Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)O)=[C:5]([CH2:18][OH:19])[CH:4]=1)#[N:2].C1(C)C=CC=CC=1>OP(O)(O)=O>[F:17][C:14]1[CH:13]=[CH:12][C:11]([CH:9]2[C:6]3[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[CH2:18][O:19]2)=[CH:16][CH:15]=1
Reactant: N#Cc1ccc(C(O)c2ccc(F)cc2)c(CO)c1
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1
Product: N#Cc1ccc2c(c1)COC2c1ccc(F)cc1
Temperature: 80 °C

Procedure:
Crude (4-cyano-2-hydroxymethylphenyl)(4-fluorophenyl)methanol (700 g) is dissolved in H3PO4 (60%, 3000 mL) and the solution is heated to 80° C. for 3 hours. Toluene (1000 mL) is added and the phases are separated. The aqueous phase is further extracted with toluene (1000 mL). The toluene phases are joined and the solvents are removed in vacuo. The remaining crystals are recrystallized from EtOH (99%). Yield 219 g (29%). DSC onset: 97° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH3:12])[C:6]3[CH2:13][CH:14]4[NH:18][CH:17]([C:5]=3[C:4]=2[C:3]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15]4.[C:26]1([S:32]([O-:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Na+]>>[C:26]1([S:32]([C:2]2[CH:10]=[CH:9][C:8]3[N:7]([CH2:11][CH3:12])[C:6]4[CH2:13][CH:14]5[NH:18][CH:17]([C:5]=4[C:4]=3[C:3]=2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15]5)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=S([O-])c1ccccc1
Reactant: CCn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Agent: [Na+]
Product: CCn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccccc4)ccc31)C1CCC(C2)N1
Yield: 36 %

Procedure:
The product of step A was coupled with sodium benzenesulfinate following the procedure of Example 27, step C. The crude material was purified by flash column chromatography (SiO2, 4:1 to 1:1 hexane/ethyl acetate) to give tert-butyl 2-phenylsulfonyl-5-ethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (0.12 g, 36%) as a white solid: 1H NMR (CDCl3, 300 MHz) δ 8.20 (s, 1H), 7.94-7.99 (m, 2H), 7.40-7.53 (m, 4H), 7.31 (d, J=8.7 Hz, 1H), 5.20-5.33 (m, 1H), 4.55-4.81 (m, 1H), 3.95-4.11 (m, 2H), 3.19-3.50 (m, 1H), 2.47 (d, J=16.2 Hz, 1H), 2.15-2.38 (m, 2H), 1.91-2.01 (m, 1H), 1.53-1.62 (m, 1H), 1.34 (s, 9H), 1.25-1.31 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)([O-])=O.C([OH:13])C.[OH-].[Na+]>CN(C)C=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:13])=[CH:6][CH:5]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Nc1ccc(C=O)cc1
Temperature: 80 °C
Yield: 71.9 %

Procedure:
To a 1-liter flask were added 66.7 g (0.487 mol) of p-nitrotoluene, 223 g of ethanol and 2.7 g (4.1% by weight of the p-nitrotoluene) of N, N-dimethylformamide to form a mixture which was dissolved, maintained at 80° C. and then incorporated dropwise over a period of time of 2 hours with an aqueous alkali solution prepared by adding 51.5 g of a 50% aqueous solution of sodium hydroxide to said aqueous solution of sodium polysulphide. After the end of the incorporation with the aqueous alkali solution, the whole mass was refluxed for an additional two hours thereby completing the reaction. The resulting reaction mixture was subjected to steam distillation to obtain 42.3 g (0.350 mol) of p-aminobenzaldehyde in purified form. The yield of the p-aminobenzaldehyde so obtained was 71.8%, based on the weight of p-nitrotoluene used.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:17]([O:21][C:22]([N:24]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30])[CH3:25])=[O:23])([CH3:20])([CH3:19])[CH3:18].Cl.N1C=CC=C(CC(O)=O)C=1>>[CH2:10]([N:5]1[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][CH:34]=[C:26]([N:24]([C:22]([O:21][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:23])[CH3:25])[CH:27]=2)[N:3]=[CH:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(C(=O)O)c1
