Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:47])[O:3][C:4]1[CH:46]=[CH:45][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18]3[S:19][C:20]4[C:25](Cl)=[N:24][C:23]([C:27]([F:30])([F:29])[F:28])=[N:22][C:21]=4[N:31]=3)[CH2:15][CH2:14][N:13]2[S:32]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)(=[O:34])=[O:33])=[O:11])=[CH:6][CH:5]=1.C([O-])=O.[NH4+].CO>C(O)C.[C].[Pd]>[F:47][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18]3[S:19][C:20]4[CH:25]=[N:24][C:23]([C:27]([F:30])([F:29])[F:28])=[N:22][C:21]=4[N:31]=3)[CH2:15][CH2:14][N:13]2[S:32]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)(=[O:33])=[O:34])=[O:11])=[CH:45][CH:46]=1
Reactant: O=C(NCc1ccc(OC(F)F)cc1)[C@H]1CN(c2nc3nc(C(F)(F)F)nc(Cl)c3s2)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCO
Product: O=C(NCc1ccc(OC(F)F)cc1)[C@H]1CN(c2nc3nc(C(F)(F)F)ncc3s2)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 85 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
Under a nitrogen atmosphere, to a solution of the compound (1.09 g) obtained in Step 9 and ammonium formate (895 mg) in ethanol (15 ml)-methanol (5 ml) was added 10% palladium carbon (1.0 g). After stirring at 85° C. for 1 hr, the catalyst was filtered off. The filtrate was concentrated under reduced pressure, and the residue was partitioned by adding ethyl acetate and water. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1) to give the title compound (596 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](Cl)=[O:5].C[O:13][C:14]([C:16]1[C:20]([NH2:21])=[CH:19][NH:18][N:17]=1)=[O:15].C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH:21][C:20]1[C:16]([C:14]([OH:15])=[O:13])=[N:17][NH:18][CH:19]=1)=[O:5]
Reactant: COC(=O)c1n[nH]cc1N
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(O)c1n[nH]cc1NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.3 %

Procedure:
2,6-Dichlorobenzoyl chloride (8.2 g; 39.05 mmol) was added cautiously to a solution of 4-amino-1H-pyrazole-3-carboxylic acid methyl ester (5 g; 35.5 mmol) and triethylamine (5.95 ml; 42.6 mmol) in dioxan (50 ml) then stirred at room temperature for 5 hours. The reaction mixture was filtered and the filtrate treated with methanol (50 ml) and 2M sodium hydroxide solution (100 ml), heated at 50° C. for 4 hours, and then evaporated. 100 ml of water was added to the residue then acidified with concentrated hydrochloric acid. The solid was collected by filtration, washed with water (100 ml) and sucked dry to give 10.05 g of 4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid as a pale violet solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([F:36])([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:19]=[C:20]([C:26]5[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=5)[S:21][C:22]=4[CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(N(CC)CC)C.