Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].[H][H]>[Pd].C(O)(=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(C#N)ccc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc(CN)ccc1F
Reaction time: 8 h
Yield: 134 %

Procedure:
Add 4-fluoro-3-methoxy-benzonitrile (2 g, 0.01 mol), 10% palladium on carbon (0.400 g) and glacial acetic acid (120 ml) to a pressure vessel. Purge the reaction vessel with nitrogen, purge the reaction vessel with hydrogen, pressurize the reaction mixture with hydrogen (415 Kpa), seal the vessel, and agitate the reaction. After 8 hours stop the agitation, vent the excess hydrogen from the vessel and purge the vessel with nitrogen. Filter the reaction mixture to remove the 5% palladium on carbon and return the filtrate for product isolation. Concentrate the crude solution, re-dissolve in CH2Cl2 (80 mL) and washe with 5N NaOH (35 mL). Separate the organic and aqueous phases and extract the aqueous with additional CH2Cl2 (20 mL). Combine the organic solutions, dry, filter and concentrate to give the crude material 2.08 g (100%). The title compound as the major product (Rf=0.12, 10% MeOH/CH2Cl2) is used without further purification. MS (ES+) 156.1 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 7.01 (dd, 1H, J=8.2, 11.4), 6.95 (dd, 1H, J=2.1, 8.4), 6.80 (m, 1H), 3.89 (s, 3H), 3.82 (s, 2H), 1.54 (br s, 2H).
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH3:7])(=[O:4])=[O:3].[Li]CCCC.[P:13](Cl)([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14].[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH2:16]([O:15][P:13]([CH2:1][S:2]([O:5][CH2:6][CH3:7])(=[O:4])=[O:3])([O:18][CH2:19][CH3:20])=[O:14])[CH3:17]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CCOS(C)(=O)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOP(=O)(CS(=O)(=O)OCC)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
A solution of ethyl methanesulfonate (4.27 mL, 40.3 mmol) in 100 mL of dry THF was treated at -78° C. with 19.3 mL (44.4 mmol) of n-BuLi in hexane. After 15 min. diethyl chlorophosphate (3.30 ml, 22.2 mmol) was added. The solution was kept at -78° C. for 0.5 h and allowed to stay at -50° C. for 1 h. Saturated ammonium chloride (75 mL) was added to the solution and the mixture warmed to room temperature. The mixture was concentrated (THF removed), diluted with water and extracted with methylene chloride (3×70 mL). The combined organic fractions were dried (MgSO4), concentrated and purified by distillation to yield 3.86 g (70%) of title compound.
Reaction SMILES: O=O.[CH3:3][O:4]/[C:5](=[CH:9]\[C:10]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:12][CH:11]=1)/[C:6]([OH:8])=[O:7].C1([C@@H](N)C)C=CC=CC=1.[H][H]>ClCCl>[CH3:3][O:4][C@H:5]([CH2:9][C:10]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: [H][H]
Reactant: CO/C(=C\c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Agent: C[C@H](N)c1ccccc1
Agent: O=O
Solvent: ClCCl
Product: CO[C@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a glove box (O2 content≦2 ppm), a 50-ml stainless steel autoclave was charged with 0.66 mg of [Ru(η5-2,4-DMP)((R)—(S)—PPF—PtBu2)(NCMe)]BF4 (0.0008 mmol, S/C 3,000) and 5 ml of dichloromethane. The resulting violet solution was stirred for 2 h at r.t. Then, 1.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (2.30 mmol), 10 ml of dichloromethane and 0.06 ml of (S)-1-phenylethylamine (0.47 mmol) were added. The autoclave was sealed and the hydrogenation was run under stirring at 40° C. under 30 bar of hydrogen. After 16 h the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford (R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 99.5% (99.9% conversion) and an enantiomeric purity of 90%.
