Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:54])[C@H:25]([NH:34][C:35]([C@@H:37]2[CH2:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:39][N:38]2C(OC(C)(C)C)=O)=[O:36])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:20][CH2:19]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]1[CH2:19][CH2:20][N:21]([C:24](=[O:54])[C@H:25]([NH:34][C:35]([C@@H:37]2[CH2:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:39][NH:38]2)=[O:36])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)NCCNc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCNc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2)CC1
Reaction time: 0.5 h

Procedure:
The title compound was prepared according to the procedure described in Example 3 (Step b) using tert-butyl 3-[N-((1R)-2-{4-[2-({2-[(tert-butoxy)carbonyl-amino]ethyl}-amino)phenyl]-piperidyl}-1-[(4-chlorophenyl)methyl]-2-oxoethyl)carbamoyl](3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Step a) (386 mg, 0.5 mmol) and 50% TFA in CH2Cl2 (20 mL). Purification by reverse phase preparative HPLC [Phenomenex; 5 μm 250×21.2 mm, 5% to 95% CH3CN (0.1% TFA) in H2O (0.1% TFA) over 30 min, then 100% CH3CN (0.1% TFA) for 2 min) provided the title compound (TFA salt) as a white foam (162 mg). MS (ESI, pos. ion) m/z: 560 (M+1); (ESI, neg. ion) m/z: 558 (M−1). Calc'd for C32H38ClN5O2: 559.27. Anal. Calcd for C32H38ClN5O2-3C2HF3O2: C, 50.59; H, 4.58; N, 7.76. Found: C, 50.98; H, 4.87; N, 8.01.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].CC(C)([O-])C.[K+].Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>CS(C)=O>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[CH:20][CH:21]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C

Procedure:
12.0 g (74.9 mmol) diethyl malonate were dissolved in 50 ml DMSO and 8.6 g (76.6 mmol) potassium t-butoxide were added. A solution of 7.9 g (50.1 mmol) 1-chloro-4-nitrobenzene in 50 ml DMSO was added via a dropping funnel. The mixture was heated at 100° C. for 4 h and poured on to crushed ice. It was extracted twice with ethyl acetate, the combined organic layers washed with brine, dried over sodium sulfate, and evaporated in vacuo to afford a brown oil, which contained the title compound in an amount of about 75% and which was used in the reaction of the next step.
Reaction SMILES: O[CH:2]1[CH2:5][N:4]([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:16][C@H:15]([CH2:17][O:18][C:19]4[CH:23]=[CH:22][O:21][N:20]=4)[O:14][C:13]3=[O:24])=[CH:8][C:7]=2[F:25])[CH2:3]1.FC1C=C(N2C[C@H](CO)OC2=O)C=C[C:32]=1[N:33]1C=C(C)N=C1>>[F:25][C:7]1[CH:8]=[C:9]([N:12]2[CH2:16][C@H:15]([CH2:17][O:18][C:19]3[CH:23]=[CH:22][O:21][N:20]=3)[O:14][C:13]2=[O:24])[CH:10]=[CH:11][C:6]=1[N:4]1[CH:3]=[C:2]([CH3:5])[N:33]=[CH:32]1
Reactant: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CC(O)C2)c(F)c1
Reactant: Cc1cn(-c2ccc(N3C[C@H](CO)OC3=O)cc2F)cn1
Product: Cc1cn(-c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)cn1

