Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5]O)(C)(C)C.C(CC(C)(C)C)(C)C.[CH2:15]([OH:27])/[CH:16]=[CH:17]/[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C(Cl)Cl.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH2:18]([C@@H:17]1[O:5][C@H:16]1[CH2:15][OH:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CC(C)(C)OO
Reactant: CCCCCCCCC/C=C/CO
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Solvent: ClCCl
Solvent: CC(C)CC(C)(C)C
Product: CCCCCCCCC[C@@H]1O[C@H]1CO
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
A suspension of 1.00 g of 4a powdered molecular sieves in 50 ml of dry CH2Cl2 was cooled to 0.° C. under argon. To the cooled suspension was added 308 mg (1.09 mmole) of Ti(OiPr)4 and 356 mg (1.52 mmole) of L(+)diisopropyl tartrate via syringe. The mixture was stirred for 15 min and cooled to -20° C. A solution of tert-butyhydroperoxide in isooctane (3.8M, 4.30 ml, 16.4 mmole) was added slowly to the mixture and the catalyst was allowed to "age" for 30 min at -20° C. A solution fo 2.00 g (10.9 mmole) of E-2-dodecen-1-ol in 10 ml of CH2Cl2 was dried over 3A molecular sieves for 15 min before being added to the mixture slowly, with stirring, at -20°. The solution was then placed in the freezer (-30° C.) and allowed to stand for 24 H. The mixture was warmed to 0° C. and poured into a solution of 1.00 g of citric acid and 3.50 g of FeSO4 in 15 ml H2O. The organic layer was separated and the aqueous layer washed twice with 20 ml of CH2Cl2. The CH2Cl2 layers were combined, dried over MgSO4, filtered and evaporated to yield a sticky white solid. Recrystallization from Et2O: petroleum ether afforded 1.98 g of white solid, mp 62°-4° C. 1H NMR δ3.92 (ddd, 1, J=2.5, 6, 12 Hz), 3.63 (ddd, 1, J=4, 7, 12 Hz), 2.95 (m, 2), 1.69 (dd, 1, J=7, 6 Hz), 1.6-1.2 (m, 16), 0.88 (t, 3, J=6 Hz). Mass Spectra: M-31(-CH2OH)(0.4)169, M(100)55.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH:7]([CH2:10][CH2:11][CH2:12]O)[C:6]=2[CH:14]=1.CN(C)C=O.S(Cl)([Cl:22])=O>ClCCl>[Cl:22][CH2:12][CH2:11][CH2:10][CH:7]1[C:6]2[CH:14]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:9][CH2:8]1
Reactant: O=S(Cl)Cl
Reactant: OCCCC1COc2ccc(F)cc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Fc1ccc2c(c1)C(CCCCl)CO2
Reaction time: 3 h

