Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:9][N:10]=[CH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]=[CH:14][CH:13]=2)[N:4]([CH2:23][CH2:24][CH3:25])[C:3]1=[O:26].C([NH:31][S:32]([C:35]1[CH:39]=[C:38]([CH:40]=O)[N:37]([CH3:42])[CH:36]=1)(=[O:34])=[O:33])(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[C:12]2[CH2:11][N:10]1[C:40]([C:38]2[N:37]([CH3:42])[CH:36]=[C:35]([S:32]([NH2:31])(=[O:34])=[O:33])[CH:39]=2)=[C:6]2[C:5]([N:4]([CH2:23][CH2:24][CH3:25])[C:3](=[O:26])[N:2]([CH3:1])[C:7]2=[O:8])=[N:9]1
Reactant: Cn1cc(S(=O)(=O)NC(C)(C)C)cc1C=O
Reactant: CCCn1c(NN=Cc2ccnc3ccc(Cl)cc23)cc(=O)n(C)c1=O
Solvent: O=C(O)C(F)(F)F
Product: CCCn1c(=O)n(C)c(=O)c2c(-c3cc(S(N)(=O)=O)cn3C)n(Cc3ccnc4ccc(Cl)cc34)nc21

Procedure:
Following the method of Example 180, this compound was made by preparation of 6-chloroquinoline-4-carbaldehyde (1-methyl-2,6-dioxo-3-propyl-1,2,3,6-tetrahydropyrimidin-4-yl)hydrazone, condensation with N-(tert-butyl)-5-formyl-1-methyl-1H-pyrrole-3-sulfonamide and treatment with TFA.
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.O[CH2:17][C:18]1[S:19][C:20]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:21]([C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)[C:22]=1[CH2:23][C:24]([OH:26])=[O:25]>C(Cl)Cl>[CH3:34][S:33][C:30]1[CH:31]=[CH:32][C:27]([C:21]2[C:22]3[CH2:23][C:24](=[O:26])[O:25][CH2:17][C:18]=3[S:19][C:20]=2[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[CH:28][CH:29]=1
Reactant: CSc1ccc(-c2c(-c3ccccc3)sc(CO)c2CC(=O)O)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Product: CSc1ccc(-c2c(-c3ccccc3)sc3c2CC(=O)OC3)cc1
Reaction time: 8 h

Procedure:
(+)-10-camphorsulfonic acid (5 mg) was added to a solution of [2-hydroxymethyl-4-(4-methylsulfanylphenyl)-5-phenylthiophen-3-yl] acetic acid (100 mg) (Step 3) in CH2Cl2 (5 mL) and the resulting solution was stirred overnight. The solution was diluted with CH2Cl and washed with a saturated solution of NaHCO3, dried over MgSO4, filtered and the solvent was evaporated under vacuum. Purification by silica gel chromatography using 20% of EtOAc in hexane gave the title compound.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C.O>C(Cl)Cl>[Br:1][CH2:2][C:3]([N:15]1[CH2:16][CH2:17][N:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]=2)[CH2:13][CH2:14]1)=[O:4]
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CBr)N1CCN(c2ccccn2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
6.95 mL bromacetylbromide was dropped to 11.68 mL 1-pyridin-2-yl-piperazine and 11.23 mL triethylamine in 300 mL DCM at 0° C. The reaction was stirred 2 h at 0° C. The reaction mixture was added to water and extracted with DCM. The organic layer was dried with magesium sulfate and evaporated The residue was purified by chromatography on silica gel (DCM/MeOH 0-20%; 0.1% ammonia) to yield 23.6 g of the desired compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:27])[CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[C:5]([CH3:28])[CH:4]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>CN(C=O)C>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([CH2:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:4][C:5]=3[CH3:28])=[O:27])[C:12](=[O:26])[CH:13]=2)=[N:20][CH:21]=1
Reactant: C1CCNC1
Reactant: Cc1cc(CBr)ccc1C(=O)Cn1ccc(OCc2ccc(F)cn2)cc1=O
Solvent: CN(C)C=O
Product: Cc1cc(CN2CCCC2)ccc1C(=O)Cn1ccc(OCc2ccc(F)cn2)cc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-[2-(4-bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-fluoro-pyridin-2-ylmethoxy)-1H-pyridin-2-one (preparation 2b, 111 mg, 0.25 mmol) in DMF (2 mL) is added pyrrolidine (63 μL, 0.75 mmol). The reaction mixture is stirred for 60 min at room temperature. The mixture is purified via reverse phase HPLC chromatography (Gilson Xbridge C18 5 μm, gradient 5%→90% acetonitrile in water+0.3% NH4OH, 120 mL/min).
Reaction SMILES: C([Mg]Cl)(C)C.[NH:6]1[C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[CH:8]=[CH:7]1.[CH2:15]([O:17][C:18](=[O:32])[C:19](=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:16]>C1COCC1.[Cl-].[Cl-].[Zn+2]>[CH2:23]([O:22][C:20](=[O:21])[CH:19]([CH:25]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:8]1[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][C:14]=2[NH:6][CH:7]=1)[C:18]([O:17][CH2:15][CH3:16])=[O:32])[CH3:24]
Reactant: c1cc2[nH]ccc2cn1
Reactant: CCOC(=O)C(=Cc1ccccc1)C(=O)OCC
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C(c1ccccc1)c1c[nH]c2ccncc12
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 70 %