Procedure:
Using essentially the same procedure as for the intermediate of Example 65, but starting with 3-(3-fluoro-4-(4-methyl-imidazol-1-yl)phenyl)-5(R)-hydroxymethyloxazolidin-2-one (see Example 141; 81 mg, 0.29 mmol), and purifying by chromatography on a 5 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 2.5% MeOH in dichloromethane, gave the title compound (80 mg). MS (ESP): 359 (MH+) for C17H15FN4O4.
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][C:10]([O:12][CH3:13])=[O:11].[F:14][C:15]1[CH:16]=[C:17]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:34][CH2:33][NH:32][CH2:31]3)=[C:26]([CH3:35])[CH:25]=2)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1>C(Cl)Cl>[CH3:13][O:12][C:10](=[O:11])[CH2:9][N:32]1[CH2:33][CH2:34][CH:30]([C:27]2[CH:28]=[CH:29][C:24]([S:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([F:14])[CH:16]=3)(=[O:23])=[O:22])=[CH:25][C:26]=2[CH3:35])[CH2:31]1
Reactant: Cc1cc(S(=O)(=O)c2cccc(F)c2)ccc1C1CCNC1
Reactant: COC(=O)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CN1CCC(c2ccc(S(=O)(=O)c3cccc(F)c3)cc2C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.2 %

Procedure:
Triethylamine (0.387 mL, 1.533 mmol) and methyl bromoacetate (0.146 mL, 1.533 mmol) were added at 0° C. to a solution of 3-[4-(3-fluoro-benzenesulfonyl)-2-methyl-phenyl]-pyrrolidine (0.445 g, 1.393 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 4 hours, then concentrated under reduced pressure, and the crude residue was purified via flash chromatography (DCM/MeOH/NH4OH) to give 0.410 g (84% yield) of {3-[4-(3-fluoro-benzenesulfonyl)-2-methyl-phenyl]-pyrrolidin-1-yl}-acetic acid methyl ester as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12]Br)=[CH:6][CH:5]=1.Cl.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)=[C:20]2[CH3:32]>>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][N:22]2[C:23]3[C:19](=[CH:18][C:17]([Cl:16])=[CH:25][CH:24]=3)[C:20]([CH3:32])=[C:21]2[C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:6][CH:5]=1
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(Cl)cc12
Reactant: COC(=O)c1ccc(OCCBr)cc1
Agent: Cl
Product: COC(=O)c1ccc(OCCn2c(-c3cccnc3)c(C)c3cc(Cl)ccc32)cc1

Procedure:
4-(2-Bromo-ethoxy)-benzoic acid methyl ester (Example 61a) and 5-chloro-3-methyl-2-pyridin-3-yl-indol-1-yl (Example 2) are processed according to the method described in Example 59 to give 4-[2-(5-chloro-3-methyl-2-pyridin-3-yl-indol-1-yl)-ethoxy]-benzoic acid methyl ester. MS (ESI) m/z 421.01.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: OCc1ccc(Br)nc1
Product: OCc1ccc(-c2ccc(Br)cc2)nc1

Procedure:
In accordance with Example 11-(1), but using (6-bromopyridin-3-yl)methanol instead of 4-bromobenzyl bromide, and 4-bromophenylboronic acid instead of [3-(hydroxymethyl)phenyl]boronic acid, [6-(4-bromophenyl)pyridin-3-yl]methanol was afforded as a white solid (yield 51%).
Reaction SMILES: [CH3:1][CH:2]([CH2:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:3][CH2:4][C:5]1[CH:41]=[CH:40][C:8]([C:9]([C:11]2[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[C:17]([C:23](=O)[C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH:32]([CH3:38])[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:26][CH:25]=3)=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=O)=[CH:7][CH:6]=1.[H][H]>O1CCCC1.[Pd]>[CH3:38][CH:32]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:31][CH2:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][C:17]2[CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]([CH2:9][C:8]3[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH:2]([CH3:1])[CH2:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[CH:41][CH:40]=3)=[CH:19][C:18]=2[C:20]([OH:22])=[O:21])=[CH:25][CH:26]=1
Reactant: [H][H]
Reactant: CC(CCc1ccc(C(=O)c2cc(C(=O)O)c(C(=O)c3ccc(CCC(C)CC(C)(C)C)cc3)cc2C(=O)O)cc1)CC(C)(C)C
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(CCc1ccc(Cc2cc(C(=O)O)c(Cc3ccc(CCC(C)CC(C)(C)C)cc3)cc2C(=O)O)cc1)CC(C)(C)C