Procedure:
3-(2,3-Dihydro-5-fluoro-benzofuran-3-yl)-1-propanol, prepared as described in EXAMPLE 11, (51 g) was dissolved in 300 ml of dichloromethane and 0.5 ml of dimethyl formamide was added. During 20 min 50 ml of thionyl chloride was added dropwise followed by stirring for 3 h. Ice cold water was added, the organic phase separated, dried over magnesium sulfate and concentrated in vacuo giving 46 g of 3-(3-chloro-1-propyl)-2,3-dihydro-5-fluoro-benzofuran as an oil. Sodium cyanide (12 g) was suspended in dimethyl sulfoxide (180 ml) and heated to 80° C. A solution of 3-(3-chloro-1-propyl)-2,3-dihydro-5-fluoro-benzofuran (42 g) in 40 ml of dimethyl sulfoxide was added dropwise followed by heating to 140° C. for 15 min. After cooling ether and water were added, the ether phase separated, washed with water and dried over magnesium sulfate. Removal of solvent in vacuo left a viscous oil which was applied to a silica gel column giving 4-(2,3-dihydro-5-fluoro-benzofuran-3-yl)butyronitrile as an oil (20 g). The cyanide was dissolved in 100 ml of glacial acetic acid followed by addition of concentrated hydrochloric acid (200 ml). After reflux for 5 h, water was added followed by extraction with ethyl acetate. Drying of the organic phase over magnesium sulfate and removal of solvent in vacuo gave 4-(2,3-dihydro-5-fluoro-benzofuran-3-yl)butyric acid (20 g). The acid (8 g) was dissolved in 50 ml of dichloromethane and 0.5 ml of dimethyl formamide was added. Thionyl chloride (20 ml) was added followed by reflux for 1.5 h. The reaction mixture was concentrated twice with heptane in vacuo giving 4-(2,3-dihydro-5-fluoro-benzofuran-3-yl)-butyric acid chloride (7 g) as an oil. A solution of spiro[isobenzofuran-1(3H),4'-piperidine] (2 g) and triethyl amine (3 ml) in dichloromethane (50 ml) was cooled to 5° C. and a solution of 4-(2,3-dihydro-5-fluoro-benzofuran-3-yl)-butyric acid chloride (3 g) in dichloromethane (25 ml) was added dropwise. After stirring for 1 h at room temperature the reaction mixture was washed with salt water and dried over magnesium sulfate. Removal of the solvent in vacuo gave 4.4 g of a viscous oil which was dissolved in 25 ml of dry tetrahydrofuran and added dropwise to a suspension of lithium aluminium hydride (2.6 g) in 60 ml of dry tetrahydrofuran. The reaction mixture was heated to reflux for 2 h and hydrolyzed with water. Filtration and removal of solvent in vacuo gave a viscous oil which was applied to a silica gel column (eluent:heptane/ethyl acetate/triethyl amine=70:25:5) giving 2.9 g of the title compound, 12, which crystallized as the oxalate salt from acetone by addition of oxalic acid. Yield: 2.2 g, mp: 102°-3° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[C:12]3=O)[CH2:5][CH2:4][O:3]1.C(O)(C(F)(F)F)=O.[H][H]>C(O)(=O)C.[Pd]>[O:1]=[C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12]3)[CH2:5][CH2:4][O:3]1
Reactant: [H][H]
Reactant: O=C1Nc2ccc(CCN3CCOC3=O)cc2C1=O
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: O=C1Cc2cc(CCN3CCOC3=O)ccc2N1

Procedure:
To a solution of the compound obtained in Step E (7.68 mmoles) in acetic acid (15 ml) there are added TFA (7 ml) and Pd/C 10% (400 mg). The reaction mixture is stirred at 50° C. under 4 bars of hydrogen overnight. The catalyst is filtered off on a bed of Celite and is then washed with acetic acid (20 ml). The filtrate is evaporated to dryness and the residual acetic acid is removed by azeotropic distillation with toluene. The solid obtained is recrystallised from a mixture of EtOH/ethyl ether to yield the title product after drying in vacuo.
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[CH:13]=[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]4[CH:33]=[CH:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]=4)[CH:17]=3)[CH:11]=[CH:10][C:6]=2[C:7](=[O:9])[CH:8]=1)#[N:2].[N-:34]=[N+:35]=[N-:36].[Na+].Cl.N1C=CC=CC=1.CN(C)C=O>O>[N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[CH2:23][O:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][O:14][C:12]1[CH:11]=[CH:10][C:6]2[C:7](=[O:9])[CH:8]=[C:3]([C:1]3[NH:36][N:35]=[N:34][N:2]=3)[O:4][C:5]=2[CH:13]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cc(=O)c2ccc(OCc3cccc(OCc4ccc5ccccc5n4)c3)cc2o1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: O=c1cc(-c2nnn[nH]2)oc2cc(OCc3cccc(OCc4ccc5ccccc5n4)c3)ccc12
Temperature: 100 °C

Procedure:
2-cyano-7-(3-(quinolin-2-ylmethoxy)benzyloxy)-4-oxo-4H-1-benzopyran (2.97 mmoles), sodium azide (965 mg), pyridine hydrochloride (1.72g) and dimethylformamide (7 ml) are combined and heated at 100° C. for 48 hours. The reaction mixture is poured into cold water and the resulting precipitate is collected. The precipitate is dissolved in hot ethanol and reprecipitated by addition of water to give 5-(7-(3-(quinolin-2-ylmethoxy)benzyloxy)-4-oxo-4H-1-benzopyran-2-yl)tetrazole which decomposes at 203° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:11][C:12]1[C:21]([O:22][CH3:23])=[CH:20][C:15]2[NH:16][C:17](=[O:19])[S:18][C:14]=2[CH:13]=1>>[CH3:23][O:22][C:21]1[C:12]([NH:11][C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:13][C:14]2[S:18][C:17](=[O:19])[NH:16][C:15]=2[CH:20]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: COc1cc2[nH]c(=O)sc2cc1N
Product: COc1cc2[nH]c(=O)sc2cc1Nc1ncnc2[nH]ccc12