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Agent: Cl
Agent: O=C(O)Cc1cccnc1
Product: CN(C(=O)OC(C)(C)C)c1cccc(C(=O)Nc2ncn(Cc3ccccc3)c2C(N)=O)c1
Yield: 81 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 17, using 0.65 g (3.0 mmol) of 4-amino-1-benzyl-5-imidazolecarboxamide which was prepared in the same manner as in Reference Example 2 and 3-(N-t-butyloxycarbonyl-N-methylamino)benzoic acid, instead of 3-pyridylacetic acid hydrochloride, to obtain 1.09 g of 1-benzyl-4-(3-(N-t-butyloxycarbonyl-N-methylamino)benzoylamino)-5-imidazole carboxamide (yield 81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8](C(OC(C)(C)C)=O)[CH:7]=[C:6]2[C:19]1[N:31]([S:32]([C:35]2[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[C:22]2=[N:23][CH:24]=[C:25]3[CH:29]=[N:28][N:27]([CH3:30])[C:26]3=[C:21]2[CH:20]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[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:19]1[N:31]([S:32]([C:35]2[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[C:22]2=[N:23][CH:24]=[C:25]3[CH:29]=[N:28][N:27]([CH3:30])[C:26]3=[C:21]2[CH:20]=1
Reactant: COc1ccc2c(c1)c(-c1cc3c4c(cnc3n1S(=O)(=O)c1ccc(C)cc1)cnn4C)cn2C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2[nH]cc(-c3cc4c5c(cnc4n3S(=O)(=O)c3ccc(C)cc3)cnn5C)c2c1
Temperature: 25 °C
Yield: 76.9 %

Procedure:
tert-Butyl 5-methoxy-3-(1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-1H-indole-1-carboxylate (1.75 g, 3.06 mmol; Preparation #D.1) in DCM (30 mL) was treated with TFA (5.9 mL, 77 mmol) and then stirred at rt. After about 3 h the mixture was concentrated and diluted with water (50 mL). The mixture was extracted with DCM (3×25 mL) then the combined organics were dried over anhydrous MgSO4, filtered then concentrated under reduced pressure. The material was purified by flash chromatography on 80 g of silica gel using 8:2 DCM/EtOAc as an eluent to give 7-(5-methoxy-1H-indol-3-yl)-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (1.11 g, 77%): LC/MS (Table 2, Method a) Rt=2.34 min; MS m/z 472 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)[CH3:9].[CH2:27]([O:29][C:30](=[O:49])[C:31]([CH3:48])([C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)[CH3:32])[CH3:28]>>[CH2:27]([O:29][C:30](=[O:49])[C:31]([C:33]1[CH:38]=[CH:37][C:36]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:25])[C:13]=3[NH:12][C:11]([O:10][C@@H:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH3:9])=[O:26])=[CH:19][CH:20]=2)=[CH:35][CH:34]=1)([CH3:48])[CH3:32])[CH3:28]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1F