Procedure:
A mixture containing 20.0 grams of 2,5-bis[4-(3,5,5-trimethylhexyl)benzoyl]terephthalic acid in 1500 mL of tetrahydrofuran (THF) and 1.4 grams of 10% palladium on carbon (as a catalyst) was heated to 90° C. in an atmosphere of hydrogen at 620 kPa and 90° C. for 17 hours. The mixture was filtered through Celite™ diatomaceous earth filter agent to remove the catalyst. The filtrate was concentrated in vacuo to give 2,5-bis[4-(3,5,5-trimethylhexyl)benzyl]terephthalic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[Cl-].[CH2:11]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[O:19][CH2:18][CH2:17][CH:16]2[NH3+:23])[CH3:12].C(N(CC)CC)C>CN(C)C(=O)C>[CH2:11]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[O:19][CH2:18][CH2:17][CH:16]2[NH:23][C:2]1[CH:3]=[N:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1)[CH3:12]
Reactant: N#Cc1ncc(Br)cn1
Reactant: CCc1ccc2c(c1)C([NH3+])CCO2
Agent: [Cl-]
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CCc1ccc2c(c1)C(Nc1cnc(C#N)nc1)CCO2
Yield: 9.8 %

Procedure:
0.20 g (1.09 mmol) of 5-bromo-2-cyanopyrimidine (ABCR 245244), 0.325 g (1.52 mmol) of 6-ethyl-3,4-dihydro-2H-chromen-4-aminium chloride and 0.35 g (3.3 mmol) of triethylamine in 1.5 ml of N,N-dimethylacetamide are heated in a closed cuvette in the microwave at 200° C. for 120 minutes (Biotage Initiator, http://www.biotage.com/DynPage.aspx?id=22001). The crude mixture obtained in this manner is applied to silica gel and purified by column chromatography using the mobile phase heptane/ethyl acetate. Concentration gives 0.03 g of 5-[(6-ethyl-3,4-dihydro-2H-chromen-4-yl)amino]pyrimidine-2-carbonitrile (wax-like) (yield 8% at a purity of 80%).
Reaction SMILES: [C:1]1([C:7]2([CH2:16][CH:17]=[CH2:18])[CH2:11][CH2:10][CH2:9][CH:8]2[C:12]([O:14]C)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>>[C:1]1([C:7]2([CH2:16][CH:17]=[CH2:18])[CH2:11][CH2:10][CH2:9][CH:8]2[C:12]([OH:14])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCC1(c2ccccc2)CCCC1C(=O)OC
Agent: [K+]
Agent: [OH-]
Product: C=CCC1(c2ccccc2)CCCC1C(=O)O

Procedure:
2-Phenyl-2-(2-propenyl)-1-methoxycarbonylcyclopentane was hydrolyzed by reaction with aqueous potassium hydroxide to provide 2-phenyl-2-(2-propenyl)-1-hydroxycarbonylcyclopentane.
Reaction SMILES: [C:1]1([S:7]([NH:10][CH:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:20](=[O:27])[CH2:21][CH2:22][C:23]([O:25]C)=[O:24])[CH:17]=3)[CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C>[C:1]1([S:7]([NH:10][CH:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:20](=[O:27])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:17]=3)[CH2:12]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCC(=O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2
Solvent: CCO
Product: O=C(O)CCC(=O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2
Reaction time: 2 h

Procedure:
2.7 ml of 15N sodium hydroxide solution are added to 8.3 g (21.4 mmol) of methyl 4-[2-benzenesulphonamidoindan-5-yl]-4-oxobutyrate in 20 ml of ethanol and the mixture is boiled for 2 hours. The mixture is evaporated in vacuo, the residue is taken up in water, and the reaction product is precipitated with hydrochloric acid. It is crystallised from ethyl acetate/diisopropyl ether.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Br:18])=[CH:16][C:5]2[C:6]([C:12](=[O:15])[NH:13][CH3:14])=[C:7](B(O)O)[O:8][C:4]=2[CH:3]=1.Br[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[C:17]([Br:18])=[CH:16][C:5]2[C:6]([C:12]([NH:13][CH3:14])=[O:15])=[C:7]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)[O:8][C:4]=2[CH:3]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: CNC(=O)c1c(B(O)O)oc2cc(N)c(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(C#N)cc2)oc2cc(N)c(Br)cc12
Yield: 25.4 %

