Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[C@H:24]4[C@H:19]([CH2:20][CH2:21][CH2:22][CH2:23]4)[C:18](=[O:25])[NH:17][N:16]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N1N=C(C2C=CC(OC)=C(OC)C=2)[C@H]2[C@H](CCCC2)C1=O)C1C=CC=CC=1>>[CH2:26]([N:17]1[N:16]=[C:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:8]=2)[C@H:24]2[C@H:19]([CH2:20][CH2:21][CH2:22][CH2:23]2)[C:18]1=[O:25])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC1CCCC1
Reactant: ClCc1ccccc1
Agent: COc1ccc(C2=NN(Cc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(Cc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC1CCCC1

Procedure:
Prepared from compound 4 and benzylchloride as described for compound 78. Purified by chromatography [petroleum ether (60°-95° C.): ethyl acetate/4:1] and crystallized from petroleum ether (60°-95° C.)/ethyl acetate. M.p. 91°-92° C.
Reaction SMILES: Cl.[CH2:2]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)[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][CH2:16][CH3:17].O[CH:29]([OH:33])[C:30](=[O:32])[CH3:31].C(Cl)(Cl)Cl.[OH2:38]>CN(C)C1C=CN=CC=1>[CH2:2]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O:38][CH2:31][C:30]([CH2:29][OH:33])=[O:32])=[O:24])=[CH:21][CH:20]=1)[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][CH2:16][CH3:17]
Reactant: CC(=O)C(O)O
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Reactant: O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(=O)CO)cc1
Reaction time: 4 h

Procedure:
The compound 4-(n-hexadecylamino)benzoyl chloride hydrochloride (4.16 g.) is added to a mixture of 3.6 g. of dihydroxyacetone and 2.44 g. of 4-dimethylaminopyridine in an ice bath. After 4 hours at room temperature, the mixture is treated with chloroform and water. The chloroform extract is chromatographed rapidly and evaporated in vacuo to yield 3-hydroxyacetonyl 4-(n-hexadecylamino)benzoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[F:23][C:24]([F:34])([F:35])[C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:33])=[CH:29][CH:30]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)cc3)c2cc1OC
Yield: 88 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (53 mg) was dissolved in toluene (3 ml) with heat, 4-trifluoromethylphenyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 10 minutes. The separated crystals were filtered and washed with toluene to obtain 77 mg of the title compound (yield: 88%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:30])[CH:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:18]=2)C(O)=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C([N:50]([CH2:53]C)CC)C.[OH2:55]>O1CCCC1>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[O:30][C:53](=[O:55])[NH:50][CH:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:28])([F:29])[CH:25]([F:27])[F:26])[CH:18]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)c1ccc(C(O)C(Cc2cccc(OC(F)(F)C(F)F)c2)C(=O)O)cc1
Reactant: O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C2OC(=O)NC2Cc2cccc(OC(F)(F)C(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2RS,3RS)-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoic acid (2.20 g, 4.88 mmol) in tetrahydrofuran (20 ml) were added diphenylphosphoryl azide (1.37 ml, 6.35 mmol) and triethylamine (0.95 ml, 6.84 mmol) and the mixture was stirred at room temperature for 1 hr. After heating under reflux for 1 hr, water (100 ml) was added and the mixture was extracted, with ethyl acetate (100 ml×2). The extract was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1-1:3). Hexane was added to the precipitated crystals and the mixture was filtered to give the objective substance (2.07 g, 95%).
Reaction SMILES: [H-].[Na+].Br[C:4]1[C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[Cl:22])(=[O:14])=[O:13])=[N:6][CH:7]=[C:8]([CH3:10])[N:9]=1.[C:23]([OH:35])(=O)[CH2:24][C:25]([CH2:30][C:31]([OH:33])=O)(C(O)=O)O>COCCOC>[Cl:22][C:16]1[C:17]([Cl:21])=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([NH:11][C:5]1[C:4]([O:33][CH2:31][C:30]2[O:35][CH:23]=[CH:24][CH:25]=2)=[N:9][C:8]([CH3:10])=[CH:7][N:6]=1)(=[O:14])=[O:13]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OCc2ccco2)n1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
Sodium hydride (0.04 g of a 60% dispersion in oil) was added to fi rylalcohol (0.034 g) in 1,2-dimethoxyethane (1 mL). After 5 minutes N-(3-Bromo-5-methyl-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (Example 20 part a) (0.1 g) was added and the mixture heated at 40° C. After 16 h, 5% aqueous citric acid (10 mL) was added and the mixture extracted with ethyl acetate (2×50 mL). The combined extracts were washed with brine, dried (MgSO4) and the solvent evaporated. Chromatography on silica gel eluting with dichloromethane gave the title compound as a white solid (0.02 g)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH:12]([OH:14])[CH3:13])=[C:7]([O:15][CH3:16])[CH:6]=[CH:5]2.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18].[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1>CN(C=O)C>[Si:21]([O:14][CH:12]([C:8]1[C:7]([O:15][CH3:16])=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([C:12]([C:29]1[N:25]=[CH:26][NH:27][CH:28]=1)([OH:14])[CH:8]([CH3:9])[CH3:7])=[CH:3]2)[CH3:13])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc2cc(Br)ccc2c1C(C)O
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1C(C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 170.4 %

