Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]2[CH:28]=[CH:27][C:19]([C:20]([O:22]C(C)(C)C)=[O:21])=[C:18]([F:29])[CH:17]=2)=[N:4][C:5]([C@@H:8]2[CH2:13][CH2:12][C@@H:11]([OH:14])[C@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1.Cl.O1CCOCC1>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:16]2[CH:28]=[CH:27][C:19]([C:20]([OH:22])=[O:21])=[C:18]([F:29])[CH:17]=2)=[N:4][C:5]([C@@H:8]2[CH2:13][CH2:12][C@@H:11]([OH:14])[C@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2nc([C@@H]3CC[C@@H](O)[C@H](F)C3)cnc2N)cc1F
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1ncc([C@@H]2CC[C@@H](O)[C@H](F)C2)nc1-c1ccc(C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of tert-butyl 4-(3-amino-6-((1R,3R,4R)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzoate (Scheme 84: 365 mg, 0.9 mmol) in DCM (2 mL) was added 4 M HCl in dioxane (8 mL, 32.0 mmol). The reaction mixture was stirred for 3 days at room temperature. After the volatile materials were evaporated in vacuo to yield 4-(3-amino-6-((1R,3R,4R)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzoic acid, which was used for the next step without further purification. LCMS (m/z): 350.3 (MH+), 0.48 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]2=[C:4]([CH3:18])[CH:3]=1>[Pt](=O)=O>[CH3:18][CH:4]1[CH2:3][CH2:2][NH:7][CH:6]2[CH2:8][CH2:9][N:10]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH:5]12
Reactant: Cc1cc(Cl)nc2ccn(C(=O)OC(C)(C)C)c12
Agent: O=[Pt]=O
Product: CC1CCNC2CCN(C(=O)OC(C)(C)C)C12
Reaction time: 120 h

Procedure:
To the product of Step 1 (361 mg, 1.35 mmol) was added platinum(IV) oxide (310 mg, 1.37 mmol) in a Parr pressure flask. The flask was purged with nitrogen by successive evacuation/nitrogen backfills and then acetic acid (15 mL) was added. The reaction mixture was placed under hydrogen atmosphere by successive evacuation/hydrogen backfills and the reaction was shaken at 40 psi for 5 days. The reaction was then filtered through Celite and washed with AcOH and concentrated in vacuo to afford a crude oil that was taken onto the next step without further purification. LRMS calc'd for C13H25N2O2 [M+H]+, 241; found 241.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:10]=2[C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4].Br[CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH2:1]([O:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[CH:16]=[C:15]([O:17][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:14]=[CH:13][C:10]=2[C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(O)c2ccc(O)cc2oc1=O
Reactant: CCOC(=O)CCBr
Product: CCCCOc1c(O)c2ccc(OCCC(=O)OCC)cc2oc1=O

Procedure:
In the same manner as in Reference Example 3, except that an equimolar amount of 3-butoxy-4,7-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-hexyloxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and ethyl 3-bromopropionate was used in place of ethyl bromoacetate in Reference Example 3, 3-butoxy-4-hydroxy-7-(2-ethoxycarbonylethoxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([S:22][CH3:23])[C:20]=1[OH:21])[C:5]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:17])(=[O:16])[CH2:8]1)=[O:6].[OH:24]OS([O-])=O.[K+].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([S:22]([CH3:23])=[O:24])[C:20]=1[OH:21])[C:5]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:17])(=[O:16])[CH2:8]1)=[O:6]
Reactant: CSc1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(Cl)c1O
Reactant: O=S([O-])OO
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)c1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(Cl)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
3-(3-chloro-4-hydroxy-5-methylsulfanylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (51 mg) was dissolved in tetrahydrofuran (0.5 mL) and water (0.5 mL), and oxone (43 mg) was added to the solution, and then the mixture was stirred at room temperature for 1 hour. To the reaction solution, 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was crystallized from n-hexane-diethylether to obtain the title compound (45 mg) as a brown crystal.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.F[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13]>>[CH:1]1([NH:4][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N+:12]([O-:14])=[O:13])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: NC1CC1
Product: O=[N+]([O-])c1ccccc1NC1CC1
Reaction time: 18 h
Yield: 86.6 %