Procedure:
20 mg (130 μmol) 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (CAS-No. 3680-59-1) were transformed in analogy to example 1 using 6-amino-5-methoxy-1,3-benzothiazol-2(3H)-one to give after working up and purification 8.0 mg (19%) of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH:10]1[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]1=[S:12].C(N(CC)CC)C>C(O)C>[NH2:15][C:14]1[CH:16]=[CH:17][N:10]=[C:11]([S:12][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:13]=1
Reactant: CCOC(=O)CCCBr
Reactant: Nc1cc[nH]c(=S)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCSc1nccc(N)n1

Procedure:
In a nitrogen atmosphere, 28.6 ml (200 mmol) of ethyl 4-bromobutyrate was added to a solution of 25.44 g (200 mmol) of 2-thiocytosine and 30.7 ml (220 mmol) of triethylamine in 400 ml of ethanol at room temperature, followed by refluxing for 16 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4→1/9) to yield 46.31 g (96.0%, white crystal) of the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11](=[O:16])[NH:12][CH2:13][CH2:14][N:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:17](=O)[CH3:18].C([BH3-])#N.[Na+].[OH-].[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[CH2:17]([N:15]1[CH2:14][CH2:13][NH:12][C:11](=[O:16])[CH:10]1[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH3:18]
Reactant: O=C1NCCN=C1c1ccc([N+](=O)[O-])cc1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCN1CCNC(=O)C1c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
A 10-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen, charged with 31 (2.78 g, 12.7 mmol), acetaldehyde (727 mg, 16.5 mmol) and anhydrous methanol (40 mL). A solution of sodium cyanoborohydride (2.4 g, 38 mmol) and anhydrous zinc chloride (2.6 g, 19.1 mmol) in anhydrous methanol (40 mL) was added, and the reaction was stirred at room temperature for 1 h. After this time, 1N aqueous sodium hydroxide (25 mL) was added, and the methanol was evaporated under reduced pressure. The remaining aqueous solution was extracted with ethyl acetate (3×100 mL). The organic layers were combined, washed with water (100 mL) and brine (100 mL) and dried over magnesium sulfate. The drying agent was removed by filtration and the filtrate concentrated under reduced pressure to afford a 98% yield (3.20 g) of 32 as a yellow oil: 1H NMR (500 MHz, DMSO-d6) δ 8.18 (d, 2H, J=8.5 Hz), 8.02 (d, 1H, J=4.0 Hz), 7.66 (d, 2H, J=8.5 Hz), 4.06 (s, 1H), 3.39 (td, 1H, J=12.0, 4.0 Hz), 3.22 (m, 1H), 3.07 (dt, 1H, J=12.0, 3.0 Hz), 2.50 (m, 1H), 2.37 (m, 1H), 2.21 (m, 1H), 0.91 (t, 3H, J=8.5 Hz); MS (ESI+) m/z 250 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH2:9][C:10]2[NH:11][CH:12]=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)=[CH:4][CH:3]=1.[C:19](O)(=[O:22])[C:20]#[CH:21].N1(C(N2C=CN=C2)=O)C=CN=C1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:11]3[CH:12]=[C:13]([CH:15]([CH3:16])[CH3:17])[NH:14][C:10]=23)=[O:18])=[CH:4][CH:3]=1
Reactant: CC(C)c1c[nH]c(CC(=O)c2ccc(F)cc2)n1
Reactant: C#CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)c1cn2c(=O)ccc(C(=O)c3ccc(F)cc3)c2[nH]1

Procedure:
The compound is prepared as described in example 10 with 65 mg (0.26 mmol) of 1-(4-fluorophenyl)-2-(4-isopropyl-1H-imidazol-2-yl)ethanone (example XXX), 27.7 mg (0.40 mmol) of propiolic acid and 77 mg (0.48 mmol) of 1-(1H-imidazol-1-yl-carbonyl)-1H-imidazole.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10]3[C:15]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([O:19]C)=[O:18])=[C:14]([CH3:24])[N:13]=[C:12]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[I-].[Li+]>N1C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[C:7]([C:10]3[C:15]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([OH:19])=[O:18])=[C:14]([CH3:24])[N:13]=[C:12]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2ncsc2c1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)nc1-c1ccc2ncsc2c1
Temperature: 125 °C
Yield: 37.9 %

