Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=O)[CH3:9].[OH-].[Na+]>>[CH3:9][C:8]1[N:7]=[C:2]2[C:1](=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3]2
Reactant: CC(=O)Nc1ccccc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2ccccc2c2ccccc12
Temperature: 150 °C
Reaction time: 2.5 h
Yield: 86.6 %

Procedure:
A mixture of the acetamide 4 (717 mg, 3.39 mmol) and finely grinded polyphosphoric acid (10 mL, 115% H3PO4 equiv.) was stirred at 150° C. for 2.5 hours. The reaction mixture was then cooled to 0° C. and slowly basified to pH 14 with saturated NaOH (aq). The mixture was extracted with CH2Cl2 (4×30 mL), and the organic phase dried with MgSO4. Evaporation of the solvent under reduced pressure, followed by flash chromatography over silica, eluting with a gradient of 100% CH2Cl2 to 10% MeOH/90% CH2Cl2, yielded the phenanthridine 5 as a crystalline white solid (567 mg, 86.6%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>CN(C=O)C>[CH3:31][O:30][C:28](=[O:29])[CH2:27][N:7]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:23]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN(C(=O)OC(C)(C)C)c1ccc(Cl)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of (2-benzyloxy-4-chlorophenyl)-carbamic acid tert-butyl ester (14.75 g, 44.2 mmol) in DMF (150 mL) at 0° C. is added NaH (1.94 g, 60% in mineral oil, 48.6 mmol) and the mixture is stirred at 0° C. for 10 min. To this is added methyl bromoacetate (5.04 mL, 53 mmol) and the mixture is stirred at RT for 8 h. The mixture is poured into ice/water (150 mL) and is extracted with EtOAc (700 mL). The organic phase is washed with 1N HCl (3×150 mL) and brine (150 mL) then is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue purified by flash chromatography using a gradient of 5-10% EtOAc/hexane as eluent to give the title compound.
Reaction SMILES: COC1C=CC(N2C[C@H](C[N:15]3[CH2:20][CH2:19][CH:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)OC2=O)=CC=1>CS(C)=O>[O:21]([CH:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1ccc(N2C[C@H](CN3CCC(Oc4ccccc4)CC3)OC2=O)cc1
Solvent: CS(C)=O
Product: c1ccc(OC2CCNCC2)cc1

Procedure:
3-p-methoxyphenyl-5(S)-[(4-phenoxypiperidino)methyl]-2-oxazolidinone (hydrochloride), m.p. 227°-229°; [α]D =-31.6° (DMSO);
Reaction SMILES: [H-].[Na+].[CH2:3]([P:14](=[O:23])([O:19][CH:20]([CH3:22])[CH3:21])[O:15][CH:16]([CH3:18])[CH3:17])[P:4](=[O:13])([O:9][CH:10]([CH3:12])[CH3:11])[O:5][CH:6]([CH3:8])[CH3:7].Br[CH:25]([CH2:31][CH3:32])[C:26]([O:28]CC)=[O:27].[I-].[Na+]>CN(C)C=O.O>[CH:20]([O:19][P:14]([O:15][CH:16]([CH3:18])[CH3:17])([CH:3]([P:4]([O:9][CH:10]([CH3:11])[CH3:12])([O:5][CH:6]([CH3:8])[CH3:7])=[O:13])[CH2:32][CH2:31][CH2:25][C:26]([OH:28])=[O:27])=[O:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)C(Br)CC
Reactant: CC(C)OP(=O)(CP(=O)(OC(C)C)OC(C)C)OC(C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)OP(=O)(OC(C)C)C(CCCC(=O)O)P(=O)(OC(C)C)OC(C)C
Reaction time: 0.17 h
Yield: 8.7 %

