Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[C:12]2[C:13]([C:17](Cl)=[O:18])=[C:14]([CH3:16])[O:15][C:11]=2[CH:10]=[CH:9][C:8]=1[O:20][C:21]1[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=1)=[O:6])[CH:2]=[CH2:3].[CH3:31][NH:32][CH3:33].O>ClCCl>[CH3:30][O:29][C:23]1[CH:24]=[C:25]([O:27][CH3:28])[N:26]=[C:21]([O:20][C:8]2[C:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])=[C:12]3[C:13]([C:17](=[O:18])[N:32]([CH3:33])[CH3:31])=[C:14]([CH3:16])[O:15][C:11]3=[CH:10][CH:9]=2)[N:22]=1
Reactant: CNC
Reactant: C=CCOC(=O)c1c(Oc2nc(OC)cc(OC)n2)ccc2oc(C)c(C(=O)Cl)c12
Solvent: O
Solvent: ClCCl
Product: C=CCOC(=O)c1c(Oc2nc(OC)cc(OC)n2)ccc2oc(C)c(C(=O)N(C)C)c12
Reaction time: 0.5 h
Yield: 60 %

Procedure:
3.0 g of 4-allyloxycarbonyl-5-(4,6-dimethoxypyrimidin-2-yl)oxy-2-methylbenzofuran-3-carbonyl chloride was dissolved in 13 ml of dichloromethane, and 1.5 g of a 50% dimethylamine aqueous solution was dropwise added thereto under cooling with ice. After stirring for 30 minutes, the reaction solution was poured into water and extracted with dichloromethane. The organic layer was washed with water and then dried over anhydrous sodium sulfate. The oily substance obtained by concentration under reduced pressure, was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to obtain 1.84 g (yield: 60%) of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:36]1([N:42]2[C:46]3([CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)[C:45](=[O:52])[NH:44][CH2:43]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:49]3[CH2:48][CH2:47][C:46]4([N:42]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[CH2:43][NH:44][C:45]4=[O:52])[CH2:51][CH2:50]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC4(CC3)C(=O)NCN4c3ccccc3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 1-phenyl-l,3,8-triaza-spiro[4.5]decan-4-one hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [O:1]=[C:2](N1[C@H](CC2C=CC=CC=2)COC1=O)[C@H:3]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C@@H:4]([OH:8])[C:5]([CH3:7])=[CH2:6].[OH2:28].C[N+]1([O-])CC[O:33]CC1>C1COCC1.CCCCCC.C(OCC)(=O)C.O=[Os](=O)(=O)=O>[CH2:9]([C@@H:3]1[C@@H:4]([OH:8])[C:5]([CH3:7])([CH2:6][OH:33])[O:1][C:2]1=[O:28])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=C(C)[C@H](O)[C@@H](CCCCCC)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: O=[Os](=O)(=O)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCC[C@H]1C(=O)OC(C)(CO)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 100 ml round bottom flask was introduced 340 mg (0.91 mmol) of 3-(1-oxo-2-(R)-hexyl-3-(R)-hydroxy-4-methyl-4-pentenyl)-4-(R)-(phenylmethyl)-2-oxazolidinone, to which was added 14 ml THF, 0.36 ml water, and 532 mg 4-methylmorpholine N-oxide (4.55 mmol, 5 eq.). The reaction was stirred at room temperature and 0.36 ml of 0.25M OsO4 in THF was added dropwise. After 1 hour, the reaction was quenched with 2 ml of 20% aq. NaHSO3, added to 30 ml of ethyl acetate and extracted twice with 10 ml 20% aq. NaHSO3 then with 10 ml water. The organic layer was separated, dried over MgSO4, and the solvent was removed under vacuum. A 400 MHz proton NMR of the crude reaction product revealed that a mixture of diastereomers at C-4 was formed in about an 8 to 1 ratio, with the stereochemistry of the major product uncertain. The residue was taken up in 60% hexane/ethyl acetate and chromatographed on silica gel using the same solvent mixture. The two diastereomers and the chiral auxilliary proved to be difficult to cleanly separate from each other by chromatography: the minor diastereomer elutes first, followed by the major diastereomer, followed by the chiral auxilliary. Careful chromatography afforded fractions enriched in each product. The total mass of the three products combined was 318 mg (86%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[C:9]([F:19])[CH:8]=2)[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3]1.[S:25]([CH2:28][C:29]([O:31]C)=O)[C:26]#[N:27].C(O)(=O)C>C(O)C.C(Cl)Cl>[O:31]=[C:29]1[CH2:28][S:25][C:26]([N:16]2[CH2:15][CH2:14][CH:13]([C:10]3[CH:11]=[CH:12][C:7]([N:6]4[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3][C:2]4=[O:1])=[CH:8][C:9]=3[F:19])[CH2:18][CH2:17]2)=[N:27]1
Reactant: COC(=O)CSC#N
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)c(F)c2)C(=O)O1
Solvent: CCO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(C4=NC(=O)CS4)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C