[I-].Cl[CH2:53][C:54]([N:56]([CH3:58])[CH3:57])=[O:55]>C(Cl)Cl>[F:36][C:11]1([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:19]=[C:20]([C:26]5[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=5)[S:21][C:22]=4[CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH2:12][CH2:13][N:8]([CH2:53][C:54]([N:56]([CH3:58])[CH3:57])=[O:55])[CH2:9][CH2:10]1
Reactant: CN(C)C(=O)CCl
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3(F)CCN(C(=O)OC(C)(C)C)CC3)ccc1-2
Agent: [I-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3(F)CCN(CC(=O)N(C)C)CC3)ccc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-fluoro-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (45 mg, 88 μmol) in DCM (2.5 mL) was added TFA (0.8 mL) and the reaction mixture stirred at RT for 1 h before being concentrated in vacuo. The residue was dissolved in DCM (2 mL) and triethylamine (88 μL, 0.61 mmol), tetrabutylammonimum iodide (8 mg, 21 μmol) and 2-chloro-N,N-dimethyl-acetamide (14 μL, 0.1 mmol) added. The reaction mixture was stirred at RT for 16 h then diluted with DCM (20 mL) and washed with saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with DCM (3×5 mL) and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2 20% ethyl acetate in DCM then 2% MeOH in DCM) producing impure material. The material was subjected to flash chromatography (Si—NH2 eluting with DCM) to yield 523. LCMS: RT=3.43 min, [M+H]+=499 [ad823805] 1H NMR 400 MHz (d6-DMSO) δ: 8.37 (1H, d, J=8.4 Hz), 7.96 (1H, s), 7.18 (1H, dd, J=1.8, 8.4 Hz), 7.09 (1H, d, J=1.8 Hz), 5.93 (1H, sept, J=6.6 Hz), 4.37 (2H, t, J=5.1 Hz), 3.42 (2H, t, J=5.1 Hz), 3.30 (2H, s), 3.09 (3H, s), 2.93 (3H, s), 2.92-2.85 (2H, m), 2.55-2.46 (2H, m), 2.31-2.11 (2H, m), 1.97-1.87 (2H, m), 1.59 (6H, d, J=6.6 Hz)
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[O:15][CH3:16])[CH2:2][CH2:3][CH3:4].[CH2:17]([O:19][C@H:20]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:21][C:22]1[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28](O)=[O:29])=[CH:24][CH:23]=1)[CH3:18].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:1]([N:5]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[O:15][CH3:16])[C:28](=[O:29])[CH2:27][O:26][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C@H:20]([O:19][CH2:17][CH3:18])[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:32][CH:31]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Reactant: CCCCNCc1cccc(OC)c1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCN(Cc1cccc(OC)c1OC)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Reaction time: 8 h
Yield: 42.7 %

