Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34]N1C(=O)CCC1=O>C(Cl)Cl>[Br:34][CH2:13][CH2:12][CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCc1ccc2ccccc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCc1ccc2ccccc2c1
Reaction time: 21 h
Yield: 85.5 %

Procedure:
Compound 59-1 (4.33 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (6.69 g) and N-bromosuccinimide (4.54 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and further at room temperature for 21 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography to give the object product (4.95 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:22])[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][C:15]=2[Cl:21])[C:6]=1/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1B(O)O.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>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.O>[Cl:1][C:2]1[N:3]=[C:4]([CH3:22])[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:24]3[O:23][CH:27]=[CH:26][CH:25]=3)=[CH:16][C:15]=2[Cl:21])[C:6]=1/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10]
Reactant: OB(O)c1ccco1
Reactant: COC(=O)/C=C/c1c(Cl)nc(C)n1Cc1ccc(I)cc1Cl
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: O
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1c(Cl)nc(C)n1Cc1ccc(-c2ccco2)cc1Cl
Temperature: 80 °C
Reaction time: 4 h
Yield: 110.7 %

Procedure:
A mixture of tetrakis(triphenylphosphine)palladium(0) (89 mg), methyl (E)-3-(4-chloro-1-(2-chloro-4-iodobenzyl)-2-methylimidazol-5-yl)-2-propenate (350 mg), 2-furylboronic acid (135 mg), potassium carbonate powder (321 mg) and N,N-dimethylformamide (3.5 ml) was stirred under a nitrogen atmosphere at 80° C. for 4 hr. The reaction mixture was allowed to cool to room temperature and water was added. The precipitate was collected by filtration. The precipitate was dissolved in chloroform, washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (chloroform/ethyl acetate=10/1) to give methyl (E)-3-(4-chloro-1-(2-chloro-4-(2-furyl)benzyl)-2-methylimidazol-5-yl)-2-propenate (336 mg) as a pale-yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH:10]=[C:9](OC)[C:8](=[O:15])[NH:7][C:6]=2[CH:16]=1.[CH2:17]([NH2:25])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH:10]=[C:9]([NH:25][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8](=[O:15])[NH:7][C:6]=2[CH:16]=1
Reactant: NCCc1ccccc1
Reactant: COc1cc(=O)c2ccc(Cl)cc2[nH]c1=O
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)cc1NCCc1ccccc1
Temperature: 80 °C

Procedure:
8-Chloro-3-methoxy-2,5-dioxo-2,5-dihydro1H-benz[b]azepine (0.5 g) was treated with 5 mL of phenethylamine, and the mixture was heated to 80° C. for 1 hour. The reaction mixture was filtered and the solid recrystallized from 5 mL hot dimethylformamide and water. The solid was filtered, washed (water) and vacuum dried (100° C., 15 Pa) to give the title compound (0.329 g); mp 284.4-286.9° C.; NMR: 5.89 (s,1): MS: m/z=327(M+1). Analysis for C18H15ClN2O2 ·0.2 H2O: Calculated: C, 65.44; H, 4.70; N, 8.48; Found: C, 65.42; H, 4.72; N, 8.62.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([CH2:33][N:34]5[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]5)[CH:27]=4)[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17]2)[CH:5]=[C:6]([F:15])[C:7]=1[CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[N+](C1C=C[C:46]([O:49]C=O)=CC=1)([O-])=O.C(N(CC)CC)C>C1COCC1>[F:15][C:6]1[CH:5]=[C:4]([N:16]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([CH:27]=4)[CH2:33][N:34]4[CH2:39][CH2:38][N:37]([CH:46]=[O:49])[CH2:36][CH2:35]4)[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17]2)[CH:3]=[C:2]([F:1])[C:7]=1[CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: O=COc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(Nc2ncc3ccn(-c4cc(F)c(CN5CCOCC5)c(F)c4)c3n2)cc1CN1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(Nc2ncc3ccn(-c4cc(F)c(CN5CCOCC5)c(F)c4)c3n2)cc1CN1CCN(C=O)CC1