Procedure:
To cyclopropylamine (27.3 g, 33.1 mL, 0.48 mol, 2.25 equiv; [CAS RN 765-30-0]) was added dropwise 2-fluoronitrobenzene (30.0 g, 0.21 mol, 1.0 equiv; [CAS RN 1493-27-2]) over 1 hours at 30° C. and stirring of the reaction mixture continued at room temperature for 18 h. The reaction mixture was extracted from a saturated aqueous solution of sodium bicarbonate (500 mL) with ethyl acetate (three times 300 mL) and the combined organic phases were dried over magnesium sulfate. Purification by silica gel column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a mixture of n-heptane:ethyl acetate (9:1) afforded 32.4 g (86%) of the title compound as a yellow oil. MS (ISP): m/z=178.0 [M+H]+.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10].[CH3:15]O>>[NH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([O:11][CH3:15])=[O:10]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(N)c1
Yield: 93 %

Procedure:
Thionyl chloride (43 g, 361.34 mmol, 5.00 equiv) was added dropwise with stirring at 0° C. to a solution of 3-aminobenzoic acid (10 g, 72.92 mmol, 1.00 equiv) in methanol (100 mL) and allowed to react, with stifling, overnight under reflux. The resulting mixture was concentrated under vacuum and quenched by the addition of 50 mL of water/ice. The resulting solids were collected via vacuum filtration and dried in an oven under reduced pressure, affording 10.3 g (93%) of methyl 3-aminobenzoate as a white solid.
Reaction SMILES: [CH:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:9]2[N:13]=[CH:12][N:11]([CH2:14][CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[N:10]=2)[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][N:37]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>>[C:41]([O:40][C:38]([N:37]([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][N:18]1[CH2:19][CH2:20][CH:15]([CH2:14][N:11]2[CH:12]=[N:13][C:9]([C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)([OH:8])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:10]2)[CH2:16][CH2:17]1)[C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])=[O:39])([CH3:44])([CH3:43])[CH3:42]
Reactant: OC(c1ccccc1)(c1ncn(CC2CCNCC2)n1)C1CCCCC1
Reactant: CC(C)(C)OC(=O)N(CCCCCCCCCBr)C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)N(CCCCCCCCCN1CCC(Cn2cnc(C(O)(c3ccccc3)C3CCCCC3)n2)CC1)C(=O)OC(C)(C)C
Yield: 61 %

Procedure:
The title compound was prepared from cyclohexyl(phenyl)[1-(piperidin-4-ylmethyl)-1H-1,2,4-triazol-3-yl]methanol (Preparation 20, 300 mg, 0.846 mmol) and di-tert-butyl (9-bromononyl)imidodicarbonate (U.S. Pat. No. 4,167,167, 357 mg, 0.846 mmol) using the same method as described in preparation 5, to give a white foam, in 61% yield, 360 mg.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([O:13][CH3:14])[CH:10]=2)[C:5]1=[O:17])[CH:2]=[CH2:3].[CH:18](=[O:22])/C=C/C>>[CH3:14][O:13][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:15][CH3:16])[C:5](=[O:17])[CH:4]([CH2:1]/[CH:2]=[CH:3]/[CH:18]=[O:22])[CH2:12]2
Reactant: C/C=C/C=O
Reactant: C=CCC1Cc2cc(OC)c(OC)cc2C1=O
Product: COc1cc2c(cc1OC)C(=O)C(C/C=C/C=O)C2

Procedure:
The title compound 79 is prepared according to the procedure reported in step C of Example 8 with indanone 78 (0.5 g, 2.1 mmol) and crotonaldehyde (0.75 mL) as reactants. Purification by column chromatography on SiO2 (Petroleum Ether/EtOAc=1:1) afford the title compound 79 as a white solid. (Yield 0.5 g, 91%).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH2:22])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[C:23](Cl)(=[O:25])[CH3:24].C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[CH3:4][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH:22][C:23](=[O:25])[CH3:24])[S:14][C:15]=2[C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1ccc(-c2nc(N)sc2-c2ccncc2)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1nc(-c2ccc(C(C)(C)C)cc2)c(-c2ccncc2)s1
Temperature: 80 °C
Reaction time: 14 h
Yield: 50.7 %

