Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]=2[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH:21][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][C:26]([O:25][CH3:24])=[CH:27][CH:28]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]=2[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1oc2c(C)c(C)c(N)c(C)c2c1-c1ccc(C(C)C)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)Nc2c(C)c(C)c3oc(C)c(-c4ccc(C(C)C)cc4)c3c2C)cc1
Yield: 49 %

Procedure:
By using 3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-amine and 4-methoxybenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 49%. Amorphous.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([C:12](=[C:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11].Cl>C(OCC)C>[CH2:1]([C:18]1([CH:12]([C:10]#[N:11])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CCOC(=O)C(C#N)=C1CCCCC1
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)C(C#N)C1(Cc2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1 M Benzylmagnesium chloride in diethyl ether (18.92 ml) was added dropwise to ethyl 2-cyano-2-cyclohexylideneacetate (1.828 g, 9.46 mmol) in diethyl ether (6.31 ml) at 23° C. The mixture was stirred at room temperature for 3 days. Then 10% hydrochloric acid (7.83 ml, 255 mmol) was added dropwise at 0° C. while stirring. The organic layer was separated, washed with water, dried over Na2SO4, filtered, and concentrated.
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([C:23]1[CH:32]=[C:29]([O:30][CH3:31])[CH:28]=[C:25]([O:26][CH3:27])[CH:24]=1)([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14](O)=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:33][C@H:34]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:35]([CH3:37])[CH3:36].CC1C=CC(S(O)(=O)=O)=CC=1>>[NH:1]([C:17]([O:19][C:20]([C:23]1[CH:24]=[C:25]([O:26][CH3:27])[CH:28]=[C:29]([O:30][CH3:31])[CH:32]=1)([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([NH:33][C@H:34]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH:35]([CH3:37])[CH3:36])=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Reactant: COc1cc(OC)cc(C(C)(C)OC(=O)N[C@@H](CC(=O)OCc2ccccc2)C(=O)O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COc1cc(OC)cc(C(C)(C)OC(=O)N[C@@H](CC(=O)OCc2ccccc2)C(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C)c1

Procedure:
The peptide coupling is carried out by the PPA method as described for (a). Batch: 13.4 g (30 mmol) of Ddz-Asp(OBzl)-OH and 10.36 g (30 mmol) of H-Val-OBut.TsOH.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[CH3:28])[CH2:9]/[C:10](/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:42]=[CH:41][C:40]([S:43]([NH2:46])(=[O:45])=[O:44])=[CH:39][CH:38]=2)O1>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([C:37]3[CH:42]=[CH:41][C:40]([S:43]([NH2:46])(=[O:45])=[O:44])=[CH:39][CH:38]=3)=[CH:7][CH:6]=2)[CH2:9]/[C:10](=[N:11]\[OH:12])/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[C:22]([CH3:28])[CH:23]=1
Reactant: Cc1cc(F)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Product: Cc1cc(F)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
The title compound was prepared in analogy to example 166, from (+)-5-{3-(4-bromo-phenyl)-3-(4-fluoro-2-methyl-phenyl)-1-[(E)-hydroxyimino]-propyl}-1-methyl-1H-pyridin-2-one (example 405) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (CAS RN 214360-51-7). The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of dichloromethane:methanol (100:0 to 90:10). Light brown solid. MS (ESI+): m/z=520.2 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:12]=[C:13]([OH:19])[C:14]([OH:18])=[CH:15][C:16]=2[CH3:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:27](Br)[C:28]([OH:30])=[O:29]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]3[O:18][CH:27]([C:28]([OH:30])=[O:29])[O:19][C:13]=3[CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)C(Br)Br
Reactant: Cc1cc(O)c(O)cc1S(=O)(=O)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1S(=O)(=O)c1ccc(Br)cc1)OC(C(=O)O)O2