Procedure:
The compound is obtained by treating [7-(3,5-difluoro-4-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-(4-methyl-3-piperazin-1-ylmethyl-phenyl)-amine (Example 332) with formic acid 4-nitro-phenyl ester in presence of triethylamine in THF. HPLC: tR=6.84 min (Method B); MS-ES: (M+H)+=562
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[C:30]([NH:34][S:35]([CH2:38]Cl)(=[O:37])=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([NH:34][S:35]([CH2:38][N:19]1[C:18](=[O:23])/[C:17](=[CH:16]/[C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[N:7]([CH2:6][C:5]2[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=2[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]3)/[S:21][C:20]1=[O:22])(=[O:37])=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)NS(=O)(=O)CCl
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CC(C)(C)NS(=O)(=O)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
N-tert-Butyl-1-[(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methanesulfonamide was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and N-tert-butyl-1-chloromethanesulfonamide following General Procedure H.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4](OS(C)(=O)=O)[C:5]1[S:6][C:7]([CH3:10])=[CH:8][CH:9]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)C(C)C)C>CC#N>[CH3:1][O:2][C:3](=[O:16])[CH:4]([C:5]1[S:6][C:7]([CH3:10])=[CH:8][CH:9]=1)[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)C(OS(C)(=O)=O)c1ccc(C)s1
Reactant: Nc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(Nc1ccccc1)c1ccc(C)s1
Yield: 24.1 %

Procedure:
A solution of methanesulfonyloxy-(5-methyl-thiophen-2-yl)-acetic acid methyl ester (I266) (2.10 g, 7.94 mmol), aniline (1.09 mL, 11.9 mmol) and N-ethyl-N-isopropylpropan-2-amine (2.04 mL, 11.9 mmol) in MeCN (10 mL) is heated under microwave irradiation at 100° C. for 1 hour. The solvent is removed, DCM is added and the organic phase is washed with water and brine, dried over Na2SO4 and evaporated. The resulting brown oil is purified by silica gel flash chromatography (Hexane/EtOAc=9575 to 90/10) to obtain intermediate I269 as a yellow oil (500 mg, 24% yield).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([O:30]CC)=O)[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+:44]>>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:36][C@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([NH2:44])=[O:30])[C:24]=2[CH:33]=1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Agent: [Cl-]
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc3c(C(N)=O)noc3c2F)C[C@H](C)O1

Procedure:
Starting materials: Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and ammonium chloride.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]2=[N:6][C:7]=1[Cl:8].Cl.[F:14][C:15]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:8][C:7]1[N:6]=[C:5]2[CH:9]=[N:10][CH:11]=[CH:12][C:4]2=[N:3][C:2]=1[N:21]1[CH2:20][CH2:19][CH:18]([O:17][C:16]2[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:15]=2[F:14])[CH2:23][CH2:22]1
Reactant: Fc1ccc(OC2CCNCC2)c(F)c1
Reactant: Clc1nc2ccncc2nc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(OC2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
A solution of 2,3-dichloropyrido[3,4-b]pyrazine (492 mg, 2.460 mmol) in DCM (5 mL) at 0° C. was treated with 4-(2,4-difluorophenoxyl)piperidine hydrochloride (676 mg, 2.71 mmol) and DIPEA (1.29 mL, 7.38 mmol). The reaction mixture was allowed to stir overnight, gradually warming to room temperature. The reaction mixture was quenched with the addition of saturated aqueous NH4Cl and was extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography using a gradient of 20% to 60% EtOAc in heptanes to give the title compound as a pale yellow solid (736.2 mg, 79%). ESI-MS m/z [M+H]+ 377.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:15]([OH:17])=O)[N:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1.[CH3:18][O:19][CH2:20][CH2:21][N:22]([CH3:30])[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][N:24]=1>>[CH3:18][O:19][CH2:20][CH2:21][N:22]([CH3:30])[C:23]1[N:24]=[CH:25][C:26]([NH:29][C:15]([C:11]2[N:12]([CH3:14])[N:13]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH:10]=2)=[O:17])=[CH:27][CH:28]=1
Reactant: COCCN(C)c1ccc(N)cn1
Reactant: COc1ccc(-c2cc(C(=O)O)n(C)n2)cc1
Product: COCCN(C)c1ccc(NC(=O)c2cc(-c3ccc(OC)cc3)nn2C)cn1

