Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](O)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.CN(C(ON1N=[N:37][C:32]2[CH:33]=[CH:34][CH:35]=[N:36][C:31]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.N1CCC[C@@H]1C#N.CN1CCOCC1>C1COCC1>[Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([N:36]3[CH2:35][CH2:34][CH2:33][C@@H:31]3[C:32]#[N:37])=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#C[C@H]1CCCN1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)[C@H](C(=O)N1CCC[C@@H]1C#N)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 16.2 %

Procedure:
(R)-2-(6-Chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (10 mg, 0.032 mmol), HATU (15 mg, 0.039 mmol), (R)-pyrrolidine-2-carbonitrile hydrochloride (4 mg, 0.032 mmol), and N-methylmorpholine (90 μL, 0.097 mmol) were combined in THF (0.5 mL). The reaction mixture was stirred under nitrogen at 40° C. for 10 min and then at room temperature for 30 min. The solution was concentrated and purified by preparative HPLC (10-50% AcCN/H2O with 0.035% TFA) to afford the title compound as a white solid (2 mg, 18%). 1H NMR (500 MHz, CD3OD) δ 0.94 (d, J=6.9 Hz, 3H), 1.06 (d, J=6.3 Hz, 3H), 1.03-1.12 (m, 1H), 2.12-2.17 (m, 2H), 2.25-2.27 (m, 2H), 2.59-2.63 (m, 1H), 3.72-3.74 (m, 1H), 3.83-3.86 (m, 1H), 4.92 (d, J=5.9 Hz, 1H), 5.06 (d, J=13.2 Hz, 1H), 5.46 (d, J=11.8 Hz, 1H), 7.86 (s, 1H), 8.25 (s, 1H). [M+H] calc'd for C19H20ClN5O2, 386; found, 386.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10](=[O:20])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)(=O)C>CCCCCC>[C:14]1([CH2:13][CH2:12][CH2:11][CH:10]([OH:20])[CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(CCCc1ccccc1)CCCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: OC(CCCc1ccccc1)CCCc1ccccc1
Yield: 30 %

Procedure:
Using the procedure of Example 42 with the resultant compound of Example 52 gave, after silica gel chromatography using 15% ethyl acetate in hexane, the desired compound (Rf 0.23, 30% ethyl acetate in hexane) as an oil. 1H NMR (CDCl3) δ 1.4-1.8 (m, 8H), 2.62 (br t, 4 H), 3.63 (m, 1H), 7.15-7.3 (m, 10H). Mass spectrum (M+NH4)+ =286.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([N:6]([CH2:15][C@@H:16]2[O:20][C:19](=[O:21])[N:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH2:33][CH2:32][N:31]([CH:34]=[O:35])[CH2:30][CH:29]=4)=[C:24]([F:36])[CH:23]=3)[CH2:17]2)C(OCC(Cl)(Cl)Cl)=O)=[N:2]1>C(O)(=O)C.[Zn]>[O:1]1[CH:5]=[CH:4][C:3]([NH:6][CH2:15][C@@H:16]2[O:20][C:19](=[O:21])[N:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH2:33][CH2:32][N:31]([CH:34]=[O:35])[CH2:30][CH:29]=4)=[C:24]([F:36])[CH:23]=3)[CH2:17]2)=[N:2]1
Reactant: O=CN1CC=C(c2ccc(N3C[C@H](CN(C(=O)OCC(Cl)(Cl)Cl)c4ccon4)OC3=O)cc2F)CC1
Agent: [Zn]
Solvent: CC(=O)O
Product: O=CN1CC=C(c2ccc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5(R)-[N-isoxazol-3-yl-N-(2,2,2-trichloroethyloxycarbonyl)-aminomethyl]-3-[3-fluoro-4-(1-formyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl]oxazolidin-2-one (110 mg, 0.2 mM) in acetic acid (3 ml) was added zinc dust (130 mg, 2.0 mM). The mixture was held in an ultrasonic bath for 10 min. and then stirred vigorously for 48 hours under a nitrogen atmosphere at ambient temperature. The mixture was filtered through celite and the filtrate was evaporated. The residue was taken into ˜5% MeOH/CH2Cl2 (5 ml) with filtration of inorganic material and the title compound was isolated by MPLC (4% MEOH/CH2Cl2). It was obtained as a brittle glass on evaporation under high vacuum (22 mg, 28%).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH:9]([N:12]([C:20]1[S:21][CH:22]=[CH:23][N:24]=1)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:11])[CH3:10].[CH2:25]([Sn:29](Cl)([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH3:28]>C1COCC1>[CH:9]([N:12]([C:20]1[S:21][C:22]([Sn:29]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:25][CH2:26][CH2:27][CH3:28])=[CH:23][N:24]=1)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])([CH3:11])[CH3:10]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)N(C(=O)OC(C)(C)C)c1nccs1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(N(C(=O)OC(C)(C)C)C(C)C)s1
Temperature: -78 °C
Reaction time: 2 h
Yield: 40.3 %

