Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[N:11]1([CH2:16][C:17]2[CH:18]=[CH:19][C:20](Br)=[N:21][CH:22]=2)[CH:15]=[CH:14][N:13]=[CH:12]1>>[F:1][C:2]1[CH:3]=[C:4]([C:20]2[CH:19]=[CH:18][C:17]([CH2:16][N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)=[CH:22][N:21]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Product: Fc1cccc(-c2ccc(Cn3ccnc3)cn2)c1

Procedure:
Synthesized using 3-fluorophenylboronic acid (230 mg, 1.68 mmol) and 1a (200 mg, 0.84 mmol) according to Method C. Yellow solid. Yield: 135 mg, 0.53 mmol, 64%. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.19 (s, 2H), 6.93 (s, 1H), 7.11 (ddd, J=8.2, 2.5, 0.9 Hz, 1H), 7.13 (dd, J=2.5, 0.9 Hz, 1H), 7.43 (ddd, J=8.2, 7.9, 6.0 Hz, 1H), 7.50 (dd, J=8.2, 2.5 Hz, 1H), 7.59 (brs, 1H), 7.69-7.76 (m, 3H), 8.58 (dd, J=2.2, 0.6 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.0, 113.9 (d, J=23.0 Hz), 116.1 (d, J=21.1 Hz), 119.0, 120.6, 122.4 (d, J=2.9 Hz), 130.3 (d, J=7.6 Hz), 130.4, 130.7, 135.8, 137.3, 140.8 (d, J=7.6 Hz), 148.6, 156.3 (d, J=2.9 Hz), 163.5 (d, J=245.7 Hz); MS (ESI): m/z=254.13 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[Br:13]N1C(=O)CCC1=O>CN(C)C=O>[Br:13][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([F:1])[CH:3]=1)[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CCc2cccc(F)c2N1
Solvent: CN(C)C=O
Product: O=C1CCc2cc(Br)cc(F)c2N1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 8-fluoro-3,4-dihydroquinolin-2(1H)-one (1-2; 8.30 g, 50.10 mmol) in N,N-dimethylformamide (250 mL) was added N-bromosuccinimide (9.80 g, 55.10 mmol) in N,N-dimethylformamide (120 mL) at 0° C. The reaction mixture was stirred at room temperature for 18 h, cooled, and diluted with ice cold water (500 mL). The resulting precipitated was filtered and dried to obtain the title compound as a white solid; 1H NMR (DMSO-D6, 500 MHz) δ=10.20 (s, 1H), 7.37 (dd, J=2.0 Hz, JHF=10.0 Hz, 1H), 7.26 (s, 1H), 2.93 (t, J=7.0 Hz, 2H), 2.47 (t, J=7.5 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4](=[N:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:5](=[O:11])[CH2:6][C:7](OC)=[O:8]>ClC1C=CC=CC=1Cl>[CH3:1][O:2][C:3]([C:4]1[C:5]([OH:11])=[CH:6][C:7](=[O:8])[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:12]=1)=[O:20]
Reactant: COC(=O)CC(=O)C(=NNc1ccccc1)C(=O)OC
Solvent: Clc1ccccc1Cl
Product: COC(=O)c1nn(-c2ccccc2)c(=O)cc1O
Reaction time: 20 h
Yield: 99 %

Procedure:
A mixture of 3-oxo-2(phenyl-hydrazono)-pentanedioic acid dimethyl ester: (4.38 g, 15.7 mmol) in 1,2-dichlorobenzene (15 mL) was refluxed. After 20 hours, the reaction mixture was concentrated under reduced pressure to give 3.83 g (99%) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)(O)[O-].[Na+].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].NC1C=CC=CC=1>O.O1CCOCC1>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cc(F)ccc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: Nc1ccccc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(F)ccc2C(=O)O)cc1
Yield: 81.3 %