Procedure:
To a RT solution of isopropylmagnesium chloride (1.5 M in THF, 2.4 mL, 3.6 mmol) in THF (10 mL) was added a solution of 1H-pyrrolo[3,2-c]pyridine (350 mg, 3 mmol) in THF (3 mL), followed by a solution of ZnCl2 in THF (1 M, 3.4 mL). After stirring the resulting mixture at 50° C. for 5 minutes, 2-benzylidene-malonic acid diethyl ester (1.0 mL, 4.5 mmol) was added dropwise. The mixture was stirred at 50° C. for 3 h, cooled to RT, quenched by addition of a saturated solution of NH4Cl, and extracted 3 times with EtOAc. The combined extracts were dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (EtOAc), affording 2-[Phenyl-(1H-pyrrolo[3,2-c]pyridin-3-yl)-methyl]-malonic acid diethyl ester (0.77 g, 70% yield).
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[C:17]1([C:23]2[O:27][CH:26]=[N:25][C:24]=2[C:28](O)=[O:29])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]([OH:16])[C@H:2]([NH:1][C:28]([C:24]3[N:25]=[CH:26][O:27][C:23]=3[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:29])[C:7]=2[CH:8]=1)#[N:13]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: O=C(O)c1ncoc1-c1ccccc1
Solvent: CO
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=O)c2ncoc2-c2ccccc2)[C@@H]1O

Procedure:
The title compound was prepared from (3S-trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (the title B compound of Example 1) and 5-phenyl-4-oxazolecarboxylic acid by the same method as described for the title compound of Example 2 to afford an off-white solid, m.p. 196°-197° C. [α]D =-179.8° (c=0.40, MeOH).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[N:5][C:6]([NH:9][C@@H:10]2[CH2:15][C@@H:14]3[N:16](C(OC(C)(C)C)=O)[C@H:11]2[CH2:12][CH2:13]3)=[N:7][CH:8]=1.Cl>C(Cl)Cl.O1CCOCC1>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[N:5][C:6]([NH:9][C@@H:10]2[CH2:15][C@@H:14]3[NH:16][C@H:11]2[CH2:12][CH2:13]3)=[N:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1[C@H](Nc1ncc(C(F)(F)F)cn1)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: FC(F)(F)c1cnc(N[C@@H]2C[C@H]3CC[C@@H]2N3)nc1
Reaction time: 8 h

Procedure:
To the title compound of step A (355 mg, 1 mmol) in DCM (9.7 mL) was added 4M HCl in dioxane (1.2 mL). The reaction was allowed to proceed overnight then concentrated and neutralized with 5% Na2CO3 (aq) and extracted with DCM (2×). The combined organics were dried (Na2SO4) to give the title compound of step B that was used without further purification.
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.[OH:14][N:15]1[C:20]([CH3:22])([CH3:21])[CH2:19][C:18](=[O:23])[CH2:17][C:16]1([CH3:25])[CH3:24].[CH:26]1(I)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.CCCCCCC.C(OCC)(=O)C>ClC1C=CC=CC=1>[CH:26]1([O:14][N:15]2[C:20]([CH3:21])([CH3:22])[CH2:19][C:18](=[O:23])[CH2:17][C:16]2([CH3:25])[CH3:24])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CC1(C)CC(=O)CC(C)(C)N1O
Reactant: IC1CCCCC1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: Clc1ccccc1
Product: CC1(C)CC(=O)CC(C)(C)N1OC1CCCCC1

