
Reaction SMILES: [C:1]1([CH:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]([CH2:26][C:27]([O:29]CC)=[O:28])[C:18]3=[O:32])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>O>[OH2:28].[C:33]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]([CH2:26][C:27]([OH:29])=[O:28])[C:18]3=[O:32])[CH2:12][CH2:13]2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1.[C:1]1([CH:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]([CH2:26][C:27]([OH:29])=[O:28])[C:18]3=[O:32])[CH2:10][CH2:9]2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cn1c(=O)n(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cn1c(=O)n(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc21

Procedure:
A mixture of 9.8 parts of ethyl 3-{3 -[4-(diphenylmethyl)1-piperazinyl]propyl}-2,3-dihydro-2-oxo-1H-benzimidazole-1-acetate, 1.2 parts of sodium hydroxide and 150 parts of water is stirred and refluxed for 5 minutes (+80° C.). The reaction mixture is filtered and the filtrate is acidified with acetic acid to pH 5.8-6: a sticky precipitate is formed. It is separated and crystallized from ethanol and water. The product is filtered off and dried in vacuo at 100° C. for 3 hours, yielding 6 parts of 3-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-2,3-dihydro-2-oxo-1H-benzimidazole-1-acetic acid hemihydrate; mp. 138.7° C.
Reaction SMILES: [I-].[K+].C[Si](C)(C)Cl.[CH2:8]([C:10]1[CH:11]=[C:12]([C:19]2[O:23][C:22]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)=[O:25])=[CH:21][CH:20]=2)[C:13]([CH3:18])=[N:14][C:15]=1[O:16]C)[CH3:9]>C(#N)C.O>[CH2:8]([C:10]1[C:15](=[O:16])[NH:14][C:13]([CH3:18])=[C:12]([C:19]2[O:23][C:22]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:28][CH2:27]3)=[O:25])=[CH:21][CH:20]=2)[CH:11]=1)[CH3:9]
Reactant: CCc1cc(-c2ccc(C(=O)N3CCN(c4ccccc4)CC3)o2)c(C)nc1OC
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCc1cc(-c2ccc(C(=O)N3CCN(c4ccccc4)CC3)o2)c(C)[nH]c1=O
Temperature: 70 °C

Procedure:
Two equivalents of potassium iodide and two equivalents of trimethylchlorosilane are added to a solution of one equivalent of [5-(5-ethyl-6-methoxy-2-methylpyridin-3-yl)-furan-2-yl]-(4-phenylpiperazin-1-yl)-methanone in anhydrous acetonitrile (3-5 ml/mmol) under argon, the latter being prepared in accordance with the procedure set out in PREPARATION 6, and the cloudy mixture is heated at 60-80° C. for 1-3 h. The mixture is then cooled to rt and diluted with water. The precipitated product is filtered off with suction, washed with water and dried in a vacuum oven at 40° C. The filtrate is extracted with ethyl acetate and, after concentration, occasionally affords further product, which is purified by chromatography on silica gel. MS: m/e=392 (M+H). 1H NMR (D6-DMSO, δ ppm): 11.79 (s, 1H); 7.53 (s, 1H); 7.27 (m, 2H); 7.13 (d, 1H); 6.99 (m, 2H); 6.85 (m, 1H); 6.69 (d, 1H); 3.85 (br s, 4H); 3.23 (m, 4H); 2.50 (m, 5H); 1.12 (t, 3H).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:29])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:27])=[O:26])=[CH:21][C:20]=3[F:28])[CH:13]=2)[CH2:9][C:10]=1[OH:11])(=O)[CH2:2][CH3:3].Cl.[CH2:31]([O:33][NH2:34])[CH3:32].C([O-])(=O)C.[Na+].O>C(Cl)Cl.C(O)C>[CH2:31]([O:33][N:34]=[C:1]([C:5]1[C:6](=[O:29])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:27])=[O:26])=[CH:21][C:20]=3[F:28])[CH:13]=2)[CH2:9][C:10]=1[OH:11])[CH2:2][CH3:3])[CH3:32]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2cccc(Oc3ccc(S(C)=O)cc3F)c2)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CCON=C(CC)C1=C(O)CC(c2cccc(Oc3ccc(S(C)=O)cc3F)c2)CC1=O
Reaction time: 16 h

Procedure:
A solution of 0.45 g (1.0 mmol) of 2-propionyl-3-hydroxy-5-(3-(2-fluoro-4-(methylsulfinyl)phenoxy)-phenyl)cyclohex-2-en-1-one in 3 mL of methYlene chloride and 10 mL of absolute ethanol, at room temperature was treated with 0.14 g (1.5 mmol) of ethoxyamine hydrochloride and 0.12 g (1.5 mmol) of anhydrous sodium acetate. After stirring under a nitrogen atmosphere for 16 hours, the mixture was poured into 100 mL of water and extracted twice with 30 mL portions of methylene chloride. The combined extracts were dried over MgSO4, filtered and the solvent evaporated off leaving the product as a yellow oil. Purification via flash chromatography (silica gel, methylene chloride/acetone) gave the above named product as a yellow oil in a yield of 0.33 g (66 percent of theoretical). 1H NMR (CDCl3): δ1.10-1.50 (m, 6H, both --CH2CH3 's), 2.60-3.55 (m includes s at 2.75 for CH3SO--, 10H), 4.21 (q, J=7 Hz, 2H, --OCH2), 6.80-7.56 (m, 7H, aromatics), 14.5-15.0 (very broad s, enol H) (Compound 6).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:17][CH2:16][N:15](C(OCC4C=CC=CC=4)=O)[CH2:14][CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1>Cl.O>[I:11][C:10]1[N:9]=[C:8]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=12
Reactant: Nc1nccn2c(C3CCN(C(=O)OCc4ccccc4)CC3)nc(I)c12
Agent: Cl
Solvent: O
Product: Nc1nccn2c(C3CCNCC3)nc(I)c12
Temperature: 25 °C

Procedure:
Benzyl 4-(8-amino-1-iodoimidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxylate (1.00 g. 2.10 mmol) was dissolved in concentrated HCl (30 mL) at 0° C. The reaction was stirred at rt. overnight. The reaction mixture was diluted with water (30 mL) and washed with EtOAc (30 mL×3), the aqueous phase was removed under reduced pressure to give a residue which was used for next step without further purification. MS (ES+): m/z 343.78 [MH+].