Procedure:
Methyl 2-(4-(benzo[d]thiazol-6-yl)-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.041 g; 0.098 mmol) and lithium iodide (0.039 mg; 0.295 mmol) were placed in a microwave vial and dissolved in pyridine (0.7 mL). The vial was purged with nitrogen and heated to 125° C. for 48 h. The solvent was removed under reduced pressure, the residue was dissolved in water and the pH of the solution was adjusted between 2 and 3 by addition of a solution of hydrochloric acid 6N until a precipitate formed. The precipitate was collected by filtration and dried under reduced pressure over phosphorus pentoxide. Purification by flash-chromatography on silica gel using a gradient of methanol (1-10%) in dichloromethane furnished 0.015 g (35%) of the title compound as a brown solid.
Reaction SMILES: C(OC(=O)C1C=C([C:12](=O)[N:13]([O:15]CC=C)C)C=C(N)C=1)C=C.[CH2:22]([O:25][C:26](=[O:46])[C:27]1[CH:28]=[C:29]([CH:40]=[C:41]([N+:43]([O-:45])=[O:44])[CH:42]=1)[C:30]([O:32]N1C(=O)CCC1=O)=O)[CH:23]=[CH2:24].Cl.CNO>ClCCl>[CH2:22]([O:25][C:26](=[O:46])[C:27]1[CH:42]=[C:41]([N+:43]([O-:45])=[O:44])[CH:40]=[C:29]([C:30](=[O:32])[N:13]([OH:15])[CH3:12])[CH:28]=1)[CH:23]=[CH2:24]
Reactant: C=CCOC(=O)c1cc(C(=O)ON2C(=O)CCC2=O)cc([N+](=O)[O-])c1
Reactant: C=CCOC(=O)c1cc(N)cc(C(=O)N(C)OCC=C)c1
Agent: CNO
Agent: Cl
Solvent: ClCCl
Product: C=CCOC(=O)c1cc(C(=O)N(C)O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Starting material (8(c)) was prepared as follows. A mixture of 7(b) (2.00 g; see Example 7), N-methylhydroxylamine hydrochloride (1.06 g) triethylamine (1.72 ml) and dichloromethane (60 ml.) was stirred at 5° for 30 minutes. It was then allowed to warm to ambient temperature and stirred for a further 16 hours. The reaction mixture was then poured directly onto a flash column eluting with ethyl acetate/hexane (50:50) to give 3-(N-methyl-hydroxycarbamoyl)-5-nitro-benzoic acid allyl ester (8(a)) as a cream solid (1.43 g).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[CH:30]=[N:29][CH:28]=[CH:27]3)O1.C([O-])([O-])=O.[K+].[K+]>CC#N.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[CH:30]=[N:29][CH:28]=[CH:27]4)=[CH:3][N:4]=2)[N:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CC1(C)OB(c2ccc3cnccc3c2)OC1(C)C
Reactant: CCCCNc1ccc2ncc(Br)n2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCCNc1ccc2ncc(-c3ccc4cnccc4c3)n2n1
Temperature: 150 °C
Yield: 68.8 %

Procedure:
A mixture of (3-bromo-imidazo[1,2-b]pyridazin-6-yl)-butyl-amine (100 mg, 0.37 mmol), 6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-isoquinoline (from part A, ˜1 mmol), K2CO3 (153 mg, 1.11 mmol) and dichlorobis(triphenylphosphine)palladium(II) (13 mg, 0.019 mmol) in MeCN/water (4 ml/1 ml) was heated in a microwave at 150° C. for 15 min. The water layer was removed and the reaction mixture was diluted with MeCN (3 ml) and filtered. The filtrate was subjected to preparative HPLC to give the titled compound (80.8 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.03 (t, J=7.33 Hz, 3H) 1.53 (dq, J=14.97, 7.39 Hz, 2H) 1.74-1.81 (m, 2H) 3.48-3.54 (m, 2H) 4.58 (t, J=5.05 Hz, 1H) 6.54 (d, J=9.60 Hz, 1H) 7.68 (d, J=5.56 Hz, 1H) 7.75 (d, J=9.60 Hz, 1H) 8.01-8.05 (m, 2H) 8.25 (dd, J=8.72, 1.64 Hz, 1H) 8.55 (d, J=5.81 Hz, 1H) 8.86 (s, 1H) 9.25 (s, 1H). LRMS (ESI) m/z 318.2 [(M+H)]+, calc'd for C19H19N5: 317.40.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[O:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[CH3:19][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1>[O:13]=[C:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9]([C:14]([O:16][CH3:19])=[O:15])[CH2:10]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C