Procedure:
LDA (0.55M 1.1 mmol, 2M) was added to a RBF containing THF (5 mL) cooled to −78° C. A solution of tert-butyl isopropyl(thiazol-2-yl)carbamate (242 mg, 1 mmol) in THF (5 mL) was added via cannula and the resulting solution stirred for 2 h at −78° C. Tributyltin chloride (0.27 mL, 1 mmol) was added and the reaction mixture allowed to slowly warm to room temperature then stirred overnight. The reaction mixture was then quenched with NH4Cl (2 mL, sat. aq.) and diluted with water. The mixture was then extracted with EtOAc (3×25 mL) and the combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The product was isolated via column chromatography (SiO2, 2% EtOAc/heptane) to afford the product (214 mg, 40% yield) as a colorless oil.
Reaction SMILES: CS(C)=O.[CH2:5]([N:12]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:13]1[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCN(CC)CC>C(Cl)Cl>[CH2:20]([N:12]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:13]1[CH2:14][CH2:15][C:16](=[O:19])[CH2:17][CH2:18]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: OC1CCC(N(Cc2ccccc2)Cc2ccccc2)CC1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(N(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of oxalylic acid (2.03 mL, 20.31 mmol) in DCM (80 mL) at −60° C. was added dropwise DMSO (3.46 mL, 48.8 mmol). After stirring for 5 min, a solution of 4-(dibenzylamino)cyclohexanol (6 g, 20.31 mmol) in DCM (40 mL) was added slowly. The mixture was stirred for 15 min and NEt3 (14.3 mL, 103 mmol) was added slowly. After stirring for 15 min the ice bath was removed and the mixture was stirred for additional 16 hr. The mixture was diluted with water (100 mL). The separated organic layer was washed with brine (1×˜75 mL), dried over Na2SO4, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2, 120 g, EtOAc/hexane= 10/90 to 50/50] providing 4-(dibenzylamino)cyclohexanone as a white solid. Yield: 5.5 g. LCMS (m/z): 294.1 [M+H]+; Retention time=0.58 min.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([C:7]2([C:10](Cl)=[O:11])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([Cl:34])[C:20]=1[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=1)=[O:23]>>[C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([C:7]2([C:10]([O:23]/[C:22](/[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=3)=[CH:21]\[C:20]3[C:19]([Cl:34])=[CH:18][N:17]=[CH:16][C:15]=3[Cl:14])=[O:11])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(C2(C(=O)Cl)CC2)cc1
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)cc1OC
Product: COc1ccc(/C(=C/c2c(Cl)cncc2Cl)OC(=O)C2(c3ccc(C)cc3)CC2)cc1OC