Procedure:
2-Amino-4-fluorobenzoic acid (25 g, 161 mmol) was added to a solution of sodium bicarbonate (54.1 g, 645 mmol) in water (2.4 L) at room temperature and was stirred until homogeneous. The resultant solution was heated to 60° C. in an oil bath. 4-tert-Butylbenzenesulfonyl chloride (45.0 g, 193 mmol), dissolved in 200 mL p-dioxane, was subsequently added dropwise to the stirring aniline solution in a steady stream over a 30 min period. The reaction mixture was stirred at 60° C. overnight. The following day, upon LCMS verification of consumption of the aniline, the solution was poured in a slow stream into one liter of rapidly stirring 2 M HCl/H2O. The resultant precipitate was collected by vacuum filtration, washed thoroughly with water, and dried in vacuo to afford 46 g of 2-(4-tert-butyl-benzenesulfonylamino)-4-fluoro-benzoic acid as an off-white solid (82% yield): HPLC retention time=2.68; MS (ES) M+H expected 352.0, found 352.0.
Reaction SMILES: [CH:1]12[CH:9]([C:10]3[CH:23]=[CH:22][C:13]([O:14][CH2:15][C@H:16]4[O:20][C:19]([NH2:21])=[N:18][CH2:17]4)=[CH:12][CH:11]=3)[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.C([O:26][C:27](=O)[C:28]#[C:29][CH2:30][CH2:31][CH2:32][CH3:33])C>C(Cl)(Cl)Cl>[CH:1]12[CH:9]([C:10]3[CH:23]=[CH:22][C:13]([O:14][CH2:15][C@H:16]4[O:20][C:19]5=[N:21][C:27](=[O:26])[CH:28]=[C:29]([CH2:30][CH2:31][CH2:32][CH3:33])[N:18]5[CH2:17]4)=[CH:12][CH:11]=3)[CH:5]([CH2:4][CH2:3][CH2:2]1)[CH2:6][CH2:7][CH2:8]2
Reactant: NC1=NC[C@@H](COc2ccc(C3C4CCCC3CCC4)cc2)O1
Reactant: CCCCC#CC(=O)OCC
Solvent: ClC(Cl)Cl
Product: CCCCc1cc(=O)nc2n1C[C@@H](COc1ccc(C3C4CCCC3CCC4)cc1)O2

Procedure:
The title compound was prepared from (S)-5-(4-bicyclo[3.3.1]non-9-yl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (see Example 20) and hept-2-ynoic acid ethyl ester employing the procedure described in Example 95. [α]D25 −14.60 (c 0.5, CHCl3).
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15](=[O:24])[C@@H:14]2[CH2:25][CH2:26][C@@H:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[OH:28])=[CH:9][CH:8]=1)(C)(C)C.S(=O)(=O)(O)O>CC(O)C>[F:23][C:20]1[CH:19]=[CH:18][C:17]([N:16]2[C@H:13]([C:10]3[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=3)[C@@H:14]([CH2:25][CH2:26][C@@H:27]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[OH:28])[C:15]2=[O:24])=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@@H]2[C@@H](CC[C@H](O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(O)cc2)N1c1ccc(F)cc1
Temperature: 65 °C