Reactant: CCOC(=O)C(C)(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)C(C)(C)c1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3F)cc2)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-fluoro-phenyl)-ethyl ester and 2-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid ethyl ester were reacted to provide 2-(4′-{4-[(R)-1-(2-Fluoro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-2-methyl-propionic acid ethyl ester, which was hydrolyzed to the acid as described in Example 17, Step 3.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9](O)[C@H:8]([N:15](C3C=CN=CC=3)[C:16]([NH2:18])=[O:17])[C:7]=2[CH:25]=1)#[N:2].[CH2:26](N=C=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:12])([CH3:13])[CH2:9][CH:8]([NH:15][C:16]([NH:18][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:17])[C:7]=2[CH:25]=1)#[N:2]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N(C(N)=O)c2ccncc2)[C@@H]1O
Reactant: O=C=NCc1ccccc1
Solvent: CCO
Product: CC1(C)CC(NC(=O)NCc2ccccc2)c2cc(C#N)ccc2O1
Yield: 89.7 %

Procedure:
A solution of (-)-4-amino-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (2.0 g, 9.9 mmole, from Example 19, part B) and benzyl isocyanate (1.32 g, 9.9 mmole) in ethanol (15 ml) under argon was heated at reflux for two hours. The solvent ws recovered under vacuum and the crude product was triturated with isopropyl ether to obtain 2.98 g (89.7%) of the title compound as a pure white solid. m.p.=140°-141° C., [a]D25DMF=-41.2°. 1H NMR (DMSO-d6) δ7.59 (s, 1H), 7.56 (d, J=1.76 Hz, 1H), 7,38-7.22 (m, 5H), 6.89 (d, J=8.21 Hz, 1H), 6.56 (t, J=5.87 Hz, 1H), 6.49 (d, J=8.79 Hz, 1H), 4.94 (m, 1H), 4.30 (d, J=5.87 Hz, 1H), 2.11 (dd, J=6.16 and 13.19 Hz, 1H), 1.74 (d, J=12.32 Hz, 1H), 1.41 (s. 3H), 1.28 (s, 3H). 13C NMR (DMSO-d) δ158.19, 157.27, 140.80, 132.25, 132.15, 128.31, 126.98, 126.69, 126.18, 119.28, 118.13, 102.06. , 77.37, 43.08, 42.01, 37.80, 29.15, 24.47. MS: (M+H)+ @336.
Reaction SMILES: [C:1](=[O:44])([O:13][C:14]1[C:15]([CH3:43])=[C:16]2[C:21](=[C:22]([CH3:25])[C:23]=1[CH3:24])[O:20][C:19]([CH3:42])([CH2:26][CH2:27][CH2:28][CH:29]([CH3:41])[CH2:30][CH2:31][CH2:32][CH:33]([CH3:40])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:18][CH2:17]2)[O:2][CH2:3][C:4]1([CH3:12])[CH2:9][O:8]C(C)(C)[O:6][CH2:5]1>Cl.CO>[C:1](=[O:44])([O:13][C:14]1[C:15]([CH3:43])=[C:16]2[C:21](=[C:22]([CH3:25])[C:23]=1[CH3:24])[O:20][C:19]([CH3:42])([CH2:26][CH2:27][CH2:28][CH:29]([CH3:41])[CH2:30][CH2:31][CH2:32][CH:33]([CH3:40])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:18][CH2:17]2)[O:2][CH2:3][C:4]([CH2:5][OH:6])([CH2:9][OH:8])[CH3:12]
Reactant: Cc1c(C)c2c(c(C)c1OC(=O)OCC1(C)COC(C)(C)OC1)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Agent: Cl
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1OC(=O)OCC(C)(CO)CO)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Yield: 79.1 %

Procedure:
10 g of 2,2,5-trimethyl-1,3-dioxan-5-ylmethyl 2,5,7,8-tetramethyl-2-(4',8', 12'-trimethyl-tridecyl)-6-chromanyl carbonate was dissolved in a mixture of 70 ml of 2 N hydrochloric acid and 35 ml of methanol and heated under reflux for 4.5 hours. After cooling, the reaction mixture was extracted with 500 ml of ethyl acetate and 400 ml of water. The extract was washed with water, dried and concentrated. Then the obtained residue was purified by column chromatography (silica gel, hexane/ethyl acetate). Thus 7.4 g of the title compound was obtained as a colorless and starch syrup-like product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[CH:4][CH:3]=1.[C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)#[N:26].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:21]1([C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:30]5[CH:31]=[CH:32][C:27]([C:25]#[N:26])=[CH:28][CH:29]=5)=[CH:3][CH:4]=4)[C:9](=[O:24])[NH:10][N:11]=3)[CH2:15]2)=[O:20])[CH2:23][CH2:22]1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(-c2ccc(-n3c(C[C@@H]4CCN(C(=O)C5CC5)C4)n[nH]c3=O)cc2)cc1