Reaction SMILES: [F:1][C:2]1[C:7]2=[N:8][Se:9][N:10]=[C:6]2[C:5]([S:11](Cl)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH2:15]([N:17]([CH2:21]C)[CH2:18][CH2:19][NH2:20])C.C(N(CC)CC)C>C(#N)C>[F:1][C:2]1[C:7]2=[N:8][Se:9][N:10]=[C:6]2[C:5]([S:11]([NH:20][CH2:19][CH2:18][N:17]([CH3:21])[CH3:15])(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)c2n[se]nc12
Reactant: CCN(CC)CCN
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(C)CCNS(=O)(=O)c1ccc(F)c2n[se]nc12
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
7-fluoro-2,1,3-benzoselenadiazole-4-sulfonyl chloride (75 mg) was dissolved in 3 ml of acetonitrile. After the addition of N,N-diethylethylenediamine (22 mg) and triethylamine (351), the mixture was stirred on ice for 30 min. The reaction mixture was evaporated to dryness in vacuo and the residue was dissolved in CH2Cl2 and chromatographed on silica gel using CH2Cl2-CH3OH (93:7) to yield 7-fluoro-N-[2-(dimethylamino)ethyl]-2,1,3-benzoselenadiazole-4-sulfonamide (49 mg, 56%) as red powder. mp: 117-120° C. 1H-NMR δH8.09 (1H, d, J=7.5 Hz), 7.24 (1H, d, J=7.5 Hz), 2.93 (2H, t, J=6.7 Hz), 2.27 (2H, t, J=6.7 Hz), 1.98 (6H, s) in CD3OD; ESI-MSm/z 353 [(M+H)+]
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[CH3:14][S:15]([O:13][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCCC1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
Into a one liter, four-necked, round bottom flask equipped with stirrer, condenser, thermometer, and addition funnel, 25.3 parts of triethylamine, 17.2 parts of cyclopentanol, and 190.0 grams of methylene chloride were mixed under a nitrogen blanket and cooled to -40° C. with a dry ice-acetone bath. To this mixture 26.2 parts of methanesulfonyl chloride were added over one hour. The reaction mixture was stirred at -40° C. for an additional two hours and then allowed to warm to 0° C. and maintained at this temperature for eighteen hours. The mixture was vacuum filtered and then washed successively with chilled dilute sulfuric acid (twice with 200 part-portions), dilute sodium bicarbonate (three times with 200 part-portions), and water (twice with 200 part-portions). Subsequently the mixture was dried over sodium sulfate, filtered, and the solvent removed in vacuo to yield cyclopentyl methanesulfonate.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:7])[CH2:4][CH2:5][SH:6].[CH2:8]([C:15]([N:33]([CH3:35])[CH3:34])([CH2:31][CH3:32])[C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>CN(C)C=O>[CH2:8]([C:15]([N:33]([CH3:35])[CH3:34])([CH2:31][CH3:32])[C:16]([C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([S:6][CH2:5][CH2:4][CH2:3][SH:7])=[CH:26][CH:25]=2)=[CH:22][CH:23]=1)=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: SCCCS
Reactant: CCC(Cc1ccccc1)(C(=O)c1ccc(-c2ccc(Br)cc2)cc1)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(Cc1ccccc1)(C(=O)c1ccc(-c2ccc(SCCCS)cc2)cc1)N(C)C
Temperature: 100 °C
Reaction time: 2 h

Procedure:
9.2 mmol of sodium hydride are suspended in 40 ml of dry dimethylformamide and 2.3 ml (23 mmol) of 1,3-propanedithiol are added dropwise. Then 2.0 g (4.6 mmol) of 2-benzyl-1-(4'-bromo-biphenyl-4-yl)-2-dimethylamino-butan-1-one (prepared by the method described in U.S. Pat. No. 5,534,629) in 60 ml of dimethylformamide are added dropwise. After stirring the solution at 100° C. for 2 h, the solution is poured into water. The crude product is extracted with methylene chloride, washed with water, dried over MgSO4, and concentrated. The residue is purified by column chromatography on silica gel with ethyl acetate-hexane (10:90) as an eluent. The structure of the product is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm] 0.72 (t, 3H), 1.37 (t, 1H), 1.84-2.01 (m, 3H), 2.09 (dq, 1H), 2.40 (s, 6H), 2.68 (dt, 2H), 3.10 (t, 2H), 3.23 (s, 2H), 7.15-7.29 (m, 5H), 7.41 (d, 2H), 7.55-7.62 (m, 4H), 8.41 (d, 2H).