Procedure:
1-(6-Bromo-2-methoxynaphthalen-1-yl)ethanol (18.57 g) and tert-butyldimethylchlorosilane (11.40 g) were dissolved in DMF (300 ml). To the solution was added imidazole (13.20 g), and the mixture was stirred at room temperature for 14 h. The reaction mixture was concentrated, and to the residue were added water and ethyl acetate. The organic layer was washed with water and saturated solution of sodium chloride, dried and concentrated to give the titled compound (25.58 g) as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[C:13]2[C:12](=O)[N:11]([CH:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[C:10](=[O:22])[C:9]=2[CH:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:23]1[C:24](=[O:38])[NH:25][CH:26]=[CH:27][C:28]=1[NH:29][CH:30]([CH3:37])[CH2:31][C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)[NH:6]2>CC(O)=O.CO.[Zn]>[Cl:1][C:2]1[C:13]2[CH2:12][N:11]([CH:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[C:10](=[O:22])[C:9]=2[CH:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:23]1[C:24](=[O:38])[NH:25][CH:26]=[CH:27][C:28]=1[NH:29][CH:30]([CH3:37])[CH2:31][C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)[NH:6]2
Reactant: CC(Cc1cccs1)Nc1cc[nH]c(=O)c1-c1nc2c(Cl)c3c(cc2[nH]1)C(=O)N(C1CCN(C)CC1)C3=O
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: CC(Cc1cccs1)Nc1cc[nH]c(=O)c1-c1nc2c(Cl)c3c(cc2[nH]1)C(=O)N(C1CCN(C)CC1)C3
Temperature: 90 °C