Procedure:
With a procedure similar to example 16 above, 5-(4-methoxy-phenyl)-2-methyl-2H-pyrazole-3-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 5-(4-methoxy-phenyl)-2-methyl-2H-pyrazole-3-carboxylic acid (made by hydrolysis of the corresponding commercially available ethyl ester) and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C21H25N5O3 (m/e) 395, obsd 396 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH:3]=[C:2]1[C:12]([OH:14])=[O:13].[H][H]>CO.O.[Pd]>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:12]([OH:14])=[O:13]
Reactant: O=C(O)c1cc(=O)c2ccccc2o1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CO
Product: O=C(O)C1CCc2ccccc2O1
Reaction time: 2 h
Yield: 89.3 %

Procedure:
To a suspension of commercially available chromone-2-carboxylic acid (50 g, 281 mmol) in methanol (500 mL), slurry of (10% Pd/C wet, 5 g) in water (10 mL) was added under nitrogen atmosphere. The mixture was hydrogenated at 60 psi at room temperature (RT) and further maintained hydrogen reservoir up to 60 psi for 2 h. The progress of reaction was monitored by TLC. Reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to yield chromane-2-carboxylic acid as off-white solid (44.7 g, 95%). m/z-178.02.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].II>CN(C=O)C>[OH:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)=[CH:18][CH:17]=1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: O=Cc1ccc(O)cc1
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(O)cc3)nc2c1
Temperature: 70 °C
Yield: 12 %

Procedure:
2-Amino-4,6-dimethoxy-benzamide (328 mg, 1.67 mmol), 4-hydroxybenzaldehyde (204 mg, 1.67 mmol), K2CO3 (231 mg, 1.67 mmol) and I2 (508 mg, 2.0 mmol) were mixed in DMF (10 mL) and the reaction mixture was heated at 70° C. for 5 h. It was cooled to room temperature and poured into crushed ice. The solid was collected and purified by column chromatography (silica gel 230-400 mesh; 5% methanol in CH2Cl2 as eluent) to give 2-(4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (60 mg, 12%), as an off-white solid. Selected data: MS (m/z): 299.05; MP 303-305° C.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][C@H:12]1[C:25]([N:27]1[CH2:31][CH2:30][S:29][CH2:28]1)=[O:26])C1C=CC=CC=1.Br.CCOCC>C(O)(=O)C>[NH2:10][C@H:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][C@H:12]1[C:25]([N:27]1[CH2:31][CH2:30][S:29][CH2:28]1)=[O:26]
Reactant: O=C(N[C@H]1CCN(CCc2ccccc2)C[C@H]1C(=O)N1CCSC1)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: N[C@H]1CCN(CCc2ccccc2)C[C@H]1C(=O)N1CCSC1
Temperature: -10 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
(3R,4S)-[1-Phenethyl-3-(thiazolidine-3-carbonyl)-piperidine-4-yl]-carbamic acid benzyl ester (216 mg) was treated with 33% HBr in acetic acid (2.5 ml) for 2 hours at RT under argon. Ether (15 ml) was added and the resulting suspension was cooled to −10° C. and stirred for 1 hour. The solvent was then decanted and the solid washed with a small amount of EtOH. The residue was then dissolved in water (pH was adjusted to 10 with conc. NH4OH) and the aqueous layer was saturated with NaCl and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried (Na2SO4) and evaporated to give a residue that was purified by flash chromatography (gradient of MeOH in DCM containing 0.5% NH4OH) to furnish the desired product as a light yellow oil (92 mg). MS (ESI): 320.1 MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH:11]([CH3:15])[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[C:17](Cl)(=[O:28])[O:18][CH2:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:17]([O:18][CH2:19][C:20]2[CH:21]=[C:22]([Cl:27])[CH:23]=[C:24]([Cl:26])[CH:25]=2)=[O:28])[CH:11]([CH3:15])[CH2:10]1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Reactant: CC1CC(CNC(=O)OC(C)(C)C)CCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1CC(CNC(=O)OC(C)(C)C)CCN1C(=O)OCc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture comprising tert-butyl((2-methylpiperidin-4-yl)methyl)carbamate (step 2) (1.15 g, 5.04 mmol) and 3,5-dichlorobenzyl carbonochloridate (1.327 g, 5.54 mmol) in DCM (15 ml) was treated with aq. saturated sodium bicarbonate (0.504 ml, 5.04 mmol) and stirred at room temperature for 18 hours. The organic portion was separated and the aqueous phase extracted with DCM (2×10 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. Further purification by chromatography on silica, eluting in 0-20% 2M ammonia in MeOH in DCM afforded the title compound;
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=O)[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>C1(C)C=CC=CC=1.O>[C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[S:30])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Solvent: O
Solvent: Cc1ccccc1
Product: S=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Temperature: 25 °C
Yield: 68.7 %