Procedure:
The compound was obtained starting from 1-p-tolyl-cyclopropanecarbonyl chloride and 2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy -phenyl)-ethanone, following the procedure of Example 7.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13](=[O:17])[NH:14][CH2:15][CH2:16][C:11]=3[NH:10][C:9]=2[CH:18]=O)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:29]=1[NH:30][C:31](=[O:35])[CH2:32][O:33][CH3:34])[NH:26][C:25](=[O:36])[CH2:24]2>>[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:29]=1[NH:30][C:31](=[O:35])[CH2:32][O:33][CH3:34])[NH:26][C:25](=[O:36])[C:24]2=[CH:18][C:9]1[NH:10][C:11]2[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C:12]=2[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: COCC(=O)Nc1cc2c(cc1F)CC(=O)N2
Reactant: O=Cc1[nH]c2c(c1-c1ccc(F)cc1)C(=O)NCC2
Product: COCC(=O)Nc1cc2c(cc1F)C(=Cc1[nH]c3c(c1-c1ccc(F)cc1)C(=O)NCC3)C(=O)N2
Yield: 54.4 %

Procedure:
The title compound was prepared under the same conditions as described in Example 46 with 3-(4-fluoro-phenyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-methoxy-acetamide as starting materials to give N-{5-fluoro-3-[3-(4-fluoro-phenyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-methoxy-acetamide (50 mg, 54.4%) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[NH2:10])([O-:3])=[O:2].CC([O-])=O.[Na+].[Br:16]Br.C([O-])(O)=O.[Na+]>O.C(O)(=O)C>[Br:16][C:8]1[CH:7]=[N:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:9]=1[NH2:10]
Reactant: Nc1ccncc1[N+](=O)[O-]
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(Br)cncc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 76.5 %

Procedure:
A mixture of 3-nitropyridin-4-amine (XLV) (10 g, 71.94 mmol) and acetic acid (120 ml) was added to a sealed tube followed by addition of NaOAc (29.50 g, 93.52 mmol) and dropwise addition of bromine (4.7 ml 359.7 mmol) under stirring. The sealed tube was heated at 100° C. for 28 h until TLC showed consumption of starting material. The reaction mixture was concentrated to obtain a solid which was dissolved in water, basified with NaHCO3 and extracted with EtOAc. The combined organic extracts were dried and concentrated to produce 3-bromo-5-nitropyridin-4-amine (XLVI) as a yellow solid (12 g, 55 mmol, 77% yield). 1H NMR (DMSO-d6) δ ppm 9.19 (s, 1H), 8.58 (s, 1H); ESIMS found for C5H4BrN3O2 m/z 217, 219 (M+, M+2).
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([C:18]4([CH2:24][O:25]C)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[N:15][C:14]=3[C:27]([NH:29][C:30]3[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=3)[C:33]([OH:35])=[O:34])=[O:28])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.B(Br)(Br)Br.O>C(Cl)Cl>[C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([C:18]4([CH2:24][OH:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]4)=[N:15][C:14]=3[C:27]([NH:29][C:30]3[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=3)[C:33]([OH:35])=[O:34])=[O:28])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: COCC1(c2nc(C(=O)Nc3cccc(C(=O)O)c3)c(CCC34CC5CC(CC(C5)C3)C4)[nH]2)CCCCC1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1cccc(NC(=O)c2nc(C3(CO)CCCCC3)[nH]c2CCC23CC4CC(CC(C4)C2)C3)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.8 %

