Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1([CH3:18])[CH2:11][O:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8]1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH:29]=[O:30]>O1CCCC1.C1(C(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:6][C:7]1([CH3:18])[CH2:11][O:10][C:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[CH:29]([C:20]2[CH:21]=[CH:22][C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]=2)[OH:30])=[N:8]1
Reactant: CC1(C)COC(c2ccccc2)=N1
Reactant: O=Cc1ccc2ccccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Product: CC1(C)COC(c2ccccc2C(O)c2ccc3ccccc3c2)=N1
Temperature: -30 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
At −78° C., 104 ml of a 1.6M solution of butyl lithium were slowly added dropwise to 25 g (0.14 mol) of 4,4-dimethyl-2-phenyl-2-oxazolin and 0.1 g of triphenylmethane in 400 ml of anhydrous tetrahydrofuran. The mixture was stirred for 1 h. The mixture was then allowed to warm to −30° C. and a solution of 20.3 g (0.13 mol) of 2-naphthaldehyde in 200 ml of anhydrous tetrahydrofuran was added dropwise. Stirring was continued for about 1 h at −20 to −30° C. The reaction solution was then allowed to warm to room temperature and the solvent was removed under reduced pressure. The residue was introduced into ice-water which was then extracted with ether. The organic phase was dried and concentrated under reduced pressure. This residue was purified chromatographically (eluent: n-heptane/acetone=40/3), affording 25.3 g (54%) of the product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[CH3:14].[CH:15]1([CH2:18][NH:19][C:20](=[O:37])[C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[C:23](B3OC(C)(C)C(C)(C)O3)[CH:22]=2)[CH2:17][CH2:16]1>>[CH:15]1([CH2:18][NH:19][C:20]([C:21]2[CH:22]=[C:23]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)=[CH:4][C:3]=3[CH3:14])[C:24]([CH3:27])=[CH:25][CH:26]=2)=[O:37])[CH2:17][CH2:16]1
Reactant: Cc1nnc(-c2ccc(Br)c(C)c2)o1
Reactant: Cc1ccc(C(=O)NCC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1nnc(-c2ccc(-c3cc(C(=O)NCC4CC4)ccc3C)c(C)c2)o1

Procedure:
The title compound was prepared using 2-(4-bromo-3-methylphenyl)-5-methyl-[1,3,4]oxadiazole and N-cyclopropylmethyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)benzamide (Intermediate 17).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH:6]=[CH:7][CH:8]=O.[NH2:13][NH:14][C:15]([NH2:17])=[S:16]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH:6]=[CH:7][CH:8]=[N:13][NH:14][C:15]([NH2:17])=[S:16]
Reactant: NNC(N)=S
Reactant: COc1cccc(C=CC=O)c1
Product: COc1cccc(C=CC=NNC(N)=S)c1
Yield: 52 %

Procedure:
The compound is prepared according to the method described in Example 1A from 3-methoxycinnamaldehyde (2.47 mmol) and from thiosemicarbazide (2.47 mmol). Yield 52%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[C:12]1([CH2:18][N:19]2[CH2:24][CH2:23][N:22]([CH:25]3[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]3)[CH2:21][CH2:20]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1CCCC1>C(O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:28]1[CH2:29][CH2:30][CH:25]([N:22]2[CH2:21][CH2:20][N:19]([CH2:18][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:24][CH2:23]2)[CH2:26][CH:27]=1
Reactant: O=C1CCC(N2CCN(Cc3ccccc3)CC2)CC1
Reactant: COc1ccc2[nH]ccc2c1
Solvent: C1CCNC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc2[nH]cc(C3=CCC(N4CCN(Cc5ccccc5)CC4)CC3)c2c1