Procedure:
To a solution of N-butyl-N-(2,3-dimethoxybenzyl)amine (1.23 g, 5.5 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (1.48 g, 5.0 mmol) in methylene chloride (50 mL) at 0° C. were added N,N-diisopropylethylamine (2.0 mL, 11.5 mmol) followed by O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.93 g, 6.0 mmol) and the reaction mixture was stirred overnight and then concentrated in vacuo. The residue was taken up in ethyl acetate (200 mL) and the organic phase was washed with saturated aqueous NaHCO3 (3×100 mL), 5% HCl (3×100 mL), and brine (100 mL), dried over Na2SO4, and concentrated in vacuo. Purification on silica gel (120 g) with methanol (0-2% gradient) in methylene chloride as the eluent and collection of pure fractions afforded 1.07 g (43%) of a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1>CCOCC>[Cl:1][C:2]([F:8])([F:9])[C:3](=[O:5])[CH2:21][C:20]([C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=1)=[O:22]
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(F)(F)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Product: O=C(CC(=O)C(F)(F)Cl)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.4 %

Procedure:
38 g of ethyl chlorodifluoroacetate was added to 22.7 g of sodium methoxide and 300 ml of dry ether under cooling with ice. 31 g of p-chloroacetophenone was gradually added thereto under cooling with ice. The mixture was stirred at room temperature for 12 hours. The solvent was distilled off. 150 ml of 6N hydrochloric acid was added under cooling with ice, and extraction with ethyl acetate was carried out. The extract layer was washed with water, and the solvent was distilled off. The resulting crude product was purified by silica gel column chromatography (developing solvent: chloroform), and thereby 49.5 g of the desired product was obtained as a pale yellow viscous liquid. m.p. 50°-51° C.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[C:7]([O:26][CH3:27])=[C:8]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([N:23]([CH3:25])[CH3:24])=[O:22])=[N:19][CH:20]=2)[C:9]([C:13]#[N:14])=[C:10]([Cl:12])[CH:11]=1)(=[O:5])[CH3:4]>CO>[Cl:12][C:10]1[C:9]([C:13]#[N:14])=[C:8]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([N:23]([CH3:25])[CH3:24])=[O:22])=[N:19][CH:20]=2)[C:7]([O:26][CH3:27])=[C:6]([CH:3]([OH:5])[CH3:4])[CH:11]=1
Reactant: COc1c(C(C)=O)cc(Cl)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1c(C(C)O)cc(Cl)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
Sodium tetrahydroborate (320 mg, 8.4 mmol) was added to a mixture of 5-(3-acetyl-5-chloro-6-cyano-2-methoxyphenyl)-N,N-dimethylpyridine-2-carboxamide (2 g, 6 mmol) in methanol (100 mL) cooled at 0° C. The reaction was stirred at 0° C. for 1 h, quenched with water and partitioned between water and EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give crude 5-[3-chloro-2-cyano-5-(1-hydroxyethyl)-6-methoxyphenyl]-N,N-dimethylpyridine-2-carboxamide as clear oil (2.0 g, 100%). LCMS calculated for C18H19ClN3O3 (M+H)+: m/z=360.1; found: 360.1.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[N:6][CH:7]([CH3:9])[CH3:8])([CH3:3])[CH3:2].[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:5](=[N:6][CH:7]([CH3:9])[CH3:8])[NH:4][CH:1]([CH3:3])[CH3:2])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)N=C=NC(C)C
Reactant: OCc1ccccc1
Product: CC(C)N=C(NC(C)C)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A neat solution of 18.6 mL (15g, 118.8 mmol) of 1,3-diisopropylcarbodiimide and 60 mg (0.6 mmol) of cuprous chloride was placed under a blanket of argon and then cooled to 0° C. in an ice bath. To this reaction mixture was added dropwise (via syringe) 12.9 mL (13.5 g, 124.7 mmol) of benzyl alcohol. The resultant green reaction mixture was allowed to stir at 0° C. overnight, filtered through celite (rinsing with hexane) and the filtrate then Kugelrohr distilled (105° C., 2 mm Hg) to give 2-benzyl-1,3-diisopropyl isourea as a clear, colorless oil. To a solution of 650 mg (4.7 mmol) of 4-hydroxybenzoic acid in 20 mL of tetrahydrofuran was added 1.1 g (4.7 mmol) of 2-benzyl-1,3-diisopropyl isourea. The reaction mixture was allowed to stir at ambient temperature overnight, filtered (rinsing with tetrahydrofuran) and then concentrated in vacuo. Purification by flash chromatography (silica, 25% ethyl acetate in hexane) gave the title compound as a white solid. PMR (CDCl3): δ 5.22 (1 H, s), 5.35 (2 H, s), 6.87 (2 H, d, J=8.8 Hz), 7.34-7.50 (5 H, m), 8.01 (2 H, d, J=8.8 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](Cl)=[O:16])=[CH:11][CH:10]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][NH:25][C:26]([C:28]2[N:37]3[C:31]([CH2:32][NH:33][C:34]4[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=4[CH2:36]3)=[CH:30][CH:29]=2)=[O:27])[CH:19]=1.C(N(CC)C(C)C)(C)C>ClCCl.O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:33]2[C:34]3[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=3[CH2:36][N:37]3[C:28]([C:26]([NH:25][CH2:24][C:20]4[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=4)=[O:27])=[CH:29][CH:30]=[C:31]3[CH2:32]2)=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1cccc(C)c1-c1ccc(C(=O)Cl)cc1
Reactant: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1NC2
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C)c1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.9 %