Procedure:
A solution of (6-amino-5-bromo-3-(methylcarbamoyl)benzofuran-2-yl)boronic acid (1 g, 3.19 mmol), 4-bromobenzonitrile (1.17 g, 6.39 mmol), K3PO4.3H2O (1.7 g, 6.39 mmol) and Pd(dppf)Cl2 (40 mg) in dioxane/H2O (10 mL/2 mL) was stirred at 80° C. for 4 h. The mixture was filtered to remove the solid and then the mixture was diluted with water and extracted with EA. The organic layer was washed with brine, dried with Na2SO4 and concentrated. The residue was purified by column chromatography (PE:EA=5:1) to give 6-amino-5-bromo-2-(4-cyanophenyl)-N-methylbenzofuran-3-carboxamide (300 mg, yield: 26%). 1H-NMR (CDCl3, 400 MHz) δ 8.09 (d, J=8.0 Hz, 2H), 7.72 (s, 1H), 7.65 (d, J=8.4 Hz, 2H), 6.84 (s, 1H), 5.84 (s, 1H), 4.28 (s, 2H), 3.00 (d, J=4.4 Hz, 3H). MS (M+H)+: 370/372.
Reaction SMILES: [CH3:1][C:2]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:16].[H-].[Na+].[Cl:19][CH2:20][CH2:21][CH2:22]I.O>CN(C=O)C>[CH3:1][C:2]1[C:15]2[N:14]([CH2:22][CH2:21][CH2:20][Cl:19])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:16]
Reactant: ClCCCI
Reactant: Cc1ccc2c(c1C)Nc1ccccc1S2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1C)N(CCCCl)c1ccccc1S2
Temperature: 25 °C
Yield: 57.2 %

Procedure:
To a solution of 5.0 g of 1,2-dimethylphenothiazine in N,N′-dimethylformamide was added 970 mg of sodium hydride under stirring at room temperature. After stirring at room temperature for 30 min, 4.0 g of 1-chloro-3-iodopropane was added dropwise followed by stirring at room temperature overnight. After adding water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give 3.4 g of the title compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][C:12]1[CH:17]=[C:16](F)[CH:15]=[C:14]([F:19])[CH:13]=1.O>C1COCC1>[Br:11][C:12]1[CH:17]=[C:16]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:15]=[C:14]([F:19])[CH:13]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1cc(Br)cc(OCc2ccccc2)c1
Reaction time: 1 h
Yield: 98445.4 %

Procedure:
Sodium hydride (60% dispersion in oil, 24.0 g, 0.48 mol) was added portionwise to a stirred solution of anhydrous benzyl alcohol (64.5 g, 0.60 mol) in THF (1.0 L). After the mixture was stirred for 1 h, a solution of 1-bromo-3,5-difluorobenzene (76.8 g, 0.40 mmol) in THF (100 mL) was added dropwise over a period of 1 h. The reaction was stirred at room temperature for 2 d. Water (400 mL) was added and the THF was removed in vacuo. The aqueous layer was extracted with hexane (3×150 mL). The combined organic extracts were washed with 2N NaOH (2×100 mL) then, dried (Na2SO4), filtered and concentrated in vacuo to afford the sub-title compound (110.7 g, 98%) as a light yellow oil that was used without further purification.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1>C1C=CC=CC=1>[C:1]([NH:5][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:7]([Br:6])=[CH:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CC(C)(C)N
Solvent: c1ccccc1
Product: CC(C)(C)NC(=O)c1ccc(Br)cc1
Yield: 88.6 %