Temperature: 110 °C
Yield: 28.3 %

Procedure:
A vial was charged with a slurry of 4-(4-bromophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (100 mg, 0.256 mmol), (4-cyanophenyl)boronic acid (75 mg, 0.511 mmol), tetrakis(triphenylphosphine)palladium(0) (29.5 mg, 0.026 mmol) and tripotassium phosphate (217 mg, 1.022 mmol) in ethanol (4.0 mL) and water (4.00 mL) then purged with nitrogen and sealed with a standard teflon septa (crimped aluminum seal). The reaction was then heated in an aluminum block at 110° C. for 2 h. The resulting yellow slurry was diluted with ethanol, treated with silica powder (2 g) then evaporated under reduced pressure. The dried powder was placed in a column adaptor (Analogix Dasi adapter) attached to a standard stock silica column (Analogix SF25-40 g) and eluted with ethyl acetate for 10 min and then with 7% methanol in dichloromethane. The combined desired fractions were evaporated to a colorless oil that was crystallized from hexanes/ethyl acetate to afford the title compound as a white solid (30 mg, 28.1%). MS(ES)+ m/e 414.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[CH:3]=1.[F:9][C:10]1[CH:33]=[CH:32][C:13]([O:14][C:15]2[C:16](=[O:31])[NH:17][N:18]=[CH:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:12][CH:11]=1.N>O>[Cl:8][C:4]1[CH:3]=[C:2]([N:17]2[C:16](=[O:31])[C:15]([O:14][C:13]3[CH:32]=[CH:33][C:10]([F:9])=[CH:11][CH:12]=3)=[C:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:23][CH:22]=3)[CH:19]=[N:18]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Clc1cccc(Br)c1
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2Oc2ccc(F)cc2)cc1
Agent: N
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to Example 93, substituting 1-bromo-3-chlorobenzene in place of 4-bromothioanisole and 4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 108A) in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 25 mg, 5.3%). mp 211-213° C. 1H NMR (300 MHz, DMSO-d6) δ 3.30 (s, 3H), 7.15 (d, J=9 Hz, 4H), 7.51-7.64 (m, 3H), 7.71-7.75 (m, 1H), 7.91 (d, J=9 Hz, 2H), 8.06 (d, J=9 Hz, 2H), 8.41 (s, 1H). MS (DCI/NH3) m/z 471 (M+H)+, 488 (M+NH4)+. Anal. calc. for C23H16ClFN2O4S.0.5 H2O: C, 57.62; H, 3.44; N, 5.85. Found: C, 57.62; H, 3.52; N, 5.48.
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[NH:18][CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[Si](C=[N+]=[N-])(C)(C)[CH3:29]>CO>[C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[NH:18][CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)[C:7]([O:9][CH3:29])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3[nH]ccc23)cc1
Solvent: CO
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2cc[nH]c2c(=O)n1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