Procedure:
A solution of (2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (1 g, 4.3 mmol) in a 1:1 mixture of methanol and toluene (60 ml) was made. Trimethylsilyl diazomethane (6.5 ml of a 2M solution in hexanes, 13 mmol) was then added dropwise to the stirred solution at room temperature under nitrogen. After completion of the evolution of nitrogen gas, the resulting yellow solution was evaporated in vacuo, and the residue filtered through a pad of silica gel, eluting with ethyl acetate. Removal of solvent from the filtrate gave a yellow oil (1.05 g, near quantitative yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][CH:18]=1>>[N:17]1([C:2]2[N:7]=[C:6]([NH:8][C@H:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH3:10])[CH:5]=[N:4][CH:3]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[CH:18]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: C[C@H](Nc1cncc(Cl)n1)c1ccccc1
Product: C[C@H](Nc1cncc(-n2cnc3ccccc32)n1)c1ccccc1
Yield: 37.5 %

Procedure:
In a procedure analogous to example 12, reaction of 6-chloro-N-[(1S)-1-phenylethyl]pyrazin-2-amine (140 mg, 0.60 mmol) and benzimidazole (78 mg, 0.66 mmol) furnished the product (71 mg, 38%):
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:17]1[S:18][CH:19]=[CH:20][N:21]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[S:18]1[CH:19]=[CH:20][N:21]=[C:17]1[O:15][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[CH:14][CH:13]=1
Reactant: Brc1nccs1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2nccs2)cc1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 25.3 %

Procedure:
N-Boc-4-hydroxy-aniline (3.9 g, 0.019 mol) was combined with 2-bromothiazole (2.4 mL, 0.027 mol) in DMSO (20 mL) at room temperature. K2CO3 (3.9 g, 0.028 mol) was added and with rapid stirring, the reaction mixture was heated at about 140° C. for 5 hours. After cooling to room temperature, the reaction mixture was poured into water (300 mL), extracted with ethyl acetate (2×) and the combined organics were dried over MgSO4. Decolorizing charcoal was added, stirred for 30 minutes and filtered through a plug of celite and silica (1:1) to obtain an amber filtrate. The solvent was removed by rotary evaporation and the residue was purified by flash column chromatography (ethyl acetate:hexanes; 5%-50% ethyl acetate gradient) to give the title compound (1.4 g, 4.8 mmol, 25%) MS (ESI APCI) m/z 293.0 (M+H+); 1H NMR (300 MHz, DMSO-d6) δ 9.49 (s, 1H) 7.53 (d, J=9.0 Hz, 2H) 7.21-7.28 (m, 2H) 7.16-7.19 (m, 2H) 1.48 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]([O:13][C@@H:14]2[CH2:19][CH2:18][C@H:17]([N:20]3[CH2:23][C:22]([CH2:46][C:47]#[N:48])([N:24]4[CH:28]=[C:27]([C:29]5[C:30]6[CH:37]=[CH:36][N:35]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:31]=6[N:32]=[CH:33][N:34]=5)[CH:26]=[N:25]4)[CH2:21]3)[CH2:16][CH2:15]2)[CH:4]=1.C(N(CC)C(C)C)(C)C.[CH3:58][S:59](Cl)(=[O:61])=[O:60].CCOC(C)=O>C(Cl)Cl>[CH3:58][S:59]([O:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:11])([F:10])[F:12])[N:6]=[C:5]([O:13][C@H:14]2[CH2:15][CH2:16][C@@H:17]([N:20]3[CH2:21][C:22]([CH2:46][C:47]#[N:48])([N:24]4[CH:28]=[C:27]([C:29]5[C:30]6[CH:37]=[CH:36][N:35]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:43])([CH3:44])[CH3:45])[C:31]=6[N:32]=[CH:33][N:34]=5)[CH:26]=[N:25]4)[CH2:23]3)[CH2:18][CH2:19]2)[CH:4]=1)(=[O:61])=[O:60]
Reactant: CS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN([C@H]5CC[C@@H](Oc6cc(CO)cc(C(F)(F)F)n6)CC5)C4)c3)ncnc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN([C@H]5CC[C@@H](Oc6cc(COS(C)(=O)=O)cc(C(F)(F)F)n6)CC5)C4)c3)ncnc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
{1-(cis-4-{[4-(Hydroxymethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (from Example 64, 145.0 mg, 0.2124 mmol) was dissolved in methylene chloride (2.93 mL) and was cooled to 0° C. To that N,N-diisopropylethylamine (60.5 μL, 0.347 mmol) was added followed by methanesulfonyl chloride (23 μL, 0.30 mmol). The reaction was stirred at 0° C. for 1 hour. Then the reaction mixture was worked up with EtOAc and used in the next reaction. MS (ES): 761(M+1).
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]([NH:10][C@H:11]([C:16]([NH:18][C@H:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][OH:21])=[O:17])[CH2:12][CH2:13][CH2:14][NH2:15])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:34]([NH:44][C:45](=[N:48][C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])SC)([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35].CCN(C(C)C)C(C)C>CN(C=O)C>[C:49]([NH:48][C:45](=[N:44][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[NH:15][CH2:14][CH2:13][CH2:12][C@@H:11]([C:16]([NH:18][C@H:19]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:20][OH:21])=[O:17])[NH:10][C:8](=[O:9])[CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([O:51][CH2:52][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)=[O:50]
Reactant: NCCC[C@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)N[C@@H](CO)c1ccccc1
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N=C(NCCC[C@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)N[C@@H](CO)c1ccccc1)NC(=O)OCc1ccccc1)OCc1ccccc1
Yield: 45.6 %

