Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.N[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N([O-])=O.[Na+].[OH:13][N:14]1[C:19]([CH3:21])([CH3:20])[CH2:18][CH2:17][CH2:16][C:15]1([CH3:23])[CH3:22]>O.N1C=CC=CC=1.[Cu](F)F>[O:13]([N:14]1[C:19]([CH3:21])([CH3:20])[CH2:18][CH2:17][CH2:16][C:15]1([CH3:23])[CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC1(C)CCCC(C)(C)N1O
Reactant: Nc1ccccc1
Agent: F[Cu]F
Agent: Cl
Agent: O=N[O-]
Solvent: c1ccncc1
Solvent: O
Product: CC1(C)CCCC(C)(C)N1Oc1ccccc1
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
Into a solution of 5 g of water and 15.3 g (150 mmol) of concentrated hydrochloric acid is added dropwise 4.60 g (50 mmol) of aniline. The temperature of the reaction mixture during the addition step is kept under 40° C. After the addition is complete, the reaction mixture is heated to 70° C. for one hour. The reaction mixture is then cooled to 0° to 5° C. followed by a dropwise addition of an aqueous solution of 3.45 g (50 mmol) of sodium nitrite in 10 mL of water. The addition time is 20 minutes while the reaction temperature is maintained at 0° to 5° C. The reaction mixture is transferred to a cold-jacketed addition funnel and is then added dropwise into a solution of 3.9 g (25 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidine, 25 mg (0.25 mmol) of copper(II) fluoride in 120 mL of pyridine at 70° C. Evolution of nitrogen is observed during the addition. After the addition is complete, the reaction mixture is kept at 70° C. for another 30 minutes followed by cooling to ambient temperature. The reaction mixture is concentrated to a thick oil. The crude product is purified by vacuum flash chromatography (heptane) to give 3.97 g of the title as a colorless oil in 68.4% yield.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][Cl:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:22])C=1.O>ClCCl>[C:1]1([S:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][Cl:13])=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCCCCSc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: O=S(CCCCCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
5-Phenylthiopentyl chloride (1.84 g) was dissolved in dichloromethane (50 ml), and one equivalent of m-chloroperbenzoic acid was added thereto, which was followed by stirring at room temperature for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 1.20 g of 5-phenylsulfinylpentyl chloride.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][CH2:29][OH:30])[CH:22]=1>N1C=CC=CC=1>[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][CH2:29][O:30][C:2]2[N:7]=[C:6]([C:8]3[CH:20]=[CH:19][C:11]4[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=4[CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:22]=1
Reactant: OCCCc1cccnc1
Reactant: CC(=O)Nc1nc2ccc(-c3ccnc(Cl)n3)cc2s1
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(-c3ccnc(OCCCc4cccnc4)n3)cc2s1
Temperature: 120 °C