Procedure:
4-Chloro-6-(1-methyl-piperidin-4-yl)-2-[4-(1-methyl-2-thiophen-2-yl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-1H-1,3,6-triaza-s-indacene-5,7-dione (49 mg, 0.089 mmol) was mixed with zinc dust (196 mg, 1.0 mmol) in HOAc (10 mL). After it was heated at 90° C. for 40 min, the reaction mixture was cooled to 50° C. and diluted with a mixed solvent of MeOH:DCM (45 mL/5 mL) and filtered. The filtrate was evaporated at 95° C. (the bath temperature) under reduced pressure to dryness. The residue was diluted with a mixed solvent of DCM/MeOH (1:5) and basified with 28% aqueous NH4OH solution and concentrated. Chromatography of the residual crude with a mixed solvent of CH3CN/CH2Cl2/MeOH/28% aqueous NH4OH (63:10:37:1) followed by HPLC re-purification afforded the title compound in TFA salt form (6.2 mg, 11%). 1H NMR (DMSO-d6) δ 1.37 (d, J=6 Hz, 3H, CH3), 1.95-2.13 (4H), 2.52 (m, 2H), 2.80 (s, 3H, CH3), 3.15 (m, 2H), 3.50-3.65 (4H), 4.05 (m, 1H), 4.31 (m, 1H), 4.50 (br s, 2H), 6.18 (d, J=8 Hz, 1H), 6.89 (m, 1H), 7.01 (m, 1H), 7.29 (m, 1H), 7.37 (m, 1H), 7.99 (s, 1H), 9.60 (br s, 1H), 11.22 (d, J=6 Hz, 1H), 11.30 (d, J=6 Hz, 1H); ESI-MS m/z 537.3 (MH+).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Br:13][CH2:14][CH2:15]Br.[OH-].[Na+]>C(O)C>[Br:13][CH2:14][CH2:15][O:12][C:9]1[CH:10]=[CH:11][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:7][CH:8]=1
Reactant: Oc1ccc(-n2ccnc2)cc1
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: BrCCOc1ccc(-n2ccnc2)cc1
Yield: 42.8 %

Procedure:
4-(Imidazol-1-yl)phenol (5 g, 31.3 mmol), 1,2-dibromoethane (8.09 g, 93.9 mmol) and sodium hydroxide (1.25 g, 31.3 mmol) were refluxed in ethanol for 24 h. Thereafter, the solvent was evaporated and the residue was diluted with a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The extracted organic layer was washed twice with a saturated aqueous solution of sodium chloride and dried with magnesium sulfate, followed by evaporation of the solvent. The residue was purified by column chromatography on silica gel using, as an eluent, methylene chloride containing 30% ethyl acetate. The fractions containing the product were subjected to evaporation to yield the end compound 1-bromo-2-[4-(imidazol-1-yl)phenoxy]ethane (3.58 g) in a solid form.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([C:37](=[O:40])[NH:38][OH:39])[CH:16]([OH:36])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=[C:27]([CH3:35])[CH:26]=3)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:36][CH:16]([C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=[C:27]([CH3:35])[CH:26]=2)=[CH:21][CH:22]=1)[CH:15]([CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:37]([NH:38][OH:39])=[O:40]
Reactant: Cc1cc(COc2ccc(C(O)C(CN3CCN(C(=O)OC(C)(C)C)CC3)C(=O)NO)cc2)c2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(COc2ccc(C(O)C(CN3CCNCC3)C(=O)NO)cc2)c2ccccc2n1
Reaction time: 2 h
Yield: 154.7 %

Procedure:
4-{3-Hydroxy-2-hydroxycarbamoyl-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-propyl}-piperazine-1-carboxylic acid tert-butyl ester (0.077 g, 0.099 mmol) from Example 19 was taken up in methylene chloride (3 mL) and TFA (2 mL) under nitrogen atmosphere at room temperature. The reaction was complete after 2 h, was concentrated, taken up in water (5 mL), and freeze-dried to give the title compound (0.069 g, 88%) as a white solid. MS found: (M+H)+=451.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][C:35]([CH3:40])([CH2:38][OH:39])[CH2:36][OH:37])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([S:31]([NH:34][C:35]([CH2:38][OH:39])([CH3:40])[CH2:36][OH:37])(=[O:32])=[O:33])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: CC(CO)(CO)NS(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: CC(CO)(CO)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and 2-bromo-N-(1,3-dihydroxy-2-methylpropan-2-yl)benzenesulfonamide. MS (ESI): mass calcd. for C20H21FN4O4S, 432.13; m/z found, 433.1 [M+H]+.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C@@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].C1(N=C=NC2CCCCC2)CCCCC1.C(O)C1C=CC=CC=1>O1CCCC1>[C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3]
Reactant: O=C(O)C[C@@H](O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: OCc1ccccc1
Product: O=C(O)CC(O)C(=O)O