Procedure:
A solution of 5-methoxyindole (3.68 mmole), 4-[4-(phenylmethyl)-1-piperazinyl]cyclohexanone (3.68 mmole), and pyrrolidine (0.25 ml) in ethanol (10 ml) was heated at reflux for 96 hr. The solution was concentrated in vacuo and the residue purified by chromatography on silica eluting with ethyl acetate in hexane to give the product which was converted to the fumarate salt in ethyl acetate (38.4%, mp: 199-200° C.). Calc'd for C26H31N3O.2C2H2O2 : C, 64.45%; H, 6.21%; N, 6.64%. Found: C, 64.42%; H, 6.21%; N, 6.61%.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[C:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)#[N:18].Cl>N1C=CC=CC=1.CC(C)=O.O>[C:4]([C:3]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:2]=1[NH:1][S:25]([C:22]1[CH:21]=[CH:20][C:19]([C:17]#[N:18])=[CH:24][CH:23]=1)(=[O:27])=[O:26])(=[O:5])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: N#Cc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114 %

Procedure:
2-Amino-5-chlorobenzophenone (2.92 g, 12.60 mmol) was dissolved in 60 mL of pyridine and 4-cyanobenzenesulfonyl chloride (2.66 g, 13.2 mmol) in 10 mL pyridine was then added. The mixture was stirred overnight at room temperature under N2, then poured in a steady stream into 350 mL vigorously stirring chilled 6M HCl which resulted in the precipitation of a yellow solid which was collected by vacuum filtration, washed well with H2O, then dissolved in 50 mL EtOAc and the solvents removed under vacuum to get a reddish powder which was dissolved in 75 mL boiling acetone. 150 mL of H2O was added in a slow stream to the hot, stirring acetone solution. A yellow precipitate formed upon cooling which was collected by vacuum filtration and dried overnight under vacuum to get 5.7 g product as a reddish powder (quant). 1H NMR (DMSO) δ 10.28 (s, 1H) 7.92 (dd, J=1.6, 8.8, 2H) 7.70 (d, 2H) 7.64(t, 1H) 7.58-7.52 (m, 3H) 7.50-7.46 (m, 2H) 7.42 (d, J=2.8 Hz, 1H) 7.03 (d, 8.8 Hz, 1H). MS: m/z =397.0 (M++1).
Reaction SMILES: [CH:1]1([CH:5]([OH:7])[CH3:6])[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:11]1[C:16]2[N:17]([CH2:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]3)[CH:18]=[N:19][C:15]=2[CH:14]=[C:13]([Cl:28])[N:12]=1>CN(C=O)C>[Cl:28][C:13]1[N:12]=[C:11]([O:7][CH:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)[CH3:6])[C:16]2[N:17]([CH2:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]3)[CH:18]=[N:19][C:15]=2[CH:14]=1
Reactant: CC(O)C1CCC1
Reactant: C[C@H]1CC[C@H](Cn2cnc3cc(Cl)nc(Cl)c32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Oc1nc(Cl)cc2ncn(C[C@H]3CC[C@H](C)CC3)c12)C1CCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 1-cyclobutylethan-1-ol (1.76 g, 17.60 mmol) in DMF (10 mL) was added 60% NaH (1.4 g, 35.19 mmol) in several portions at 0° C. After stirring for 20 minutes, 4,6-dichloro-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine (Preparative Example 2.3, 3.5 g, 11.73 mmol) in DMF (30 mL) was added slowly over a time period of 10 minutes. The reaction was then warmed to room temperature and stirred for 16 h. After this time, the reaction was quenched with ice, diluted with water (80 mL), and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with water (25 mL) and brine (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with (12-15% EtOAc/petroleum ether) to yield 6-chloro-4-(1-cyclobutylethoxy)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine. MS ES/APCI calc'd. for C20H28ClN3O [M+H]+ 362. found 362.
Reaction SMILES: [Cl:1][CH:2](Cl)[B:3]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]([CH3:11])([CH3:10])[O:4]1.[CH2:13]([Mg]Br)[CH3:14]>O1CCCC1>[Cl:1][CH:2]([B:3]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]([CH3:11])([CH3:10])[O:4]1)[CH2:13][CH3:14]
Reactant: CC[Mg]Br
Reactant: CC1(C)OB(C(Cl)Cl)OC1(C)C
Solvent: C1CCOC1
Product: CCC(Cl)B1OC(C)(C)C(C)(C)O1
Temperature: -78 °C
Reaction time: 18 h
Yield: 79.8 %