Procedure:
Tributyltin hydride is added to a solution of excess 1-oxyl-2,2,6,6-tetramethylpiperidin-4-one and cyclohexyl iodide in chlorobenzene. The mixture is passed through silica gel with heptane/ethyl acetate to obtain 1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-one, which is free of any bis(4-oxo-2,2,6,6-tetramethylpiperidin-1-yloxy)cyclohexane bridged material.
Reaction SMILES: [ClH:1].[NH2:2][C:3](=[O:33])[C@@H:4]([NH:11][C:12](=[O:32])[CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[CH:25]=2)=[C:19]([F:31])[CH:18]=1)=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.N[C@H](C1C=CC=CC=1)C(N)=O>>[ClH:1].[NH2:2][C:3](=[O:33])[C@H:4]([NH:11][C:12](=[O:32])[CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[CH:25]=2)=[C:19]([F:31])[CH:18]=1)=[O:15])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: NC(=O)[C@@H](NC(=O)CC(=O)Nc1ccc(Oc2ccnc(N)c2)c(F)c1)c1ccccc1
Agent: Cl
Agent: NC(=O)[C@H](N)c1ccccc1
Product: NC(=O)[C@H](NC(=O)CC(=O)Nc1ccc(Oc2ccnc(N)c2)c(F)c1)c1ccccc1
Yield: 29.5 %

Procedure:
3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoic acid (Compound C of Example 102, 30 mg, 0.10 mmol) was coupled with (R)-2-amino-2-phenylacetamide hydrochloride (Bachem, 28 mg, 0.15 mmol) in a manner similar to that which is described in Step C of Example 1 to give (R)-N1-(2-amino-2-oxo-1-phenylethyl)-N3-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)malonamide, hydrochloride salt (14 mg, 30% yield). 1H NMR (DMSO-d6) δ 10.65 (s, 1H), 8.76 (d, 1H, J=8.0 Hz), 7.92 (d, 1H, J=7.0 Hz), 7.75-7.88 (m, 4H), 7.20-7.43 (m, 8H), 6.66 (m, 1H), 6.09 (s, 1H), 5.35 (d, 1H, J=8.0 Hz), 3.45 (d, 1H, J=15.0 Hz), 3.37 (d, 1H, J=15.0 Hz); MS(ESI+) m/z 438.23 (M+H)+.
Reaction SMILES: C(OC([CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:29]1CCCC1>>[OH:29][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)CCc1c(-c2cccnc2)[nH]c2ccccc12
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCCc1c(-c2cccnc2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 10.0 g of 3-(2-ethoxycarbonylethyl)-2-(3-pyridyl)indole in 400 ml of dry tetrahydrofuran at 0° is added 60 ml of a 1M solution of lithium aluminum hydride in tetrahydrofuran. This is allowed to stir at room temperature for 1 hour, then cooled by an ice bath and quenched successively with 2.26 ml of water, 2.26 ml of a 15% sodium hydroxide solution, and 6.78 ml of water. The mixture is filtered, concentrated in vacuo, and the residue dissolved in ether, washed with a saturated NaHCO3 solution, dried over MgSO4 and concentrated in vacuo to give 3-(2-hydroxyethyl)-2-(3-pyridyl)-indole.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].CS[C:17](SC)=[CH:18][N+:19]([O-:21])=[O:20].[C:24](#[N:26])C>>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]([NH:26][CH3:24])=[CH:18][N+:19]([O-:21])=[O:20])=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: CC#N
Product: CNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1