Procedure:
In an example of the process wherein the cyclic anhydride is formed with a diimide, D-malic acid is dissolved in tetrahydrofuran and 1.1 molar equivalents of dicyclohexylcarbodiimide are added to the solution. The reaction mixture is stirred for about an hour and is then filtered to remove the precipitate of dicyclohexylurea. An excess (ca. 1.5 to 2.0 equiv.) of benzyl alcohol is added to the filtrate containing the malic acid cyclic anhydride and the solution is stirred for about 6 to about 12 hours. The reaction mixture is evaporated and the impure monobenzyl malate is dissolved in a water immiscible solvent such as ethyl acetate. The product is extracted with a base such as aqueous sodium bicarbonate, and after acidification of the extract the ester is extracted with ethyl acetate or other suitable solvent. The extract is dried and evaporated to yield the monobenzyl ester of malic acid represented by the formula ##STR51##
Reaction SMILES: O[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:36])C(=O)C1>C(Cl)Cl>[Br:36][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(O)c1ccccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(Br)c1ccccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To (±)-2-(1-hydroxyethyl)-pyridine (Bull. Chem. Soc. Jpn. 1990, 63, 461-465) (10.0 g, 81.3 mmol) in DCM (120 mL) at 0° C., add with stirring triphenylphosphine (22.39 g, 85.365 mmol) followed by NBS (15.2 g, 85.4 mmol) in portions. Warm the reaction mixture to ambient temperature and continue stirring for 3 h. Concentrate in vacuo and purify by chromatography on silica gel eluting with hexane/EtOAc (19:1) to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=1[CH:16]([CH3:18])[CH3:17])[CH3:2].[H-].[Na+].[CH:22]([O:24][CH2:25]C)=O.IC>COCCOC>[CH2:1]([O:3][C:4](=[O:19])[C:5]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=1[CH:16]([CH3:18])[CH3:17])=[CH:22][O:24][CH3:25])[CH3:2]
Reactant: CCOC=O
Reactant: CCOC(=O)COc1cc(C)c(OC)cc1C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CI
Product: CCOC(=O)C(=COC)Oc1cc(C)c(OC)cc1C(C)C
Temperature: 85 °C
Reaction time: 0.08 h
Yield: 23.2 %

Procedure:
To a solution of (2-isopropyl-4-methoxy-5-methyl-phenoxy)-acetic acid ethyl ester (4.42 g, 16.6 mmol) in anhydrous 1,2-dimethoxy ethane (60 ml) was added sodium hydride (60% in mineral oil, 3.5 g, 87.5 mmol) at room temperature. After 5 minutes of stirring, ethyl formate (40 ml, 495 mmol) was added. The mixture was heated at 85° C. for 7 hours. After cooling to room temperature, iodomethane was added and stirring was continued overnight. Solvent was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over anhydrous sodium sulfate. After removal of drying agent, the organic solution was concentrated under reduced pressure. The residue was purified with silica gel chromatography (10% to 30% ethyl acetate in hexane) to yield 2-(2-isopropyl-4-methoxy-5-methyl-phenoxy)-3-methoxy-acrylic acid ethyl ester as a pale yellow oil (1.19 g, 23%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2CCN[C:11](=[O:15])[C:10]3[S:16][C:17]([I:19])=[CH:18][C:9]2=3)=[CH:4][CH:3]=1.[Li+].C[Si]([N-:25][Si](C)(C)C)(C)C.[CH3:30][CH2:31][CH2:32]CCC.CI>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[NH:25][CH2:32][CH:31]([CH3:30])[C:11](=[O:15])[C:10]3[S:16][C:17]([I:19])=[CH:18][C:9]2=3)=[CH:6][CH:7]=1
Reactant: O=C1NCCC(c2ccc(Cl)cc2)c2cc(I)sc21
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCCCCC
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1CNC(c2ccc(Cl)cc2)c2cc(I)sc2C1=O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 53 %

