Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][C:11](=[O:13])[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][C:21](C)([O-])[CH3:22].[K+].C(Br)C#C>CN(C=O)C.C1(C)C=CC=CC=1.CCOCC>[C:1]1([C:7]2[N:12]([CH2:22][C:21]#[CH:20])[C:11](=[O:13])[CH2:10][CH:9]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CC(c2ccccc2)NC(c2ccccc2)=N1
Agent: C#CCBr
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C#CCN1C(=O)CC(c2ccccc2)N=C1c1ccccc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a stirred solution of 3.95 g (15.8 mmol) of 5,6-dihydro-2,6-diphenylpyrimidin-4-one in 15 mL of DMF was added 2.07 g (18.5 mmol) of solid potassium t-butoxide. The mixture was stirred for 10 rain and 2.60 g (17.5 mmol) of an 80% by weight solution of propargyl bromide in toluene was added. The mixture was stirred at room temperature for 4 days, diluted with 175 mL of ether, washed with four 50 mL portions of water and dried over MgSO4. Removal of the solvent on the rotovap left 2.47 g of crude product which was purified by flash chromatography on silica gel eluted with an ether-hexane gradient to afford 0.72 g of 5,6-dihydro-2,6-diphenyl-3-propargylpyrimidin-4-one (Compound 15) as an oil.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[Cl:15][C:16]1[CH:17]=[C:18]([C@@H:26]([CH2:40][CH:41]2[CH2:45]C[CH2:43][CH2:42]2)[C:27](NC2C=CN(CCC(O)=O)N=2)=[O:28])[CH:19]=[CH:20][C:21]=1[S:22]([CH3:25])(=O)=O.ICC1C[CH2:51][O:50]C1.CN1CCCN(C)C1=[O:61]>O1CCCC1.C(OCC)(=O)C>[CH3:51][O:50][C:27](=[O:28])[CH:26]([C:18]1[CH:19]=[CH:20][C:21]([S:22][CH3:25])=[C:16]([Cl:15])[CH:17]=1)[CH2:40][CH:41]1[CH2:42][CH2:43][O:61][CH2:45]1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)O)n2)cc1Cl
Reactant: CN1CCCN(C)C1=O
Reactant: ICC1CCOC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCOC1)c1ccc(SC)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 76.4 %

Procedure:
In a round bottom flask was placed tetrahydrofuran (20 mL) and 1,1,1,3,3,3-hexamethyldisilazane (0.97 mL, 4.66 mmol) and it was cooled to −78° C. in a dry ice/acetone bath. To this cooled solution was then added n-butyl lithium (2.5 M solution in hexanes, 1.75 mL, 4.37 mmol) and it was stirred for 15 min at −78° C. To this was then added a solution of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid methyl ester (prepared as in PCT WO 2003/095438 A1, Example 4, 0.96 g, 4.16 mmol) in tetrahydrofuran (6 mL) dropwise. The reaction was then stirred for 15 min at −78° C. then at 0° C. for 1 h which resulted in a yellow solution. After such time, the reaction was cooled back to −78° C. and a solution of 3-iodomethyl-tetrahydro-furan (1.32 g, 6.23 mmol) in tetrahydrofuran (6 ml) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.75 mL, 6.24 mmol) was added dropwise at −78° C. The reaction was stirred at −78° C. for 15 min, at 0° C. for 2.5 h and then was stored in a freezer overnight. After such time, the reaction was diluted with ethyl acetate and washed with a saturated aqueous ammonium chloride solution followed by a saturated sodium chloride solution wash. The organics were dried over sodium sulfate, filtered and then concentrated in vacuo. Purification on an AnaLogix Intelliflash system (120 g column, 20% ethyl acetate/hexanes to 30% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-(tetrahydro-furan-3-yl)-propionic acid methyl ester (1.0 g, 77%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ ppm 1.42-1.62 (m, 1H, CH of CH2), 1.79-1.94 (m, 1H, CH of CH2), 1.94-2.21 (m, 3H, CH and CH2), 2.47 (s, 3H, SCH3), 3.26-3.38 (m, 1H, OCH of OCH2), 3.45-3.52 (m, 1H, ArCH), 3.65-3.75 (m, 1H, OCH of OCH2), 3.67 (s, 3H, OCH3), 3.76-3.94 (m, 2H, 2×OCH of OCH2), 7.11 (d, Jo=8.2 Hz, 1H, Ar), 7.19 (dd, Jo=8.2 Hz, Jm=1.7 Hz, 1H, Ar), 7.30 (d, Jm=1.7 Hz, 1H, Ar).