Procedure:
A stirred solution of 2′,6′-dimethyl-1,1′-biphenyl-4-carboxylic acid of Step A (0.790 g, 3.5 mmol) in dichloromethane (15 mL) was treated under nitrogen with a catalytic amount of N,N-dimethylformamide followed by dropwise addition of 2N oxalyl chloride in dichloromethane (2.8 mL). After the gas evolution ceased the mixture was refluxed for 4 hours, cooled, and evaporated. The residue was azeotroped twice with benzene and dried in vacuo to provide 2′,6′-dimethyl-1,1′-biphenyl-4-carboxylic acid chloride. The crude 2′,6′-dimethyl-1,1′-biphenyl-4-carboxylic acid chloride (0.856 g, 3.5 mmol) was dissolved in dichloromethane (7 mL) and added dropwise to a suspension of N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 12 (0.450 g, 1.41 mmol) in anhydrous tetrahydrofuran 10 mL) containing N,N-diisopropylethyl amine (0.860 mL). The mixture was stirred for 18 hours at room temperature and evaporated to dryness. The residue was dissolved in dichloromethane, the solution washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous potassium carbonate and evaporated. The residue was chromatographed over silica gel Merck-60 eluting with a gradient from 0 to 4% methanol in 1:1 hexane-ethyl acetate to provide the title compound (0.452 g) as a white solid after trituration with hexane, m.p. 216-218° C. (dec).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[N:9][CH:8]=1)(=[NH:3])[NH2:2].NC(N)=S.[OH-].[Na+].[CH3:21][N:22]=[C:23]=[S:24].Cl>CS(C)=O>[NH2:2][C:1]1[N:4]([C:23]([NH:22][CH3:21])=[S:24])[N:5]=[C:6]([C:7]2[CH:8]=[N:9][C:10]([Cl:13])=[CH:11][CH:12]=2)[N:3]=1
Reactant: CN=C=S
Reactant: N=C(N)NNC(=O)c1ccc(Cl)nc1
Agent: Cl
Agent: NC(N)=S
Agent: [Na+]
Solvent: CS(C)=O
Product: CNC(=S)n1nc(-c2ccc(Cl)nc2)nc1N
Temperature: 180 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
The synthesis method of Example 1-(2) was applied. The compound (5.4 g) obtained in (1) above and dimethylsulfoxide (50 ml) were used as reagents and the mixture was stirred at 180° C. for 1 hour. After the reaction, the reaction mixture was ice-cooled and used as it was in the next reaction. The conversion to a thiourea compound was performed according to the method of Example 7-(3). The above-mentioned solution, a 1N aqueous sodium hydroxide solution (20 ml) and methyl isothiocyanate (1.5 g) were used as reagents. After the reaction, the mixture was neutralized with 3N hydrochloric acid and the resulting powder was collected by filtration. The powder was subjected to silica gel column chromatography (chloroform) and recrystallization (chloroform) to give 2.9 g of white crystals (yield 29%).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([O:10][C:11](=[O:25])[CH:12]([CH2:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:13](=O)[CH3:14])[CH3:9].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.CCOCC>[CH2:8]([O:10][C:11]([C:12]1[CH:16]=[C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:13]=1[CH3:14])=[O:25])[CH3:9]
Reactant: NC1CCCCC1
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)n(C2CCCCC2)c1C

Procedure:
Cyclohexylamine (5 mmol, 0.5 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.2 g) and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting residue was resuspended in ether, then washed with water and brine. The organic layer was dried over MgSO4, and the solids were separated and the solvents removed under vacuum. Purification of the oil yielded the named product, 1H-NMR (CDCl31 ppm): 1.0 bm (2H), 1.23 t (3H), 1.6-1.7 bm (8H), 2.66 s (3H), 4.16 q (2H), 6.39 s (1H), and 7.25 bm (5H).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[C:5]([CH3:11])=[C:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:3]=1[CH3:20].C([Li])CCC.[CH3:26][CH:27]([C:29]1[CH:34]=[CH:33][C:32]([C:35]([CH3:37])=[O:36])=[CH:31][CH:30]=1)[CH3:28].O>C1COCC1>[OH:36][C:35]([C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[C:5]([CH3:11])=[C:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:3]=1[CH3:20])([C:32]1[CH:33]=[CH:34][C:29]([CH:27]([CH3:28])[CH3:26])=[CH:30][CH:31]=1)[CH3:37]
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)OC(C)(C)C)CCO2
Reactant: CC(=O)c1ccc(C(C)C)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1c2c(c(C(C)(O)c3ccc(C(C)C)cc3)c(C)c1NC(=O)OC(C)(C)C)OCC2
Reaction time: 0.5 h
Yield: 19 %