Procedure:
2.64 g (12.5 mmol) of 2-(dichloromethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were dissolved in 30 ml of tetrahydrofuran and the solution was cooled under a nitrogen atmosphere to -78° C. 11.8 ml (12.5 mmol) of 1.06M ethylmagnesium bromide were added dropwise and the solution was stirred at room temperature for 18 hours. The solution was partitioned between ethyl acetate, saturated sodium chloride solution and 2M hydrochloric acid solution. The aqueous layer was extracted with ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulphate. After filtration and evaporation the oil obtained was distilled to give 2.04 g of 2-[1(RS)-chloropropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane; b.p. 53° C./0.8 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8]C)[C:3]=1[C:10]1[C:18]2[C:17]([NH:19][C@H:20]([C:22]3[N:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:26](=[O:34])[C:25]4=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]4[N:23]=3)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=2[N:12](COCC[Si](C)(C)C)[CH:11]=1.B(Br)(Br)Br.N>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:10]1[C:18]2[C:17]([NH:19][C@H:20]([C:22]3[N:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:26](=[O:34])[C:25]4=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]4[N:23]=3)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=2[NH:12][CH:11]=1
Reactant: COc1cccc(F)c1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Agent: BrB(Br)Br
Agent: N
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5c(O)cccc5F)c34)n(-c3ccccc3)c(=O)c12
Yield: 34.6 %

Procedure:
2-((1S)-1-((5-(2-Fluoro-6-methoxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.07 mmol) was treated with boron tribromide (1M in dichloromethane, 680 μl, 0.68 mmol) and a solution of ammonia (7N in methanol, 1 mL, 7 mmol) according to the method described in Example 41 to give 12 mg (36% yield) of the title compound as a white solid. Purity 97%.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][C:8](=O)[CH2:7][N:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4].[Br:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[CH2:22][NH:23][CH3:24].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O>[CH2:11]([N:6]1[CH2:7][CH:8]([N:23]([CH2:22][C:21]2[CH:25]=[CH:26][CH:27]=[C:19]([Br:18])[CH:20]=2)[CH3:24])[CH2:9][CH:5]1[C:3]([OH:2])=[O:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CNCc1cccc(Br)c1
Reactant: COC(=O)C1CC(=O)CN1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(Cc1cccc(Br)c1)C1CC(C(=O)O)N(Cc2ccccc2)C1
Reaction time: 3 h
Yield: 64.8 %

Procedure:
To a solution of 1-benzyl-4-oxo-pyrrolidine-2-carboxylic acid methyl ester (1 mmol), (3-bromo-benzyl)-methyl-amine (1 mmol) in 2 mL of CH2Cl2 were added NaBH(OAc)3 (2 mmol) and 5 drops of AcOH, and the resulting mixture was stirred for 3 h. The mixture was treated with aq. NaHCO3, extracted by CH2Cl2 (3×5 mL), and the combined extracts were washed by brine (10 mL), dried over Na2SO4, and concentrated to give 261.3 mg of crude product in 65% yield.
Reaction SMILES: [F:1][C:2]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]([O:8]C(=O)C)[NH:6][C:5](=[O:12])[NH:4][C:3]1=[O:13].[CH:19](=[N:25]/O)\[C:20]1[O:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.O>N1C=CC=CC=1>[F:1][C:2]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]([O:8]/[N:25]=[CH:19]/[C:20]2[O:24][CH:23]=[CH:22][CH:21]=2)[NH:6][C:5](=[O:12])[NH:4][C:3]1=[O:13]
Reactant: CCOC(=O)C1(F)C(=O)NC(=O)NC1OC(C)=O
Reactant: O/N=C/c1ccco1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C1(F)C(=O)NC(=O)NC1O/N=C/c1ccco1
Temperature: 25 °C
Reaction time: 15 h
Yield: 52.4 %