Procedure:
In a manner analogous to that described in Example 15, 60.0 g of 4-(4-bromophenylsulphonyl)-5-methyl-1,2-benzenediol are reacted in the presence of 120 g of potassium carbonate in 300 ml of dimethylformamide with a solution of 76.2 g of dibromoacetic acid in 100 ml of dimethylformamide. After working up and chromatographic purification in a manner analogous to that described in Example 15 and crystallisation from 1,2-dichloroethane, 5-(4-bromophenylsulphonyl)-6-methyl-1,3-benzodioxole-2-carboxylic acid is obtained in the form of sand-coloured crystals having a melting point of 170°-172.5°.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[N:31]=[C:30]([CH3:32])[C:29]([C:33]([OH:35])=O)=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C.[CH3:45][C:46]1[CH:47]=[C:48]([CH:51]=[CH:52][C:53]=1[S:54]([N:57]1[CH2:62][CH2:61][NH:60][C@@H:59]([CH3:63])[CH2:58]1)(=[O:56])=[O:55])[C:49]#[N:50]>CN(C=O)C>[Cl:25][C:26]1[N:31]=[C:30]([CH3:32])[C:29]([C:33]([N:60]2[CH2:61][CH2:62][N:57]([S:54]([C:53]3[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][C:46]=3[CH3:45])(=[O:56])=[O:55])[CH2:58][C@@H:59]2[CH3:63])=[O:35])=[CH:28][CH:27]=1
Reactant: Cc1nc(Cl)ccc1C(=O)O
Reactant: Cc1cc(C#N)ccc1S(=O)(=O)N1CCN[C@@H](C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C#N)ccc1S(=O)(=O)N1CCN(C(=O)c2ccc(Cl)nc2C)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
HATU (425 mg, 1.12 mmol) was added to a solution of 6-chloro-2-methyl-3-pyridinecarboxylic acid (commercially available, e.g. from Anichem, or may be prepared according to known methods) (160 mg, 0.93 mmol) in DMF (3 ml) and the mixture was treated with DIPEA (0.407 ml, 2.33 mmol). This mixture was stirred for ca. 10 min at ambient temperature. 3-Methyl-4-{[(3S)-3-methyl-1-piperazinyl]sulfonyl}benzonitrile (may be prepared as described in Description 11) (313 mg, 1.12 mmol) was added as a solution in DMF (2 ml) and stirring was continued for ca. 1 hour. The reaction mixture was partitioned between DCM and sat aq. NaHCO3 solution (20 ml each). The layers were separated and the aqueous was washed with further DCM (2×20 ml). The combined organic layers were dried (hydrophobic frit) and concentrated to leave a dark brown gum. Purification by silica chromatography (Biotage SP4, 25S cartridge), eluting with 12-100% ethyl acetate in isohexane, gave the title compound as a pale cream foam (376 mg).
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].[CH:6]1([Na])[CH:10]=[CH:9][CH:8]=[CH:7]1>O1CCCC1>[CH3:1][Si:2]([C:7]1[CH2:6][CH:10]=[CH:9][CH:8]=1)([CH3:4])[CH3:3]
Reactant: [Na]C1C=CC=C1
Reactant: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: C[Si](C)(C)C1=CC=CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
11 g of trimethylsilyl chloride was dissolved in 30 mol of well dried tetrahydrofuran in a 300 ml flask whose inside had been substituted by nitrogen, and the obtained solution was cooled to −78° C. 100 ml of a tetrahydrofuran solution (2.0 mol/l) of cyclopentadienyl sodium was added dropwise to the above solution in a stream of nitrogen over 1 hour. The solution was stirred at −78° C. for 1 hour and returned to room temperature over 6 hours. A salt precipitated in the mixture solution was removed by filtration in a nitrogen atmosphere, and the residual solution was distilled to obtain 8 g of trimethylsilyl cyclopentadiene.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:18]=[C:17]([N:19]=[N:20][C:21]2[CH:26]=[C:25]([CH3:27])[C:24]([S:28](O)(=[O:30])=[O:29])=[C:23]([CH3:32])[CH:22]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:10]=1[OH:38])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(#N)C.P(Cl)(Cl)([Cl:44])=O>CN(C)C(=O)C>[C:1]([NH:5][S:6]([C:9]1[CH:18]=[C:17]([N:19]=[N:20][C:21]2[CH:26]=[C:25]([CH3:27])[C:24]([S:28]([Cl:44])(=[O:30])=[O:29])=[C:23]([CH3:32])[CH:22]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:10]=1[OH:38])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(N=Nc2cc(S(=O)(=O)NC(C)(C)C)c(O)c3cccc(NS(C)(=O)=O)c23)cc(C)c1S(=O)(=O)O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: Cc1cc(N=Nc2cc(S(=O)(=O)NC(C)(C)C)c(O)c3cccc(NS(C)(=O)=O)c23)cc(C)c1S(=O)(=O)Cl