Procedure:
To a mixed solution of tert-butyl (7-bromo-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 222 (500 mg, 1.46 mmol) and cerous chloride (360 mg, 3.21 mmol) in THF (8 mL) was added dropwise at −78° C. under an argon atmosphere n-butyllithium (1.6 M hexane solution, 2.0 mL, 3.21 mmol). The mixture was stirred at the same temperature for 30 minutes, and then to the reaction solution was added dropwise a solution of 4-isopropylacetophenone (261 mg, 1.61 mmol) in THF (4 mL) and the resulting mixture was stirred for 30 minutes and elevated to room temperature. Water was added to the reaction solution and the product was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:3) to obtain 118 mg (yield: 19%) the title compound. Melting point: 185-186° C. (ethyl acetate-hexane).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]([C@:14]1([C:26]([N:28]2[CH2:33][C:32]3[CH:34]=[C:35]([C:38]([F:41])([F:40])[F:39])[CH:36]=[CH:37][C:31]=3[O:30][CH2:29]2)=[O:27])[CH2:18][CH2:17][C@@H:16]([N:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)[CH2:15]1)([CH3:13])[CH3:12].C(N(CC)CC)C.C(=O)=O.CC(C)=O>C(Cl)Cl>[CH:11]([C@:14]1([C:26]([N:28]2[CH2:33][C:32]3[CH:34]=[C:35]([C:38]([F:39])([F:40])[F:41])[CH:36]=[CH:37][C:31]=3[O:30][CH2:29]2)=[O:27])[CH2:18][CH2:17][C@@H:16]([N:19]2[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]2)[CH2:15]1)([CH3:13])[CH3:12]
Reactant: CC(C)[C@]1(C(=O)N2COc3ccc(C(F)(F)F)cc3C2)CC[C@@H](N2CCC(O)CC2)C1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CS(C)=O
Product: CC(C)[C@]1(C(=O)N2COc3ccc(C(F)(F)F)cc3C2)CC[C@@H](N2CCC(=O)CC2)C1
Temperature: -78 °C
Reaction time: 0.42 h

Procedure:
A solution of oxalyl chloride (35.0 μL, 0.402 mmol) in 15 mL of DCM was cooled to −78° C. DMSO (57.0 L, 0.805 mmol) was added drop-wise to the stirring solution. After 5 min 1-((1R,3S)-3-isopropyl-3-{[6-(trifluoromethyl)-2H-1,3-benzoxazin-3(4H)-yl]carbonyl}cyclopentyl)piperidin-4-ol (EXAMPLE 13, TABLE 1, 88 mg) in 5 mL of DCM was added drop-wise over 3 min to the reaction. After stirring for an additional 25 min at −78° C., triethylamine (224.0 μL, 1.609 mmol) in 5 mL of DCM was added drop-wise over 1 min. The reaction mixture was stirred at −78° C. for 10 min before the dry ice/acetone bath was removed. The reaction was allowed to warm to rt and stirred for 1.5 h. The reaction mixture was then diluted with DCM (50 mL) and washed with 1N HCl solution (1×75 mL), sodium bicarbonate solution (1×75 mL), and brine (1×75 mL). The aqueous layers were combined and extracted with dichloromethane (5×100 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by preparatory TLC (silica gel, 0.4% ammonium hydroxide, 3.6% MeOH, 96% DCM) afforded 1-((1R,3S)-3-isopropyl-3-{[6-(trifluoromethyl)-2H-1,3-benzoxazin-3(4H)-yl]carbonyl}cyclopentyl)piperidin-4-one. ESI-MS calculated for C23H29F3N2O3: 438.48, found 457 (hydrate+H).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:28][C:29]([N:33]([CH2:35][CH2:36][O:37][CH3:38])[CH3:34])([CH3:32])[C:30]#[CH:31]>>[CH3:32][C:29]([N:33]([CH2:35][CH2:36][O:37][CH3:38])[CH3:34])([CH3:28])[C:30]#[C:31][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:26])([F:27])[F:1])=[CH:8][CH:7]=3)=[N:10][S:11][C:12]=2[CH:17]=1
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1)C(F)(F)F
Reactant: C#CC(C)(C)N(C)CCOC
Product: COCCN(C)C(C)(C)C#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 14.1, Trifluoro-methanesulfonic acid 3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester and (1,1-Dimethyl-prop-2-ynyl)-(2-methoxy-ethyl)-methyl-amine were converted to yield {1,1-Dimethyl-3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-(2-methoxy-ethyl)-methyl-amine as brown oil, MS: 433 (MH+).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:12])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[I-:13].[Na+]>CC(C)=O>[I:13][CH2:2][C@@H:3]([OH:12])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OC(CCl)COc1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O[C@H](CI)COc1ccccc1