Procedure:
In 20 ml of pyridine were dissolved 5.24 g (20 mmol) of ethyl 5-fluoro-6-acetoxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate and 2.62 g (23.6 mmol) of (E)-furfuraldoxime, and 2.02 g (20 mmol) of triethylamine was added to the solution, followed by stirring at room temperature for 15 hours. The reaction solution was poured into 200 ml of ice-cooled water, and crystals precipitated were collected by filtration and washed with water. The crystals were dried under reduced pressure and recrystallized from ethanol to give 3.28 g of ethyl 5-fluoro-6-(E)-furfurylideneaminooxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate. m.p. 189°-190° C.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[CH2:14][N:13]([C:15]2[CH:16]=[CH:17][C:18]3[O:19][CH2:20][C:21](=[O:25])[NH:22][C:23]=3[N:24]=2)[C:12](=[O:26])[CH2:11]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][CH2:9][C@H:10]1[CH2:14][N:13]([C:15]2[CH:16]=[CH:17][C:18]3[O:19][CH2:20][C:21](=[O:25])[NH:22][C:23]=3[N:24]=2)[C:12](=[O:26])[CH2:11]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1COc2ccc(N3C[C@H](CO)CC3=O)nc2N1
Temperature: 25 °C
Reaction time: 7 h
Yield: 49.5 %

Procedure:
In tetrahydrofuran (20 ml) was dissolved 6-[(4R)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (1.93 g, 5.12 mmol). Tetrabutyl ammonium fluoride (1M tetrahydrofuran solution; 6.14 ml, 6.14 mmol) was added to this solution and the mixture was stirred at room temperature for 7 hours. The reaction solution was concentrated under reduced pressure and ethyl acetate and water were added to the obtained residue. The aqueous layer was extracted with ethyl acetate and washed with saturated sodium chloride solution. The solution was dried over anhydrous sodium sulfate, the drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield 667 mg (49%) of the title compound in the form of a light yellow solid.
Reaction SMILES: [CH2:1]([N:5]1[CH:11]([CH3:12])[CH2:10][C:9]([CH3:14])([CH3:13])[NH:8][C:7]([CH3:16])([CH3:15])[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].[CH3:18]C(CC)=O>>[CH2:1]([N:5]1[CH:11]([CH3:12])[CH2:10][C:9]([CH3:14])([CH3:13])[NH:8][C:7]([CH2:15][CH3:18])([CH3:16])[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C(C)(C)NC(C)(C)CC1C
Reactant: CCC(C)=O
Product: CCCCN1C(=O)C(C)(CC)NC(C)(C)CC1C

Procedure:
The title compound was prepared as described by Pyong-nae Son, J. T. Lai.: J. Org. Chem. 46, 323 (1981) for 1-butyl-3,3,5,5,7-pentamethyl-[1,4]diazepan-2-one, but using methylethylketon instead of acetone.
Reaction SMILES: [OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([S:22][CH:23]([CH3:25])[CH3:24])=[C:8]2[C:12]([O:14]CC1C=CC=CC=1)=[O:13])[CH3:3].O.C(=O)(O)[O-].[Na+:31].C>O1CCOCC1.[Pd]>[OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([S:22][CH:23]([CH3:25])[CH3:24])=[C:8]2[C:12]([O-:14])=[O:13])[CH3:3].[Na+:31]
Reactant: CC(C)SC1=C(C(=O)OCc2ccccc2)N2C(=O)C(C(C)O)C2C1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)SC1=C(C(=O)[O-])N2C(=O)C(C(C)O)C2C1
Reaction time: 1 h

Procedure:
Benzyl 6-(1-hydroxyethyl)-3-isopropylthio-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (25 mg) is dissolved in dioxane (2 ml) and the solution is treated with water (1 ml) containing sodium bicarbonate (6 mg) and 10% palladium on powdered charcoal (25 mg). The resulting mixture is hydrogenated at 40 psi for 1 hr. The catalyst is filtered off and washed with water (3 ml). The combined filtrate is extracted with ethyl acetate (3×2 ml), concentrated in vacuo, and lyophilized to afford sodium 6-(1-hydroxyethyl)-3-isopropylthio-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@:13]1([C:30]2[CH:35]=[C:34]([Br:36])[CH:33]=[CH:32][C:31]=2[F:37])[CH2:18][O:17][C@@H:16]([CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:15][C@H:14]1[CH2:28][OH:29]>ClCCl>[CH2:21]([O:20][CH2:19][C@@H:16]1[O:17][CH2:18][C@@:13]([NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:11])([C:30]2[CH:35]=[C:34]([Br:36])[CH:33]=[CH:32][C:31]=2[F:37])[C@H:14]([CH2:28][OH:29])[CH2:15]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N[C@@]1(c2cc(Br)ccc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: O=C(NC(=S)N[C@@]1(c2cc(Br)ccc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.8 %