Temperature: 0 °C

Procedure:
To a solution containing 30 g of the naphthol compound obtained in Step (1) above, 250 ml to acetonitrile and 45 ml of phosphorus oxychloride, 15 ml of N,N-dimethylacetamide was added dropwise at a temperature below 60° C. with stirring. The mixture was stirred at 60° C. for 3 hours and poured into 1 l of ice water. The cyrstals thus-precipitated were collected by filtration and washed with 100 ml of acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][S:13](O)(=[O:15])=[O:14]>>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([N+:9]([O-:11])=[O:10])=[CH:4][C:5]=1[S:13]([Cl:12])(=[O:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: O=S(=O)(O)Cl
Product: O=[N+]([O-])c1cc(S(=O)(=O)Cl)c(Cl)cc1Cl
Temperature: 130 °C
Reaction time: 26 h
Yield: 59.6 %

Procedure:
2,4-Dichloronitrobenzene (10 g, 52 mmol) was added ClSO3H (8 ml, 120 mmol) dropwise under ice-water bath. The mixture was stirred at 130° C. for 26 h. The mixture was cooled to rt and poured onto ice-water. The resulting precipitates were collected by filtration and dried under reduced pressure to give 9 g (60%) of the title compound as brown solids.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19]C)[CH:13]=[C:12]([O:21]C)[C:11]=2[C@@H:23]1[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]1[CH2:29][OH:30].Cl.N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([OH:19])[CH:13]=[C:12]([OH:21])[C:11]=2[C@@H:23]1[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]1[CH2:29][OH:30]
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccccc3Br)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4ccccc4Br)oc23)[C@@H]1CO
Temperature: 180 °C

Procedure:
A mixture of compound of example 16 (0.36 g, 0.76 mmol) and dry pyridine hydrochloride (3.6 g, 31.6 mmol) was heated at 180° C. for 1.5 h. The reaction mixture was cooled to room temperature, treated with water (50 mL) and basified using an aqueous saturated Na2CO3 solution. It was extracted using CHCl3 (3×100 mL). The organic extract was washed with water, dried (anhydrous Na2SO4) and concentrated. Traces of pyridine were removed using high vacuum. Purification was carried out using a silica gel column and a mixture of 5% methanol+1% liquor ammonia in CHCl3 as eluant to obtain title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)C.[Si:10]([O:17][C@@H:18]([CH3:51])[CH2:19][CH2:20][CH2:21][C:22](=[O:50])/[CH:23]=[CH:24]/[C@H:25]1[C@H:29]([O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH2:28][C@@H:27]([Cl:37])[C@@H:26]1[CH2:38][CH2:39][CH2:40][C:41]1[S:45][C:44]([C:46]([O:48][CH3:49])=[O:47])=[CH:43][CH:42]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>C1COCC1>[Si:10]([O:17][C@@H:18]([CH3:51])[CH2:19][CH2:20][CH2:21][C@H:22]([OH:50])/[CH:23]=[CH:24]/[C@H:25]1[C@H:29]([O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH2:28][C@@H:27]([Cl:37])[C@@H:26]1[CH2:38][CH2:39][CH2:40][C:41]1[S:45][C:44]([C:46]([O:48][CH3:49])=[O:47])=[CH:43][CH:42]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: COC(=O)c1ccc(CCC[C@@H]2[C@@H](/C=C/C(=O)CCC[C@H](C)O[Si](C)(C)C(C)(C)C)[C@H](OC3CCCCO3)C[C@H]2Cl)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)c1ccc(CCC[C@@H]2[C@@H](/C=C/[C@@H](O)CCC[C@H](C)O[Si](C)(C)C(C)(C)C)[C@H](OC3CCCCO3)C[C@H]2Cl)s1
Temperature: -85 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