Procedure:
N-(6-(2-Chloropyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (59.4 mg, 195 μmol) and 3-pyridinepropanol (0.25 mL, 1.9 mmol) were suspended in pyridine (0.80 mL) in a microwave vial, which was then sealed and heated in a microwave (CEM brand) at 120° C. and 300 watts using a ramp time of 5 minutes and a run time of 20 minutes. The reaction was cooled to RT, concentrated, and purified on HPLC (10% to >95% MeCN/water with 0.1% TFA over 40 minutes) to afford N-(6-(2-(3-(pyridin-3-yl)propoxy)pyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide. MS (ESI pos. ion) m/z: 406. Calculated exact mass for C21H19N5O2S: 405. 1H NMR (400 MHz, DMSO-d6): 12.51 (s, 1H), 8.83 (d, J=5.5 Hz, 2H), 8.71 (d, J=5.0 Hz, 1H), 8.64 (d, J=5.5 Hz, 1H), 8.39 (d, J=8.0 Hz, 1H), 8.25 (d, J=8.5 Hz, 1H), 7.84-7.89 (m, 2H), 7.75 (d, J=5.0 Hz, 1H), 4.47 (t, J=7.5 Hz, 2H), 2.98 (t, J=7.5 Hz, 2H), 2.23 (s, 3H), 2.17-2.22 (m, 2H).
Reaction SMILES: O[CH:2]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]3=[O:24])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.[Cl-].[NH4+]>ClCCl.C(OCC)C>[C:25]1([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([N:9]3[CH2:10][CH2:11][CH:12]([N:15]4[CH2:23][C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:16]4=[O:24])[CH2:13][CH2:14]3)=[CH:5][CH:4]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C1c2ccccc2CN1C1CCN(c2ccc(C(O)c3ccccc3)cc2)CC1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1c2ccccc2CN1C1CCN(c2ccc(Cc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a solution of Example 278 compound (300 mg, 0.75 mmol) and triethylsilane (0.24 mL, 1.50 mmol) in dichloromethane (5 mL) at 0° C. was added dropwise a solution of boron trifluoride etherate (0.18 mL, 1.50 mmol). The reaction was stirred at RT overnight. Saturated ammonium chloride solution (2 mL) was added to quench the reaction. Ethyl ether (100 mL) was added and the organic layer was washed with water (2×30 mL), brine (2×30 mL) and dried over MgSO4. Purification was performed by flash chromatography on silica gel (50 g), loaded and eluted with 30% acetone in hexane. Pure fractions were combined and evaporated to give title compound (96 mg, 34%) as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.FC1C=CC(CNC2C=NC=CC=2[N+]([O-])=O)=CC=1.S1C=CC=C1C[N:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[NH:41]C1CCN(CC#N)CC1.[OH-].[Na+]>O1CCCC1.O>[N:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[NH:34][C:33]=1[NH2:41]
Reactant: N#CCN1CCC(Nc2nc3ccccc3n2Cc2cccs2)CC1
Agent: Cl
Agent: O=[N+]([O-])c1ccncc1NCc1ccc(F)cc1
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc2ccccc2[nH]1
Reaction time: 3 h

Procedure:
To a stirred mixture of 2.5 parts of lithium aluminum hydride and 225 parts of tetrahydrofuran was added dropwise a solution of 13 parts of 4-[[1-(2-thienylmethyl)-1H-benzimidazol-2-yl]amino]-1-piperidineacetonitrile in tetrahydrofuran under nitrogen atmosphere. Upon completion, stirring was continued for 3 hours at reflux. The reaction mixture was cooled in an ice bath and decomposed by the successive additions of 2.5 parts of water, 7.5 parts of a sodium hydroxide solution 15% and 7.5 parts of water. The whole was filtered over Hyflo and the filtrate was evaporated. The residue was crystallized from acetonitrile, yielding 9.5 parts (72%) of N-[1-(2-aminoethyl)-4-piperidinyl]-1-(2-thienylmethyl)-1e,uns/H/ -benzimidazol-2-amine; mp. 137.1° C. (intermediate 108).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:27]=[CH:26][C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C([O:35][C:36]1[CH:46]=[CH:45][C:39]([O:40][CH2:41][C@@H:42]2[CH2:44][O:43]2)=[CH:38][CH:37]=1)C1C=CC=CC=1.CCCCCC>ClCCl.CO>[OH:43][C@H:42]([CH2:41][O:40][C:39]1[CH:45]=[CH:46][C:36]([OH:35])=[CH:37][CH:38]=1)[CH2:44][NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:16])[CH2:11][CH2:10]2)=[CH:26][CH:27]=1
Reactant: CCCCCCCCNC(=O)N1CCC(Oc2ccc(CCN)cc2)CC1
Reactant: c1ccc(COc2ccc(OC[C@@H]3CO3)cc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCCNC(=O)N1CCC(Oc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1