Procedure:
A mixture of (S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 20, 310 mg), methyl thiocyanatoacetate (121 mg, Bull. Chem. Soc. Jpn. 1972, 45(5), 1507) and glacial acetic acid (55 mg) in absolute ethanol (5 mL) is stirred at reflux under N2 for 4 hrs and then cooled to ambient temperature, diluted with methylene chloride (45 mL), washed with water (2×15 mL) and saline (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel (230-400 mesh, 45 g), eluting with methanol/methylene chloride (4/96), and those fractions with an Rf =0.47 by TLC (methanol/chloroform, 10/90) are pooled and concentrated to give the title compound, mp 222-224° C. (decomp.).
Reaction SMILES: [CH:1]1([CH:4]=[C:5]2[C:14](=O)[C:13]3[C:8](=[CH:9][C:10]([C:16]([O:18]C)=[O:17])=[CH:11][CH:12]=3)[O:7][CH2:6]2)[CH2:3][CH2:2]1.Cl.[NH:21]([C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([CH3:31])[CH:24]=1)[NH2:22]>>[C:27]([C:26]1[CH:29]=[CH:30][C:23]([N:21]2[CH:4]([CH:1]3[CH2:2][CH2:3]3)[CH:5]3[CH2:6][O:7][C:8]4[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[CH:11]=[CH:12][C:13]=4[C:14]3=[N:22]2)=[CH:24][C:25]=1[CH3:31])#[N:28]
Reactant: Cc1cc(NN)ccc1C#N
Reactant: COC(=O)c1ccc2c(c1)OCC(=CC1CC1)C2=O
Agent: Cl
Product: Cc1cc(N2N=C3c4ccc(C(=O)O)cc4OCC3C2C2CC2)ccc1C#N

Procedure:
The title compound was prepared from methyl 3-(cyclopropylmethylene)-4-oxochroman-7-carboxylate (Preparation 33), and 4-hydrazinyl-2-methylbenzonitrile hydrochloride (Preparation 2) according to Method B and Method C. The crude product was purified by reverse-phase HPLC (65 to 85% acetonitrile/water/0.05% trifluoroacetic acid) to give the title compound (yellow solid, 23 mg). The title compound was largely present as (±)-(3RS,3aSR)-2-(4-cyano-3-methylphenyl)-3-cyclopropyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.11 (br. s., 1H), 7.94 (d, J=7.8 Hz, 1H), 7.58 (dd, J=8.2, 1.6 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.47 (d, J=1.6 Hz, 1H), 7.23 (d, J=1.6 Hz, 1H), 7.11 (dd, J=8.6, 2.0 Hz, 1H), 4.84 (dd, J=10.5, 5.9 Hz, 1H), 4.45 (dd, J=12.9, 10.5 Hz, 1H), 4.31 (t, J=10.0 Hz, 1H), 3.89 (ddd, J=13.0, 9.9, 5.7 Hz, 1H), 2.42 (s, 3H), 0.71-0.81 (m, 1H), 0.62-0.70 (m, 1H), 0.49-0.58 (m, 1H), 0.35-0.43 (m, 1H), 0.17-0.24 (m, 1H). ES-MS m/z 374 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][OH:30])=[O:25])[CH:17]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:31][N:32](C)[C:33](=O)OC(C)(C)C)[CH:9]=1.Cl.[C:42](=O)(O)[O-].[Na+].[O:47]1[CH2:52][CH2:51]OCC1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=2)[O:22][CH2:23][C:24]([NH:26][C:27]2[CH:28]=[CH:29][CH:42]=[C:52]([OH:47])[CH:51]=2)=[O:25])(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:31][NH:32][CH3:33])[CH:9]=1.[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=2)[O:22][CH2:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][OH:30])=[O:25])(=[O:14])=[O:15])[CH:11]=[C:10]([CH2:31][NH:32][CH3:33])[CH:9]=1
Reactant: CN(Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(OCC(=O)NCCCO)c2)c1)C(=O)OC(C)(C)C
Reactant: O=C([O-])O
Reactant: C1COCCO1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CNCc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(OCC(=O)NCCCO)c2)c1
Product: CNCc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(OCC(=O)Nc3cccc(O)c3)c2)c1
Reaction time: 3 h