A solution of the crude 2-(tert-butoxy)-2-(6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetic acid in Methanol (4 mL) was treated with TMS-diazomethane (1.481 mL, 2.96 mmol) and then resultant was allowed to stir at ambient temperature for 10 minutes. The mixture was concentrated and then purified on silica gel (0-10% MeOH/DCM) to give the desired product (67 mg, 41% yield over 2 two steps). 1H NMR (400 MHz, CHLOROFORM-d) d=9.71 (br. s., 1H), 7.47-7.32 (m, 3H), 7.31-7.23 (m, 1H), 7.19 (t, J=2.4 Hz, 1H), 6.10 (t, J=2.1 Hz, 1H), 5.39 (s, 1H), 3.82 (s, 3H), 3.72 (s, 3H), 2.44 (s, 3H), 0.94 (s, 9H); LC/MS (m/z) ES+=383 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]2[CH2:19][CH:18]=[C:17]([CH:20]=O)[C@@H:7]2[C@H:8]([O:11][CH:12]([O:14][CH2:15][CH3:16])[CH3:13])[O:9][CH:10]=1)=[O:4].CI.[Mg].[Cl-].[NH4+].[O:27]1CCC[CH2:28]1>>[CH3:1][O:2][C:3]([C:5]1[C@H:6]2[CH2:19][CH:18]=[C:17]([CH2:20][CH2:28][OH:27])[C@@H:7]2[C@H:8]([O:11][CH:12]([O:14][CH2:15][CH3:16])[CH3:13])[O:9][CH:10]=1)=[O:4]
Reactant: CCOC(C)O[C@@H]1OC=C(C(=O)OC)[C@H]2CC=C(C=O)[C@H]12
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CI
Product: CCOC(C)O[C@@H]1OC=C(C(=O)OC)[C@H]2CC=C(CCO)[C@H]12
Temperature: -78 °C
Yield: 77 %

Procedure:
An anhydrous tetrahydrofuran solution containing 100 mg of (1S,4aS,7aR)-1-[1-(ethoxy)ethoxy]-7-formyl-1,4a,5,7a-tetrahydrocyclopenta[c]pyrane-4-carboxylic acid methylester was cooled to -78° C. under argon gas atmosphere followed by dropping 0.38 ml of magnesium methyliodide (0.98 M tetrahydrofuran solution). Two hours later, saturated aqueous ammonium chloride solution was added to the reaction mixture followed by extraction with ethyl acetate. After washing the organic phase with brine, it was dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a pale yellow oil from the hexane-ether eluate in the form of (1S,4aS,7aR)-1-[1-(ethoxy)ethoxy]-7-[2-(hydroxy)ethyl]-1,4a,5,7a-tetrahydrocyclopenta[c]pyrane-4-carboxylic acid methylester (81 mg, yield: 77%). the physicochemical properties of this compound are described below. 1H-NMR (δ ppm, in CDCl3): 1.03-1.39 (9H,m), 1.68-3.24 (5H,m), 3.72 (3H,s), 3.40-3.88 (2H,m), 4.72-5.08 (2H,m), 5.52 (1H,br,s), 7.47-7.49 (1H,m)
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10](=[O:13])[NH:11][CH3:12])(C)(C)C.[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18]>ClCCl>[NH2:7][CH2:8][CH2:9][C:10]([NH:11][CH3:12])=[O:13].[C:17]([OH:19])([C:16]([F:21])([F:20])[F:15])=[O:18]
Reactant: CNC(=O)CCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)CCN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2-Methylcarbamoyl-ethyl)-carbamic acid tert-butyl ester (534 mg, 2.64 mmol) was dissolved in dichloromethane (10 mL) and the solution was treated with trifluoroacetic acid (3 mL). The reaction was allowed to stir overnight at room temperature. The solvent and excess TFA was then concentrated to afford 3-Amino-N-methyl-propionamide as a crude TFA salt. The crude material (270 mg) was used without further purification.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([CH3:21])=[C:18]([NH2:20])[CH:19]=1)=[O:14]>>[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([CH3:21])=[C:18]([NH:20][C:9]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH:19]=1)=[O:14]
Reactant: O=C=NCc1ccccc1
Reactant: COC(=O)c1cc(N)c(C)s1
Product: COC(=O)c1cc(NC(=O)NCc2ccccc2)c(C)s1

Procedure:
The title compound was prepared according to the procedure described for Example 13 using benzyl isocyanate (0.4 g, 3.2 mmol) and 5-methyl-4-amino-thiophene-2-carboxylic acid methyl ester from Step 1 to afford 0.77 g of 5-methyl-4-(3-benzyl-ureido)-thiophene-2-carboxylic acid methyl ester. Recrystallization of a sample from acetonitrile gave product with a mp 185-187° C.
