Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[CH2:18])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=1)=[O:4].C(O)(C(F)(F)F)=[O:20].OO>C(Cl)Cl>[C:12]([C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3]([C:2]2([CH3:1])[CH2:18][O:20]2)=[O:4])=[CH:7][C:8]=1[C:14]([F:15])([F:16])[F:17])#[N:13]
Reactant: C=C(C)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Reactant: O=C(O)C(F)(F)F
Agent: OO
Solvent: ClCCl
Product: CC1(C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)CO1
Reaction time: 8 h

Procedure:
2-Methyl-N-(4-cyano-3-trifluoromethyl-phenyl)-acrylamide (1.35 g, 5.0 mmol) in CH2Cl2 (15 ml) was treated by TFA (3.0 ml) at 0° C. To the reaction mixture was then added H2O2 (30%, 1.0 ml, 10.0 mmol) dropwise. The reaction mixture was stirred overnight and quenched by NaHCO3, then extracted by ethyl acetate. The organic layers were combined and dried over Na2SO4, concentrated and purified by silica gel column using hexanes:ethyl acetate 4:1 as eluent to yield the title compound as a white solid.
Reaction SMILES: [P:1](OC)(OC)[O:2][CH3:3].[CH3:8][CH:9]([OH:13])[CH:10]([OH:12])[CH3:11]>CO>[CH3:3][O:2][P:1]1[O:13][CH:9]([CH3:8])[CH:10]([CH3:11])[O:12]1
Reactant: CC(O)C(C)O
Reactant: COP(OC)OC
Solvent: CO
Product: COP1OC(C)C(C)O1
Temperature: 100 °C

Procedure:
A mixture of 300 g of trimethyl phosphite and 200 ml of 2,3-butanediol was heated to 100° C. and the methanol formed was distilled off to obtain 170 g of 2-methoxy-4,5-dimethyl-1,3,2-dioxaphospholane with a boiling point of 66° C. at 20 mm Hg, 37 g of the said product were added over two hours to 62.5 g of tert.-butyl bromoacetate heated to 115° C. under reduced pressure of 140 mm Hg and the volatile products were removed under reduced pressure to obtain 59 g of 2-tert.-butoxycarbonylmethyl-4,5-dimethyl-2-oxo-1,3,2-dioxaphospholane which slowly crystallized.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=O)[CH2:6]1.Cl.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30]N)=[CH:26][CH:25]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:21])[CH:4]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:5]1[CH2:10][CH2:9][C:8]2[C:28]3[C:27](=[CH:26][CH:25]=[C:24]([Cl:23])[CH:29]=3)[NH:30][C:7]=2[CH2:6]1
Reactant: NNc1ccc(Cl)cc1
Reactant: COC(=O)C(C1CCCC(=O)C1)S(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)C(C1CCc2c([nH]c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
To 5 g (0.016 mol) of benzenesulfonyl-(3-oxo-cyclohexyl)-acetic acid methyl ester in glacial acetic acid (30 mL), 3.17 g (0.018 mol, 1.1 eq) of 4-chlorophenylhydrazine hydrochloride were added and the reaction mixture was stirred at 40° C. for 2 hours. An aqueous solution of NaHCO3 was added until pH=7 was reached, and the mixture was extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. A column chromatography on silica gel followed by a trituration from Et2O yielded 4.3 g (64%) of benzenesulfonyl-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-acetic acid methyl ester as a racemic mixture of diastereomers, light brown crystals, MS: 418 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH:12]1[C:24](O)=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH:12]1[CH:24]=[O:25])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1c2[nH]c3ccccc3c2CCN1C(=O)OCc1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=CC1c2[nH]c3ccccc3c2CCN1C(=O)OCc1ccccc1
Reaction time: 4 h