Procedure:
Benzoyl isothiocyanate (3.40 mL, 25.3 mmol) was added to a solution of [(2R,4R,5S)-5-amino-2-[(benzyloxy)methyl]-5-(5-bromo-2-fluorophenyl)tetrahydro-2H-pyran-4-yl]methanol (C30) (10.84 g, 25.55 mmol) in dichloromethane (255 mL). The reaction mixture was stirred at room temperature for 48 hours and then concentrated under reduced pressure to afford the product as a light yellow solid (9.49 g), which was taken directly to the following step. LCMS m/z 587.0 [M−H+].
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#N.[Li].[C-]#[C-].[Li+].[Li+].[CH3:14][Si:15]([C:18]#C)([CH3:17])[CH3:16].C([Li])CCC>C1COCC1.C(#N)C1C=CC=CC=1>[CH3:14][Si:15]([C:18]#[C:1][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)([CH3:17])[CH3:16]
Reactant: N#Cc1ccncc1
Reactant: C#C[Si](C)(C)C
Agent: [C-]#[C-]
Agent: [Li+]
Agent: [Li]
Solvent: C1CCOC1
Solvent: N#Cc1ccccc1
Product: C[Si](C)(C)C#Cc1ccncc1
Reaction time: 20 h
Yield: 56 %

Procedure:
The procedure was identical to Example 1, with the exception that 4-cyanopyridine (0.208 g; 2.00 mmol) was used as a substrate instead of benzonitrile and lithium trimethylacetylide (8.00 ml; 4.00 mmol; 0.5 M in THF) was used instead of the in situ derived lithium acetylide made from trimethylsilylacetylene and n-butyllithium. GC analysis of the organic phase of the hydrolyzed reaction sample after 20 h at 65° C. showed the presence of 1.12 mmol (56% yield) of 4-(trimethylsilylethynyl)pyridine and no remaining 3-cyanopyridine in the reaction mixture.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([OH:11])=[CH:9][N:8]([CH3:12])[C:7]=1[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5])[CH3:2].[Cl:19][CH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].FC(F)(F)S(O)(=O)=O.C(=O)(O)[O-].[Na+]>O.C(Cl)Cl>[Cl:19][CH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([C:9]1[N:8]([CH3:12])[C:7]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:10]=1[OH:11])=[O:24]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(O)cn1C
Reactant: O=C(Cl)c1ccccc1CCl
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Cc1c(C(=O)OCC)c(O)c(C(=O)c2ccccc2CCl)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
Ethyl 3-ethoxycarbonyl-4-hydroxy-1-methylpyrrole-2-acetate (510 mg, 2.0 mmol) is mixed with o-(chloromethyl)benzoyl chloride (565 μl, 4.0 mmol) under nitrogen, and 2.0 ml anhydrous trifluoromethanesulfonic acid is added. The reaction mixture is stirred at room temperature for one hour followed by dilution with methylene chloride (50 ml), and then water (30 ml). Solid sodium bicarbonate is slowly added until the acid is neutralized. The organic layer is separated and the aqueous layer is washed with methylene chloride (50 ml). The combined organic layers are washed with water (20 ml) and saturated brine (50 ml). Subsequently, the washed layers are dried with sodium sulfate and the solvent is removed in vacuo to give a red solid which is recrystallized from ethanol to give 525 mg (64.5%) of ethyl 5-[o-(chloromethyl)benzoyl]-3-ethoxycarbonyl-4-hydroxy-1-methylpyrrole-2-acetate.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[OH-].[Na+].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>C1(C)C=CC=CC=1>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][C:11](=[O:12])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(CN)OC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COC(CNC(=O)OCc1ccccc1)OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 98.6 %