Procedure:
To a solution of 4-(4-chlorophenyl)-2-iodo-4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one (95.0 mg, 0.235 mmol, prepared in an analogous manner as described in Example 33) in tetrahydrofuran (8.6 mL) at −78° C. under an atmosphere of argon was added LiHMDS in hexane (1 M, 0.259 mL, 0.259 mmol). After stirring at −78° C. for 5 min, methyl iodide (0.293 mL, 4.70 mmol) was added and the resulting yellow solution was stirred at rt for 16 hr. The mixture was quenched with saturated NH4Cl aqueous solution, the volatiles were removed and the obtained residue was purified by silica gel column chromatography (elution with 0-50% EA/hexane) to give the title compound as a white solid (52.8 mg, 53% yield). LCMS: (FA) ES+ , 417/419. 1H NMR (300 MHz, DMSO) δ 7.37 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.4 Hz, 2H), 6.75 (d, J=11.3 Hz, 1H), 4.36 (dt, J=30.3, 15.3 Hz, 1H), 3.59-3.34 (m, 2H), 3.03 (d, J=8.8 Hz, 3H), 2.38-2.15 (m, 1H), 2.12-1.92 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10](OC)[CH2:11][N:12]=2)=[CH:4][C:3]=1[CH:15](Br)Br.C1CCN2C(=NCCC2)CC1.N1CC[O:32]CC1.CC(C)([O-])C.[K+].Cl>CCOC(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)=[CH:4][C:3]=1[CH:15]=[O:32]
Reactant: COC1CN=C(c2ccc(Br)c(C(Br)Br)c2)O1
Reactant: C1COCCN1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: O=Cc1cc(-c2ncco2)ccc1Br
Temperature: 60 °C
Reaction time: 5 h
Yield: 72.3 %

Procedure:
A 1 L round bottom flask was charged with 2-[4-bromo-3-(dibromomethyl)-phenyl]-5-methoxy-oxazoline (27.8 g, 67.1 mmol), DBU (24.1 mL, 161.2 mmol) and morpholine (56.4 mL, 646.7 mmol). The mixture was heated at 60° C. for 2.5 hours. HPLC indicated the starting material had disappeared. The reaction mixture was cooled to −10° C. to 0° C. in an ice/acetone bath. The stirring stopped. Potassium tert-butoxide (1 M in THF, 350 mL) was added dropwise in 0.5 hours. The stirring started after ˜20 mL of potassium tert-butoxide THF solution was added. The reaction mixture was warmed up to RT and stirred at RT for 5 hours. It was put aside in a −40° C. freezer for 13 hours and then was stirred at RT for another 2 hours. The reaction mixture was cooled to −10° C. to 0° C. in an ice/acetone bath. HCl (6N, cold, 214 mL) was added dropwise in 15 minutes. The mixture was stirred at 0° C. to RT in 0.5 hours. It was transferred to a 2 L separatory funnel, diluted with EtOAc (300 mL) and water (300 mL). The aqueous layer was separated and extracted with EtOAc (300 mL×2). The organic layers were combined and the combined organic phase was washed with brine/1N HCl mixture (200 mL/30 mL ), brine/water mixture (200 mL/30 mL×2) and brine (230 mL×2). It was dried over MgSO4 (50 g) for 0.5 hours and concentrated to 21.3 g of semi solid. The crude semi solid was dissolved in warm THF (60 mL). The THF solution was added dropwise to a mixture of refluxing cyclohexane (600 mL) and charcoal (3.6 g). The mixture was stirred without heat for 0.5 hours and was heated to reflux. It was filtered through a celite pad and the pad was washed with a hot mixture of cyclohexane/THF (90 mL/9 mL×3). The filtrate was concentrated to 14.1 g of yellowish white solid. The charcoal treated crude product was dissolved in cyclohexane (300 mL) at reflux. Crystallization occurred upon cooling to RT. The mixture was stirred at RT for 4 hours and then at 4° C. for 13 hours. The 2-[4-Bromo-3-(formyl)-phenyl]oxazole was collected by filtration and was suction dried at RT for 13 h. It was obtained as an off-white solid in 72.3% yield, HPLC area percent 99.8. The 1H NMR and mass spectra were consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N@:11]1[CH2:13][CH:12]1[C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:18][CH2:17]1)=[O:15])(=[O:10])=[O:9].[I-].[Na+].[CH:34]1([N:37]=[C:38]=[O:39])[CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:13][C@@H:12]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([C:28]([F:30])([F:29])[F:31])=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[N:37]([CH:34]2[CH2:36][CH2:35]2)[C:38]1=[O:39])(=[O:9])=[O:10]
Reactant: O=C=NC1CC1
Reactant: O=C(C1C[N@@]1S(=O)(=O)c1ccccc1Cl)N1CCN(c2ncccc2C(F)(F)F)CC1
Agent: [I-]
Agent: [Na+]
Product: O=C([C@@H]1CN(S(=O)(=O)c2ccccc2Cl)C(=O)N1C1CC1)N1CCN(c2ncccc2C(F)(F)F)CC1