Procedure:
A solution of 1,3,4,9-tetrahydro-beta-carboline-1,2-dicarboxylic acid 2-benzyl ester (3.7 mg, 9.4 mmol) in THF (100 ml) under N2 was cooled to −78° C. 1.5M DIBAL in toluene solution (31.2 ml, 47 mmol) was added over 2 hours. After stirring for 4 hours the reaction mixture was quenched with methanol and water, extracted into EtOAc and washed with dilute aqueous HCl. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. LCMS purity 50%, m/z 335 [M++H]+ The material was used in the next stage without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][N:5]=[C:4]([CH3:10])[C:3]=1[OH:11].Cl.[H-].[Na+].[CH2:15](I)[CH3:16].C(=O)([O-])O.[Na+]>CN(C)C=O.C(OCC)(=O)C.O1CCCC1>[CH2:15]([O:11][C:3]1[C:2]([CH3:1])=[C:7]([CH2:8][OH:9])[CH:6]=[N:5][C:4]=1[CH3:10])[CH3:16]
Reactant: Cc1ncc(CO)c(C)c1O
Reactant: CCI
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1c(C)ncc(CO)c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 44 %

Procedure:
A suspension of 4-deoxypyridoxine hydrochloride (0.99 g, 5.2 mmol) in dimethylformamide (10 ml) was added dropwise to a suspension of 60% NaH (0.42 g, 10.5 mmol) in dimethylformamide (10 ml) while cooling on ice, and the mixture was stirred at room temperature for 1 day. Ethyl iodide (0.44 ml, 5.5 mmol) was then added dropwise at room temperature and stirring was continued for 17 hours. After confirming completion of the reaction by thin layer chromatography, the mixture was poured into semi-saturated aqueous sodium hydrogencarbonate and extraction was performed with ethyl acetate-tetrahydrofuran (1:1). The extract was washed with brine and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: methylene chloride-methanol) to yield the title compound (0.415 g, 44%).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH2:6][O:7][CH2:8][C:9]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)OCC[O:10]1.Cl>C1COCC1>[F:1][C:2]([F:27])([F:28])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:22]=1)[CH2:6][O:7][CH2:8][C:9]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:10]
Reactant: FC(F)(F)c1cc(COCC2(c3ccccc3)OCCO2)cc(C(F)(F)F)c1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Yield: 96.4 %

Procedure:
2-(3,5-Bis(trifluoromethyl)benzyloxymethyl)-2-phenyl-[1,3]dioxolane (50.72 g, 140 mmol) was dissolved in THF (300 mL), 60 mol/L hydrochloric acid (50 mL) was added thereto and the mixture was heated to reflux for 20 hours. After the solvent was evaporated in vacuo, water was added to the residue followed by extracting with chloroform. The organic layers were combined, washed with water and a saturated saline solution and dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo to give 2-(3,5-bis(trifluoromethyl)-benzyloxy)-1-phenylethanone (48.90 g, 96%) as an oily product. 1H-NMR (DMSO-d6) δ: 4.82 (s, 2H), 5.07 (s, 2H), 7.53-7.57 (m, 2H), 7.66-7.69 (m, 1H), 7.94-7.96 (m, 2H), 8.03 (s, 1H), 8.11 (s, 2H).
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([CH3:16])[CH:14]=O)=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C1(C)C=CC=CC=1.Cl>C(O)=O.O>[C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([CH3:16])[CH2:14][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(C)(C)c1ccc(CC(C)C=O)cc1
Reactant: C1CCNCC1
Agent: Cl
Solvent: O=CO
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(C)(C)c1ccc(CC(C)CN2CCCCC2)cc1
Temperature: 75 °C

Procedure:
21.8 G. of 3-(p-tert.-amyl-phenyl)-2-methyl-propionaldehyde and 11.3 g. of piperidine are heated at reflux in 15 ml. of toluene in a water-separator under nitrogen gasification until the water-cleavage has been completed (6 hours). Subsequently, there are added dropwise at room temperature with stirring 6.9 g. of formic acid, the temperature rising to 36°-40° C. Then, the mixture is heated to 75° C. for 2 hours, 50 Ml. of 2 N hydrochloric acid are added to the cooled solution. The toluene solution is separated. The aqueous-hydrochloric acid solution is made alkaline with 40 ml. of 6 N sodium hydroxide and the product is extracted with ether. The combined ether extracts are washed with water, dried over sodium sulfate and evaporated. By distillation, there is obtained pure 1-[3-(p-tert.-amyl-phenyl)-2-methyl-propyl]-piperidine having a boiling point of 160° C./0.15 Torr.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([Br:9])[N:3]=1.[C:10]([O-])([O-])=O.[K+].[K+].CI.O>CS(C)=O>[Br:1][C:2]1[C:7]([O:8][CH3:10])=[CH:6][CH:5]=[C:4]([Br:9])[N:3]=1
Reactant: Oc1ccc(Br)nc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CI
Product: COc1ccc(Br)nc1Br
Temperature: 25 °C