Procedure:
Under a nitrogen atmosphere, 60% sodium hydride (2.56 g) was suspended in dry N,N-dimethylformamide (20 ml), and tetraisopropyl methylenebisphosphonate (20.0 g) was added dropwise thereto at room temperature. After stirring for 10 minutes, ethyl bromobutyrate (8.4 ml) was added dropwise thereto and the resulting mixture was stirred at 100° C. for 1 hour. Then, sodium iodide (0.85 g) was added thereto and stirred for 4 hours. Water was added thereto, followed by extraction (twice) with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in methanol (50 ml), followed by adding thereto a 2N aqueous sodium hydroxide solution (10 ml), and the resulting mixture was stirred with heating under reflux for 3 hours. The mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure, and then the residue was purified by a silica gel column chromatography to obtain 5,5-bis(diisopropoxyphosphinoyl)valeric acid (1.88 g, yield 8.7%). 1H-NMR (CDCl3) δ: ppm; 1.34 (12H, d, J=6.3 Hz), 1.34 (12H, d, J=5.9 Hz), 1.8-2.4 (7H, m), 4.7-4.9 (4H, m).
Reaction SMILES: O.[F:2][C:3]1[C:21]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:20][C:6]([O:7][C:8]2[C:9]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:10][CH:11]=[CH:12][CH:13]=2)=[C:5]([N+:35]([O-])=O)[CH:4]=1>C(O)(=O)C.[Fe]>[NH2:35][C:5]1[CH:4]=[C:3]([F:2])[C:21]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:30])([F:32])[F:31])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:20][C:6]=1[O:7][C:8]1[C:9]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Reaction time: 2 h
Yield: 85 %

Procedure:
To a mixture of 0.3 g of iron powder, 3 ml of acetic acid, and 0.3 ml of water was added dropwise a solution of 0.30 g of 3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-2-(methoxycarbonyl)methoxypyridine in 2 ml of acetic acid, while the temperature of the reaction mixture was kept at 35° C. or lower. After completion of the dropwise addition, the mixture was stirred for 2 hours and then filtered through Celite. The filtrate was diluted with ethyl acetate, and the mixture was neutralized with saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.24 g of 3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine.
Reaction SMILES: C([N:3](CC)CC)C.[O:8]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC(OC)=O.N>C1COCC1>[O:8]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([NH2:3])=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Agent: COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)c1cccc(Oc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (5.6 g) was added at 0° C. under N2 to a stirred solution of 3-phenoxybenzoic acid (10.7 g, Aldrich) in THF (75 ml), followed by the addition of methyl chloroformate (4.7 g) at less than 5° C. After additions were complete, the mixture was stirred at 0° C. for 30 minutes. 0.88 Ammonia (30 ml) was added and the mixture stirred at room temperature for 20 hours, then evaporated in vacuo and the residue taken up in ethyl acetate (100 ml) and water (100 ml). The aqueous phase was separated, extracted with ethyl acetate and the combined ethyl acetate solutions washed with 5% w/v aqu. Na2CO3 (2×50 ml), 2N aqu. HCl (50 ml) and water (100 ml), dried over Na2SO4 and evaporated in vacuo to give the desired product as a colourless solid which was recrystallised from ethyl acetate/60-80 pet. ether (1:2 v/v), mp 125°-127° C. (6.5 g). The 200 MHz 1H NMR was consistent with the proposed structure.
Reaction SMILES: Cl.C(O[CH:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[NH2:6])C.[NH2:23][NH:24][C:25](=O)[CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]1.C[O-].[Na+].Cl>CO>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]4[NH:6][C:25]([CH2:26][N:27]5[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]5)=[N:24][N:23]=4)[CH:8]=3)[NH:12][N:11]=2)=[CH:21][CH:20]=1
Reactant: CCOC(N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: NNC(=O)CN1CCC(O)CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: OC1CCN(Cc2nnc(-c3ccc4[nH]nc(-c5ccc(F)cc5)c4c3)[nH]2)CC1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 7.3 %

Procedure:
A solution of ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methaneamine hydrochloride (521 mg, 1.63 mmol), N-amino-2-(4-hydroxypiperidyl)acetamide (850 mg, 4.9 mmol), and sodium methoxide (1.2 mL, 4.9 mmol) in methanol (˜8 mL) was taken up in a sealed tube and allowed to stir at room temperature for 25 minutes and then heated at 95° C. overnight. The reaction was acidified with hydrochloric acid to neutral pH. The product was extracted using ethyl acetate. The material was concentrated and purified by semipreprative HPLC. The purified material was taken up in ethyl acetate and washed with an aqueous solution of sodium bicarbonate to yield the title compound (47 mg, 7% yield). 1H NMR (DMSO-d6) δ 13.4 (br s, 1H), 8.6 (s, 1H), 8.0 (m, 3H), 7.6 (m, 1H), 7.4 (t, 2H), 3.6–3.8 (m, 2H), 3.4 (m, 2H), 3.2 (d, 1H), 2.4 (m, 2H), 2.0 (s, 4H)H, ES-MS (m/z) 393 [M+1]+.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[C:5]([F:12])[CH:4]=1)#[N:2].C(N1C=CN=C1)([N:15]1C=CN=C1)=O.[OH-].[NH4+]>C(#N)C>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:15])=[O:8])=[C:5]([F:12])[CH:4]=1)#[N:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Product: N#Cc1ccc(C(N)=O)c(F)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 59.3 %