Procedure:
The preparation of Example 1 was repeated with the changes that tert-butyl amine (4.02 g, 0.055 mole) and 4-bromobenzoyl chloride (6.04 g, 0.0275 mole) were the starting reactants and benzene was the reaction medium. This reaction produced 6.24 g crystals (89% yield), mp 130°-133° C. Proton nuclear magnetic resonance (89.55 MHz) showed absorptions at 7.562 ppm (s, 4H; aryl H); 5.910 ppm (bs, 1H; N-H); 1.464 ppm (s, 9H; tert-butyl H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][C:6]1[CH:19]=[C:9]2[NH:10][C:11](=[O:18])[C:12]3[C:17]([N:8]2[N:7]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3.[NH:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:28]=[C:24]1[CH2:25][CH2:26][CH2:27][N:23]1[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][C:6]1[CH:19]=[C:9]2[NH:10][C:11](=[O:18])[C:12]3[C:17]([N:8]2[N:7]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: O=C1CCCN1
Reactant: O=c1[nH]c2cc(Cc3cccc(Br)c3)nn2c2ccccc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: O=C1CCCN1c1cccc(Cc2cc3[nH]c(=O)c4ccccc4n3n2)c1

Procedure:
A mixture of Example 61B (0.1 g, 0.282 mmol), pyrrolidin-2-one (0.048 g, 0.565 mmol) cesium carbonate (0.130 g, 0.395 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.026 g, 0.028 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.025 g, 0.043 mmol) in DME (2 mL) was heated in a microwave (Personal Chemistry SmithSynthesizer) at 200° C. for 60 minutes. The mixture was filtered evaporated. The residue was purified by chromatography on silica gel with 20% to 80% ethyl acetate in hexane to provide the desired product. 1H NMR (500 MHz, DMSO-d6) δ ppm 2.01-2.08 (m, 2 H) 2.47 (t, J=8.09 Hz, 2 H) 3.81 (t, J=7.02 Hz, 2 H) 3.99 (s, 2 H) 5.67 (s, 1 H) 7.08 (d, J=7.63 Hz, 1 H) 7.30 (t, J=7.78 Hz, 1 H) 7.43-7.50 (m, 2 H) 7.66 (s, 1 H) 7.80-7.88 (m, 1 H) 8.04 (d, J=8.24 Hz, 1 H) 8.12 (d, J=7.93 Hz, 1 H).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[C:17]([F:24])[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C1COCC1.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>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:3]=2)=[C:17]([F:24])[CH:16]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: CC(=O)Nc1cc(Cl)c(C=O)cn1
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: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(-c2ccc(Cl)cc2F)c(C=O)cn1
Temperature: 85 °C
Yield: 59.6 %