Procedure:
A solution of aminoacetaldehyde dimethyl acetal (25 mL, 229 mmol) in toluene (120 mL) is treated at 0° C. with a 4.85 M sodium hydroxide solution (70.8 mL, 343.5 mmol). The mixture is stirred at 0° C. for 10 minutes and benzyl chloroformate (33.8 mL, 229 mmol) is added keeping the internal temperature below 20° C. during the addition. The mixture is warmed to room temperature over 4 hours. The organic layer is separated, washed with brine, dried over sodium sulfate, and concentrated to dryness to give the title compound (54 g, 98%). ES/MS (m/e): 240 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@H:18]3[N:23]([CH2:24][C:25](O)=[O:26])[CH2:22][C:21]([CH3:29])([CH3:28])[O:20][CH2:19]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C([O-])(=O)C.[NH4+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@@H:18]3[CH2:19][O:20][C:21]([CH3:29])([CH3:28])[CH2:22][N:23]3[CH2:24][C:25]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:26])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CC1(C)CN(CC(=O)O)[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Reactant: C1COCCN1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC1(C)CN(CC(=O)N2CCOCC2)[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Yield: 86 %

Procedure:
The desired compound was prepared according to Method F from [(S)-5-(6-Chloro-9H-beta-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholin-4-yl]-acetic acid and morpholine in 86% yield. 1H-NMR (300 MHz, DMSO-d6): δ 1.17 (s,3H), 1.30 (s,3H), 2.19 (d,1H), 2.71 (d,1H), 3.03 (d,1H), 3.16 (d,1H), 3.22 (dd,1H), 3.45-3.72 (m,7H), 3.80-3.98 (m, 3H), 7.94 (d,1H), 8.15 (d,1H), 8.21 (d,1H), 8.37 (d,1H), 9.03 (s,1H), 10.35 (s,1H), 11.28 (s,1H). Retention Time (LC, method: ammonium acetate standard): 1.56 min. MS (M+H+): 486.3.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:31])[C:26](OCC)=[O:27])=[CH:20][C:19]=1[F:32])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:31])[C:26]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:27])=[CH:20][C:19]=1[F:32])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(=O)Nc1ccc(OCc2ccccc2)c(F)c1
Reactant: NCCc1ccccc1
Product: O=C(NCCc1ccccc1)C(=O)Nc1ccc(OCc2ccccc2)c(F)c1
Yield: 98 %

Procedure:
Phenethyl-amine (33 mL, 520 mmol) was added to ethyl [(4-benzyloxy-3-fluorophenyl)amino](oxo)acetate (81 g, 260 mmol) and the mixture was sonicated at room temperature for 30 min. The resulting solid was filtered, washed with water and dried to give N-(4-benzyloxy-3-fluorophenyl)-N′-(2-phenylethyl)ethanediamide (100 g, 99%). 1H NMR (400 MHz, d6-DMSO): δ 10.72 (br s, 1H), 9.05 (m, 1H), 8.78 (m, 1H), 7.77 (m, 1H), 7.59 (m, 1H), 7.46-7.19 (m, 8H), 5.16 (m, 2H), 3.45 (m, 2H), 2.83 (m, 2H); IR (cm−1): 2980, 2883, 1653, 1522, 1506, 1441, 1385, 1221, 1122, 951, 808, 746, 696, 584; LC/MS (M+H=393).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([C@H:11]3[CH2:16][CH2:15][C@H:14](C(OC)=O)CC3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.ClC1C(CNC([C@H]2CC[C@H](C(OC)=O)CC2)=O)=NC=CN=1.C1(C(O)=O)CCC1>>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:16][CH2:15][CH2:14]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: COC(=O)[C@H]1CC[C@H](c2ncc3c(Cl)nccn32)CC1
Agent: COC(=O)[C@H]1CC[C@H](C(=O)NCc2nccnc2Cl)CC1
Agent: O=C(O)C1CCC1
Product: Clc1nccn2c(C3CCC3)ncc12

Procedure:
This compound was prepared using procedures analogous to that described for trans-methyl 4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxylate and its precursor trans-methyl 4-({[(3-chloropyrazin-2-yl)methyl]amino}carbonyl)cyclohexanecarboxylate, using cyclobutanecarboxylic acid in place of 4-(methoxycarbonyl)cyclohexanecarboxylic acid.