Procedure:
To a suspension of 3-{[5-(2-adamantan-1-yl-ethyl)-2-(1-methoxymethyl-cyclohexyl)-1H-imidazole-4-carbonyl]-amino}-benzoic acid (Example 203) (300 mg, 0.58 mmol) in DCM (10 ml) was added 1 M solution of boron tribromide in DCM (1.72 ml, 1.72 mmol) at 0° C. The mixture was stirred at room temperature for 16 h, cooled to 0° C., and water (20 ml) was added slowly. The product was extracted with DCM/MeOH (3×20 ml of 9:1 mixture), the organic phase was dried (MgSO4) and the solvent was evaporated. The crude product was purified by flash column chromatography (silica, DCM/MeOH, 95:5) to afford the title compound as a white solid (40.5 mg, 14%). 1H NMR (300 MHz, d6-DMSO) 9.51 (1H, s), 8.38 (1H, s), 7.92 (1H, d), 7.60 (1H, d), 7.40 (1H, t), 3.41 (2H, s), 2.87 (2H, m), 2.05 (2H, m), 1.94 (3H, br s), 1.65 (6H, m), 1.52 (11H, m), 1.34 (5H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 60.86; H, 8.33; N, 7.76%. C37H56N4O9.1.6 H2O requires: C, 60.86; H, 8.18; N, 7.67%.
Reaction SMILES: [N:1](=[C:3]([C:5]1[CH:18]=[CH:17][C:16]2[O:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[S:8][C:7]=2[CH:6]=1)[CH3:4])[OH:2].B.N1C=CC=CC=1.Cl>C(O)C>[NH:1]([CH:3]([C:5]1[CH:18]=[CH:17][C:16]2[O:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[S:8][C:7]=2[CH:6]=1)[CH3:4])[OH:2]
Reactant: CC(=NO)c1ccc2c(c1)Sc1ccccc1O2
Agent: B
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(NO)c1ccc2c(c1)Sc1ccccc1O2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89.9 %

Procedure:
The oxime from Step 1 (450 mg, 1.75 mmol) was suspended in ethanol (9 mL) and, at 0° C., there was added pyridine-borane (325 mg, 3.5 mmol) and 4M ethanolic hydrogen chloride (HCl) (1.33 mL, 5.32 mmol). The mixture was stirred at 0° C. for 20 minutes, then at room temperature for 1 hour. The ethanol was evaporated and the residue partitioned between water and ether. The aqueous portion was basified with 1N aqueous sodium hydroxide and extracted twice with ether. Drying of the ether and evaporation afforded the title product (408 mg) as an oil which slowly became a white solid, m.p.: 64°-67° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.[S:9]1[CH2:13][C:12](=[O:14])[NH:11][C:10]1=[O:15].N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:13]2[S:9][C:10](=[O:15])[NH:11][C:12]2=[O:14])[S:5][CH:6]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1cc(Br)cs1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2cc(Br)cs2)S1
Yield: 87.2 %