Reaction SMILES: Br[C:2]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:34])[C:26]2[C:31]([Cl:32])=[CH:30][N:29]=[CH:28][C:27]=2[Cl:33])=[CH:20][CH:19]=1)=[C:3]([NH:8][C:9]([C:11]1[C:12]([Cl:17])=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10])[C:4]([O:6][CH3:7])=[O:5].[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>COCCOC.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:17][C:12]1[C:11]([C:9]([NH:8][C:3](=[C:2]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:34])[C:26]3[C:31]([Cl:32])=[CH:30][N:29]=[CH:28][C:27]=3[Cl:33])=[CH:20][CH:19]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:4]([O:6][CH3:7])=[O:5])=[O:10])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)C(NC(=O)c1cccnc1Cl)=C(Br)c1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1
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: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: COC(=O)C(NC(=O)c1cccnc1Cl)=C(c1ccccc1)c1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1

Procedure:
Tetrakis(triphenylphosphine)palladium (O) (10 mol %, 58 mg) was added to a mixture of the compound of Example 13, Isomer A (288 mg, 0.493 mmol) and phenyl boronic acid (90 mg, 0.74 mmol) in DME (10 ml) and sodium carbonate (2M, 0.986 mmol, 0.493 ml). The mixture was heated at 80° overnight, dlute with CH2Cl2 (200 ml), washed with diluted HCl and sodium hydrogen carbonate solution, dried (Na2SO4) and evaporated in vacuo. Chromatography (SiO2; CH2Cl2/MeOH, 93:7) gave the title compound as a white solid (133 mg). δH (DMSO-d6), 11.04 (1H, s, CONH), 10.40 (1H, s, CONH), 8.79 (2H, s, Cl2PyH), 8.48 (1H, dd, J 4.9, 1.9 Hz, PyH), 7.85 (1H, dd, J 7.5, 1.9 Hz, PyH), 7.66 (2H, d, J 8.7 Hz, ArH), 7.51 (1H, dd, J 7.5, 4.9 Hz, PyH), 7.39-7.35 (3H, m, ArH), 7.23 (2H, d, J 8.7 Hz, ArH), 7.07 (2H, m, ArH) and 3.45 (3H, s, CO2Me); m/z (ESI, 60V) 581 (MH+).
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([N:5]([CH2:14][CH3:15])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)[CH3:4].[C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])[CH3:17]>C(O)C>[CH2:3]([N:5]([CH2:14][CH3:15])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]([CH2:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:1])[CH2:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])=[CH:8][CH:7]=1)[CH3:4]
Reactant: CC(=O)c1ccccc1
Reactant: CCN(CC)c1ccc(C=O)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CCN(CC)c1ccc(C(CC(=O)c2ccccc2)CC(=O)c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
18 g of 50% by weight sodium hydroxide solution were added dropwise to 17.7 g of p-diethylaminobenzaldehyde and 26.4 g of acetophenone in 150 ml of ethanol at 20° C. The mixture was then stirred at 20° C. for 2 hours and at 50° C. for 5 hours. The precipitate was filtered off and washed with ethanol until the residue was only pale yellowish and then with water until neutral. 33.6 g of 3-(p-diethylaminophenyl) -1,5-diphenylpentane-1,5-dione were obtained. The almost colorless crystals melt at 110° C.