Procedure:
To a solution of 52.5 g 2,6-dibromopyridin-3-ol (example E1) in 90 ml DMSO were added 26.2 g K2CO3 and 43.8 ml methyl iodide and the reaction mixture was stirred under reflux for one hour. The mixture was allowed to cool down to room temperature and poured into 1 l of water and stirred for 3 h at 80° C. After cooling to room temperature the resulting solid was filtered, the filter cake was washed with ice cold water and dried under vacuum to yield the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=[O:4].[CH3:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[C:27](O)=[O:28]>>[F:20][C:16]1[CH:15]=[C:14]([CH:6]([NH:5][C:3]([CH2:2][NH:1][C:27]([C:23]2[S:24][CH:25]=[CH:26][C:22]=2[CH3:21])=[O:28])=[O:4])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: NCC(=O)NC(c1cccc(F)c1)c1cccc(F)c1
Reactant: Cc1ccsc1C(=O)O
Product: Cc1ccsc1C(=O)NCC(=O)NC(c1cccc(F)c1)c1cccc(F)c1

Procedure:
Prepared in analogy to example 1.12 from 2-amino-N-[bis-(3-fluoro-phenyl)-methyl]-acetamide (example 3.4) and 3-methyl-thiophene-2-carboxylic acid.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[N:13]=[CH:14][C:15]3[N:16]([CH:27]=[N:28][CH:29]=3)[C:17]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[O:11])[CH2:4][O:3]1.Cl.O1CCOCC1.S([O-])([O-])(=O)=O.[Na+].[Na+]>CO>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[N:13]=[CH:14][C:15]2[N:16]([CH:27]=[N:28][CH:29]=2)[C:17]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=1[F:26])=[O:11]
Reactant: CC1(C)OC[C@H](CONC(=O)c2ncc3cncn3c2Nc2ccc(I)cc2F)O1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(NOC[C@H](O)CO)c1ncc2cncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.2 %

Procedure:
To a heterogeneous mixture of (R)—N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-5-(2-fluoro-4-iodophenylamino)imidazo[1,5-a]pyrazine-6-carboxamide (69.5 mg, 0.13 mmol) in anhydrous methanol (1.6 mL) was added 4M HCl in 1,4-dioxane (0.13 mL, 0.5 mmol, 4.0 eq). The reaction mixture was stirred at room temperature for 10 minutes. Solid sodium sulfate (200 mg) was then added. The reaction mixture was absorbed onto silica and then subjected to flash chromatography (Si-PPC, gradient 0% to 40% methanol in dichloromethane) to give the title compound as yellow foam (43.2 mg, 67.3%). 1H NMR (DMSO-d6, 400 MHz) δ ppm 11.90 (s, 1H), 10.30 (s, 1H), 8.82 (s, 1H), 7.95 (s, 1H), 7.91 (s, 1H), 7.74 (d, J=9.6 Hz, 1H), 7.44 (d, 8.4 Hz, 1H), 6.60 (t, J=8.4 Hz, 1H), 4.86 (d, J=4.4 Hz, 1H), 4.55 (broad s, 1H), 3.99-3.91 (m, 1H), 3.79-3.69 (m, 2H), 3.39 (broad s, 2H); LCMS (method E2): RT=8.40 min, [M+H]+=488.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([N:22]4[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]4)=[O:21])=[CH:17][CH:18]=3)[N:13]([CH3:31])[CH:12]=2)[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].Cl.C(N1CCC(C2C3C(=CC(C(N4CCN(C(C)C)CC4)=O)=CC=3)NC=2)CC1)C(C)C.BrC[CH:65]([F:67])[F:66]>>[F:66][CH:65]([F:67])[CH2:31][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[C:16]([C:20]([N:22]3[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]3)=[O:21])[CH:15]=2)[C:11]([CH:8]2[CH2:7][CH2:6][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:10][CH2:9]2)=[CH:12]1
Reactant: FC(F)CBr
Reactant: CC(C)CN1CC=C(c2cn(C)c3cc(C(=O)N4CCN(C(C)C)CC4)ccc23)CC1
Agent: CC(C)CN1CCC(c2c[nH]c3cc(C(=O)N4CCN(C(C)C)CC4)ccc23)CC1
Agent: Cl
Product: CC(C)CN1CCC(c2cn(CC(F)F)c3cc(C(=O)N4CCN(C(C)C)CC4)ccc23)CC1