Procedure:
To a solution of 4-cyano-2-fluorobenzoic acid (500 mg, 3.0 mmol) in acetonitrile (20 ml) was added 1,1′-carbonyldiimidazole (736 mg, 4.5 mmol). The mixture was stirred at room temperature for 45 min, before addition of aqueous ammonium hydroxide solution (35%, 10 ml). The reaction mixture was stirred for 45 min and ice cold water (15 ml) was added. The precipitate was collected by filtration and dried in a vacuum oven at 60° C. for 18 h to give the title compound (292 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(N(CC)C(C)C)(C)C.[Cl:19][S:20]([C:23]1[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[C:24]=1[C:25]([O:27][CH3:28])=[O:26])(=[O:22])=[O:21].Cl>O1CCCC1>[ClH:19].[N:4]1([CH2:3][CH2:2][NH:1][S:20]([C:23]2[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[C:24]=2[C:25]([O:27][CH3:28])=[O:26])(=[O:21])=[O:22])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)Cl
Reactant: NCCN1CCCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCN1CCCCC1

Procedure:
A solution of 1-(2-aminoethyl)piperidine (0.23 g, 1.79 mmol) and N,N-diisopropylethylamine (0.23 g, 1.79 mmol) in tetrahydrofuran (5 ml) is added over 15 minutes to a stirred solution of methyl 2-chlorosulfonyl-6-nitrobenzoate (0.50 g, 1.79 mmol) in tetrahydrofuran (25 ml) cooled with an ice bath. The product is isolated following the procedure of Example 1 and converted to the hydrochloride salt with anhydrous ethanolic hydrogen chloride.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[CH3:23].[CH3:24][O:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:31]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.O.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:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([CH3:23])=[C:2]([C:30]4[CH:29]=[N:28][CH:27]=[C:26]([O:25][CH3:24])[CH:31]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(C)sc2n1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cncc(-c2c(C)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 120 °C
Yield: 24.8 %

Procedure:
Under nitrogen, N-(3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 61) (65 mg, 0.151 mmol) was dissolved in 1,4-dioxane (1.5 mL) and water (0.7 mL). 3-(Methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (53.1 mg, 0.226 mmol), tetrakis(triphenylphosphine)palladium(0) (17.40 mg, 0.015 mmol) and potassium carbonate (62.4 mg, 0.452 mmol) were added and the mixture heated in a microwave at 120° C. for 10 min. Ethyl acetate (10 mL) was then added and the mixture washed with water (2×5 mL). The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by normal phase chromatography, eluting with a gradient of 0-5% MeOH in DCM, and then further purified by MDAP (acidic conditions), to give the title compound (17.2 mg). LCMS (A) m/z: 460 [M+1]+, Rt 0.90 min (acidic).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]([C:24]1[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=1)=[CH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12]1([CH2:18][N:17]([C:19](=[O:23])[CH:20](C)[CH3:21])[CH2:16]1)[O:11][CH2:10]2)=O.[NH2:35][NH2:36]>C(O)C.C(OCC)(=O)C>[Cl:32][C:26]1[CH:25]=[C:24]([C:3]2([C:2]([F:34])([F:33])[F:1])[NH:36][N:35]=[C:5]([C:7]3[CH:8]=[C:9]4[C:13](=[CH:14][CH:15]=3)[C:12]3([CH2:18][N:17]([C:19](=[O:23])[CH2:20][CH3:21])[CH2:16]3)[O:11][CH2:10]4)[CH2:4]2)[CH:29]=[C:28]([Cl:30])[C:27]=1[Cl:31]
Reactant: CC(C)C(=O)N1CC2(C1)OCc1cc(C(=O)C=C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc12
Reactant: NN
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCC(=O)N1CC2(C1)OCc1cc(C3=NNC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)ccc12