Reaction SMILES: [OH: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][NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH3:30])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1)=[O:16].C(N(CC)CC)C.N1C=CC=CC=1.[S:44](Cl)([CH3:47])(=[O:46])=[O:45]>C(Cl)(Cl)Cl>[S:44]([O: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][NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH3:30])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1)=[O:16])([CH3:47])(=[O:46])=[O:45]
Reactant: CS(=O)(=O)Cl
Reactant: CCN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCO)cn2)CC1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCOS(C)(=O)=O)cn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.26 g of N-(12-hydroxydodecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide in 20 ml of chloroform were added 4.2 ml of triethylamine, 5 ml of pyridine and 1.0 ml of mesyl chloride and the mixture was stirred at room temperature for 30 minutes. The reaction solution was washed successively with water, 3N-hydrochloric acid and a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue thus obtained was chromatographed over a silica gel column to afford 1.11 g of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2.[OH:28][C@:29]([CH3:41])([C:33]([NH:35][CH2:36][C:37]([F:40])([F:39])[F:38])=[O:34])[C:30](O)=[O:31]>>[CH2:13]([O:12][CH2:11][CH2:10][N:7]1[C:8](=[O:9])[C@@H:2]([NH:1][C:30](=[O:31])[C@@:29]([OH:28])([CH3:41])[C:33]([NH:35][CH2:36][C:37]([F:38])([F:39])[F:40])=[O:34])[C:3]2[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=2[C:5]2[CH:23]=[CH:22][CH:21]=[CH:20][C:6]1=2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@](O)(C(=O)O)C(=O)NCC(F)(F)F
Reactant: N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Product: C[C@@](O)(C(=O)NCC(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-benzyloxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and (R)-2-hydroxy-2-methyl-N-(2,2,2-trifluoro-ethyl)-malonamic acid, the title compound was prepared in the same manner as described for example 1c. Colorless, amorphous solid (96%). MS: m/e=556(M+H+).
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[CH3:23][CH:24]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1>CS(C)=O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:3]2[C:2]([N:26]3[CH2:27][CH2:28][CH2:29][CH:24]([CH3:23])[CH2:25]3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=3)[N:4]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Reactant: CC1CCCNC1
Solvent: CS(C)=O
Product: CC1CCCN(c2nc3cc(C(=O)O)ccc3nc2-c2ccc(F)cc2)C1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (200 mg, 0.63 mmol, 1.00 equiv), 3-methylpiperidine (313 mg, 3.16 mmol, 5.00 equiv), DMSO (3 mL). The resulting solution was stirred for overnight at 110° C. in an oil bath. The reaction was then quenched by the addition of water. The pH value of the aqueous solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting solids were collected by filtration. The crude product (240 mg) was purified by Prep-HPLC under the following conditions (1#-UV1-SHIMADZU-SPD-20A): Column, SunFire Prep C18, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (30% CH3CN up to 100% in 8 min, hold 100% in 1.5 min, down to 30% in 1 min); Detector, Gilson UV Detector 220 nm. This resulted in 75 mg (32%) of 2-(4-fluorophenyl)-3-(3-methylpiperidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: N([O-])=O.[Na+].N[C@@H:6]([C:14]([OH:16])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br-:17].[K+]>S(=O)(=O)(O)O>[CH:12]1[CH:13]=[C:8]([CH2:7][CH2:6][C:14]([OH:16])=[O:15])[C:9]([Br:17])=[CH:10][CH:11]=1
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: [Br-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)CCc1ccccc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
Sodium nitrite (10.3 g, 280 mmol) was added to a solution of D-phenylalanine (30.0 g, 181 mmol) and potassium bromide (73.5 g) in sulfuric acid (2.5N, 365 ml) over a period of one hour while maintaining the temperature of the reaction mixture at 0° C. The mixture was stirred for an additional hour at 0° C. and then for one hour at room temperature. The reaction solution was extracted with ether, the ether was back extracted with water, and the ether layer was dried over sodium sulfate. Ether was removed in vacuo, and distillation of the oily residue afforded 25.7 g of (R)-2-bromo-3-benzenepropanoic acid; b.p. 141° C. (0.55 mm of Hg); [α]D =+14.5° (c=2.4, chloroform).