Procedure:
5.0 g (9.6 mmol) (3R,4S)-4-[4-(tert-butyl-dimethyl-silanyl-oxy)-phenyl]-1-(4-fluorophenyl)-3-[(S)-3-(4-fluorophenyl)-3-hydroxypropyl]-azetidin-2-on (XI, R4=TBDMS) was solved in 35 ml 2-propanol and 10 ml 2M sulphuric acid solution is added. The solution is heated at 60-70° C. for 1-2 h, and then it was allowed to cool. The product was crystallized by adding ion-free water. The crystalline product was filtered out and washed with water to neutral.
Reaction SMILES: CS(O[CH:6]([C:8]1[CH:9]=[CH:10][C:11]2[O:17][CH2:16][CH2:15][N:14]3[CH:18]=[C:19]([C:21]4[N:25]([CH:26]([CH3:28])[CH3:27])[N:24]=[CH:23][N:22]=4)[N:20]=[C:13]3[C:12]=2[CH:29]=1)[CH3:7])(=O)=O.[N:30]1([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCOCC1>[CH:26]([N:25]1[C:21]([C:19]2[N:20]=[C:13]3[C:12]4[CH:29]=[C:8]([CH:6]([N:38]5[CH2:39][CH2:40][CH:35]([N:30]6[CH2:34][CH2:33][CH2:32][CH2:31]6)[CH2:36][CH2:37]5)[CH3:7])[CH:9]=[CH:10][C:11]=4[O:17][CH2:16][CH2:15][N:14]3[CH:18]=2)=[N:22][CH:23]=[N:24]1)([CH3:27])[CH3:28]
Reactant: CC(OS(C)(=O)=O)c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Reactant: C1CCN(C2CCNCC2)C1
Solvent: C1COCCO1
Product: CC(c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2)N1CCC(N2CCCC2)CC1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)ethyl methanesulfonate from Example 146 (246 mg, 0.590 mmol) and 4-(pyrrolidin-1-yl)piperidine (435 mg, 2.82 mmol) in 1,4-dioxane (4 mL) was stirred at 90° C. for 16 h under nitrogen atmosphere. After concentration, the residue was purified by reverse phase Combiflash eluting with a 0-50% gradient of CH3CN in 0.3% NH4HCO3 to give 157. The enantiomers were separated by chiral HPLC (OD column, 30% EtOH (0.1% DEA) in n-hexane isocratic) to give: 52 mg of one enantiomer and 49 mg of the other (42% total yield)
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[C:5]=1[CH2:14][CH2:15][CH3:16])[CH:2]=C.[O:17]=[O+][O-].CSC>CO>[O:11]=[C:8]1[C:7]2[CH:12]=[CH:13][C:4]([CH2:1][CH:2]=[O:17])=[C:5]([CH2:14][CH2:15][CH3:16])[C:6]=2[CH2:10][O:9]1
Reactant: O=[O+][O-]
Reactant: C=CCc1ccc2c(c1CCC)COC2=O
Solvent: CO
Solvent: CSC
Product: CCCc1c(CC=O)ccc2c1COC2=O
Temperature: 25 °C

Procedure:
To the flask charged with 5-allyl-4-propyl-2-benzofuran-1(3H)-one (60 mg) was added methanol (10 mL). The solution was chilled to −78° C. before ozone was bubbled through. Ozone was stopped when the solution turned light blue. Excess ozone was removed by bubbling nitrogen through the solution, which was followed by addition of dimethyl sulfide (170 mg, 2.8 mmol). The mixture was allowed to warm to RT. The desired product, (1-oxo-4-propyl-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde, was purified by silica gel chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:13]([CH2:24][OH:25])=[N:12][C:11]=2[CH:26]([CH3:28])[CH3:27])[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClC(Cl)(Cl)[C:31]([N:33]=C=O)=[O:32].C(N(CC)CC)C.O>O1CCCC1.CO>[C:31]([O:25][CH2:24][C:13]1[N:14]([CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:26]([CH3:28])[CH3:27])[N:12]=1)(=[O:32])[NH2:33]
Reactant: CC(C)c1nc(CO)n(CCCc2ccccn2)c1Sc1cc(Cl)cc(Cl)c1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1nc(COC(N)=O)n(CCCc2ccccn2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: -40 °C
Yield: 83 %

Procedure:
In 10 ml of tetrahydrofuran was dissolved 110 mg of 5-(3,5-dichlorophenylthio)-4-isopropyl-2-hydroxymethyl-1-(3-(2-pyridyl)propyl)-1H-imidazole, and the mixture was cooled to -40° C. Under stirring, 45.1 μl of trichloroacetylisocyanate was added, the mixture was allowed to warm up to room temperature, and stirred for 30 minutes. Added were 100 μl of triethylamine, 600 μl of water and 600 μl of methanol, and the mixture was stirred at 70° C. for 1 hour. After completion of the reaction, the solution was distilled off under reduced pressure, an aqueous sodium hydrogen carbonate solution was added, extracted with ethyl acetate, the extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:methanol=10:1)to give 80 mg of Compound I-130 (yield 83%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[OH:20])=[N:7][CH:8]=[N:9]2)=[C:4]([F:21])[CH:3]=1.[CH2:22]([O:24][C:25](=[O:29])[C@@H:26](O)[CH3:27])[CH3:23].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[O:20][C@H:26]([CH3:27])[C:25]([O:24][CH2:22][CH3:23])=[O:29])=[N:7][CH:8]=[N:9]2)=[C:4]([F:21])[CH:3]=1
Reactant: CCOC(=O)[C@H](C)O
Reactant: Oc1cc(F)ccc1Nc1ncnc2cc(Br)cc(F)c12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](C)Oc1cc(F)ccc1Nc1ncnc2cc(Br)cc(F)c12