Procedure:
To a stirred solution of N-(4-chloro-5-formylpyridin-2-yl)acetamide (3 g, 15.11 mmol), (4-chloro-2-fluorophenyl)boronic acid (2.63 g, 15.11 mmol), cesium carbonate (9.84 g, 30.2 mmol) in a mixture of water (8 mL) and THF (25 mL) was added Pd(PPh3)4 (19.19 mg, 0.017 mmol) and the reaction was heated to 85° C. for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water, brine, dried over sodium sulphate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using hexane/ethyl acetate as eluant yielding N-(4-(4-chloro-2-fluorophenyl)-5-formylpyridin-2-yl)acetamide (2.8 g, 9.01 mmol, 60% yield) as an off-white solid. LCMS (ESI) m/e 291.0 [(M)−, calcd for C14H9ClFN2O2 291.0] LC/MS retention time (method A): tR=1.69 min; 1H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 9.84 (d, J=Hz, 1H), 8.88 (s, 1H), 8.13 (s, 1H), 7.61 (dd, J=2.00, 10.00 Hz, 1H), 7.46-7.48 (m, 2H), 2.11 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[N:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1)=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:27]([O:30][CH2:31][C:32]1[CH2:39][S:38][CH:37]2[N:34]([C:35](=[O:41])[CH:36]2[NH2:40])[C:33]=1[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])(=[O:29])[CH3:28]>O1CCCC1>[C:27]([O:30][CH2:31][C:32]1[CH2:39][S:38][CH:37]2[N:34]([C:35](=[O:41])[CH:36]2[NH:40][C:9](=[O:11])[CH2:8][N:4]2[CH:5]=[CH:6][CH:7]=[C:3]2[CH:1]=[O:2])[C:33]=1[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])(=[O:29])[CH3:28]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)C2SC1
Reactant: O=Cc1cccn1CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)Cn3cccc3C=O)C2SC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of (2-formyl-1-pyrryl)acetic acid (3.1 g, 0.02 m) in tetrahydrofuran (THF) is cooled to about 0° C. and 4.12 g (0.02 m) of dicyclohexylcarbodiimide is added in one portion with stirring for five minutes. Then 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, tert-butyl ester (6.08 g, 0.02 m) in THF is added. The temperature is maintained at 0° C. for one hour and then the temperature is increased to 20° for about 18 hours and the solution filtered. The THF is removed at reduced pressure and the residue is taken up in ethyl acetate. The ethyl acetate is extracted with 1.0% aqueous sodium bicarbonate and water. The ethyl acetate is then filtered, dried and evaporated to give the title compound.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[C:10]([C:15](=O)[CH3:16])[C:11]([O:13][CH3:14])=[O:12].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[SH:27]>CN(C)C=O.C(OCC)(=O)C>[CH3:16][C:15]1[NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27][CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:19])([F:18])[F:1])[C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(=Cc1ccccc1C(F)(F)F)C(C)=O
Reactant: Nc1ccccc1S
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(C)Nc2ccccc2SC1c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 2-[[2-(trifluoromethyl)phenyl]methylene]-3-oxobutanoic acid, methyl ester (1.8 g., 6.61 mmole) in dimethylformamide (5 ml.) is treated with 2-aminothiophenol (919 mg., 6.61 mmole) at room temperature. The reaction is stirred at room temperature for about 72 hours. The reaction is then heated at 65°-70° (oil bath temperature) for 10 hours. It is cooled to room temperature and diluted with ethyl acetate (50 ml.). The solution is thoroughly washed with water, sodium bicarbonate, and brine. After drying over anhydrous magnesium sulfate, the solvent is stripped off to give a yellow solid. Recrystallization from isopropyl ether-dichloromethane gives 783 mg. of product as fluffy needles. The mother liquor is purified by flash chromatography (20% ethyl acetate in hexane) and the resulting solid is recrystallized from isopropyl ether-dichloromethane to give 153 g. of additional product. Recrystallization from isopropyl ether-dichloromethane gives an analytically pure sample of 2,5-dihydro-4-methyl-2-[2-(trifluoromethyl)phenyl]-1,5-benzothiazepine-3-carboxylic acid, methyl ester; m.p. 165°-166.5°. TLC (silica gel, hexane: ethyl acetate, 60:40) Rf =0.36.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])=CC=1)([O-])=O.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH:34]=1>O1CCCC1>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:43][CH2:42][CH2:41][CH2:40][CH2:39][C:35]1[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=1)=[O:10]
Reactant: NCCCCc1cccnc1
Reactant: COc1ccccc1C(=C/C=C/C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccccc1OC
Solvent: C1CCOC1
Product: COc1ccccc1C(=C/C=C/C(=O)NCCCCc1cccnc1)c1ccccc1OC
Yield: 83.6 %

Procedure:
As before in Example 134, a solution of (E)-5,5-bis(2-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (2.1 g)and 3-pyridinebutanamine (0.9 g) in tetrahydrofuran (20 mL) was stirred overnight at room temperature and then worked up in the normal manner. The crude was purified by HPLC (ethyl acetate) and then crystallized from ether to yield 1.8 g of (E)-5,5-bis(2-methoxyphenyl)-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide, mp 103.5°-104.5° C.