Procedure:
2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (4.25 g) and 1,1-bis(methylthio)-2-nitroethene (3.3 g) were refluxed in acetonitrile (50 ml) for 14 hr. Solvent was removed and the residue dissolved in 36% methanolic methylamine (50 ml) and the solution refluxed for 8 hr. Solvents were removed and the residue in methanol treated with charcoal. Filtration and evaporation of the solvent gave the title compound as Example 15 (5.0 g).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:3]=1[C:4](O)=[N:5][CH:6]=[N:7]2.S(Cl)([Cl:17])=O.CN(C)C=O>>[Cl:17][C:4]1[C:3]2[C:8](=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:2]=2[F:1])[N:7]=[CH:6][N:5]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(F)c2c(O)ncnc2c1
Solvent: CN(C)C=O
Product: COc1cc(F)c2c(Cl)ncnc2c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 94.9 %

Procedure:
To a suspension of 5-fluoro-7-methoxyquinazolin-4-ol (0.125 g, 0.644 mmol) in thionyl chloride (1.410 mL, 19.31 mmol) was added N,N-dimethylformamide (0.028 mL, 0.361 mmol). The reaction was stirred at 80° C. for 6 hours and concentrated in vacuo. The residue was suspended in saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was concentrated in vacuo to generate the title compound (0.13 g, 0.611 mmol) as a yellow solid. LC/MS (ESI+) m/z=213 (M+H).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([CH:9]2[C:18](=[O:19])[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10]2)=[O:8])=[CH:4][CH:3]=1.NC1C=CC(C(N)=[O:26])=CC=1C.CC1C=CC(S(O)(=O)=O)=CC=1>CCO>[Br:1][C:2]1[O:6][C:5]([C:7](=[O:8])[CH2:9][CH2:10][C:11]2([CH2:16][CH2:17][C:18]([OH:19])=[O:26])[O:12][CH2:13][CH2:14][O:15]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(C(N)=O)ccc1N
Reactant: O=C1CCC2(CC1C(=O)c1ccc(Br)o1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: O=C(O)CCC1(CCC(=O)c2ccc(Br)o2)OCCO1
Yield: 30 %