Procedure:
To a solution of [4-[4-(1,1-dimethylethyl)phenyl]-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (0.40 g, 1.29 mmol) and 4-dimethylaminopyridine (0.05 g, 0.39 mmol) in N,N-dimethylacetamide (4 mL) was added acetyl chloride (0.15 g, 1.94 mmol) and the mixture was stirred at 80° C. for 14 h. To the reaction mixture was poured aqueous sodium hydrogencarbonate and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. Crude crystals were recrystallized from ethanol to give the title compound (0.23 g, yield 50%).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:31])[CH2:14][CH2:15][CH:16]3[C@@:21]4([CH3:30])[CH2:22][CH2:23][CH:24]([O:26][C:27](Cl)=[O:28])[CH2:25][C:20]4=[CH:19][CH2:18][CH:17]3[CH:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[CH2:32]([CH2:37][O:38][CH2:39][CH2:40][NH2:41])[O:33][CH2:34][CH2:35][NH2:36]>ClCCl>[CH3:1][C@@H:2]([C@@H:9]1[C@:13]2([CH3:31])[C@H:12]([C@H:17]3[C@H:16]([CH2:15][CH2:14]2)[C@:21]2([CH3:30])[C:20]([CH2:25][C@@H:24]([O:26][C:27](=[O:28])[NH:36][CH2:35][CH2:34][O:33][CH2:32][CH2:37][O:38][CH2:39][CH2:40][NH2:41])[CH2:23][CH2:22]2)=[CH:19][CH2:18]3)[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CCC2C3CC=C4CC(OC(=O)Cl)CC[C@]4(C)C3CC[C@@]21C
Reactant: NCCOCCOCCN
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NCCOCCOCCN)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of cholesteryl chloroformate (1 g, 2.23 mmol) in 25 mL dichloromethane was added dropwise under stirring to a solution of 2,2′-(ethylenedioxy)bis-(ethylamine) (495 mg, 3.34 mmol) in 75 mL dichloromethane. The reaction was stirred overnight at room temperature. The reaction was diluted with dichloromethane and extracted with water. The organic extract was dried over anhydrous MgSO4 dihydrate, filtered and evaporated. After purification on amino-modified silica gel (eluent: MeCl2→MeCl2/MeOH=975:25 v/v) the product (615 mg) was obtained as a white, waxy solid. MS (ISP): (M+H) 561.5
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([O-:10])=O)=[CH:6][CH:5]=1.[CH3:14][C:15]1([CH3:22])[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][NH2:21]>>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:21][CH2:20][CH:16]2[CH2:17][CH2:18][CH2:19][C:15]2([CH3:22])[CH3:14])=[O:10])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Reactant: CC1(C)CCCC1CN
Product: COC(=O)c1ccc(C(=O)NCC2CCCC2(C)C)cc1