Procedure:
To the stirred solution of 4,4,4-trifluoro-1-(1-isobutyryl-3′H-spiro[azetidine-3,1′-isobenzofuran]-5′-yl)-3-(3,4,5-trichlorophenyl)but-2-en-1-one (Preparation 27, 0.5 g, 0.938 mmol, 1 eq) in ethanol (5 mL) was added hydrazine (1.0M solution in THF, 1.40 mL, 1.41 mmol, 1.5 eq). Resulting reaction mixture was refluxed for 2 hours under nitrogen atmosphere. After consumption of starting material, Reaction mixture was concentrated to get crude compound. Crude compound was dissolved in minimum quantity of ethyl acetate and adsorbed on silica gel (100-200 mesh). Crude compound purified by Combiflash chromatography using 40 g Redisep column. Desired compound was eluted in 55% ethyl acetate in hexane to afford title compound as off white solid (0.16 g, 31%). 1H NMR (400 MHz, DMSO-d6) δ: 1.00-1.06 (m, 6H), 2.53-2.56 (m, 1H), 3.75-3.88 (m, 2H), 4.10 (s, 2H), 4.40-4.45 (m, 2H), 5.08 (s, 2H), 7.57-7.58 (m, 2H), 7.66 (d, J=8.44 Hz, 1H), 7.88 (s, 2H), 8.91 (s, 1H). LC-MS (m/z): 546.0 (M+H). HPLC Purity: 96.43%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18](O)=[O:19])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.Cl.[O:23]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[Na+]>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:15][CH:16]([C:18]([N:26]3[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:23][CH2:24][CH2:25]3)=[O:19])[CH2:17]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Reactant: c1ccc2c(c1)CNCCO2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1)N1CCOc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.3 %

Procedure:
To a solution of crude intermediate 17, 3-(3-chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (˜4.3 mL ˜0.65 mmol) was added 2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine hydrochloride (239 mg, 1.29 mmol), triethylamine (0.18 ml, 1.29 mmol) and T3P (50% solution in EtOAc, 0.62 ml, 0.97 mmol). The resulting reaction mixture was stirred at RT for 1 hr and then 25 ml of 1N NaOH and 100 ml of EtOAc were added and the layers were separated. The aqueous layer was subjected to EtOAc extraction (2×60 ml) again and the combined organic layers were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using a 40 g ISCO™ column, eluting with 5% MeOH/CH2Cl2 containing 0.25% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound 104 mg, 37% yield. Rf=0.50 (15% MeOH/CH2Cl2+0.2% NH4OH); LRMS m/z Calcd for C25H29Cl N2 O3, 440.9, found, 441.2 (M+1) APCI; 100 MHz 13C NMR (CDCl3) 1:1 mixture of rotomers, diagnostic peaks, δ 175.4, 173.9, 159.5, 159.3, 134.2, 134.1, 131.4, 131.3, 122.0, 121.3, 121.0, 74.9, 72.6, 72.2, 56.3, 54.1, 53.9, 49.3, 48.7, 41.2, 41.0, 28.8, 28.5, 23.7, 23.6.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:14])=[O:13])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[CH3:32][N:33]([CH3:43])[C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:32][N:33]([CH3:43])[C:34]1[CH:39]=[CH:38][C:37]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:13])=[O:14])[CH:9]=3)[NH:4][N:3]=2)=[CH:36][CH:35]=1
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)c1ccc(-c2n[nH]c3ccc(NS(=O)(=O)c4ccccc4S(C)(=O)=O)cc23)cc1
Yield: 24.5 %

Procedure:
N-[3-(4-Dimethylaminophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 59 from 1 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 570 mg of 4-dimethylaminophenylboronic acid, 40 ml of dimethylformamide, 3.2 ml of a saturated aqueous solution of sodium hydrogencarbonate and 50 mg of tetrakis(triphenylphosphine)palladium[0]. 200 mg of N-[3-(4-dimethylaminophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of a yellow solid melting above 260° C. (analysis C22H22N4O4S2 % calculated C, 56.15; H, 4.71; N, 11.91; O, 13.60; S, 13.63. % found C, 55.74; H, 4.81; N, 12.03; S, 13.34).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH:10]=[CH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pt]>[Br:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: COc1nc(Br)ccc1C=CC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pt]
Solvent: CCOC(C)=O
Product: COc1nc(Br)ccc1CCC(=O)OC(C)(C)C
Yield: 89.8 %