Procedure:
7-(5-bromofuran-2-carbonyl)-1,4-dioxaspiro[4.5]decan-8-one. (2.00 g, 5.78 mmol), 4-amino-3-methylbenzamide (1.04 mg, 6.90 mmol) and TsOH (100 mg, 0.578 mmol) were taken up into EtOH (20 mL). The resulted mixture was heated to reflux for 61 h. After evaporation under reduced pressure, the crude product was purified by a silica gel column chromatography (EA:PE=1:1) to afford 3-(2-(3-(5-bromofuran-2-yl)-3-oxopropyl)-1,3-dioxolan-2-yl)propanoic acid as a yellow solid (760 mg, yield: 30%).
Reaction SMILES: O.C[Si]([Cl:6])(C)C.[CH3:7][N:8]([CH2:10][CH:11]1[CH2:17][CH2:16][CH:15]2[CH:13]([CH2:14]2)[C:12]1([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=1)[OH:18])[CH3:9]>CC(=O)CC>[ClH:6].[CH3:9][N:8]([CH2:10][CH:11]1[CH2:17][CH2:16][CH:15]2[CH:13]([CH2:14]2)[C:12]1([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=1)[OH:18])[CH3:7]
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CC1CCC2CC2C1(O)c1cccc(O)c1
Solvent: O
Solvent: CCC(C)=O
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add H2O (10 mg, 0.560 mmol) and TMSCl (33 mg, 0.308 mmol) to a solution of 3-dimethylaminomethyl-2-(3-hydroxy-phenyl)-bicyclo[4.1.0]heptan-2-ol (73 mg, 0.280 mmol) in 2-butanone (10 mL). Then stir the mixture at room temperature for 2 hours. Evaporate the mixture under vacuum to give 3-dimethylaminomethyl-2-(3-hydroxyl-phenyl)-bicyclo[4.1.0]heptan-2-ol hydrochloride as white solid (83 mg, Yield: 100%). 1H NMR (400 MHz, Methanol-d4) δ 7.21-7.25 (t, J=16.0, 1H), 7.17-7.18 (t, J=4.4, 1H), 7.11-7.13 (m, 1H), 6.76-6.79 (d, J=10.0, 1H), 3.23-3.25 (m, 1H), 2.68-2.69 (m, 7H), 2.14-2.17 (m, 1H), 2.04-2.09 (m, 1H), 1.76-1.81 (m, 1H), 1.62-1.64 (m, 1H), 1.47-1.49 (m, 1H), 1.11-1.16 (m, 1H), 0.93-1.05 (m, 1H), 0.73-0.84 (m, 1H), 0.50-0.53 (m, 1H).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].C(=O)([O-])O.[Cs+].[C:15]([O:23][CH:24](Cl)[CH:25]([CH3:27])[CH3:26])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O:6][CH:24]([O:23][C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:22])[CH:25]([CH3:27])[CH3:26])=[O:5]
Reactant: CC(C)C(Cl)OC(=O)c1ccccc1
Reactant: COC(=O)/C=C/C(=O)O
Agent: O=C([O-])O
Agent: [Cs+]
Product: COC(=O)/C=C/C(=O)OC(OC(=O)c1ccccc1)C(C)C
Yield: 15.4 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (0.50 g, 3.82 mmol) was reacted with CsHCO3 (5.76 mmol) and chloroisobutyl benzoate (1.1 g, 5.17 mmol) at ca. 55° C. to afford 0.18 g (15% yield) of the title compound (46) after purification by silica gel flash chromatography (Biotage) using a mixture of ethyl acetate (EtOAc) and hexanes (1:7). 1H NMR (CDCl3, 400 MHz): δ 8.04-8.01 (m, 2H), 7.58-7.55 (m, 1H), 7.45-7.41 (m, 2H) 6.98 (d, J=4.8 Hz, 1H), 6.90 (d, J=16.0 Hz, 1H), 6.84 (d, J=16.0 Hz, 1H), 3.78 (s, 3H), 2.25-2.21 (m, 1H), 1.10-1.07 (m, 6H); MS (ESI): m/z 307.11 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(Cl)(Cl)Cl>[CH3:9][C:3]([CH3:8])([CH:2]([NH:1][S:32]([C:29]1[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=1)(=[O:34])=[O:33])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C(C)(C)C(N)Cc1ccc(OC)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)C(Cc1ccc(OC)cc1)NS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
To a solution of 251 g of methyl 3-amino-2,2-dimethyl-4-(p-methoxyphenyl)butyrate and 121 g of triethylamine in 750 ml of chloroform, there is added, with mechanical stirring and cooling with ice water, a solution of 210 g of p-toluenesulphonyl chloride in 500 ml of chloroform. After completion of the addition, which is carried out at such a rate that the temperature of the reaction mixture does not exceed 25° C., stirring is continued for 1.5 hours. Then the solution is washed with water, dilute hydrochloric acid and again with water, subsequently. After drying, the organic solvent is stripped off in vacuo. The residue is treated with ether, resulting in the crystallization of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:39]=[CH:38][C:28]([C:29]([NH:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:30])=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)=[O:18])[CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl>>[OH2:2].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([C:17]([N:19]3[CH2:20][CH2:21][N:22]([C:25]4[CH:26]=[CH:27][C:28]([C:29]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:30])=[CH:38][CH:39]=4)[CH2:23][CH2:24]3)=[O:18])[CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)CNC(=O)c1ccc(N2CCN(C(=O)c3cccc(-c4ccc(OC)c(OC)c4)n3)CC2)cc1
Agent: Cl
Product: COc1ccc(-c2cccc(C(=O)N3CCN(c4ccc(C(=O)NCC(=O)O)cc4)CC3)n2)cc1OC
Product: O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To 233 mg of ethyl [(4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}benzoyl)amino]acetate was added 0.8 ml of conc. hydrochloric acid, followed by overnight stirring at room temperature. After the reaction solution was concentrated under reduced pressure, crystallization was carried out from 2-propanol-diisopropyl ether to collect [(4-f4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}benzoyl)amino]acetic acid hydrochloride by filtration. The filtrate was concentrated under reduced pressure, and the residue was crystallized from hexane to obtain 88 mg of [(4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}benzoyl)amino]acetic acid hydrate as pale brown crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13][C:14](=[O:16])[CH3:15])[CH2:9][CH2:8]2.C(Cl)Cl.[I:20]I>C(OC(F)(F)F)(=O)C.[Ag].O>[I:20][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:12]2[C:7]=1[CH2:8][CH2:9][CH:10]([NH:13][C:14](=[O:16])[CH3:15])[CH2:11]2
Reactant: II
Reactant: COc1cccc2c1CC(NC(C)=O)CC2
Agent: [Ag]
Agent: CC(=O)OC(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1ccc(I)c2c1CC(NC(C)=O)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 2.19 g. (0.01 mol.) of N-(1,2,3,4-tetrahydro-8-methoxy-2-naphthalenyl) acetamide and 2.21 g (0.01 mole) of silver trifluoromethyl acetate in 80 ml. of methylene chloride was added dropwise a solution of iodine (2.52 g.; 0.02 mole) in 80 ml. of methylene chloride. The reaction mixture was stirred for one hour at room temperature, filtered and evaporated to leave an oil to which 100 ml. of water was added. After 30 minutes the oil solidified. The crystals were collected, dried and recrystallized from ethanol to give N-(1,2,3,4-tetrahydro-5-iodo-8-methoxy-2-naphthalenyl) acetamide as a white solid m.p. 202°-3°.
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11].C1(C)C(C)=CC=CC=1>[Cl-].C[N+](C)(C)C>[F:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: [F-]
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: C[N+](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1ccccc1F
Temperature: 150 °C
Reaction time: 21 h
Yield: 73.9 %