Procedure:
The title compound was prepared from monomethylterephthalate and 2,2-dimethylcyclopentylmethyl amine (title B compound of Example 1) in a manner as described for the title A compound of Example 24.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][C@H:17]([OH:19])[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](=O)([O-])[O-].[Cs+].[Cs+].IC>CO>[CH3:20][O:14][C:13](=[O:15])[C@@H:12]1[CH2:16][C@@H:17]([OH:19])[CH2:18][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CI
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of N-benzyloxycarbonyl-4-hydroxy-L-trans-proline 9 (47.5 g; 179 mmol) in anhydrous methanol (900 ml) is adjusted to pH=9.0-9.5 using caesium carbonate. The mixture is subsequently stirred at room temperature for 30 min., and then concentrated. After having been dried for 30 minutes under high vacuum, the residue is taken up in anhydrous N,N-dimethylformamide (900 ml). Iodomethane (28.0 g; 197 mmol) is added, and the mixture is stirred at room temperature for 21 h. The solution is concentrated, and the residue is subsequently distilled repeatedly with toluene, taken up in chloroform (1.8 l), and then extracted by shaking once with each of water and a 10% solution of sodium hydrogen carbonate, and once again with water (600 ml on each occasion). The organic phase is dried (magnesium sulphate) and concentrated. Yield: 50.0 g (quantitative).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:24][CH2:23][C@@H:22]3[C@@H:18]([CH2:19][NH:20][CH2:21]3)[C@@H:17]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:34]1(=O)[CH2:38][CH2:37][C:36](=[O:39])[CH2:35]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:24][CH2:23][C@@H:22]3[C@@H:18]([CH2:19][N:20]([C:34]4[CH2:38][CH2:37][C:36](=[O:39])[CH:35]=4)[CH2:21]3)[C@@H:17]2[C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: O=C1CCC(=O)C1
Reactant: C[C@@H](O[C@H]1CC[C@H]2CNC[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C[C@@H](O[C@H]1CC[C@H]2CN(C3=CC(=O)CC3)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
To a solution of 12.3 mg (0.26 mmol) of (3aR,4R,5S,7aR)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}4-(4-fluorophenyl)octahydro-1H-isoindole (Example 2) in -2 mL dry toluene was added 2.7 mg (0.028 mmol) cyclopentane-1,3-dione and a catalytic amount (˜0.5 mg) of PTSA. The resulting mixture was heated at reflux for 16 hr. The solvent was removed vacuum and the residue was purified by prep TLC eluting with EtOAc/MeOH (95/5) to afford the title compound. 1H-NMR (CDCl3): δ: 7.73 (1H, s), 7.20 (2H, s), 7.03-6.90 (2H, m), 4.98, 4.80 (1H, s), 4.50 (1H, m), 3.62-3.18 (2H, m), 3.30-3.18 (3H, m), 3.15, 2.97 (1H, d, J=11.2 Hz), 2.68 (2H, m), 2.55-2.40 (4H, m), 2.17 (1H, m), 2.20 (1H, m), 2.00 (1H, m), 1.85 (1H, m), 1.62 (1H, m), 1.33 (3H, d, J=6.2 Hz). MS: (MH)+556.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[O:5][C:6]=1Br.C([Mg]Cl)(C)C.O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[O:5][CH:6]=1
Reactant: COC(=O)c1cc(Br)c(Br)o1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(Br)co1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
To a solution of methyl 4,5-dibromo-2-furancarboxylate (3.3 g, 11.62 mmol) in tetrahydrofuran (46 ml) at −40° C. was added isopropylmagnesium chloride (6.97 ml, 13.95 mmol). After 1 h, Water (11 ml) was added and the solution warmed to 25° C. The reaction mixture was then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified by column chromatography (3% EtOAc in hexanes) affording methyl 4-bromo-2-furancarboxylate (1.4 g, 6.49 mmol, 56% yield) as a yellow solid: LCMS (ES) m/e 205, 207 (M, M+2)+.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[C:11]1([S:17]([NH2:20])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[C:11]1([S:17]([NH:20][C:6](=[O:8])[C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:10][CH:9]=2)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(O)c1ccc(I)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1ccccc1)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.4 %

Procedure:
5 g of 4-iodobenzoic acid is added to a solution of 3.3 g of benzenesulfonamide, 2.68 g of 4-dimethylaminopyridine and 4.04 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in 100 ml of dichloromethane, and the suspension is stirred for 18 hours at room temperature. The reaction mixture is diluted with 400 ml of dichloromethane, washed in succession with 400 ml portions of 10% hydrochloric acid, water and saturated common salt solution, the organic phase is dried on sodium sulfate and concentrated by evaporation. The residue is suspended in diethyl ether/ethyl acetate=1/1, and the crystallizate is suctioned off. 3.15 g of N-benzenesulfonyl-4-iodobenzoic acid amide of melting point 192°-193° C. is obtained.
Reaction SMILES: Cl[C:2]1([C:8]([O:10][CH3:11])=[O:9])[C:6](=[O:7])[CH:5]=[CH:4][S:3]1.[ClH:12]>C(O)(=O)C>[Cl:12][C:4]1[S:3][C:2]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([OH:7])[CH:5]=1
Reactant: COC(=O)C1(Cl)SC=CC1=O
Reactant: Cl
Solvent: CC(=O)O
Product: COC(=O)c1sc(Cl)cc1O
Reaction time: 72 h

Procedure:
A solution of 2-chloro-2-methoxycarbonylthiophene-3(2H)-one (30 mmol) in acetic acid (20 ml) was saturated with dry hydrogen chloride gas. After standing for 3 days the solvent was removed under reduced pressure and the oily residue distilled to give a yellow liquid which crystallised on addition of aqueous acetic acid (m.p. 42°-44° C.).
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].C(O[CH:11]=[C:12]([C:18]#[N:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])C.C([O-])(=O)C.[Na+]>C(O)C>[CH2:16]([O:15][C:13]([C:12]1[CH:11]=[N:7][N:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[C:18]=1[NH2:19])=[O:14])[CH3:17]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: CC(C)(C)NN
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnn(C(C)(C)C)c1N
Temperature: 0 °C
Yield: 76.6 %