Procedure:
According to the procedure described for the synthesis of [3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-methyl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone; hydrochloride (example 42) the title compound was prepared from [3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 2, free base) and 2-bromo-1,1-difluoroethane (commercially available). MS (m/e): 475.2 (MH+).
Reaction SMILES: [CH:1]#[C:2][C:3]([NH2:6])([CH3:5])[CH3:4].C(N(CC)CC)C.[CH3:14][Si:15]([CH3:18])([CH3:17])Cl>O1CCCC1>[CH:1]#[C:2][C:3]([NH:6][Si:15]([CH3:18])([CH3:17])[CH3:14])([CH3:5])[CH3:4]
Reactant: C[Si](C)(C)Cl
Reactant: C#CC(C)(C)N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CC(C)(C)N[Si](C)(C)C
Reaction time: 1.5 h

Procedure:
In a 5000 ml flask were combined 250 g of commercial HC≡CCMe2NH2, 581.8 g of triethylamine, and 1637.5 g of tetrahydrofuran solvent. The flask and contents were cooled at 17° and addition of 625.5 g of trimethylchlorosilane begun with rapid stirring under nitrogen. The addition was completed in 90 min, followed by stirring for 85 min. Analysis by gas chromatography (GC) showed a small amount of HC≡CCMe2NH2, which was converted to product by an additional 53.4 g of trimethylchlorosilane. Reaction mixture was pressure-filtered and the solids triturated with fresh tetrahydrofuran and refiltered. The organic solutions were combined and distilled, providing the desired product, HC≡CCMe2NHSiMe3, as a liquid boiling at 135° at atmospheric pressure. Its structure was confirmed by NMR analysis.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:11]=1[C:12](=[O:15])[CH2:13]Br)[CH3:8].[SH:21][C:22]1[N:29]=[CH:28][CH:27]=[CH:26][C:23]=1[C:24]#[N:25]>CN(C=O)C.C(OCC)(=O)C>[NH2:25][C:24]1[C:23]2[C:22](=[N:29][CH:28]=[CH:27][CH:26]=2)[S:21][C:13]=1[C:12](=[O:15])[C:11]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:10]=1[O:9][CH2:7][CH3:8]
Reactant: N#Cc1cccnc1S
Reactant: CCOc1ccc(F)cc1C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccc(F)cc1C(=O)c1sc2ncccc2c1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of potassium carbonate (0.189 g, 1.37 mmol), 2-ethoxy-5-fluorophenacyl bromide and 2-mercaptonicotine nitrile in dry DMF (8 ml) is stirred at room temperature for 16 h. The resulting mixture is diluted with ethyl acetate and washed with water. Drying over sodium sulfate, filtering, evaporating the solvent and purification of the residue by silicagel column chromatography yields the title compound, having a m.p. of 130° C.
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:17]=[C:18]([CH2:23][C:24](O)=[O:25])[CH:19]=[CH:20][C:21]=1[Cl:22]>>[C:1]([C:5]1[C:6]([NH:14][C:24](=[O:25])[CH2:23][C:18]2[CH:19]=[CH:20][C:21]([Cl:22])=[C:16]([Cl:15])[CH:17]=2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Product: CC(C)(C)c1c(NC(=O)Cc2ccc(Cl)c(Cl)c2)nn2cccnc12