Reaction SMILES: [I-].[CH3:2][N+:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[Br-:20].[C:21]([CH2:24][CH2:25][CH2:26][CH2:27][N+:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[S:30][C:29]=1[CH3:37])([OH:23])=[O:22].[Br-].CC1SC2C=CC=CC=2[NH+]=1>C(Cl)Cl>[Br-:20].[CH3:2][N+:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:37]=[C:29]2[N:28]([CH2:27][CH2:26][CH2:25][CH2:24][C:21]([OH:23])=[O:22])[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[S:30]2)=[CH:5][CH:4]=1
Reactant: C[n+]1cccc2ccccc21
Reactant: Cc1sc2ccccc2[n+]1CCCCC(=O)O
Agent: Cc1[nH+]c2ccccc2s1
Agent: [Br-]
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[n+]1ccc(C=C2Sc3ccccc3N2CCCCC(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Next, 1.36 g (5.0 mmol) of N-methylquinolinium iodide (Compound III) (FW 271.10), 7.0 mL (50 mmol) of triethylamine (FW 101.19, d=0.726), and 100 mL of methylene chloride were added to 3.24 g of mixture (crude product) containing Compound 112 (3-(4-carboxybutyl)-2-methylbenzothiazolium bromide) and 2-methylbenzothiazolium bromide. As a result, a transparent solution was obtained. This solution was stirred at 25° C. for 16 hours. Thereafter, the solvent was evaporated under reduced pressure. Acetone (200 mL) was then added to the residue and the precipitate obtained thereby was filtered, which then was washed with acetone. The residue thus obtained was dried under reduced pressure, and the red residue obtained after drying was washed with distilled water (50 mL). This further was filtered, which was washed with distilled water and then dried under reduced pressure. Thus a target substance (Compound 107) was obtained as red powder (654 mg, 1.39 mmol, 28%). This red powder was confirmed to be the target substance (Compound 107) through a comparison in 1HNMR spectrum with the reference value. Peak values from 1HNMR and 13CNMR (DMSO-d6) and the measured values of HRMS (ESI) are indicated below. Furthermore, FIG. 6 shows the 1HNMR spectrum (DMSO-d6) of Compound 107. Compound 107: 1HNMR (DMSO-d6): δ 8.74 (d, J=8.3 Hz, 1H), 8.51 (d, J=7.3 Hz, 1H), 7.94-7.89 (m, 3H), 7.74-7.70 (m, 1H), 7.65 (d, J=8.3 Hz, 1H), 7.55-7.51 (m, 1H), 7.36-7.32 (m, 1H), 7.21 (d, J=7.3 Hz, 1H), 6.83 (s, 1H), 4.47 (t, J=7.1 Hz, 2H), 4.07 (s, 3H), 2.22 (t, J=6.6 Hz, 1H), 1.77-1.63 (m, 4H);
Reaction SMILES: C([O:5][C:6](=[O:30])[CH:7]([NH:17][C:18]([NH:20][CH:21]([C:27]([OH:29])=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:19])[CH2:8][CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])(C)(C)C.O1CCOCC1.[I:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1>O>[C:27]([CH:21]([NH:20][C:18](=[O:19])[NH:17][CH:7]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:6]([OH:5])=[O:30])[CH2:22][CH2:23][CH2:24][CH2:25][NH:26][S:44]([C:41]1[CH:42]=[CH:43][C:38]([I:37])=[CH:39][CH:40]=1)(=[O:46])=[O:45])([OH:29])=[O:28]
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)CCC(NC(=O)NC(CCCCN)C(=O)O)C(=O)OC(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CCC(NC(=O)NC(CCCCNS(=O)(=O)c1ccc(I)cc1)C(=O)O)C(=O)O
Temperature: 50 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