Procedure:
4-[4-(2-Aminoethyl)phenoxy]N-octyl-1-piperidinecarboxamide (0.825 g, 2.2 mmol) was reacted with (2S)-2-{[4-(benzyloxy)phenoxy]methyl}oxirane (0.564 g, 2.2 mmol) according to Procedure G (eluant: 33:1 going to 9:1 dichloromethane-methanol) to give the title compound following crystallization from hexane (0.533 g, 0.84 mmol).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11].[C:13]1([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH3:8][C:6]1[NH:5][C:4](=[O:9])[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([N:22]2[CH2:23][CH2:24][CH:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:20][CH2:21]2)[N:7]=1
Reactant: Cc1nc(Br)c([N+](=O)[O-])c(=O)[nH]1
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N2CCC(c3ccccc3)CC2)c([N+](=O)[O-])c(=O)[nH]1

Procedure:
In analogy to the procedure described in example 1, the 6-bromo-2-methyl-5-nitro-3H-pyrimidin-4-one (as prepared in Eur. Pat. Appl. EP 1074549 A2) was treated with the 4-phenylpiperidine in N,N-dimethylformamide in the presence of N-ethyldiisopropyl-amine at room temperature to yield the 2-methyl-5-nitro-6-(4-phenyl-piperidin-1-yl)-3H-pyrimidin-4-one as yellowish solid; m.p. 210-213° C.; MS: [M+H]+=315.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1I.BrC1C=CC=C(F)C=1N>>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[S:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(S)cc1
Reactant: Fc1cccc(Br)c1I
Agent: Nc1c(F)cccc1Br
Product: COc1ccc(Sc2c(F)cccc2Br)cc1

Procedure:
Prepared from 4-methoxy-benzenethiol and 1-bromo-3-fluoro-2-iodo-benzene (prepared from 2-bromo-6-fluoro-phenylamine by diazotization according to the general procedure by Tunney and Stille J. Org. Chem. 1987, 52, 748-753).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]([C:14](=[O:31])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=1)[CH3:13].Br[C:34]1[C:35]([CH3:41])=[CH:36][C:37]([Cl:40])=[N:38][CH:39]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]([C:14](=[O:31])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:34]2[CH:39]=[N:38][C:37]([Cl:40])=[CH:36][C:35]=2[CH3:41])[CH:16]=1)[CH3:13]
Reactant: COC(=O)COc1ccccc1N(C)C(=O)c1ccc(Cl)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1cc(Cl)ncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)COc1ccccc1N(C)C(=O)c1ccc(Cl)c(-c2cnc(Cl)cc2C)c1
Temperature: 95 °C

Procedure:
A mixture of (2-{[4-chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoyl]-methyl-amino}-phenoxy)-acetic acid methyl ester (45 mg, 0.11 mmol), 5-bromo-2-chloro-4-methyl-pyridine (25 mg, 0.12 mmol), Pd(PPh3)4 (6.5 mg, 0.0056 mmol), and K2CO3 (38 mg, 0.28 mmol) in dioxane (600 ul), was heated at 95° C. for 12 hrs. The mixture was purified after a filtration by prep. LCMS to yield (2-{[4-chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-acetic acid methyl ester 3-1. MS [M+H]+: 459.0; tR=7.70 min; (method 2)
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:8][CH:7]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24]([CH:28]=1)[C:25](Cl)=[O:26]>>[CH3:2][N:3]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1)[C:25](=[O:26])[C:24]1[CH:28]=[C:20]([Cl:19])[CH:21]=[CH:22][C:23]=1[O:29][CH3:30]
Reactant: CCOC(=O)CCc1ccc(CCNC)cc1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Agent: Cl
Product: COc1ccc(Cl)cc1C(=O)N(C)CCc1ccc(CCC(=O)O)cc1

Procedure:
By the reaction of ethyl β-{4-[2-(N-methylamino)-ethyl]-phenyl}-propionate hydrochloride (m.p. 162°-164° C.) with 5-chloro-2-methoxybenzoyl chloride, there is obtained β-{4-[2-(N-methyl-5-chloro-2-methoxybenzamido)-ethyl]-phenyl}-propionic acid; m.p. 152°-153° C., after recrystallization from toluene.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[O:10]=[C:11]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[S:14][C:13]([C:21]2[N:26]=[C:25]([CH2:27]S([O-])(=O)=O)[CH:24]=[CH:23][CH:22]=2)=[N:12]1.C(OCC)(=O)C>CN(C=O)C.O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[S:1][CH2:27][C:25]1[N:26]=[C:21]([C:13]2[S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:11](=[O:10])[N:12]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: O=c1nc(-c2cccc(CS(=O)(=O)[O-])n2)sc2ccccc12
Reactant: Sc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1nc(-c2cccc(CSc3ccccn3)n2)sc2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.4 %