Procedure:
To a mixture of 4-bromothiophene-2-carboxaldehyde (1.91 g, 10.0 mmol) and 2,4-thiazolidinedione (1.40 g, 12.0 mmol) in ethanol (30 mL) was added piperidine (1.0 mL, 10.0 mmol). The reaction mixture was heated at reflux for 3 h, then cooled on an ice-bath, and the precipitated products were collected by filtration. The cake was washed with 40% ethanol and dried to afford 5-(4-bromothiophen-2-ylmethylene)-2,4-thiazolidinedione (2.53 g, 87%).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[Br:1][C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH2:15][N:16]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:18][CH:19]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1
Reactant: BrCc1ccccc1
Reactant: O=c1c(Br)cc(-c2ccccn2)cn1-c1cccnc1
Solvent: CC#N
Product: O=c1c(Br)cc(-c2ccccn2)cn1C1=CCCN(Cc2ccccc2)C1
Temperature: 70 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
718 mg of 3-bromo-5-(2-pyridyl)-1-(3-pyridyl)-1,2-dihydropyridin-2-one was dissolved in 40 ml of acetonitrile. 383 mg of benzyl bromide was added thereto, followed by stirring at 70° C. overnight. Further, 383 mg of benzyl bromide was added thereto, followed by stirring at 70° C. for 2 nights. After cooling to room temperature, the mixture was evaporated. The residue was dissolved in 30 ml of methanol, followed by cooling to 0° C. under stirring. 265 mg of sodium borohydride was added thereto, followed by stirring overnight under heating from 0° C. to room temperature. Water was added thereto, the solvent was evaporated, and then the residue was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate system), to give 550 mg of 3-bromo-5-(2-pyridyl)-1-(1-benzyl-1,2,3,6-tetrahydropyridin-5-yl)-1,2-dihydropyridin-2-one. 270 mg of the product was dissolved in 20 ml of dimethylformamide. 179 mg of 2-(2-cyanophenyl)-1,3,2-dioxaborinate, 313 mg of cesium carbonate and 15 mg of tetrakistriphenylphosphinepalladium were added thereto, followed by stirring at 120° C. for 1 hour. After cooling to room temperature, water was added thereto, followed by extracting with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate system), to give 174 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([CH3:21])[C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[O:11][CH2:12][CH2:13][C:14](O)=[O:15])=[O:7])=[CH:4][C:3]=1[C:24]1[CH:25]=[N:26][C:27]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:29]=1[C:30]#[N:31].[C:36]([O:40][C:41](=[O:46])[NH:42][CH2:43][CH2:44][NH2:45])([CH3:39])([CH3:38])[CH3:37].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[C:36]([O:40][C:41](=[O:46])[NH:42][CH2:43][CH2:44][NH:45][C:14](=[O:15])[CH2:13][CH2:12][O:11][C:10]1[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=1[N:8]([C:6](=[O:7])[C:5]1[CH:22]=[CH:23][C:2]([Cl:1])=[C:3]([C:24]2[CH:25]=[N:26][C:27]([C:32]([F:34])([F:35])[F:33])=[CH:28][C:29]=2[C:30]#[N:31])[CH:4]=1)[CH3:21])([CH3:39])([CH3:37])[CH3:38]
Reactant: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1OCCC(=O)O
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1OCCC(=O)NCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionic acid 11-4 (50 mg, 0.10 mmol) and (2-amino-ethyl)-carbamic acid tert-butyl ester (51.5 mg, 0.54 mmol) in DMF (500 μL), EDCl (22 mg, 0.12 mmol), HOBt (16 mg, 0.12 mmol) and DIPEA (34 μl, 0.19 mmol) were added. The mixture was stirred for 48 hrs at rt, diluted with MeOH (500 μL) and purified by prep HPLC to afford {2-[3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionylamino]-ethyl}-carbamic acid tert-butyl ester. After treatment with 50% TFA in DCM (1 mL) for 2 hrs, followed by concentration in vacuo, N-{2-[2-(2-amino-ethylcarbamoyl)-ethoxy]-phenyl}-4-chloro-3-(4-cyano-trifluoromethyl-pyridin-3-yl)-N-methyl-benzamide 53-1 was obtained. MS [M+H]+546.1; tR=5.66 min (method 2).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:11]=[C:12]([C:16]2[CH:25]=[C:24]3[C:19]([C:20]([OH:39])=[C:21]([C:28]([NH:30][CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])=[O:29])[C:22](=[O:27])[N:23]3[CH3:26])=[CH:18][CH:17]=2)[CH:13]=[CH:14][CH:15]=1)#[N:9].O>ClCCl>[C:8]([C:10]1[CH:11]=[C:12]([C:16]2[CH:25]=[C:24]3[C:19]([C:20]([OH:39])=[C:21]([C:28]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])[C:22](=[O:27])[N:23]3[CH3:26])=[CH:18][CH:17]=2)[CH:13]=[CH:14][CH:15]=1)#[N:9]
Reactant: Cn1c(=O)c(C(=O)NCC(=O)OC(C)(C)C)c(O)c2ccc(-c3cccc(C#N)c3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cn1c(=O)c(C(=O)NCC(=O)O)c(O)c2ccc(-c3cccc(C#N)c3)cc21
Yield: 74 %

