Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2](C)([CH3:31])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:5]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.NC1C=CN(C[C@H]2[O:66][C:65](=O)[NH:64]C2)N=1>ClCCl>[O:66]=[C:65]1[NH:64][CH2:31][C@@H:2]([CH2:3][N:4]2[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]3[CH2:20][C:19]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])=[CH:18][C:17]3=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:5]2)[O:1]1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(CC(C)(C)O)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Reactant: Nc1ccn(C[C@@H]2CNC(=O)O2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2CNC(=O)O2)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.3 %

Procedure:
A solution of (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 64, 425 mg, 1.30 mmol) in dichloromethane (20 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride salt (275 mg, 1.45 mmol), 1-hydroxybenzotriazole (195 mg, 1.45 mmol) and (S)-5-(3-amino-pyrazol-1-ylmethyl)-oxazolidin-2-one (285 mg, 1.57 mmol). The reaction mixture was stirred for 18 h at 25° C., under nitrogen and then diluted with dichloromethane, washed with 2N hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The crude product obtained after concentration, was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% to 10% methanol/dichloromethane) to afford (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((S)-2-oxo-oxazolidin-5-ylmethyl)-1H-pyrazol-3-yl]-amide (370 mg, 58%) as a white powder: LR-ES-MS m/z calculated for C23H26ClN5O5 [M]+ 487, observed 488 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.4 Hz, 3H), 0.94 (d, J=6.4 Hz, 3H), 1.35-1.50 (m, 1H), 1.50-1.66 (m, 1H), 1.68-1.87 (m, 1H), 3.28 (dd, J=8.8, 6.0 Hz, 1 H), 3.55 (t, J=8.9 Hz, 1H), 4.21 (d, J=18.4 Hz, 1H), 4.27 (d, J=5.1 Hz, 2H), 4.61 (d, J=18.4 Hz, 1H), 4.79 (s, 1H), 4.80-4.95 (m, 2H), 6.47 (d, J=2.1 Hz, 1H), 7.37 (td, J=7.8, 1.2 Hz, 1H), 7.42-7.50 (m, 1H), 7.50-7.57 (m, 2H), 7.61 (d, J=2.1 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 10.85 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([CH:18]([C:23]([O:25]C)=O)[C:19]([O:21][CH3:22])=[O:20])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.C[O-].[Na+].Cl>CO>[CH3:22][O:21][C:19]([CH:18]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:23]1=[O:25])=[O:20]
Reactant: COC(=O)C(C(=O)OC)C(Cc1ccccc1N)c1ccc(OC)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1C(=O)Nc2ccccc2CC1c1ccc(OC)cc1
Temperature: 25 °C

Procedure:
A solution containing 11.97 (33.5 mmol) of [2-(2-aminophenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester and 9.2 ml of 25% sodium methoxide (40.2 mmol) in 80 ml of methanol was refluxed for 1.5 hours and cooled to room temperature. Excess 1M hydrochloric acid solution was then added and the resulting precipitated product was removed by filtration to give 9.18 g of pure material, melting point 217°-219° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([CH:15]([OH:24])[CH:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[OH:17])[CH:11]=[CH:12][C:13]=1[Cl:14].C(N(CC)CC)C>ClCCl.CS(C)=O>[Cl:7][C:8]1[CH:9]=[C:10]([C:15](=[O:24])[C:16]([C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[O:17])[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: OC(c1ccncc1)C(O)c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C(=O)c1ccc(Cl)c(Cl)c1)c1ccncc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 85.3 %

Procedure:
Dimethylsulfoxide (37 ml, 0.53 mol) was dissolved in dichloromethane (250 ml) and cooled to −78° C. Oxalyl chloride (34.5 ml, 0.40 mol) was added dropwise and the solution stirred for 20 min. A solution of the product of Step 1 (34 g, 0.12 mol) in dimethylsulfoxide (40 ml) and dichloromethane (200 ml) was added dropwise at −78° C., and the solution stirred for 30 minutes. Triethylamine (104 ml, 0.74 mol) was added dropwise and the solution became floculent such that overhead stirring became necessary. The solution was allowed to stir at room temperature over 2 hours then was poured on to ice/saturated sodium bicarbonate solution. The aqueous layer was separated, and re-extracted with dichloromethane. The combined organic phases were concentrated under reduced pressure to a green-yellow solid. The solid was redissolved in dichloromethane and washed with water and brine, dried (MgSO4) and evaporated to a solid. The crude solid was purified by silica gel chromatography eluting with dichloromethane, to afford the title compound (28.66 g, 85%) as a yellow solid; MS(-ve ion) m/e 279/281/283 [M−H]−.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[CH3:9][S:10][C:11]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:12]=1[C:13](O)=[O:14]>>[CH3:9][S:10][C:11]1[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:16][C:12]=1[C:13]([NH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8])=[O:14]
Reactant: NC1CCCCC1=O
Reactant: CSc1cc(C(F)(F)F)ccc1C(=O)O
Product: CSc1cc(C(F)(F)F)ccc1C(=O)NC1CCCCC1=O