In a round bottom flask 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di t-butyl ester (300 mg, 0.62 mmol) is suspended in water (10 mL) and 1,4dioxane (10 mL) and TEA (1.75 mL, 1.25 mmol) was added followed by 4-iodo-benzenesulfonyl chloride and the mixture stirred overnight at 50° C. The reaction mixture was evaporated to dryness, taken up in DCM and chromatographed over silica gel to afford the desired product (375 mg, 80%) as a clear oil. The compound was deprotected using the previously described methods followed by HPLC purification to afford the desired product MIP-1097 as a whiter solid (270 grams, 90% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.97 (d, 2H), 7.68 (t, 1H), 7.53 (d, 2H), 6.35 (dd, 2H), 4.10 (m, 1H), 4.00 (m, 1H), 2.65 (m, 2H), 2.22 (m, 2H), 1.9 (m, 1H), 1.7 (m, 1H), 1.55 (m, 1H), 1.45 (m, 1H), 1.35 (m, 2H), 1.25 (m, 2H), (3 CO2H not seen). ESMS m/z: 565 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:18]=3)[NH:13][C:12]=2[N:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB(/[CH:34]=[CH:35]/[CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)O1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([C:8]1[N:9]=[C:10](/[CH:34]=[CH:35]/[CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:18]=3)[NH:13][C:12]=2[N:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3ccccc3)nc(Cl)c12
Reactant: CC1(C)OB(/C=C/CCN2CCCCC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3ccccc3)nc(/C=C/CCN3CCCCC3)c12
Temperature: 110 °C
Reaction time: 24 h
Yield: 42.6 %

Procedure:
In a 2-5 mL microwave vial was added methyl 2-benzyl-4-chloro-9H-pyrimido[4,5-b]indole-7-carboxylate (0.100 g, 0.284 mmol), (E)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl)piperidine (0.113 g, 0.426 mmol), potassium carbonate (0.106 g, 0.768 mmol) and Pd(Ph3P)4 (0.05 g, 0.044 mmol). The vial was purged with N2 (3 vacuum+refill cycles). DME (2.84 mL) and water (0.398 mL) were added and the vial was flushed with N2 (one vacuum+refill) and then heated to 110° C. while stirred for 24 hours. After cooling, the mixture was concentrated to dryness under reduced pressure and the residue was purified by flash chromatography to give (E)-methyl 2-benzyl-4-(4-(piperidin-1-yl)but-1-en-1-yl)-9H-pyrimido[4,5-b]indole-7-carboxylate (55 mg, 0.121 mmol, 42.6% yield) as a light yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (s, 2H) 1.50-1.61 (m, 4H) 2.30-2.47 (m, 4H) 2.53-2.59 (m, 2H) 2.59-2.70 (m, 2H) 3.91 (s, 3H) 4.27 (s, 2H) 7.16-7.24 (m, 1H) 7.29 (t, J=7.6 Hz, 2H) 7.34-7.43 (m, 4H) 7.88 (dd, J=8.2, 1.4 Hz, 1H) 8.07 (d, J=1.4 Hz, 1H) 8.41 (d, J=8.2 Hz, 1H) 12.48 (s, 1H); HRMS m/z 455.2442 (M+H)+; HPLC 100% @ 220 nm and 99.4% @ 254 nm, RT=1.84 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=O)[C:11]3([CH2:20][CH3:21])[CH2:18][CH3:19])[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[S:31])[C:11]3([CH2:20][CH3:21])[CH2:18][CH3:19])[CH:5]=[CH:6][CH:7]=1
Reactant: CCC1(CC)C(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCC1(CC)C(=S)Nc2ccc(-c3cccc(Cl)c3)cc21

Procedure:
The title compound was prepared from 5-(3-chloro-phenyl)-3,3-diethyl-1,3-dihydro-indol-2-one compound (100 mg) and Lawesson's reagent (100 mg) in toluene (10 ml) at reflux, according to General Procedure A, to afford the product (0.023 g) as a yellow solid: 1H NMR (DMSO-d6) δ 12.73 (br s, 1H), 7.77 (t, 1H, J=1.8 Hz), 7.75 (d, 1H, J=1.6 Hz), 7.68-7.62 (m, 2H), 7.48 (t, 1H, J =7.9 Hz), 7.40 (d, 1H, J=8.3 Hz), 7.09 (d, 1H, J=8.1 Hz), 2.07-2.00 (m, 2H), 1.86-1.79 (m, 2H) and 0.37 (t, 6H, J=7.3 Hz): MS ((−)-APCI) m/z 314/316 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:21][CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[S:18])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:23][CH2:24][C:25](=O)[CH2:26]Cl>O1CCOCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:21][CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:18][CH:26]=[C:25]([CH2:24][Cl:23])[N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=S)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Solvent: C1COCCO1