Procedure:
Compound 12 (48.6 mg, 0.18 mmol) in toluene (2 mL) was treated with Lawesson's reagent (75 mg, 0.18 mmol) at room temperature. The solution was heated at reflux for 2 h, then allowed to cool to room temperature and diluted with water. The mixture was extracted with EtOAc (3×5 mL). The organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated. The crude product was crystallized (CH2Cl2/hexanes) to give the thioamide 34.4 mg (68%) as a yellow solid. mp 223-226° C. (dec.); 1H NMR (300 MHz, d6-DMSO) δ 3.10 (m, 2H), 3.50 (m, 2H), 7.23 (app t, 1H, J=7.8 Hz), 7.57 (m, 1H), 7.61 (m, 3H), 7.69 (m, 2H), 8.19 (d, 1H, J=7.6 Hz), 10.56 (br t, 1H), 11.68 (br s, 1H); HRMS (FAB, MH+) Calcd for C17H15N2S: 279.0956, Found: 279.0952; Anal. (C17H14N2S.0.25 H2O) C, H, N, S.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[O:16][CH:15]([CH2:18][NH2:19])[CH2:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(N(C(C)C)CC)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[O:16][CH:15]([CH2:18][NH:19][C:30](=[O:31])[O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2cccc3c2OC(CN)C3)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(-c2cccc3c2OC(CNC(=O)OCc2ccccc2)C3)c1
Yield: 89.6 %