Reaction SMILES: [Br:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1>>[BrH:1].[CH2:6]([O:5][C:3](=[O:4])[CH2:2][N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]1=[NH:8])[CH3:7]
Reactant: Nc1ccccn1
Reactant: CCOC(=O)CBr
Product: Br
Product: CCOC(=O)Cn1ccccc1=N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 39 mL (0.35 mol) of ethyl bromoacetate is added 9.4 g (0.1 mol) of 2-aminopyridine portionwise at 0° C. The resulting mixture is allowed to warm to room temperature and stirred at this temperature for 30 minutes. The precipitate is collected and washed with hexane to give the desired compound as light tan solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.[C:18]1([NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH2:24]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:25][C:18]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:24]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccccc1N
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccccc1
Solvent: CCO
Product: Brc1ccc(-c2nc3ccccc3nc2-c2ccccc2)cc1
Yield: 69.7 %

Procedure:
8.2 g (29 mmol) of 1-(4-bromophenyl)-2-phenylethanedione, 3.1 g (31 mmol) of o-phenylenediamine, and 100 mL of ethanol were placed into a 300-mL flask, and the mixture was refluxed for 2 hours. After the reaction, the precipitated solid was collected by suction filtration. The collected solid washed with ethanol and dried. 7.3 g of a light-yellow solid was obtained as the target substrate in 69% yield.
Reaction SMILES: C(Cl)CCl.ClC1C=CC(C(NC2C=CC(OC)=CC=2)C(F)(F)F)=C(C=1)C[NH:12][C:13](=[O:19])[C@@H:14]1[CH2:18][CH2:17][CH2:16][NH:15]1.[C:35]([OH:45])(=O)[C@@H:36]([CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[OH:37].C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[CH:38]1([C@@H:36]([OH:37])[C:35]([N:15]2[CH2:16][CH2:17][CH2:18][C@H:14]2[C:13]([NH2:12])=[O:19])=[O:45])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: COc1ccc(NC(c2ccc(Cl)cc2CNC(=O)[C@@H]2CCCN2)C(F)(F)F)cc1
Reactant: O=C(O)[C@H](O)C1CCCCC1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: NC(=O)[C@@H]1CCCN1C(=O)[C@H](O)C1CCCCC1
Reaction time: 16 h
Yield: 116.4 %

Procedure:
EDC (44.0 mg, 0.23 mmol) was added to a stirred mixture of N-(5-chloro -2-{1-[(4-methoxyphenyl)amino]-2,2,2-trifluoroethyl}benzyl)-L-prolinamide (68 mg, 0.15 mmol), (R)-(−)-hexahydromandelic acid (24.2 mg, 0.15 mmol) and HOAT (10.4 mg, 0.076 mmol), in DMF (2 mL). After 16 h, the mixture was concentrated and the residue was partitioned between EtOAc and 10% NaHCO3 solution. The organic layer was washed with water and brine, dried (Na2SO4) and evaporated. The residue was purified by chromatography on silica (eluting with EtOAc/CHCl3, 1:2) to give N-(5-chloro-2-{1-[(4-methoxyphenyl)amino]-2,2,2-trifluoroethyl)}benzyl)-1-[(2R)-2-cyclohexyl-2-hydroxyethanoyl]-L-prolinamide (44.4 mg) as a glass: MS: 582.4 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].Br.[Br:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20]Br.C(=O)([O-])[O-].[Na+].[Na+]>CO>[BrH:15].[CH3:13][O:12][C:8]1[CH:7]=[C:5]([N:6]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:4]=[C:3]([O:2][CH3:1])[C:9]=1[O:10][CH3:11]
Reactant: BrCCNCCBr
Reactant: COc1cc(N)cc(OC)c1OC
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(N2CCNCC2)cc(OC)c1OC
Temperature: 25 °C
Yield: 114.2 %

Procedure:
18.3 grams of 3,4,5-trimethoxyaniline and 31.2 g of bis(β-bromoethyl)amine monohydrobromide are mixed with 170 ml of methanol and refluxed by heating under a nitrogen gas stream for 10 hours. After cooling the reaction mixture, 5.3 g of anhydrous sodium carbonate are added to the mixture and refluxed by heating for additional 10 hours. Under reduced pressure, about 70 ml of methanol are removed off by distillation, and the mixture is allowed to staand to cool at room temperature. The crystals thus precipitated are collected by filtration and washed with a small amount of ethanol. Recrystallization from ethanol obtains 38 g of 4-(3,4,5-trimethoxyphenyl)piperazine monohydrobromide in the form of colorless plate-like crystals with a melting point of 227°-228° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[NH:14][C:13]1=[O:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:33][C:34]#[N:35]>CN(C)C=O>[C:34]([CH2:33][N:14]1[C:15]2[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=2[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:18][CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[C:13]1=[O:29])#[N:35]