Procedure:
A solution containing t-butylhydrazine hydrochloride salt (10 g, 80.3 mmol), ethyl (ethoxymethylene)-cyanoacetate (13.6 g, 80.4 mmol), and anhydrous sodium acetate (8.2 g, 100 mmol) in 100 mL ethanol was stirred and refluxed for 16 hours. The solution was poured into ice-water. The separated aqueous phase was extracted three times with dichloromethane. The combined organic phases were washed successively with water and saturated brine solution and dried with sodium sulfate. The solvent was removed in vacuo to give 5-amino-1-tert-butyl-1H-pyrazole-4-carboxylic acid ethyl ester (13 g, 77%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][C:12]([OH:14])=[O:13].OS(O)(=O)=O.[CH3:20][CH2:21]O>>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][C:12]([O:14][CH2:20][CH3:21])=[O:13]
Reactant: COc1cccc(CC(=O)O)c1OC
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cccc(OC)c1OC

Procedure:
To a solution of 2,3-dimethoxyphenylacetic acid (2.52 g, 12.8 mmol) in EtOH (abs.; 20 mL) was added H2SO4 (30 μL), and the solution was refluxed for 20 hours. The resultant solution was concentrated, dissolved in ether, and the ether solution was washed with NaHCO3/aq (2×30 mL) and brine, dried (MgSO4) and concentrated to yield the sub-title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20](O)=[O:21])[CH:9]=2)=[CH:4][CH:3]=1.[CH:23]1([C:26]2[O:30][N:29]=[C:28]([CH2:31][NH2:32])[CH:27]=2)[CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:17])([F:19])[F:18])=[CH:12][N:11]=[C:10]([C:20]([NH:32][CH2:31][C:28]3[CH:27]=[C:26]([CH:23]4[CH2:25][CH2:24]4)[O:30][N:29]=3)=[O:21])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: NCc1cc(C2CC2)on1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Product: O=C(NCc1cc(C2CC2)on1)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example D) and 5-cyclopropyl-3-isoxazolemethanamine (CAS Registry No. 1060817-49-3) as starting materials; LC-MS (UV peak area/ESI) 98.6%, 452.0979 (M+H)+.
Reaction SMILES: [Cl:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[N:7]1[C:12]2[NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16](=[O:18])[NH:17][C:11]=2[CH:10]=[CH:9][CH:8]=1>O1CCOCC1>[Cl:1][CH:2]([CH3:6])[C:3]([N:13]1[C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16](=[O:18])[NH:17][C:11]2[CH:10]=[CH:9][CH:8]=[N:7][C:12]1=2)=[O:4]
Reactant: CC(Cl)C(=O)Cl
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Solvent: C1COCCO1
Product: CC(Cl)C(=O)N1c2ccccc2C(=O)Nc2cccnc21

Procedure:
A solution of 2-chloropropionyl chloride and 5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepine-6-one in dioxane were reacted to obtain 11-(2-chloropropionyl)-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one which melted at 215°-218° C. under crystallization from ethanol.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:30]([NH:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=2)=[O:31])[C:3]1=[O:20]
Reactant: COc1cccc(N=C=O)c1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Product: COc1cccc(NC(=O)NC2N=C(c3ccccc3)c3ccccc3N(C)C2=O)c1
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 3-methoxyphenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 245°-246° C.
Reaction SMILES: [C:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([Cl:13])[C:5]=1[S:14]([NH2:17])(=[O:16])=[O:15])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[CH:25]=[CH2:26].Cl>CN(C)C=O>[CH2:26]([NH:17][S:14]([C:5]1[C:6]([Cl:13])=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]=1[C:1](=[O:3])[CH3:2])(=[O:15])=[O:16])[CH:25]=[CH2:24]
Reactant: CC(=O)c1c([N+](=O)[O-])ccc(Cl)c1S(N)(=O)=O
Reactant: C=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1C(C)=O
Temperature: 60 °C
Yield: 12 %

Procedure:
A mixture of 2-acetyl-6chloro-3-nitrobenzenesulfonamide (150 mg, 0.51 mmol), potassium carbonate (84 mg, 0.61 mmol) and allyl bromide (0.18mL, 2.mmol) in 3 mL of N, N-dimethylformamide was heated to 60° C. for 4 days. The mixture was acidified with 1 N aq. HCl, then extracted with ethyl acetate. The solvent was concentrated to give the crude material. Colurnt chromatography on silica gel, eluting with ethyl acetate/hexane/acetic acid (50/49/1, v/v/v), gave the desired product (40 mg, 12%). EI-MS (m/z) 333.3, 335.2 (M−).