Procedure:
tert-Butyl ((5-(2-fluorophenyl)-1-((3-(2-((3-hydroxypropyl)amino)-2-oxoethoxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 11a (99 mg, 0.17 mmol) was dissolved in 5 mL of dichloromethane, and the reaction solution was cooled in an ice bath, followed by dropwise addition of a solution of hydrogen chloride in 1,4-dioxane (4 N, 2 mL), and then the reaction solution was stirred for 3 h. The pH of the reaction solution was adjusted to 7 to 8 with the saturated sodium bicarbonate solution, and it was extracted with dichloromethane (50 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by thin layer chromatography with elution system A to obtain the title product 2-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)-N-(3-hydroxypropyl)acetamide 11 (80 mg, a light yellow oil) in 97% yield.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][N:24]([CH3:47])[C:25]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:30][CH2:29][CH:28]([CH:31]([OH:40])[CH2:32][O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:27][CH2:26]1.C(OCC)C>C(Cl)Cl>[CH3:23][N:24]([CH3:47])[C:25]1([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:30][CH2:29][CH:28]([C:31](=[O:40])[CH2:32][O:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:27][CH2:26]1
Reactant: CN(C)C1(c2ccccc2)CCC(C(O)COc2ccccc2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: CN(C)C1(c2ccccc2)CCC(C(=O)COc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 15% solution of Dess-Martin periodinane in methylene chloride (22.9 g, 8.10 mmol) was added to a solution of 1-(4-dimethylamino-4-phenylcyclohexyl)-2-phenoxyethanol (800 mg, 2.35 mmol) in anhydrous methylene chloride (25 ml). The mixture was stirred at room temperature for 4 h and then at 40° C. for 1.5 h and diethyl ether (100 ml) was then added. The suspension was washed with 25% potassium carbonate solution, 5% sodium bicarbonate solution, 1 M sodium thiosulfate solution and water (50 ml of each). The organic phase was dried with sodium sulfate and concentrated i. vac.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5]([F:15])=[C:4]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.[NH2:25][NH2:26]>O1CCOCC1>[F:8][C:7]1[C:2]([NH:25][NH2:26])=[N:3][C:4]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[C:5]([F:15])[C:6]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: NN
Reactant: Fc1nc(OCCN2CCOCC2)c(F)c(N2CCOCC2)c1F
Solvent: C1COCCO1
Product: NNc1nc(OCCN2CCOCC2)c(F)c(N2CCOCC2)c1F
Temperature: 100 °C

Procedure:
4-[2,3,5-Trifluoro-6-(2-morpholin-4-yl-ethoxy)-pyridin-4-yl]-morpholine (1.2 g; 3.5 mmol) and hydrazine (2 g) were added to dioxane (10 mL) and heated to 100° C. for six hours. The solvent was evaporated, and the residue was dissolved in dichloromethane (20 mL) and washed with a 10% sodium carbonate solution (2 mL). It was dried over magnesium sulfate, and evaporated, to give crude [3,5-Difluoro-4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazine. The crude product was then dissolved in ethanol. To the solution was added one drop of acetic acid, and m-tolylaldehyde (600 mL; 5 mmol) and it was heated at 60° C. overnight. The solvent was then evaporated, and the residue was purified by column chromatography to give Compound 12 (850 mg). Theoretical Mass Ion: 461.1; observed MH+ peak: 462.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.O>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][O:8][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH2:4][O:3]1
Reactant: CC1(C)OCC(CO)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Yield: 88.9 %