Reactant: N#CCCl
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCN1C(=O)C(NC(=O)OCc2ccccc2)N=C(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
1,3-Dihydro-3(R,S)-[(benzyloxycarbonyl)amino]-5-phenyl-2H-1,4-benzodiazepin-2-one (1.5 g) was dissolved in 25 ml of dry N,N-dimethylformamide at 0° C. To this solution was added 218 mg of (60%) sodium hydride and the resulting reaction mixture was stirred for 15 minutes. Chloroacetonitrile in 1 ml of dry N,N-dimethylformamide was then added and the reaction mixture was allowed to warm to room temperature. After 1 hour the reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and 10% citric acid solution. The organic phase was washed with brine, then dried (sodium sulfate), and concentrated to give a solid. The title compound (1.53 g, 93%) was obtained in pure form after flash silica gel chromatography employing ethyl acetate-hexane (1:2 v/v) as eluant.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4][CH2:3]1.[CH2:14]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH:34](OS(C)(=O)=O)[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:26][CH2:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OC(=O)C)C>[CH2:14]([O:21][C:22]([N:24]1[CH2:25][CH2:26][CH:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH:34]([NH:1][C@@H:2]2[C:8](=[O:9])[NH:7][C:6]3[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=3[S:4][CH2:3]2)[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:28][CH2:29]1)=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)OS(C)(=O)=O
Reactant: N[C@H]1CSc2ccccc2NC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CSc2ccccc2NC1=O
Yield: 44.2 %

Procedure:
A mixture of 3(R)-amino-2,3-dihydro-1,5(5H)-benzothiazepin-4-one (2.7 g) and ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-methanesulfonyloxyhexanoate (5.4 g) is heated at 100°-130° C. for 3 hours. After cooling, the mixture is dissolved in ethylacetate (200 ml) and the solution is washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 3(R)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]amino-2,3-dihydro-1,5(5H)-benzothiazepin-4-one (2.9 g) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:26])[C:15]2[CH:20]=[C:19]([Cl:21])[N:18]=[C:17]([C:22](O)=[O:23])[C:16]=2[Cl:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:69][CH2:70][C:71]1[C:72](=[O:79])[NH:73][C:74]([CH3:78])=[CH:75][C:76]=1[CH3:77]>CN(C=O)C>[Cl:25][C:16]1[C:17]([C:22](=[O:23])[NH:69][CH2:70][C:71]2[C:72](=[O:79])[NH:73][C:74]([CH3:78])=[CH:75][C:76]=2[CH3:77])=[N:18][C:19]([Cl:21])=[CH:20][C:15]=1[N:14]([CH3:26])[CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: CN(c1cc(Cl)nc(C(=O)O)c1Cl)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(CNC(=O)c2nc(Cl)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2Cl)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-({1-[(tert-butoxy)carbonyl]piperidin-4-yl}(methyl)amino)-3,6-dichloropyridine-2-carboxylic acid (75 mg, 0.19 mmol) in DMF (2 ml) cooled to 0° C. h was added DIPEA (48 μl, 0.28 mmol) followed by PyBOP (116 mg, 0.22 mmol) and 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89% purity, 35 mg, 0.2 mmol). The reaction mixture was then stirred at room temperature for 16 h after which the reaction was poured onto water (30 ml) and extracted with EtOAc (3×50 ml) after which the combined organics were washed with brine (50 ml) and dried (Na2SO4) and evaporated. The crude product was purified using a 5 g silica Isolute column eluting with a gradient of 0% to 100% EtOAc in heptane to afford the title compound as a white solid which contained ˜45% w/w tripyrrolidinophosphene oxide by NMR—this compound was used in the next stage of the synthesis without any further purification. LC-MS 93%, 1.97 min (3.5 minute LC-MS method), m/z=538.0/539.45/542.05, 1H NMR (500 MHz, Chloroform-d) δ 10.03 (br. s, 1H), 8.13-7.97 (m, 1H), 6.79 (s, 1H), 5.87 (s, 1H), 4.50 (d, J=6.1 Hz, 2H), 4.16 (br. m, 2H), 3.78-3.62 (m, 1H), 2.72 (s, 3H), 2.65 (br. m, 2H), 2.35 (s, 3H), 2.22 (s, 3H), 1.73-1.63 (m, 4H), 1.44 (s, 9H).