Procedure:
The title compound, off-white solid, MS: m/e=332.1 [(M+H)+], was prepared in accordance with the general method of intermediate B from 2-amino-cyclohexanone and 2-methylsulfanyl-4-trifluoromethyl-benzoic acid (intermediate C).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[CH2:4][NH:5][C:6](=[O:44])[C@H:7]([CH2:39][O:40][CH2:41][CH:42]=[CH2:43])[NH:8][C:9](=[O:38])[C@H:10]([CH:35]([CH3:37])[CH3:36])[NH:11][C:12](=[O:34])[C@H:13]([CH:31]([CH3:33])[CH3:32])[NH:14][C:15](=[O:30])[C@H:16]([CH2:25][O:26][CH2:27][CH:28]=[CH2:29])[NH:17]C(OC(C)(C)C)=O.CCOCC.[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]>C(Cl)Cl>[F:54][C:53]([F:56])([F:55])[C:51]([OH:57])=[O:52].[CH3:1][O:2][C:3](=[O:45])[CH2:4][NH:5][C:6](=[O:44])[C@H:7]([CH2:39][O:40][CH2:41][CH:42]=[CH2:43])[NH:8][C:9](=[O:38])[C@H:10]([CH:35]([CH3:36])[CH3:37])[NH:11][C:12](=[O:34])[C@H:13]([CH:31]([CH3:33])[CH3:32])[NH:14][C:15](=[O:30])[C@H:16]([CH2:25][O:26][CH2:27][CH:28]=[CH2:29])[NH2:17]
Reactant: C=CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H](COCC=C)C(=O)NCC(=O)OC)C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: C=CCOC[C@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](N)COCC=C)C(C)C)C(C)C)C(=O)NCC(=O)OC
Yield: 96 %

Procedure:
N-tert-butoxycarbonyl O-allyl L-seryl L-valyl L-valyl O-allyl L-seryl glycine methyl ester 22 (SEQ ID NO: 1) (0.734 g, 1.14 mmol) was dissolved in a 50% (v/v) solution of TFA in CH2Cl2 (16 mL). The reaction mixture was stirred for 1 h 30 min before the solvent and bulk of excess TFA were evaporated affording an oil. Addition of Et2O (25 mL) resulted in the precipitation of a white solid. The mixture was centrifuged and the Et2O decanted off. The residue was washed with an additional 2×25 mL Et2O and dried under reduced pressure overnight affording a fine white powder (0.719 g, 96%); δH (300 MHz; d6-DMSO) 8.48 (1H, d, J 9, NH(Valx)), 8.41 (1H, t, J 6, NH(Gly)), 8.24 (3H, br s, NH3+), 8.01-7.98 (2H, m, NH(Valy)/NH(Ser(All)2)), 5.90-5.77 (2H, m, CH═CH2), 5.30-5.10 (4H, m, CH═CH2), 4.56-4.50 (1H, m, CαH(Ser(All)2)), 4.32 (1H, dd, J 7 and 9, CαH(Valx)), 4.24 (1H, dd, J 7 and 8, CαH(Valy)), 4.10 (1H, br s, CαH(Ser(All)1)), 3.98-3.93 (4H, m, CH2CH═CH2), 3.86-3.84 (2H, m, CαH2(Gly)), 3.72-3.52 (4H, m, CH2(Ser(All)1)/CH2(Ser(All)2)), 3.61 (3H, s, OCH3), 2.08-1.89 (2H, m, CH(CH3)2), 0.88-0.80 (12H, m, CH3); δC (75 MHz; d6-DMSO) 170.6, 170.4, 169.9, 169.8, 166.2, 158.3 (q, JCF 37) 134.8, 134.4, 117.1, 116.9 (q, JCF 293), 116.5, 71.4, 71.0, 69.5, 68.3, 57.9, 57.6, 52.4, 52.2, 51.6, 40.6, 30.6, 30.4, 19.1, 18.1, 17.9; m/z (ESI) 542.3181 (M+; C25H44N5O8 requires 542.3189)
Reaction SMILES: [OH:1][C@@H:2]([CH3:7])[CH2:3][C:4]([OH:6])=O.O.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C.FC(F)(F)C(O)=O.[N:38]1([C:44]2[N:52]=[C:51]([C:53]3[CH:54]=[N:55][C:56]([NH2:59])=[N:57][CH:58]=3)[N:50]=[C:49]3[C:45]=2[N:46]=[C:47]([N:65]2[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]2)[N:48]3[CH2:60][C:61]([F:64])([F:63])[F:62])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>C(N(CC)CC)C.CN(C)C=O>[NH2:59][C:56]1[N:57]=[CH:58][C:53]([C:51]2[N:50]=[C:49]3[C:45]([N:46]=[C:47]([N:65]4[CH2:70][CH2:69][N:68]([C:4](=[O:6])[CH2:3][C@@H:2]([OH:1])[CH3:7])[CH2:67][CH2:66]4)[N:48]3[CH2:60][C:61]([F:62])([F:64])[F:63])=[C:44]([N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)[N:52]=2)=[CH:54][N:55]=1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCNCC4)n(CC(F)(F)F)c3n2)cn1
Reactant: C[C@H](O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: C[C@H](O)CC(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CC1
Reaction time: 15 h
Yield: 50.1 %