Procedure:
A mixture of 55 g (0.29 mol) of 1-chloro-2-hydroxy-3-phenoxypropane, 170 g (1.1 mol) sodium iodide in 1.0 of acetone is refluxed in the dark under a nitrogen atmosphere for 3 days. The acetone is removed in vacuo, the residue slurried in chloroform, filtered and the filtrate stripped to afford the title compound.
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:17](=[O:27])(=[O:26])[NH:18][CH:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)=[CH:5][C:6]=1[C:7]1[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=1[CH3:16].C([Li])CCC>C1COCC1>[OH:25][C@@H:22]1[CH2:23][CH2:24][C@H:19]([NH:18][S:17]([C:4]2[S:3][CH:2]=[C:6]([C:7]3[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=3[CH3:16])[CH:5]=2)(=[O:26])=[O:27])[CH2:20][CH2:21]1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)NC3CCC(O)CC3)sc2Br)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2csc(S(=O)(=O)N[C@H]3CC[C@@H](O)CC3)c2)s1
Temperature: -70 °C
Reaction time: 8 h

Procedure:
N-{5-[2-Bromo-5-(4-hydroxy-cyclohexylsulfamoyl)-thiophen-3-yl]-4-methyl-thiazol-2-yl}-acetamide obtained in Step I as described above (120 mg; 0.24 mmol; 1 eq), is dissolved anhydrous THF (10 ml). The reaction mixture is cooled down to −70° C. and put under nitrogen. n-Butyllithium (1.5 ml; 1.6 M; 2.43 mmol; 8 eq) is added dropwise. The reaction is stirred overnight and quenched with water. Solvents are evaporated and the resulting crude product is purified by preparative HPLC, affording Compound (33) as white-off powder (28 mg; 21%).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH:4]([CH2:21]Cl)[CH:5]1[C:14]2[C:9](=[CH:10][C:11]([O:18][CH2:19][CH3:20])=[C:12]([O:15][CH2:16][CH3:17])[CH:13]=2)[CH2:8][CH2:7][NH:6]1>C(O)C.CCOCC>[ClH:2].[Cl:2][CH2:3][CH:4]1[CH:5]2[C:14]3[C:9]([CH2:8][CH2:7][N:6]2[CH2:21]1)=[CH:10][C:11]([O:18][CH2:19][CH3:20])=[C:12]([O:15][CH2:16][CH3:17])[CH:13]=3
Reactant: CCOc1cc2c(cc1OCC)C(C(CCl)CCl)NCC2
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCOc1cc2c(cc1OCC)C1C(CCl)CN1CC2
Yield: 75 %

Procedure:
Following the procedure described in Example 2 but using 1-[bis(chloromethyl)-methyl]-6,7-diethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride as a starting material, the aimed compound is obtained with a melting point of 130° to 131° C. (ethanol/ether).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][C:11](I)=[CH:10][N:9]=2)=[C:4]([CH3:15])[CH:3]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][C:11]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])=[CH:10][N:9]=2)=[C:4]([CH3:15])[CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(Cl)ccc1-c1cnc(I)cn1
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)ccc1-c1cnc(C#C[Si](C)(C)C)cn1

Procedure:
The product was prepared analogously to Example 48.1c from 1.70 g (5.14 mmol) of 2-(4-chloro-2-methylphenyl)-5-iodopyrazine and 0.80 mL (5.66 mmol) of trimethylsilylacetylene (using triethylamine as base). Yield: 700 mg (45% of theoretical); C16H17ClN2Si (M=300.858); calc.: molpeak (M+H)+:301/303 (Cl); found: molpeak (M+H)+:301/303 (Cl); Rf value: 0.5 (silica gel, PE/EtOAc 9:1).