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:21])[CH:7](OC(=O)C)[NH:8][C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10])[CH2:2][CH2:3][CH3:4].[C:22]1([O:28][CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]([O:5][C:6](=[O:21])[CH:7]([C:25]1[CH:26]=[CH:27][C:22]([O:28][CH3:29])=[CH:23][CH:24]=1)[NH:8][C:9]([O:11][CH2:12][C:13]([Cl:14])([Cl:15])[Cl:16])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)C(NC(=O)OCC(Cl)(Cl)Cl)OC(C)=O
Reactant: COc1ccccc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCOC(=O)C(NC(=O)OCC(Cl)(Cl)Cl)c1ccc(OC)cc1

Procedure:
A solution of 0.91 g. (3.0 mmol.) of N-(β,β,β-trichloroethoxycarbonyl)-2-acetoxyglycine n-butyl ester and 0.3 g. (2.8 mmol.) of anisole in 20 ml. of methylene chloride containing two drops of boron trifluoride etherate was maintained at 25° for 5 hours. The solvent was then evaporated in vacuo and 2:1 hexane-methylene chloride was added. Chromatography on silica gel with methylene chloride containing increasing amounts of ethyl acetate gave the title compound.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Br:4][C:5]1[CH:6]=[C:7](F)[CH:8]=[C:9]([Br:11])[CH:10]=1>CO.CN(C)C=O>[Br:4][C:5]1[CH:6]=[C:7]([O:2][CH3:1])[CH:8]=[C:9]([Br:11])[CH:10]=1
Reactant: Fc1cc(Br)cc(Br)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium methoxide (8.80 ml of a 4.5M solution in methanol, 39.6 mmol) was added dropwise to a stirred solution of 3,5-dibromofluorobenzene (5.00 g, 19.0 mmol) in N,N-dimethylformamide (95 ml) at 0° C. under nitrogen. The reaction was allowed to warm to room temperature, stirred for 1 hour and then concentrated under reduced pressure. The residue was dissolved in ether (500 ml) and the resulting solution was washed with water (3×300 ml) and brine (300 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to provide the title compound (5.13 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:35][C:36]([OH:38])=[O:37])[CH:5]=[CH:6][C:7]=1[N:8]1[C:16](=[O:17])[C:15]2[C:14]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[C:13]3[CH:24]=[CH:25][CH:26]=[CH:27][C:12]3=[C:11]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:10]=2[C:9]1=[O:34].[BH4-].[Na+]>C(O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:35][C:36]([OH:38])=[O:37])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:16]([OH:17])[C:15]2[C:14]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[C:13]3[CH:24]=[CH:25][CH:26]=[CH:27][C:12]3=[C:11]([O:28][CH2:29][C:30]([F:32])([F:33])[F:31])[C:10]=2[C:9]1=[O:34]
Reactant: O=C(O)Cc1ccc(N2C(=O)c3c(c(OCC(F)(F)F)c4ccccc4c3OCC(F)(F)F)C2=O)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)Cc1ccc(N2C(=O)c3c(c(OCC(F)(F)F)c4ccccc4c3OCC(F)(F)F)C2O)c(Cl)c1
Reaction time: 0.17 h
Yield: 93.3 %

Procedure:
To a solution of (3-chloro-4-{1,3-dioxo-4,9-bis[(2,2,2-trifluoroethyl)oxy]-1,3-dihydro-2H-benzo[f]isoindol-2-yl}phenyl)acetic acid (0.250 g, 0.45 mmol) in ethanol (10 ml) and tetrahydrofuran (20 ml), was added sodium borohydride (0.059 g, 1.56 mmol) in portions. A further addition of sodium borohydride (0.059 g, 1.56 mmol) was made and stirring continued for 10 minutes. The mixture was evaporated and then quenched with aqueous saturated ammonium chloride solution until the mixture was pH 7. This was extracted ×2 with ethyl acetate, washed with brine, dried over magnesium sulphate and evaporated to give the crude product (0.235 g, 0.42 mmol). LC/MS: Rt=3.28, [MH]+564.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.S(Cl)(Cl)=O.[NH2:13][C:14]([CH3:18])([CH3:17])[CH2:15]O.C(N(CC)CC)C>C(#N)C>[NH:1]1[CH:5]=[C:4]([C:6]2[O:8][CH2:15][C:14]([CH3:18])([CH3:17])[N:13]=2)[N:3]=[CH:2]1