Procedure:
18.8 ml (151 mmol) (2,2-dimethyl-[1,3]dioxolan-4-yl) -methanol and 28.6 g (150 mmol) toluene-4-sulfonyl chloride were stirred for 16 h at room temperature in 7 ml pyridine, it was poured onto 400 ml water, extracted twice with ethyl acetate, the combined ethyl acetate phases were washed with water, the organic phase was dried with sodium sulfate, filtered, the solvent was removed in a vacuum and 38.2 g (88%) toluene-4-sulfonic acid-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-ester was obtained as a colourless oil. MS (m/e)=286.
Reaction SMILES: [CH2:1]([SH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1)([O-:20])=[O:19].N1C=CC=CC=1>C(#N)C>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:29])[S:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:25][CH:26]=1)([O-:20])=[O:19]
Reactant: CCCCCCCCCCCCCCCCS
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCSC(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.1 %

Procedure:
In a three necked flask equipped with a dropping funnel, a thermometer and a reflux condenser, n-hexadecanethiol (165 g) was dissolved in acetonitrile (1000 ml). To the solution, p-nitrophenyl isocyanate (100 g) was gradually added, then pyridine (4 ml) was added dropwise, and the mixture was stirred at room temperature for 10 minutes, and then heat-refluxed for 30 minutes. When the reaction mixture was cooled to room temperature, crystals precipitated. The crystals were collected by filtering and washed with acetonitrile. S-n-hexadecyl p-nitrophenylthiocarbamate (250 g) was obtained at a yield of 97%.
Reaction SMILES: [CH3:1][P:2]([O-:8])[O:3][CH2:4][CH:5]([CH3:7])[CH3:6].[C:9](#[N:12])[CH:10]=[CH2:11].[Na].C(O)(=O)C>C(O)C>[C:9]([CH2:10][CH2:11][P:2]([CH3:1])(=[O:8])[O:3][CH2:4][CH:5]([CH3:7])[CH3:6])#[N:12]
Reactant: C=CC#N
Reactant: CC(C)COP(C)[O-]
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)COP(C)(=O)CCC#N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 15.0 g of isobutyl P-methylphosphonite and 5.3 g of acrylonitrile in 50 ml of dry ethanol is added to a stirred mixture of 0.5 g of sodium (50% dispersion in oil) in 25 ml of ethanol, at 0° C., under an atmosphere of nitrogen. The reaction mixture is allowed to warm to room temperature, and stirred for 4 hours. 1 ml of glacial acetic acid is added and the mixture is concentrated under reduced pressure. The resulting crude product is dissolved in 50 ml of ethyl acetate, washed twice with 20 ml of water, and the organic extract is dried over magnesium sulphate, and then concentrated under reduced pressure. The crude product is distilled to give isobutyl P-(2-cyanoethyl)-P-methyl-phosphinate, b.p. 140°/0.2 mbar, 31P-NMR spectrum: δ=+50.5 ppm (CDCl3).
Reaction SMILES: C[Mg]Br.[C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH:10]=[C:9]2[C@@H:25]1[CH2:27][C@H:26]1[C:28](N(OC)C)=[O:29])#[N:5].[CH2:34]1COCC1>C(OCC)C>[C:28]([C@@H:26]1[CH2:27][C@H:25]1[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([C:4]#[N:5])[CH:7]=2)[N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:16])=[O:17])[CH:10]=1)(=[O:29])[CH3:34]
Reactant: C1CCOC1
Reactant: CON(C)C(=O)[C@@H]1C[C@H]1c1cn(S(=O)(=O)c2ccc(C)cc2)c2ccc(C#N)cc12
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(=O)[C@@H]1C[C@H]1c1cn(S(=O)(=O)c2ccc(C)cc2)c2ccc(C#N)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
A solution of methylmagnesium bromide (3.0 M in diethyl ether, 0.826 ml, 2.48 mmol, 1.05 equiv) was added to a suspension of [trans-2-[5-cyano-1-(p-toluenesulfonyl)indol-3-yl]cycloprop-1-yl]-N-methoxy-N-methylcarboxamide (1 g, 2.36 mmol) in anhydrous diethyl ether (25 ml). The resulting mixture was stirred at 0° C. for 2 h. The reaction mixture was diluted anhydrous THF (15 ml) and stirred for an additional 3 h at 0° C. The cold mixture was quenched with aqueous 1 M hydrochloric acid (200 ml) and extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with brine (50 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude reaction mixture was purified by silica gel column chromatography using a step gradient [2:1, 1:1 (hexanes/ethyl acetate)] to afford 0.518 g (58% yield) of trans-3-(2-acetyl-cyclopropyl)-1-(toluene-4-sulfonyl)-1H-indole-5-carbonitrile as a white solid: LC-MS (column=Phenomenex Luna C18 S10, 3×50 mm, start %B=0, final %B=100, gradient time=2 min, flow rate=5 ml/min) m/e 379 (M+H)+, tR 2.45 min.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:7][OH:8])([CH2:5][OH:6])[CH3:4].[CH3:9][C:10]([CH3:12])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(=O)C.[Na+]>O>[OH:1][CH2:2][C:3]1([CH3:4])[CH2:7][O:8][C:10]([CH3:12])([CH3:9])[O:6][CH2:5]1
Reactant: CC(CO)(CO)CO
Reactant: CC(C)=O
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Product: CC1(CO)COC(C)(C)OC1
Yield: 90 %