Procedure:
Treatment of (±)-1-[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (2.4 g, 9.4 mmol) with diisopropylethylamine (1.82 g, 14.10 mmol) followed by benzyl chloroformate (1.92 g, 11.28 mmol) generally according to the procedure described for Intermediate 12 provided 3.28 g (90%) of (±)-benzyl {[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a colorless oil. Rf=0.51 (silica, ethyl acetate:hexanes 2:8); Anal. calcd. for C24H23NO4: C, 74.02; H, 5.95; N, 3.6. Found: C, 73.52; H, 6.06; N, 3.28. Chiral HPLC separation of (±)-benzyl {[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (Chiralpak OD, ethanol) provided two fractions. Fraction 1 (Rt=6.220 min, Chiralpak OD, ethanol); Fraction 2 (Rt=8.373 min, Chiralpak OD ethanol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:11]3[CH2:16][CH2:15][CH:14]([CH2:17][OH:18])[CH2:13][CH2:12]3)=[N:9][N:10]=2)[CH:7]=1.CCN(CC)CC.[CH:26]([Si:29](OS(C(F)(F)F)(=O)=O)([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])([CH3:28])[CH3:27]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:11]3[CH2:12][CH2:13][CH:14]([CH2:17][O:18][Si:29]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:26]([CH3:28])[CH3:27])[CH2:15][CH2:16]3)=[N:9][N:10]=2)[CH:7]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: OCC1CCN(c2nnc3ccc(F)cn23)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[Si](OCC1CCN(c2nnc3ccc(F)cn23)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
To a solution of Intermediate 54a (470 mg, 1.88 mmol) and Et3N (390 μL, 2.82 mmol) in DCM (5 mL) was added triisopropylsilyltrifluoromethane sulfonate (607 μL, 2.26 mmol) and the mixture stirred at RT for 0.5 h. The mixture was washed with sat. aq. NaHCO3 solution, dried and concentrated in vacuo. The residue was purified by FCC, using 0-100% EtOAc in cyclohexane, then 10% MeOH in EtOAc, to give the title compound as a pale yellow solid (565 mg, 74%). LCMS (Method 3): Rt 5.21 min, m/z 407 [MH+].
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[CH3:16][Si:17]([CH3:30])([CH3:29])[CH2:18][CH2:19][O:20][CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[C:23]1[C:27]#[N:28].Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C1COCC1>[CH2:35]([O:34][C:32]([C:26]1[N:22]([CH2:21][O:20][CH2:19][CH2:18][Si:17]([CH3:30])([CH3:29])[CH3:16])[C:23]([C:27]#[N:28])=[N:24][CH:25]=1)=[O:33])[CH3:36]
Reactant: C[Si](C)(C)CCOCn1ccnc1C#N
Reactant: CCOC(=O)Cl
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(C#N)n1COCC[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
To a solution of 2,2,6,6-tetramethyl-piperidine (0.365 mL, 2.17 mmol) in 4 mL of THF at −50° C. was added n-BuLi (1.08 mL, 2.17 mmol, 2M in pentane) and the mixture allowed to stir for 10 min at 0° C. The mixture was cooled to −50° C. and a solution of 1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonitrile (prepared in the previous step) (0.440 g, 1.97 mmol) in 2 mL of THF was added and the reaction stirred for 1 h at −50° C. and then ethyl chloroformate (0.210 mL, 2.17 mmol) was added. After 10 min at −50° C. the reaction was quenched with brine (20 mL) and extracted with EtOAc (2×20 mL) and the organic layer dried (Na2SO4) and concentrated. The title compound was eluted from a 20-g SPE column with 20% EtOAc/hexanes to give 0.280 g (48%) of a colorless oil. 1H-NMR (CDCl3, 400 MHz): δ 7.81 (s, 1H), 5.89 (s, 2H), 4.40 (q, J=7.1 Hz, 2H), 3.65 (m, 2H), 1.41 (t, J=7.1 Hz, 3H), 0.96 (m, 2H), 0.00 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C13H21N3O3Si, 296.1 (M+H), found 295.5.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](/[CH:10]=[CH:11]/[C:12]([OH:14])=O)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[NH:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[F:9][C:8]1[CH:7]=[CH:6][C:5](/[CH:10]=[CH:11]/[C:12](=[O:14])[N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1cc(/C=C/C(=O)O)ccc1F
Reactant: C1CCN(C[C@@H]2CCCN2)CC1
Product: N#Cc1cc(/C=C/C(=O)N2CCC[C@H]2CN2CCCCC2)ccc1F

Procedure:
300 mg of the title compound were synthesized as described for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-(3-cyano-4-fluorophenyl)acrylic acid instead of (E)-4-bromocinnamic acid and 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[C:4]1[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:6][C:7]2[C:12]([N:13]=1)=[CH:11][C:10]([C:14]([O:16]C)=[O:15])=[CH:9][CH:8]=2)[CH3:2].[OH-].[Na+].Cl>CO.O>[CH2:24]([N:3]([CH2:1][CH3:2])[C:4]1[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:6][C:7]2[C:12]([N:13]=1)=[CH:11][C:10]([C:14]([OH:16])=[O:15])=[CH:9][CH:8]=2)[CH3:25]
Reactant: CCN(CC)c1nc2cc(C(=O)OC)ccc2nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCN(CC)c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(diethylamino)-2-phenylquinoxaline-6-carboxylate (117 mg, 0.35 mmol, 1.00 equiv) in methanol (15 mL). This was followed by the addition of a solution of sodium hydroxide (69.9 mg, 1.75 mmol, 5.00 equiv) in water (2 mL) dropwise with stiffing. The resulting solution was stirred overnight at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting mixture was concentrated under vacuum. The crude product (110 mg) was purified by Prep-HPLC with the following conditions: Column, SunFire Prep C18, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and methanol (70% methanol up to 90% in 10 min); Detector, UV 254 nm. This resulted in 70 mg (62%) of 3-(diethylamino)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.