Procedure:
2-mercaptopyridine (0.21 g, 1.89 mmol) and sodium hydride (60% in oil, 0.083 g, 2.06 mmol) were dissolved in DMF (30 ml), and 6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridylmethanesulfonate (0.60 g, 1.72 mmol) was added thereto. The reaction mixture was stirred at room temperature for 18 hrs and combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.54 g, 87%) as pale yellow crystals.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15]Cl)=[CH:9][CH:8]=1)C.[C:20]1([C:26]2[C:30]3[CH:31]=[CH:32][C:33]([OH:35])=[CH:34][C:29]=3[O:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Na+].[I-]>CN(C=O)C>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][O:35][C:33]2[CH:32]=[CH:31][C:30]3[C:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:27][O:28][C:29]=3[CH:34]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(C#CCCl)cc1)OC
Reactant: Oc1ccc2c(-c3ccccc3)coc2c1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H](Cc1ccc(C#CCOc2ccc3c(-c4ccccc4)coc3c2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Step A (0.071 mmol, 1 eq) in 0.7 ml of DMF in a 16×100 mm tube treated with 3-phenyl-6-hydroxybenzofurane (0.078 mmol, 1.1 eq) Cesium Carbonate (0.213 mmol 3 eq) and NaI (0.071 mmol, 1 eq) and stirred at room temperature overnight. The reactants were filtered and washed with DMF several times. The solvent was evaporated under vacuo and the residue reconstituted in a mixture of Ethanol (2 ml) and NaOH (1M) (1 ml) and stirred at room temperature until reaction is completed by HPLC-MS. Then HCl (1M) was added (until pH=3) and the solvent were eliminated under vacuo. The residue was reconstituted in CH2Cl2/H2O and filtered through a hidrofobic syringer. The organic layer was separated, concentrated and purified by HPLC-MS to get the title compound. MS(ES) for C27H22O5 [M+H]+: 427.2.
Reaction SMILES: C([C:4]1[NH:5][C:6](C(OCC)=O)=[C:7]([CH3:16])[C:8]=1[CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])(O)=O>[OH-].[Na+]>[C:11]([CH2:10][CH2:9][C:8]1[C:7]([CH3:16])=[CH:6][NH:5][CH:4]=1)([OH:13])=[O:12]
Reactant: CCOC(=O)CCc1c(C(=O)O)[nH]c(C(=O)OCC)c1C
Agent: [Na+]
Agent: [OH-]
Product: Cc1c[nH]cc1CCC(=O)O
Temperature: 10 °C
Yield: 474.7 %

Procedure:
2-Carboxy-5-ethoxycarbonyl-3-(2-ethoxycarbonylethyl)-4-methylpyrrole (50.5 g) and 400 mL of 10% sodium hydroxide solution was heated to 180° C. in a Parr autoclave for 90 min. This process was repeated 4 more times on a total of 252.5 g of 2-carboxy-5-ethoxycarbonyl-3-(2-ethoxycarbonylethyl)-4-methylpyrrole. The five solutions were combined and rotary evaporated to a volume of about 1.8 L of thick black residue. The mixture was cooled to 10° C. in a water bath, and 50% sulfuric acid was slowly added until the pH was 2, keeping the temperature <20° C. Ethyl ether (1400 mL) was added and the mixture filtered, saving the precipitate. The precipitate was extracted in a Soxhlet apparatus with 500 mL of ether. The combined ether layers were washed with 250 mL, and then 150 mL, of water, and the water layers back extracted with 150 mL of ether. All the ether layers were rotary evaporated and the residue dried to give 123.5 g of 3-(2-carboxyethyl)-4-methylpyrrole.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]([C:13](=[CH:34][CH:35]=[CH:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]([CH3:45])[CH3:44])=[CH:39][CH:38]=1)[N:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:12]>C(#N)C>[CH:43]([C:40]1[CH:39]=[CH:38][C:37]([C:36]2[CH:35]=[CH:34][C:13]([C:11]([O:10][CH3:9])=[O:12])=[N:14][C:1]=2[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:42][CH:41]=1)([CH3:44])[CH3:45]
Reactant: COC(=O)C(=CC=Cc1ccc(C(C)C)cc1)N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1
Solvent: CC#N
Product: COC(=O)c1ccc(-c2ccc(C(C)C)cc2)c(-c2ccccc2)n1