Procedure:
A mixture of 30 g of 1,1,1-tris(hydroxymethyl)ethane (Aldrich Chemical Co., Milwaukee, WI), 85 ml of acetone and 80 ml of petroleum ether (b.p. 30°-75° C.) was acidified with 1.0 g of p-toluenesulfonic acid monohydrate and this mixture was refluxed for 24 hours with removal of water by azeotropic distillation. This was followed by neutralization with 1 g of sodium acetate and complete drying with anhydrous sodium sulfate. The liquid was filtered and the solvents removed under reduced pressure. The residue was distilled under vacuum to give 5-hydroxymethyl-2,2,5-trimethyl-1,3-dioxane in 90% yield.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]2[CH2:9][N:8]([S:10]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)(=[O:12])=[O:11])[CH2:7][C:5]2(O)[N:6]=1.CS(Cl)(=O)=O.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[S:3][C:4]2[CH2:9][N:8]([S:10]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)(=[O:11])=[O:12])[CH2:7][C:5]=2[N:6]=1
Reactant: CC1=NC2(O)CN(S(=O)(=O)c3ccc(C)cc3)CC2S1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2Cc3nc(C)sc3C2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of the product from Step A (150 mg) in dichloromethane (2 mL) was added methanesulfonyl chloride (0.074 mL) at 0° C. followed by triethylamine (0.67 mL). After 15 min the reaction mixture was warmed to ambient temperature and stirred for 45 min. The mixture was concentrated in vacuo and purified by preparative thin layer chromatography using an Analtech® 1500 micron plate (8% ethyl acetate/dichloromethane) to give the title compound as a white solid. LC/MS 295.2 (M+1).
Reaction SMILES: [OH:1][C@H:2]1[C@@:6]2([O:9][CH2:8][CH2:7]2)[C@H:5]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]2=[O:17])[O:4][C@@H:3]1[CH2:18][OH:19].CN1C=CN=C1.Cl[C:27]1[CH:43]=[CH:42][CH:41]=[CH:40][C:28]=1[O:29][P:30](=[N:32][C:33]([CH3:39])([CH3:38])[C:34]([O:36][CH3:37])=[O:35])=[O:31]>C1COCC1>[O:17]=[C:11]1[NH:12][C:13](=[O:16])[CH:14]=[CH:15][N:10]1[C@@H:5]1[O:4][C@H:3]([CH2:18][O:19][C:40]2[CH:41]=[CH:42][CH:43]=[CH:27][C:28]=2[O:29][P:30](=[N:32][C:33]([CH3:39])([CH3:38])[C:34]([O:36][CH3:37])=[O:35])=[O:31])[C@@H:2]([OH:1])[C@:6]21[O:9][CH2:8][CH2:7]2
Reactant: COC(=O)C(C)(C)N=[P+]([O-])Oc1ccccc1Cl
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@]23CCO3)c(=O)[nH]1
Agent: Cn1ccnc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)N=[P+]([O-])Oc1ccccc1OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@@]2(CCO2)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.4 %