Procedure:
The product from Example 105B and 2-(3,4-dichlorophenyl)acetic acid were processed using the method analogous to that described in Example 137 to afford the title compound. 1H NMR (400 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.87 (d, J=5.9 Hz, 1H), 8.49 (dd, J=4.0, 1.8 Hz, 1H), 7.59-7.62 (m, 2H), 7.32-7.36 (m, 1H), 7.01 (dd, J=7.0, 4.0 Hz, 1H), 3.67-3.70 (bs, 2H), 1.39 (s, 9H); MS (ESI) m/z 377, 379 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6](=[O:12])[CH2:5]2.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:31][C:32]1[CH:33]=[N:34][C:35]([N:38]2[CH2:43][CH2:42][CH:41]([C@H:44]3[CH2:46][C@H:45]3[CH2:47][CH:48]=O)[CH2:40][CH2:39]2)=[N:36][CH:37]=1>ClCCCl.CCOC(C)=O>[Cl:31][C:32]1[CH:33]=[N:34][C:35]([N:38]2[CH2:43][CH2:42][CH:41]([C@H:44]3[CH2:46][C@H:45]3[CH2:47][CH2:48][NH:1][C:2]3[CH:3]=[C:4]4[C:8](=[C:9]([F:11])[CH:10]=3)[NH:7][C:6](=[O:12])[CH2:5]4)[CH2:40][CH2:39]2)=[N:36][CH:37]=1
Reactant: Nc1cc(F)c2c(c1)CC(=O)N2
Reactant: O=CC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C1Cc2cc(NCC[C@@H]3C[C@@H]3C3CCN(c4ncc(Cl)cn4)CC3)cc(F)c2N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-amino-7-fluoro-1,3-dihydro-2H-indol-2-one from step 2 of this example (33 mg, 0.20 mmol) was slurried in DCE (0.9 ml) and acetic acid (51 uL, 0.89 mmol) and NaBH(OAc)3 (76 mg, 0.36 mmol) added. {(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}acetaldehyde (50 mg, 0.18 mmol) from Example 3 was added and the mixture stirred at RT for 2 hours. The mixture was diluted with EtOAc (30 ml), and partitioned across 4:1 water:saturated sodium bicarbonate (50 ml). The layers were separated, the aqueous phase extracted with EtOAc (2×30 ml), the organic fractions combined, dried over Na2SO4, filtered, and the volatiles removed in vacuum. The product was purified by chromatography on SiO2 eluting with 40% acetone:hexanes. This was followed by a second purification using chromatography on SiO2 eluting with 30% acetone:hexanes to give the titled compound. LRMS calc: 429.17; obs: 430.19 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)([CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:30])[C:5]([O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)([CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(Cl)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
2-(4-Chlorophenoxy-3-(4-benzyloxyphenyl)-2-methyl-propionic acid ethyl ester (2.1 mmol) was dissolved in ethyl acetate (30 mL) and treated with 5% palladium on carbon (300 mg), and stirred under an atmosphere of hydrogen for 1 h. The suspension was filtered through celite and concentrated in vacuo to an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.Br[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4](=[O:8])[CH:3]=1
Reactant: O=c1cc(Br)cc[nH]1
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)Cn1ccc(Br)cc1=O

Procedure:
4.9 g (28.4 mmol) of 4-bromopyridin-2(1H)-one and 1.2 eq. of tert-butyl 2-bromoacetate were reacted according to General Method 4B at 120° C. After aqueous work-up, the crude product was reacted further without further purification. Yield: 8.6 g (purity 91%, 95% of theory)
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH2:6][O:7][C:8](=[O:21])[C@H:9]([CH:18]([CH3:20])[CH3:19])[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:3]([OH:5])=[O:4].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:41][CH2:42]I>O1CCOCC1>[Cl:41][CH2:42][O:4][C:3](=[O:5])[C:2]([CH3:1])([CH3:22])[CH2:6][O:7][C:8](=[O:21])[C@H:9]([CH:18]([CH3:19])[CH3:20])[NH:10][C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12]
Reactant: ClCI
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(C)(C)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(C)(C)C(=O)OCCl
Reaction time: 18 h

Procedure:
2,2-dimethyl-3-(N-Boc-L-valyloxy)propionic acid (3.9 g, 12.3 mmole) was dissolved in dioxane (60 ml). To the solution was added tetrabutylammonium hydroxide aqueous solution (40%, 7.78 ml, 12 mmole). The solution was dried in vacuo, and it was coevaporated with toluene for several times. The residue was dissolved in methylene chloride and then chloroiodomethane (18.9 ml, 260 mmole) was added to the solution. After 18 hr, the reaction solution was evaporated and the product was isolated with silica gel column chromatography to yield 3.7 g.
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([I:18])=[C:5]([NH:10]C(=O)OC(C)(C)C)[C:6]([F:9])=[CH:7][CH:8]=1>O1CCOCC1.C1COCC1>[F:2][C:3]1[C:4]([I:18])=[C:5]([C:6]([F:9])=[CH:7][CH:8]=1)[NH2:10]
Reactant: CC(C)(C)OC(=O)Nc1c(F)ccc(F)c1I
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Nc1c(F)ccc(F)c1I
Reaction time: 8 h
Yield: 48 %