Procedure:
10% platinum-activated carbon was added to a solution of tert-butyl 3-(6-bromo-2-methoxypyridin-3-yl)acrylate (727 mg) in ethyl acetate (7.3 mL), and the mixture was stirred for four hours in a hydrogen atmosphere. The reaction solution was filtered through celite and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to give the title compound as a colorless oil (657 mg, 90%).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[Br:11][C:12]1[CH:31]=[CH:30][CH:29]=[CH:28][C:13]=1[C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:27])[CH2:23][C:24]([OH:26])=O)[CH2:18][CH2:17]1)=[O:15].CCN=C=NCCCN(C)C.Cl.[N:44]1([C:50]2[CH:55]=[CH:54][C:53]([NH2:56])=[CH:52][CH:51]=2)[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Br:11][C:12]1[CH:31]=[CH:30][CH:29]=[CH:28][C:13]=1[C:14]([N:16]1[CH2:17][CH2:18][N:19]([C:22](=[O:27])[CH2:23][C:24]([NH:56][C:53]2[CH:52]=[CH:51][C:50]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:55][CH:54]=2)=[O:26])[CH2:20][CH2:21]1)=[O:15]
Reactant: O=C(O)CC(=O)N1CCN(C(=O)c2ccccc2Br)CC1
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CC(=O)N1CCN(C(=O)c2ccccc2Br)CC1)Nc1ccc(N2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
HOBt (31 mg, 0.23 mmol) and DMAP (42 mg, 0.34 mmol) were added to a stirred solution of 3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-3-oxo-propionic acid (75 mg, 0.2 mmol) in DMF (1 mL). The reaction mixture was cooled to 0° C. and EDCI.HCl (48 mg, 0.25 mmol) followed by 4-morpholin-4-yl-phenylamine (41 mg, 0.23 mmol) were added. The reaction mixture was stirred at room temperature overnight then diluted with water. The resulting precipitate was filtered and washed with hexane to afford 45 mg (41%) of 3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-N-(4-morpholin-4-yl-phenyl)-3-oxo-propionamide. LCMS: 516.12 (M+1)+, 97.57%, 1H NMR: (DMSO-d6): δ 7.7 (m, 1H), 7.5-7.32 (m, 5H), 6.9-6.8 (m, 2H), 3.8-3.7 (bs, 5H), 3.6-3.4 (m, 7H), 3.2-3.08 (m, 2), 3.04-2.98 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:27]([F:30])([F:29])[F:28])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24](O)=[O:25])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClC1C=C(C2(C(F)(F)F)ON=C(C3C4C(=CC=CC=4)C(C(OC)=O)=CC=3)C2)C=C(Cl)C=1.CCCP(=O)=O.[F:68][C:69]([F:73])([F:72])[CH2:70][NH2:71]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:27]([F:28])([F:30])[F:29])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]([NH:71][CH2:70][C:69]([F:73])([F:72])[F:68])=[O:25])=[CH:16][CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Reactant: NCC(F)(F)F
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Agent: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Solvent: ClCCl
Product: O=C(NCC(F)(F)F)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-1-naphthalenecarboxylic acid (i.e. the product from Step C) (190 mg, 0.42 mmol), 4-(dimethylamino)pyridine (77 mg, 0.63 mmol), propylphosphonic anhydride (0.38 mL, 0.63 mmol, 50% in ethyl acetate) and 2,2,2-trifluoroethylamine (0.033 mL, 0.42 mL) in dichloromethane (5 mL) was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was purified by column chromatography on silica gel using hexanes/ethyl acetate as eluent to give the title product, a compound of the present invention, as a white solid (71 mg).
Reaction SMILES: S(Cl)([Cl:3])=O.[Na+].[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O-:23])(=O)=[O:21])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C=O)C>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([Cl:3])(=[O:23])=[O:21])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=S(=O)([O-])c1ccc(OCc2ccccc2)cc1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1

Procedure:
Thionyl chloride (200 mL, 326.2 grams, 2742 mmol) is added to the solid title A compound, 4-benzyloxybenzenesulfonic acid sodium salt, followed by 10 drops of DMF. The mixture is heated to reflux overnight and then concentrated under vacuum. Hot toluene (250 mL) is added, and the mixture is filtered. The filtrate is concentrated under vacuum. Toluene is again added to the residue followed by filtration and concentration under vacuum to give 4-benzyloxybenzenesulfonyl chloride as a white solid.