Lithium aluminum hydride (7.5 mL of a 1.0M solution in THF, 7.5 mmol) was added to an oven-dried 200 mL flask. A freshly prepared solution of absolute ethanol (11.9 mL of a 1.0M solution in THF, 7.50 mmol) was added dropwise at 23° C. After 15 min a solution of (S)-(−)-1,1′-binaphthol (2.18 g, 7.62 mmol) in THF (10 mL) was added dropwise. The milky-white solution was cooled to −85° C. and a solution of the enone 14 (1.60 g, 2.50 mmol) in THF (9 mL) was added over a 5-10 min period. The reaction solution was stirred for 1 h and then warmed to −78° C. and allowed to stir an additional 3 h. The reaction was then quenched by careful addition of MeOH (3.1 mL). The reaction was then allowed to warm to room temperature and was extracted with EtOAc (2×). The combined organic portions were washed with 1N HCl, saturated aqueous NaHCO3, and brine. The organic portion was then dried over anhydrous MgSO4), filtered and concentrated in vacuo. FCC (silica gel, 6:1 hex/EtOAc) afforded 1.20 g (75%) of (S)-alcohol 15.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1Cl.C(=O)([O-])[O-].[K+].[K+].[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:23][CH2:22]1>C(#N)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:23][CH2:22]1
Reactant: COc1ccccc1N1CCN(CCCCN)CC1
Reactant: Clc1cc(Cl)c(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccccc1N1CCN(CCCCNc2cc(Cl)nnc2Cl)CC1
Yield: 54.2 %

Procedure:
9.25 g (0.050 mol) of 3,4,6-trichloropyridazine are stirred with 6.90 g (0.050 mol) of powdered anhydrous potassium carbonate and 13.15 g (0.050 mol) of 1-(4-aminobutyl)-4-(2-methoxyphenyl)piperazine in 1350 ml of dry acetonitrile at room temperature for 96 hours. The mixture is subsequently filtered with suction, and the filtrate is concentrated in vacuo. The residue is taken up in ethanol, and the trihydrochloride of 3,6-dichloro-4-((4-(4-(2-methoxyphenyl)-1-piperazinyl)butyl)amino)pyridazine of m.p.: 155°-170° C. is precipitated with ethereal HCl; yield: 54.2% of theory.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)=[CH:7][C:6]=1[CH3:27].[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C)C=O>[CH3:27][C:6]1[CH:7]=[C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[CH2:4][CH2:3][CH2:2][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C1CCNC1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(CCCBr)c(C)c3)nc2c1
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(CCCN4CCCC4)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(3-bromo-propyl)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.40 g, 0.92 mmol) in N,N-dimethylformamide (10 mL) was added pyrrolidine (0.39 g, 5.52 mmol) and the reaction mixture was stirred at room temperature for 16 hours. DMF was removed under reduced pressure, the residue was purified by column chromatography (silica gel 230-400 mesh; 5% methanol ammonia in dichloromethane as eluent) to give the title compound as a white solid. Yield: 0.27 g (69%). MP 194-196° C. 1H NMR (400 MHz, DMSO-d6): δ 11.79 (br s, 1H), 7.81 (s, 2H), 6.72 (d, J=2.3 Hz, 1H), 6.50 (d, J=2.3 Hz, 1H), 4.00 (s, 3H), 3.87 (s, 3H), 2.67-2.63 (m, 2H), 2.49-2.46 (m, 6H), 2.33 (s, 6H), 1.70-1.67 (m, 4H), 1.59-1.53 (m, 2H). MS (ES+) m/z: 422.17 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([C:20]([OH:22])=O)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:23])=[CH:4][N:3]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][C:25]1=[O:30]>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([N:27]3[CH2:28][CH2:29][NH:24][C:25](=[O:30])[CH2:26]3)=[O:22])=[CH:10][C:9]=2[F:23])=[N:6][CH:7]=1
Reactant: Nc1cnc(-c2ccc(-c3ccccc3C(=O)O)cc2F)cn1
Reactant: O=C1CNCCN1
Product: Nc1cnc(-c2ccc(-c3ccccc3C(=O)N3CCNC(=O)C3)cc2F)cn1

Procedure:
The title compound was prepared using methods analogous to those described in Step C of Example 504 using 4′-(2-aminopyrazin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid and piperazin-2-one. MS (ESI): mass calcd. for C21H18FN5O2, 391.14; m/z found, 392.1 [M+H]+. 1H NMR (400 MHz, CDCl3) Complex due to the presence of multiple conformations on the NMR time-scale, peaks listed for identification purposes only: δ 8.58-8.55 (m), 8.50-8.40 (m), 8.10 (d, J=1.5), 8.04-7.98 (m), 7.56-7.41 (m), 7.37-7.27 (m), 6.75 (s), 6.43 (s), 5.06 (s), 4.83 (s), 4.45 (d, J=19.2), 4.05-3.95 (m), 3.72-3.46 (m), 3.27 (s), 3.14 (s), 2.97 (s), 2.67 (s).