Procedure:
4M HCl (7.60 mL, 30.4 mmol) in dioxane was added to a solution of tert-butyl (3,6-difluoro-2-iodophenyl)carbamate (1.08 g, 3.04 mmol) in THF (7.60 ml) at room temperature and then stirred overnight. The solvent was removed in vacuo, and then the contents were partitioned between DCM (3×50 mL) and sat'd aqueous sodium bicarbonate. The organics were dried over MgSO4, filtered and concentrated. The crude material was purified on silica gel, eluting 0-50% EtOAc in hexanes over 16 minutes to afford 3,6-difluoro-2-iodoaniline (373 mg, 1.46 mmol) as a tan oil. MS (ESI): m/z=256.2 (M+H-Boc).
Reaction SMILES: [C:1]1(=[O:7])[CH2:5][CH2:4][C:3](=[O:6])[CH2:2]1.[C:8]12([C:18]3[CH:19]=[C:20]([C:26]4[CH:27]=[C:28]5[C:33](=[CH:34][CH:35]=4)[CH:32]=[C:31](OS(C4C=CC(C)=CC=4)(=O)=O)[CH:30]=[CH:29]5)[CH:21]=[CH:22][C:23]=3[O:24][CH3:25])[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[C:8]12([C:18]3[CH:19]=[C:20]([C:26]4[CH:27]=[C:28]5[C:33](=[CH:34][CH:35]=4)[CH:32]=[C:31]([C:2]4[C:1](=[O:7])[CH2:5][CH2:4][C:3]=4[OH:6])[CH:30]=[CH:29]5)[CH:21]=[CH:22][C:23]=3[O:24][CH3:25])[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2
Reactant: O=C1CCC(=O)C1
Reactant: COc1ccc(-c2ccc3cc(OS(=O)(=O)c4ccc(C)cc4)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Product: COc1ccc(-c2ccc3cc(C4=C(O)CCC4=O)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 100 °C

Procedure:
A flame-dried Schlenk tube containing a Teflon coated stir bar was charged with Pd(OAc)2 (20 mg, 0.088 mmol), (2-dicyclohexylphosphino)-2′,4′,6′-triisopropyl biphenyl (105 mg, 0.22 mmol), 1,3-cyclopentanedione (65 mg, 0.66 mmol), toluene-4-sulfonic acid 6-(3-adamantan-1-yl-4-methoxyphenyl)-naphthalen-2-yl ester (238 mg, 0.44 mmol) and finely ground K3PO4 (233 mg, 1.1 mmol). The tube was capped with a septum, evacuated and backfilled with nitrogen three times, 2 mL of dry dioxane was injected and the mixture was heated to 100° C. for 3 h. The mixture was then cooled, diluted with EtOAc, washed with 1N HCl, dried over Na2SO4 and filtered. The filtrate was concentrated and purified by flash chromatography using MeOH—CH2Cl2.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[S:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][NH:9][CH2:8][CH2:7]1>ClCCl>[C:1]([N:9]1[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:6][CH2:7][CH2:8]1)(=[O:4])[CH2:2][CH3:3]
Reactant: c1ccc2c(c1)CNCCS2
Reactant: CCC(=O)Cl
Solvent: ClCCl
Product: CCC(=O)N1CCSc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of propionyl chloride (2.39 g) in dichloromethane (50 ml) was added dropwise at room temperature to a stirred solution of 2,3,4,5-tetrahydro-1,4-benzothiazepine (8.58 g, prepared as described in the first paragraph of Example 6 above) in dichloromethane (100 ml). The reaction mixture was stirred at room temperature for 45 minutes, washed with water, dried and the solvent was removed by evaporation. Purification of the residue by flash chromatography using dichloromethane/ethanol (98:2) as eluent gave 4-propionyl-2,3,4,5-tetrahydro-1,4-benzothiazepine as an oil. Yield 2.9 g.