Procedure:
In a 2-liter flange flask fitted with a distillation bridge and impeller stirrer, 290.5 g (5.0 mol) of potassium fluoride, 71.1 g (0.1 mol) of trimethyl(ethoxypolyoxypropyl)ammonium chloride and 17.0 g (0.16 mol) of tetramethylammonium chloride were introduced at 120° C. into the melt of 630 g (4.0 mol) of 2-chloronitrobenzene. Subsequently, 100 g (0.38 mol) of xylene were added and the reaction suspension was heated to 150° C., the xylene was removed under reduced pressure and the mixture was stirred for 21 hours at this temperature. Subsequently, the reaction suspension was cooled to 70° C. and filtered with suction. The salts separated off were washed twice with a total of 360 g of xylene and the combined organic 35 phases were fractionated. 417 g (74% of theory) of 2-fluoronitrobenzene were isolated. Amount of 2-fluoronitrobenzene formed, according to GC analysis:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=O.[NH:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:24][C@H:13]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[CH2:24][C@H:13]23)=[O:7])[CH:8]=[CH:9][C:10]=1[OH:11]
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc(O)c(Cl)c1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 32 %

Procedure:
The title compound is prepared from 3-chloro-4-hydroxy-benzoic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 32% of theory; LC (method 4): tR=1.96 min; Mass spectrum (ESI+): m/z=328/330 (Cl) [M+H]+.
Reaction SMILES: [CH3:1][O:2][C@H:3]([CH3:9])[C@@H:4]([C:6]([OH:8])=[O:7])[NH2:5].Cl[C:11]([O:13][CH3:14])=[O:12]>C(=O)(O)[O-]>[CH3:1][O:2][C@H:3]([CH3:9])[C@H:4]([NH:5][C:11]([O:13][CH3:14])=[O:12])[C:6]([OH:8])=[O:7]
Reactant: CO[C@H](C)[C@H](N)C(=O)O
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Product: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.3 %

Procedure:
A solution of O-methyl-L-threonine (1.01 g, 7.59 mmol) in saturated bicarbonate solution (93 mL) was treated dropwise with methyl chloroformate (900 μL, 1.10 g, 11.61 mmol), followed by stirring at RT for 24 h. The mixture was extracted methyl t-butyl ether and cooled to 0° C. The mixture was adjusted to pH 1-2 by addition of concentrated hydrochloric acid solution. The mixture was extracted with ethyl acetate (3×) and the combined extracts were extracted with saturated sodium chloride solution and dried (Na2SO4). The solution was concentrated in vacuo to afford the title compound (1.31 g, 90%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 5.44 (d, J=8.7 Hz, 1H), 4.39 (dd, J=8.7, 2.3 Hz, 1H), 4.00 (dd, J=6.2, 2.4 Hz, 1H), 3.71 (s, 3H), 3.36 (s, 3H), 1.21 (t, J=7.2 Hz, 3H). MS (+ESI) m/z (rel abundance) 192 (60, M+H), 209 (100, M+NH4).