Reaction SMILES: [CH3:1]/[C:2](=[CH:6]\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)/[C:3]([OH:5])=O.C(Cl)(=O)C(Cl)=O.[N:19]([CH2:22][CH2:23][NH2:24])=[N+:20]=[N-:21].C(N(CC)CC)C>ClCCl>[N:19]([CH2:22][CH2:23][NH:24][C:3](=[O:5])/[C:2](/[CH3:1])=[CH:6]/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+:20]=[N-:21]
Reactant: C/C(=C\c1ccccc1)C(=O)O
Reactant: [N-]=[N+]=NCCN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C/C(=C\c1ccccc1)C(=O)NCCN=[N+]=[N-]
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a 25 mL round-bottomed flask equipped with a magnetic stir bar was added (E)-2-methyl-3-phenylacrylic acid (0.0.512 g, 3.15 mmol) and dichloromethane (10 mL). Oxalyl chloride (0.400 g, 3.15 mmol) was added dropwise to the reaction mixture and allowed to stir for one hour. Then, the reaction mixture was concentrated de vacuo. To the crude mixture was then added dichloromethane (10 mL), 2-azidoethanamine (0.299 g, 3.47 mmol) and then triethylamine (0.351 g, 3.47 mmol) and allowed to stir for two hours. The reaction mixture was then concentrated de vacuo and then purified via silica gel column chromatography (100% dichloromethane to 1:40 methanol:dichloromethane) to give (E)-N-(2-azidoethyl)-2-methyl-3-phenylacrylamide (0.698 g, 96% yield). 1H NMR (300 MHz, CDCl3) δ 7.39 (m, 6H), δ 7.01 (s, 1H), δ 3.51 (t, 2H), δ 3.45 (t, 2H), δ 2.13 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 170.5, 136.2, 134.5, 132.0, 130.3, 129.6, 128.9, 128.6, 128.3, 50.9, 39.8, 14.5 ppm; HRMS (ESI) calcd for C12H14N4O (M+) 230.1168, found 230.1165.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=O)=[CH:4][CH:3]=1.[C:14]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C>O=S(Cl)Cl>[C:14]([C:18]1[CH:19]=[CH:20][C:21]([NH:22][C:6]([C:5]2[CH:4]=[CH:3][C:2]([C:1]([O:12][CH3:13])=[O:11])=[CH:10][CH:9]=2)=[O:8])=[CH:23][CH:24]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C(=O)Nc2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
mono-Methyl terephthalate (1.02 g, 5.67 mmol) was refluxed in SOCl2 (10 mL) for 1 hour, allowed to cool to room temperature, and concentrated under reduced pressure. The residue was taken up in tetrahydrofuran (30 mL) and treated with 4-tert-butylaniline (0.9 mL, 5.65 mmol) and DIEA (5 mL, 28.8 mmol) at room temperature. After stirring overnight, the mixture was concentrated under reduced pressure and the residue was taken up in ethyl acetate. The ethyl acetate was washed with H2O and brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with 3:2 hexanes:ethyl acetate and the solid air-dried to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.08 (m, 4H), 7.69 (m, 2H), 7.39 (m, 2H), 3.90 (s, 3H), 1.29 (s, 9H); MS (ESI+) m/z 312 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH:19][O:20][CH3:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>ClCCl>[CH3:21][O:20][N:19]([CH3:18])[C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CNOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 30 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)piperidin-4-carboxylic acid (5.0 g, 21.8 mmol) in dichloromethane (80 mL) were added N,O-dimethylhydroxylamine hydrochloride (2.55 g, 26.1 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (9.95 g, 26.1 mmol), N-ethyl-N-isopropylpropan-2-amine (8.46 g, 65.42 mmol) and stirred at 30° C. for 16 hours. The reaction was quenched by adding water (100 ml) and extracted with ethyl acetate (200 ml*3). The combined organic layers was washed with brine, dried over sodium sulfate and concentrated under vacuum to give tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (5.7 g, yield 97.6%). LRMS (M+H+) m/z: calcd 272.17. found 273.17.