Procedure:
To a mixture of 28 g (79.5 mmol) 2-[(7-bromo-5-fluoro-quinazolin-4-yl)amino]-5-fluoro-phenol, 9.4 g (79.5 mmol) (S)-2-Hydroxy-propionic acid ethyl ester, 25.1 g (95.6 mmol) PPh3 and THF 22 g (95.4 mmol) di-tert-butyl azodicarboxylate are added and the mixture stirred over night. The solvent is evaporated and isopropanol is added, the precipitate is filtered off and dried furnishing ethyl (2R)-2-[2-[(7-bromo-5-fluoro-quinazolin-4-yl)amino]-5-fluoro-phenoxy]propanoate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[CH2:30][CH:29]([N:34]([CH3:36])[CH3:35])[CH2:28]5)[N:19]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[CH2:42][C:43](Cl)=[O:44]>>[CH3:35][N:34]([CH3:36])[CH:29]1[CH2:28][C:27]2[C:31](=[CH:32][CH:33]=[C:25]([NH:24][C:20]3[N:19]=[C:18]([C:17]4[C:9]([C:4]5[CH:5]=[CH:6][C:7]([F:8])=[C:2]([NH:1][C:43](=[O:44])[CH2:42][C:38]6[S:37][CH:41]=[CH:40][CH:39]=6)[CH:3]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:23]=[CH:22][N:21]=3)[CH:26]=2)[CH2:30]1
Reactant: CN(C)C1Cc2ccc(Nc3nccc(-c4c(-c5ccc(F)c(N)c5)nn5ccccc45)n3)cc2C1
Reactant: O=C(Cl)Cc1cccs1
Product: CN(C)C1Cc2ccc(Nc3nccc(-c4c(-c5ccc(F)c(NC(=O)Cc6cccs6)c5)nn5ccccc45)n3)cc2C1

Procedure:
The title compound was prepared from {4-[2-(3-amino-4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}[2-(dimethylamino)-2,3-dihydro-1H-inden-5-yl]amine and 2-thiopheneacetyl chloride using acylation conditions described in Example 36, Step H to generate the desired product in 76% yield. 1H NMR (400 MHz, d6-DMSO) δ 10.14 (s, 1H), 9.42 (s, 1H), 8.83 (d, J=6.9 Hz, 1H), 8.42 (d, J=8.7 Hz, 1H), 8.29 (d, J=6.6 Hz, 1H), 8.25 (d, J=5.4 Hz, 1H), 7.61 (s, 1H), 7.35-7.47 (m, 5H), 7.03-7.13 (m, 4H), 6.52 (d, J=5.4 Hz, 1H), 3.99 (s, 2H), 2.87-2.99 (m, 3H), 2.66-2.72 (m, 2H), 2.21 (s, 6H). ES-LC/MS m/z=604 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]2[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.C([Li])CCC.[Cl:17][CH2:18][C:19](N(OC)C)=[O:20]>O1CCCC1.CCOCC>[Cl:17][CH2:18][C:19]([C:6]1[S:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:3]=2[CH:2]=1)=[O:20]
Reactant: CON(C)C(=O)CCl
Reactant: Fc1cccc2scc(Br)c12
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(CCl)c1cc2c(F)cccc2s1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 15.4 %