Procedure:
Prepared according to the method described in Example 4(f) above from (R)-N2 -(diphenylacetyl)-(S)-N-(2-hydroxy-1-phenylethyl)ornithine amide (0.5 g; 1.12 mmol; from step (d) above), N,N'-bis(Cbz)-S-methyl-isothiourea (0.603 g; 1.68 mmol), DiPEA (0.2 mL) and DMF (15 mL), yielding 0.386 g of the sub-title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].CCN(CC)CC.C([O-])(O)=O.[Na+].[C:38]1([CH3:63])[CH:43]=[CH:42][C:41]([S:44]([CH2:47][CH2:48][O:49][C:50](=[O:62])[C:51]2[CH:56]=[CH:55][C:54]([CH3:57])=[C:53]([S:58](Cl)(=[O:60])=[O:59])[CH:52]=2)(=[O:46])=[O:45])=[CH:40][CH:39]=1>C(Cl)Cl.O>[C:38]1([CH3:63])[CH:43]=[CH:42][C:41]([S:44]([CH2:47][CH2:48][O:49][C:50](=[O:62])[C:51]2[CH:56]=[CH:55][C:54]([CH3:57])=[C:53]([S:58]([N:21]3[C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[N:18]=[C:17]3[S:15]([CH2:14][C:3]3[C:2]([CH3:1])=[C:7]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])[CH:6]=[CH:5][N:4]=3)=[O:16])(=[O:60])=[O:59])[CH:52]=2)(=[O:46])=[O:45])=[CH:40][CH:39]=1
Reactant: Cc1ccc(S(=O)(=O)CCOC(=O)c2ccc(C)c(S(=O)(=O)Cl)c2)cc1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)CCOC(=O)c2ccc(C)c(S(=O)(=O)n3c(S(=O)Cc4nccc(OCC(F)(F)F)c4C)nc4ccccc43)c2)cc1
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a heterogeneous mixture of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl-methanesulfinyl]-1H-benzimidazole (LANSOPRAZOLE, 700 mg, 1.89 mmol), 3 mL of Et3N, and about 1 g of NaHCO3 in CH2Cl2 (15 mL) was added the sulfonyl chloride (Intermediate 49, 1.03 g, 2.47 mmol, 1.3 eq) in CH2Cl2 (5 mL) at room temperature, and then the mixture was stirred for 2 h. Thereafter water was added, the mixture was extracted with CH2Cl2, and the organic layers were dried, and concentrated. The resulting residual oil was purified by column chromatography (CH2Cl2 to 1% MeOH in CH2Cl2) to yield 1.1 g (78%) of 3-{2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl-methanesulfinyl]-benzimidazole-1-sulfonyl}-4-methylbenzoic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 52) as a yellow foam.