Product: O=C1c2c(Cl)cccc2-n2cnc(-c3nc(CCl)cs3)c2[C@@H]2CCCN12
Reaction time: 1 h
Yield: 56.8 %

Procedure:
A suspension of 6.8 g (0.0204 mol) of (S)-8-chloro-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-thiocarboxamide in 100 ml of dioxan was treated with 2.85 g (0.0224 mol) of 1,3-dichloro-2-propanone and boiled at reflux for 48 hrs. After cooling 30 g of silica gel were added and the mixture was stirred for a further 1 hr. The mixture was concentrated in a water-jet vacuum and dried in a high vacuum. The crude product, adsorbed on silica gel, was applied to a silica gel column equilibrated with ethyl acetate and then eluted with ethyl acetate. There were obtained 4.7 g (58%) of (S)-8-chloro-1-(4-chloromethyl-thiazol-2-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in the form of white crystals.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[C:10]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:8]=[CH:7][N:6]=1.C(N(CC)CC)C.[CH3:25][C:26]([CH3:42])([N:31]1[C:39](=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]1=[O:41])[CH2:27][C:28](O)=[O:29]>C(Cl)Cl>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][O:11][C:10]1[C:5]([CH2:4][NH:3][C:28](=[O:29])[CH2:27][C:26]([N:31]2[C:39](=[O:40])[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]2=[O:41])([CH3:42])[CH3:25])=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:17]
Reactant: CC(C)(CC(=O)O)N1C(=O)c2ccccc2C1=O
Reactant: CCOC(=O)COc1cccnc1CN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1cccnc1CNC(=O)CC(C)(C)N1C(=O)c2ccccc2C1=O
Reaction time: 24 h
Yield: 62.4 %

Procedure:
To a solution of 2-aminomethyl-3-(ethoxycarbonylmethoxy)pyridine dihydrochloride (610 mg, 2.155 mmol), triethylamine (732 μl, 5.258 mmol), N,N-dicyclohexylcarbodiimide (596 mg, 2.892 mmol) and 4-(N,N-diemethylamino)-pyridine (10 mg) in 6 ml of dry methylene chloride is added β,β-dimethyl-1,3-dioxo-2-isoindolinepropionic acid (650 mg, 2.629 mmol) at ambient temperature. The mixture is stirred for 24 hours. The precipitate of dicyclohexyl urea is filtered off. The filtrate is evaporated and the residue is purified via flash chromatography on silica gel using a methylene chloride/methylene chloride-ethanolic ammonia gradient (100 to 97:3) to give 591 mg of (2-{[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-methyl-butyrylamino]-methyl}-pyridin-3-yloxy)-acetic acid ethyl ester (46%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[C:9]1[N:15]([CH3:28])[C:16](=[O:27])[C:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])=[CH:18][C:8]2=1)=O.[CH3:29][O:30][CH2:31][CH2:32][NH:33][C:34]([NH2:36])=[S:35]>>[Cl:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1[C:17]1[C:16](=[O:27])[N:15]([CH3:28])[C:9]2[N:10]([CH3:14])[C:11]3[C:7]([C:8]=2[CH:18]=1)=[CH:6][C:5]([C:3]1[N:36]=[C:34]([NH:33][CH2:32][CH2:31][O:30][CH3:29])[S:35][CH:2]=1)=[CH:13][CH:12]=3
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(C(=O)CBr)ccc3n(C)c21
Reactant: COCCNC(N)=S
Product: COCCNc1nc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)cs1

Procedure:
The process is carried out as for Example 21 above, using the compound from preparation 1.2, 6-(bromoacetyl)-3-(2,4-dichlorophenyl)-1,9-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one and 1-(2-methoxyethyl)-2-thiourea.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][C@H:14]([CH3:35])[C@H:15]([OH:34])[C@@H:16]([CH3:33])[CH:17]=[CH:18][CH2:19][CH2:20][C@@H:21]([OH:32])[C@@H:22]([CH3:31])[C@H:23]([OH:30])[C@@H:24]([CH3:29])[CH:25]=[CH:26][CH:27]=[CH2:28].O[Li].O.Cl>C1COCC1.O>[OH:34][C@H:15]([C@@H:16]([CH3:33])[CH:17]=[CH:18][CH2:19][CH2:20][C@@H:21]([OH:32])[C@@H:22]([CH3:31])[C@H:23]([OH:30])[C@@H:24]([CH3:29])[CH:25]=[CH:26][CH:27]=[CH2:28])[C@@H:14]([CH3:35])[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:36])=[O:2]
Reactant: C=CC=C[C@H](C)[C@@H](O)[C@H](C)[C@H](O)CCC=C[C@H](C)[C@@H](O)[C@@H](C)C=CCCCCCCCCC(=O)OC
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: C=CC=C[C@H](C)[C@@H](O)[C@H](C)[C@H](O)CCC=C[C@H](C)[C@@H](O)[C@@H](C)C=CCCCCCCCCC(=O)O
Temperature: 60 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
To an above solution 48 (8.0 mg) in THF-H2O (0.3 ml, 0.1 ml each) was added LiOH.H2O (1.3 mg) and the solution was warmed to 60° C. After stirring 6 h, 1N HCl (1 ml) was added and reaction mixture was extracted with CH2Cl2 (10 ml×2). After drying over MgSO4 and evaporation under vacuum, the crude was chromatographed on SiO2 (EtOAc/hexane 1:3) to yield 6.3 mg (81%) of the 49 as a colorless oil: IR (CHCl3) 3412, 2964, 2921, 2850, 2658, 1710, 1459, 1404, 1268, 971, 903 cm−1; 1H NMR (300 MHz, CDCl3) δ 6.64 (ddd, J=16.7, 10.6, 10.0 Hz, 1H), 6.20 (apparent t, J=10.9 Hz, 1H), 5.54–5.46 (m, 1H), 5.42–5.36 (m, 2H), 5.32–5.18 (m, 4H), 3.88–3.84 (m, 1H), 3.48 (d, J=9.2 Hz, 1H), 3.23 (apparent t, J=5.7 Hz, 1H), 2.86–2.76 (m, 1H), 2.69–2.60 (m, 2H), 2.34 (t, J=7.4 Hz, 2H), 2.21–2.04 (m, 5H), 1.70–1.62 (m, 5H), 1.28 (br, 13H), 1.00 (d, J=6.8 Hz, 3H), 0.98 (d, J=6.9 Hz, 3H), 0.94 (d, J=6.7 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 180.6, 134.4, 133.8, 132.1, 132.0, 132.0, 131.3, 128.8, 119.1, 80.7, 79.2, 76.2, 37.6, 35.5, 34.6, 29.8, 29.7, 29.5, 29.2, 29.1, 29.0, 27.6, 24.8, 24.2, 22.8, 18.1, 16.7, 15.4, 14.2, 4.5; LRMS (API-ES) 515.3 (M+Na)+, 493 (M+H)+, 475 (M+H-H2O)+, 457 (M+H-2H2O)+, 242; [α]20D +33.0 (c 0.23, CHCl3).
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.C([Si](C#C)(CC)CC)C.[CH2:15]([CH2:22][C:23](=[O:25])[CH3:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>CCOCC>[CH3:24][C:23]([OH:25])([CH2:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:1]#[CH:2]
Reactant: CC(=O)CCc1ccccc1
Reactant: [Li]CCCC
Agent: C#C[Si](CC)(CC)CC
Agent: Cl
Solvent: CCOCC
Product: C#CC(C)(O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8 Parts by volume of 2.5 molar n-butyl lithium is added to a solution of 3.1 parts of triethylsilyl acetylene in 20 parts by volume of ethyl ether at -30° C. The resulting solution is allowed to warm to room temperature, then it is cooled again to -30° C. and 3 parts of benzyl acetone is added. The reaction mixture is allowed to warm to room temperature and is then stirred for 1 hour. The reaction mixture is poured into ether and dilute hydrochloric acid. The ethereal layer is washed with water and dried over anhydrous sodium sulfate. The ether is removed under reduced pressure and the residual oil is dissolved in 15 parts by volume of dimethylformamide containing 2 parts of powdered potassium fluoride. This reaction mixture is stirred and heated at 70°-80° C. for 1 hour, after which time it is diluted with water and extracted with ether. The ether layer is separated and washed with water and dried over anhydrous sodium sulfate. The ether is removed under reduced pressure and the residue is chromatographed on silica gel using 30% ethyl acetate/hexane as eluent to provide 3-methyl-3-hydroxy-5-phenyl-1-pentyne.