Procedure:
A solution of 3-bromo-4-fluorobenzo[b]thiophene (0.76 g) in tetrahydrofuran (5 ml) was added dropwise under nitrogen at −60-−50° C. over 10 minutes to a stirred solution of n-butyllithium (2.5M solution in hexanes; 1.71 ml) in ether (40 ml), then the mixture was stirred at −50° C. for 30 minutes. A solution of 2-chloro-N-methoxy-N-methylacetamide (0.39 g) in tetrahydrofuran (10 ml) was added dropwise over 10 minutes, the mixture was stirred at −50° C. for 30 minutes and at 0° C. for 1 hour, then it was quenched by the addition of saturated aqueous ammonium chloride solution (30 ml). The organic layer was separated, washed with saturated aqueous sodium chloride solution (30 ml), dried (MgSO4) and the solvent was removed in vacuo. The residue was purified by flash chromatography over silica using a 10:1 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 2-chloro-1-(4-fluorobenzo[b]thiophen-2-yl]ethan-1-one (0.1 g) as a colourless solid which was used without further purification.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:42][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[CH:18][C:17]([CH2:22][NH:23][CH2:24][CH:25]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:26][NH:27][C:28]1([C:33]([OH:35])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1)=[CH:16]3.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>C1COCC1>[O:35]=[C:33]1[C:28]2([CH2:32][CH2:31][CH2:30][CH2:29]2)[NH:27][CH2:26][CH:25]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:24][N:23]1[CH2:22][C:17]1[CH:18]=[N:19][C:20]2[C:15]([CH:16]=1)=[CH:14][C:13]1[CH2:42][C@:3]3([CH2:11][C:12]=1[CH:21]=2)[C:4]1[C:5](=[N:6][CH:7]=[CH:8][CH:9]=1)[NH:10][C:2]3=[O:1]
Reactant: O=C(O)C1(NCC(CNCc2cnc3cc4c(cc3c2)C[C@@]2(C4)C(=O)Nc3ncccc32)c2ccccc2)CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1N(Cc2cnc3cc4c(cc3c2)C[C@@]2(C4)C(=O)Nc3ncccc32)CC(c2ccccc2)CNC12CCCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-{[3-({[(7,5)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-3-yl]methyl}amino)-2-phenylpropyl]-amino}cyclopentanecarboxylic acid from Step F (30 mg, 0.053 mmol) and HOBt (8.2 mg, 0.053 mmol) in THF (1 mL) were added EDCI (13.3 mg, 0.069 mmol) and triethylamine (19 μL, 0.14 mmol). This solution was stirred at ambient temperature for 18 h. The solution was then concentrated to yield a residue, which was applied to a silica gel column for purification, eluting with a gradient of 1-7% methanol in DCM. Concentration of the fractions containing the product provided the title compound. MS: m/z=544 (M+1). HRMS: m/z=544.2708, calculated m/z=544.2707 for C34H34N5O2.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[N:16][CH:17]=1)([O-:23])=[O:22]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 36.9 %

Procedure:
4-(trifluoromethyl)phenylboronic acid (500 mg, 2.63 mmol), 2-chloro-5-nitropyridine (417 mg, 2.63 mmol), potassium carbonate (908 mg, 6.58 mmol) and palladium(II) acetate (23.6 mg, 0.105 mmol) were combined in 1:1 dioxane:water (10 mL). The resulting mixture was stirred at 80° C. for 12 hours. The mixture was filtered and the solution was extracted with ethyl acetate. The organic layer was washed with water, then brine, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave 5-nitro-2-(4-(trifluoromethyl)phenyl)pyridine (260 mg, 37%). 1H NMR (400 MHz, CDCl3, δ): 9.47 (s, 1 H), 8.51 (d, 1 H), 8.14 (d, 2 H), 7.72 (d, 1 H), 7.65 (d, 2 H).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH2:9][C:8]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:7]=2[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[S:5]1(=[O:23])=[O:22].[CH3:24][NH2:25].Cl>>[F:14][C:11]1[CH:12]=[CH:13][C:7]2[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[S:5](=[O:23])(=[O:22])[N:4]([CH2:3][CH2:2][NH:25][CH3:24])[CH2:9][C:8]=2[CH:10]=1
Reactant: CN
Reactant: O=S1(=O)N(CCBr)Cc2cc(F)ccc2N1c1ccccc1F
Agent: Cl
Product: CNCCN1Cc2cc(F)ccc2N(c2ccccc2F)S1(=O)=O
Yield: 92 %

Procedure:
In an analogous manner to Example 11 step 5, 3-(2-bromoethyl)-6-fluoro-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.1 g, 0.25 mmol) was reacted to methylamine and then treated with HCl to provide 2-[6-fluoro-1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylethanamine (0.081 g, 92%) as a white solid:
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[CH3:10][C:11]1[CH:12]=[C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26])[CH:14]=[CH:15][CH:16]=1>C(Cl)Cl.O>[CH3:10][C:11]1[CH:12]=[C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH:2][OH:3])=[O:26])[CH:14]=[CH:15][CH:16]=1
Reactant: Cc1cccc(CCCCCCCCC(=O)Cl)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(CCCCCCCCC(=O)NO)c1