Procedure:
Following General Procedure K, Benzaldehyde (0.48 g, 4.6 mmol) and 3-Methoxycarbonyl-1,1,1-triphenyl-6-(4-isopropylphenyl)-2-aza-1λ5-phosphahexa-1,3,5-triene (Compound 112, 2.3 g, 4.6 mmol) in dry acetonitrile (100 ml) were reacted to produce the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=3)[CH:9]=2)=[C:4]([O:24][CH3:25])[CH:3]=1>C1COCC1.CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=3)[CH:9]=2)=[C:4]([O:24][CH3:25])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1ccnc(Nc2cccc([N+](=O)[O-])c2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(F)ccc1-c1ccnc(Nc2cccc(N)c2)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of C2 (98 mg, 0.29 mmol) in THF/MeOH 1:1 (20 mL) was added Pd/C (10% w/w, 46 mg). The reaction mixture was stirred under hydrogen atmosphere (1 atm) at RT for 15 hours. The suspension was filtered through a pad of Celite® and the solvent was removed in vacuo to leave the desired product I1 as a brown solid (89 mg, 99%). MS (ES) C18H16FN3O requires: 309. found: 310 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]3([C:30]4[C:21](=[CH:22][C:23]5[O:28][CH2:27][CH2:26][O:25][C:24]=5[CH:29]=4)[O:20][CH2:19]3)[C:11]2=[O:31])=[CH:5][CH:4]=1.[I-].[Na+].Cl[Si](C)(C)C.S(=O)(O)[O-].[Na+]>O.C(#N)C.C(OCC)(=O)C>[O:2]=[C:3]1[NH:8][CH:7]=[C:6]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]3([C:30]4[C:21](=[CH:22][C:23]5[O:28][CH2:27][CH2:26][O:25][C:24]=5[CH:29]=4)[O:20][CH2:19]3)[C:11]2=[O:31])[CH:5]=[CH:4]1
Reactant: COc1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cn1
Agent: C[Si](C)(C)Cl
Agent: O=S([O-])O
Agent: [I-]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1N(Cc2ccc(=O)[nH]c2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.3 %

Procedure:
To a stirred mixture of 1′-[(6-methoxypyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.24 g, 0.58 mmol), sodium iodide (0.29 g, 1.9 mmol), and water (2 drops) in acetonitrile (5 mL) was added chlorotrimethylsilane (0.23 mL, 1.8 mmol). The reaction mixture was stirred at ambient temperature for 16 h. Further, sodium iodide (0.14 g, 0.95 mmol) and chlorotrimethylsilane (0.12 mL, 0.95 mmol) were added and the reaction mixture was stirred at ambient temperature for 24 h. Further, sodium iodide (0.29 g, 1.9 mmol) and chlorotrimethylsilane (0.23 mL, 1.8 mmol) were added and the reaction mixture was stirred at ambient temperature for 5 days. A solution of sodium bisulfite (0.51 g, 4.9 mmol) in water (30 mL) and ethyl acetate (150 mL) were added. The layers were separated and the organic layer was washed with brine (2×50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with diethyl ether and the crude product was purified by preparative thin layer chromatography and eluted with 30% acetone in dichloromethane to afford 1′-[(6-oxo-1,6-dihydropyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.15 g, 63%) as a colorless solid: mp 249-250° C.; 1H NMR (300 MHz, CDCl3) δ7.61-7.46 (m, 2H), 7.31-7.21 (m, 1H), 7.20-7.14 (m, 1H), 7.09-7.02 (m, 1H), 6.86-6.81 (m, 1H), 6.66-6.59 (m, 1H), 6.50 (s, 1H), 6.15 (s, 1H), 4.92-4.60 (m, 4H), 4.24-4.06 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.7, 164.4, 155.2, 144.7, 142.2, 141.4, 138.3, 133.5, 132.2, 129.0, 124.2, 123.8, 120.9, 120.7, 115.8, 111.4, 108.7, 99.5, 80.0, 64.5, 63.9, 58.0, 40.6; MS (ES+) m/z 403.0 (M+1).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>C(O)C.[Pd]>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Yield: 63.3 %