Procedure:
In analogy to example 2, [(S)-1-(2-chloro-benzenesulfonyl)-aziridin-2-yl]-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone (example 72, step 3) was reacted with sodium iodide and cyclopropylisocyanate to give the title compound as a colorless foam. MS: 557.6 ([M+H]+)
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)=[C:5]([N+:13]([O-])=O)[C:4]=1[N+:16]([O-])=O)#[N:2].[OH2:19].O.[C:21](O)(=[O:25])[C:22](O)=[O:23]>C(O)C.[Pd]>[C:1]([C:3]1[C:4]2[N:16]=[C:22]([OH:23])[C:21]([OH:25])=[N:13][C:5]=2[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)(=[O:19])[NH2:2]
Reactant: O
Reactant: O=C(O)C(=O)O
Reactant: N#Cc1cc2c(c([N+](=O)[O-])c1[N+](=O)[O-])CCCC2
Agent: [Pd]
Solvent: CCO
Product: NC(=O)c1cc2c(c3nc(O)c(O)nc13)CCCC2

Procedure:
A solution of 7-cyano-1,2,3,4-tetrahydro-5,6-dinitro-naphthalene (0.18 g, 0.73 mmol) in ethanol was hydrogenated at room temperature and atmospheric pressure in the presence of 100 mg of 5% palladium-on-charcoal. The catalyst was filtered off, and the filtrate was evaporated to dryness. The solid residue was suspended in 10 ml of 1M hydrochloric acid, oxalic acid dihydrate (0.15 g, 1.2 mmol) was added, and the mixture was refluxed for 3 h. After cooling, the solid was collected and washed with water, ethanol and ether affording 80 mg (42%) of the amide.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[CH:11]=[N:12][N:13]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)[C:14]=2[S:15][CH2:16][CH2:17][CH3:18])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([NH:7][C:8]([C:10]2[CH:11]=[N:12][N:13]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=3)[C:14]=2[S:15][CH2:16][CH2:17][CH3:18])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCSc1c(C(=O)NC2CCCCC2)cnn1-c1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCSc1c(C(=O)NC2CCCCC2)cnn1-c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 4-[4-(cyclohexylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoate (363 mg, 0.94 mmol) (Intermediate #11) was dissolved in methanol (20 mL) and treated at ambient temperature with 2M aqueous sodium hydroxide solution (2.35 mL). The mixture was stirred at ambient temperature for 18 h and then volatiles were removed by evaporation under reduced pressure. The residue was dissolved in water (25 ml) and 2M HCl was added until the pH=4. The mixture was extracted with ethyl acetate (2×25 mL) and the combined extracts were washed with water (2×10 mL) and brine (10 mL), dried (MgSO4) and evaporated to give the title product as a white solid. (300 mg 85%)