Procedure:
Trifluoroacetic acid (4.00 ml, 54 mmol) was added to a suspension of tert-butyl 2-(7-(3-cyanophenyl)-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate (0.162 g, 0.37 mmol) in dichloromethane (2.00 ml). After stirring for one hour at room temperature water was added and the solids formed were collected by filtration. The solids were washed with water, ether, dried in a vacuum oven at 50° C. to afford off-white solids in 74% yield.
Reaction SMILES: [CH2:1]([C:3]1[C:4]2[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=2[S:6][C:7]=1[C:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]=1)[CH3:2]>C(O)C.FC(F)(F)CO.[Pd]>[CH2:1]([C:3]1[C:4]2[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=2[S:6][C:7]=1[CH:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)[CH3:2]
Reactant: CCc1c(C2=CCNCC2)sc2ccccc12
Agent: [Pd]
Solvent: CCO
Solvent: OCC(F)(F)F
Product: CCc1c(C2CCNCC2)sc2ccccc12
Reaction time: 24 h
Yield: 84.3 %

Procedure:
Scheme IA, Step C: To a mixture of 4-(3-ethylbenzo[b]thiophen-2-yl)-1,2,5,6-tetrahydropyridine (0.465 g, 1.91 mmol) in ethanol (15 mL) and 2,2,2-trifluoroethanol (5 mL) was added 10% palladium on carbon (0.25 g). The mixture was hydrogenated at one atmosphere for 24 hours. The mixture was carefully filtered and evaporated to give the intermediate title compound as a yellow amorphous solid (0.395 g, 84%). FDMS m/e=246 (M++1).
Reaction SMILES: [CH:1]([N:4]([CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[C:5](=[O:8])[CH2:6][Cl:7])([CH3:3])[CH3:2].C1(C)C(S(O)(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH:1]([N:4]([CH2:9][CH:10]1[O:11][CH2:12][CH2:13][CH2:16][CH2:15][O:14]1)[C:5](=[O:8])[CH2:6][Cl:7])([CH3:2])[CH3:3]
Reactant: CCOC(CN(C(=O)CCl)C(C)C)OCC
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)N(CC1OCCCCO1)C(=O)CCl

Procedure:
N-Isopropyl-N-(2,2-diethoxyethyl)-α-chloroacetamide (10 grams), butandiol-1,4 (3.52 ml) and trace amounts of toluenesulfonic acid were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated until no more ethanol was given off. After this time sodium carbonate (1 gram) was added to the mixture with stirring and the resulting mixture was distilled to yield the desired product N-isopropyl-N-(1,3-dioxepan-2-ylmethyl)-α-chloroacetamide as an oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[CH3:8][S:9](Cl)(=[O:11])=[O:10].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:8][S:9]([O:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)(=[O:11])=[O:10]
Reactant: OC1CCOCC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
At r.t. to a solution of tetrahydro-4H-pyran-4-ol (90 uL, 1 mmol; Aldrich, Cat. No. 198234) in methylene chloride (3 mL) was added methanesulfonyl chloride (91 uL, 1.2 mmol), followed by triethylamine (0.20 mL, 1.5 mmol) and 4-dimethylaminopyridine (12 mg, 0.098 mmol). The mixture was stirred at r.t. for 3 h. It was diluted with methylene chloride. The solution was washed with water and brine, dried over Na2SO4. After filtration, the filtrate was concentrated to yield 0.21 g of the product (crude) which was directly used in the next step reaction without further purification.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](Cl)(=[O:17])[CH2:15][CH3:16].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[C:14]([C:11]1[CH:10]=[CH:9][C:8]([O:7][C:1]2[CH:2]=[CH:3][C:4]([C:1](=[O:7])[CH2:2][CH3:3])=[CH:5][CH:6]=2)=[CH:13][CH:12]=1)(=[O:17])[CH2:15][CH3:16]
Reactant: CCC(=O)Cl
Reactant: c1ccc(Oc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCC(=O)c1ccc(Oc2ccc(C(=O)CC)cc2)cc1

Procedure:
Diphenyl ether (67 grams) was mixed with about 79 grams of propionyl chloride and 109 grams of aluminum chloride in about 150 ml of carbon disulfide. The product, 4-propionylphenyl ether, was isolated by hydrolysis of the mixture and conventional recrystallization techniques.