Procedure:
A mixture of 1-acetyl-4-(4-nitrophenyl)piperazine (1.8 g, 7.2 mmol) (from Step A above) and 10% palladium-on-charcoal in ethanol (50 mL) was hydrogenated at room temperature and atmospheric pressure overnight. The catalyst was filtered off and the filter cake washed thoroughly with ethanol. The mixture was evaporated under reduced pressure to give 1-acetyl-4-(4-amino-phenyl)piperazine (1.0 g, 63%) as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([CH3:15])[C:9]=2[CH3:16])=[O:5])[CH3:2].[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([CH3:29])OS1(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:27]([CH3:29])[CH2:28][NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([CH3:15])[C:9]=2[CH3:16])=[O:5])[CH3:2]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1cc2ccc(C)c(C)c2[nH]1
Product: CCOC(=O)c1cc2ccc(C)c(C)c2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound, ISP-MS: m/e=375.4 (M+H+), was prepared in accordance with the general method of example 12b) from 6,7-dimethyl-1H-indole-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[O:17]=[C:18]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[CH2:19][NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)=[O:22].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:63][C:64]1[CH:68]=[CH:67][S:66][C:65]=1[C:69](O)=[O:70]>CN(C=O)C.O>[CH3:63][C:64]1[CH:68]=[CH:67][S:66][C:65]=1[C:69]([N:38]1[CH2:39][CH2:40][N:35]([C:18](=[O:17])[CH2:19][NH:20][C:21]([C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)=[O:22])[CH2:36][CH2:37]1)=[O:70]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: Cc1ccsc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccsc1C(=O)N1CCN(C(=O)CNC(=O)c2ccc(-c3ccccc3)cc2)CC1
Reaction time: 8 h
Yield: 72.9 %

Procedure:
DIPEA (110.8 mg, 0.147 mL, 0.85 mmol) was added to a stirred solution of biphenyl-4-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide TFA salt (100 mg, 0.22 mmol) in DMF (3 mL). HOBT (28.3 mg, 0.2 mmol) and EDCI.HCl (91.25 mg, 0.47 mmol) were then added. After 2 minutes 3-methyl-thiophene-2-carboxylic acid (27 mg, 0.19 mmol) was added and the resulting mixture was stirred overnight. The reaction mixture was diluted with cold water. The product was extracted with ethyl acetate and the ethyl acetate layer was washed with NaHCO3 solution, saturated brine solution, dried over sodium sulphate and concentrated under reduced pressure to afford 62 mg (72.9% yield) of biphenyl-4-carboxylicacid {2-[4-(3-methyl-thiophene-2-carbonyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LC-MS purity: 90.22%, HPLC Purity: 92.38%, 1H NMR: (CDCl3) δ 7.9 (d, 2H), 7.75-7.6 (m, 4H), 7.5 (m, 2H), 7.4 (m, 1H), 7.3-7.4 (m, 2H), 6.9 (d, 1H), 4.3 (d, 2H), 3.7 (m, 6H), 3.5 (m, 2H), 2.4 (s, 3H).