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1c[nH]cn1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CC1(C)COC(c2c[nH]cn2)=N1
Temperature: 25 °C
Reaction time: 5 h
Yield: 60 %

Procedure:
4-Imidazolecarboxylic acid (2 grams, 17.9 mmol) and thionyl chloride (5 mL, 68.5 mmol) were heated to reflux in anhydrous acetonitrile (50 mL) under nitrogen for 1 hour. Then all volatile was removed under vacuum. The conversion to acid chloride is almost quantitative. To a solution of imidazole acid chloride in anhydrous acetonitrile (10 mL) was added dropwise a solution of 2-amino-2-methyl-1-propanol) (2.1 g, 21.4 mmol) and triethylamine (3.0 mL, 21.4 mmol) in anhydrous acetonitrile (10 mL) at 0° C. under N2. After the addition, the ice-bath was removed and the mixture was stirred at room temperature for 5 hours. The white solid of triethylamine hydrochloride was filtered out. Solvent and excess aminoalcohol were removed under vacuum. Dark brown oil was obtained. The dark brown oil was dissolved in hot acetonitrile (20 mL). After the solution was cooled down, a solution of thionyl chloride (5 mL) in anhydrous acetonitrile (10 mL) was added dropwise at 0° C. After stirring at room temperature for 2 hours, all volatile was removed under vacuum. To the oily residue was added acetonitrile (20 mL) and 10% aqueous potassium carbonate solution (20 mL). The mixture was heated to reflux for 2 hours. Two layers were observed after the mixture was cooled down. The water layer was discarded. Sodium bicarbonate solution was added to the organic layer, and the resulting mixture was extracted with ethyl acetate 3 times. After drying over magnesium sulfate and removal of solvent, flash chromatography (ethyl acetate:methanol=4:1) yielded pure 2-(imidazol-4-yl)-4,4-dimethyloxazoline as brown oil (1.75 g, 60%). 1H NMR (acetone-d6) δ1.35 (s, 6H), 4.10 (s, 2H), 7.58(s, 1H), 7.85(s, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:9]2[CH:10]=[C:11]([O:19][CH:20]([CH3:22])[CH3:21])[C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:8]=2[O:7][C:6]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:37][C:38](=[O:40])[CH3:39]>CC(=O)CC>[CH3:1][NH:2][C:3]([C:5]1[C:9]2[CH:10]=[C:11]([O:19][CH:20]([CH3:22])[CH3:21])[C:12]([N:14]([S:15]([CH3:18])(=[O:16])=[O:17])[CH2:37][C:38](=[O:40])[CH3:39])=[CH:13][C:8]=2[O:7][C:6]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[O:4]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(OC(C)C)cc12
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(CC(C)=O)S(C)(=O)=O)c(OC(C)C)cc12
Temperature: 25 °C
Yield: 94 %

Procedure:
2-(4-Fluoro-phenyl)-5-isopropoxy-6-methanesulfonylamino-benzofuran-3-carboxylic acid methylamide (0.093 g, 0.221 mmol, which can be prepared according to one of the procedures described in Example 21) was dissolved in 2-butanone (20 mL). Potassium carbonate (0.20 g, 1.45 mmol) and chloroacetone (0.10 mL, 1.25 mmol) were added at 20° C. The reaction mixture was refluxed for 2 hours, cooled to room temperature and concentrated. The crude product was dissolved in ethyl acetate and washed with 1M hydrochloric acid. The organic layer was concentrated, and the product was purified by flash chromatography (silica gel, ethyl acetate/hexanes gradient) to provide 99 mg (94%) of the title compound as a white solid