Procedure:
To a cold, stirring suspension of 1.3 gm hydroxylamine hydrochloride and 1.8 gm sodium carbonate in 25 ml CH2Cl2 was added dropwise 4 gms 9(3-methylphenyl)nonanoyl chloride. The reaction mixture was stirred at 5°-10° for 45 min, then 2.1 ml H2O was added and the mixture stirred overnight at room temperature. The suspension was then diluted with CH2Cl2 and water, shaken, and the organic layer was separated. It was washed three times with water and once with NaCl solution, dried over MgSO4, and filtered. The solvent was removed in vacuo to give an oil which solidified but which could not be crystallized. The solid was disolved in ether, shaken with 5% KOH, and the ether discarded. The aqueous layer was acidified and the precipitated solid extracted into CHCl3. The chloroform was washed twice with water and once with NaCl solution, dried over MgSO4, filtered, and evaporated in vacuo. The resulting oil was purified by silica gel column chromatography, using gradually increasing cocentrations of ethyl acetate in chloroform (0, 10%, 15%, 25%). Fractions containing the major component (detected by thin layer chromatography--Rf=0.4 in 1:1 ETOAc:CHCl3) were collected and evaporated down to give an off-white solid which was crystallized from CH2Cl2 :hexanes. Yield 1.3 gms (33%) product of m.p. 49°-50°. Elemental analysis: calculated C 72.98, H 9.57, N 5.32% found C 72.80, H 9.56, N 5.32%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][C:20]1([C:23]([O:25][CH3:26])=[O:24])[CH2:22][CH2:21]1>C(Cl)(Cl)Cl.CO>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][C:20]2([C:23]([O:25][CH3:26])=[O:24])[CH2:22][CH2:21]2)=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)C1(N)CC1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)C1(NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)CC1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 1-aminocyclopropane-1-carboxylate hydrochloride (Sigma), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.3 in 95:5 CHCl3/MeOH) and the product was purified by silica gel chromatography using 97:3 CHCl3/MeOH as the eluent.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[H-].[Na+].[C:11]1([N:17]2[C:21]3[C:22]4[C:27]([CH2:28][C:20]=3[C:19]([C:29](Cl)=[O:30])=[N:18]2)=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>O1CCOCC1>[C:1]([CH:3]([C:29]([C:19]1[C:20]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:18]=1)=[O:30])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: O=C(Cl)c1nn(-c2ccccc2)c2c1Cc1ccccc1-2
Reactant: CCOC(=O)CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(C#N)C(=O)c1nn(-c2ccccc2)c2c1Cc1ccccc1-2
Temperature: 25 °C
Yield: 58.2 %

Procedure:
Ethyl cyanoacetate (1.4 g) is treated with 50% sodium hydride (0.58 g) in anhydrous dioxane (20 ml) under stirring at room temperature until the effervescence subsides. To this solution 1,4-dihydro-1-phenyl-indeno [1,2-c]pyrazole-3-carbonyl chloride (3 g), prepared according to Example 5, dissolved in anhydrous dioxane (50 ml) is added under stirring at room temperature. The reaction mixture is allowed to react for 20 hours, then it is dilusted with ice water and acidified to pH 3 with 37% HCl. The precipitate is extracted with ethyl acetate and the organic solution washed with water and then evaporated to dryness in vacuo. The residue is purified over a SiO2 column, using hexane-ethyl acetate 80:20 as eluent, to give 2-cyano-3-(1,4-dihydro-1-phenyl-indeno[1,2-c]pyrazol-3-yl) -3-oxo-propanoic acid, ethyl ester (2.2 g), which is reacted with aniline (3.4 g) in xylene (100 ml) at the reflux temperature for 48 hours. After cooling the precipitate is filtered and washed with xylene, then crystallized from dichloro-methane/methanol to give 1.2 g of 2-cyano-3-(1,4-dihydro-1-phenyl-indeno [1,2-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide, m.p. 273°-277° C.