Procedure:
To a solution of 10 (1.0 eq., 0.28 mmol, 75 mg) in dry THF (3 mL) was added 1-methylimidazole (NMI; 12.0 eq., 3.33 mmol, 0.27 mL) at room temperature. A solution of intermediate 11 (1.4 eq., 0.39 mmol, 0.43 mL) was added dropwise and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed three times with 0.5 M HCl. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-10% methanol in CH2Cl2) to give compound 12e (24 mg, yield=15%, purity=95%) as a mixture of diastereomers. HPLC Condition A; Rt: 1.49 min, m/z=526 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33 (s, 3H), 1.37 (s, 3H), 2.42-2.43 (m, 2H), 3.56 (s, 3H), 3.70-3.79 (m, 1H), 3.80-3.88 (m, 0.4; H), 3.88-3.96 (m, 0.6; H), 4.09-4.20 (m, 1H), 4.26-4.48 (m, 3H), 5.50-5.56 (m, 1H), 5.61-5.69 (m, 1H), 5.88-5.97 (m, 1H), 5.97-6.04 (m, 1H), 7.12-7.24 (m, 3H), 7.31-7.41 (m, 2H), 7.44 (d, J=8.22 Hz, 0.4; H), 7.52 (d, J=8.02 Hz, 0.6; H), 11.49 (br. s., 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][CH3:12])=O.[NH2:13][C:14]1[CH:19]=[CH:18][NH:17][C:16](=[O:20])[CH:15]=1.O=[C:22]([CH3:31])[CH2:23][C:24]([O:26][CH2:27][CH2:28][C:29]#[N:30])=[O:25]>C(O)(C)C>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH:1]2[C:15]3[C:16](=[O:20])[NH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:22]([CH3:31])=[C:23]2[C:24]([O:26][CH2:27][CH2:28][C:29]#[N:30])=[O:25])=[C:4]([O:11][CH3:12])[CH:5]=1)#[N:8]
Reactant: COc1cc(C#N)ccc1C=O
Reactant: Nc1cc[nH]c(=O)c1
Reactant: CC(=O)CC(=O)OCCC#N
Solvent: CC(C)O
Product: COc1cc(C#N)ccc1C1C(C(=O)OCCC#N)=C(C)Nc2cc[nH]c(=O)c21
Reaction time: 72 h

Procedure:
14.63 g (90.81 mmol) of the compound from Example 10A, 10.00 g (90.81 mmol) of 4-aminopyridin-2(1H)-one [Searls, T., McLaughlin, L. W., Tetrahedron 55, 11985-11996 (1999)] and 15.65 g (90.81 mmol) of 2-cyanoethyl 3-oxobutanoate [Yamamoto, T., et al., Bioorg. Med. Chem. Lett. 16, 798-802 (2006)] are dissolved in 300 ml of isopropanol and stirred at the reflux temperature under argon for 3 days. The mixture is then concentrated and subsequently purified by column chromatography (silica gel; mobile phase: initially ethyl acetate and then dichloromethane/methanol 10:1). The resulting product fractions are concentrated and then taken up in a little ethyl acetate. The precipitated product is filtered off and dried at 40° C. in vacuo overnight. 10.11 g (27% of theory) of the title compound are obtained.
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][C:4]1O[C:8](=O)[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[N:5]=1.[NH:16]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[NH2:17].[Cl:25]CC1C=CC=CN=1>>[Cl:25][C:8]1[C:7]2[C:6](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[C:4]2[N:16]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:17]=[C:2]([CH3:15])[C:3]=12
Reactant: NNCc1ccccn1
Reactant: CC(=O)Cc1nc2ccccc2c(=O)o1
Reactant: ClCc1ccccn1
Product: Cc1nn(Cc2ccccn2)c2nc3ccccc3c(Cl)c12

Procedure:
Following the procedures described in Reference Example 2-3 and Example 2-1, the title compound was prepared from 2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one and 2-hydrazinomethylpyridine which was previously prepared from 2-chloromethylpyridine following the method described in Reference Example 2-2 (75% yield).