Procedure:
(S)-3-hydroxybutanoic acid (39 mg, 0.38 mmol), hydroxybenzotriazole hydrate (58 mg, 0.38 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (72 mg, 0.38 mmol), dimethylformamide (5 ml), and triethylamine (161 μl) were added to 5-[6-morpholin-4-yl-8-piperazin-1-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine trifluoroacetate (200 mg, 0.29 mmol) and the resulting mixture was stirred for 15 hours. The reaction mixture was partitioned with ethyl acetate and saturated aqueous sodium bicarbonate solution, the organic layer was dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol=19:1) to give the title compound (80 mg, 50%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C=O)C.O1CCOCC1.[Br:23][CH2:24][C:25](Br)=[O:26]>O>[Cl:11][C:8]1[CH:9]=[CH:10][C:2]([NH:1][C:25](=[O:26])[CH2:24][Br:23])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: O=C(Br)CBr
Solvent: CN(C)C=O
Solvent: O
Solvent: C1COCCO1
Product: O=C(CBr)Nc1ccc(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
A solution of 2-amino-5-chlorobenzoic acid (10 g, 0.06 mol), anhydrous DMF (30 mL) and dioxane (30 mL) was cooled to 0° C. in a 250 mL 3-necked flask, fitted with a magnetic stirrer, thermometer and additional funnel. Bromoacetyl bromide (11.8 g, 5 mL, 100 mol %) was added dropwise over a 20 min period, keeping the internal temperature between 0° C to 1° C. After the addition was completed, the solution was allowed to warm to room temperature and stirring was continued overnight at rt. The reaction mixture was cooled in an ice-bath, stirred for 30 min and diluted with water (80 mL). The resulting light yellow precipitate was filtered, washed with water, and dried in vacuum oven (20 h, 40-45° C.), to afford 11.4 g (67%) of the title compound, mp 210-212° C. (decomp.); 1H NMR (CD3OD) δ 8.58 (d, 1H, J=9.2), 8.03 (d, 1H, J=2.8), 7.55 (dd, 1H, J=2.4, J=6.4), 4.11 (s, 2H); 13C NMR (CD3OD) δ 196.94, 169.69, 140.49, 134.86, 131.94, 129.49, 122.87, 119.47, 30.04; MS (EI, m/z) 293 (M+)
Reaction SMILES: ClC1C=CC(OC2C=C(F)C(S(=O)(=O)N(CC3C=CC(OC)=CC=3OC)C3SN=CN=3)=CC=2F)=C(C2C=CC3ON=C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)C=3C=2)C=1.[Cl:61][C:62]1[CH:63]=[CH:64][C:65]([O:92][C:93]2[CH:98]=[C:97]([F:99])[C:96]([S:100](=[O:108])(=[O:107])[NH:101][C:102]3[N:103]=[CH:104][S:105][CH:106]=3)=[CH:95][C:94]=2[Cl:109])=[C:66]([C:68]2[CH:69]=[CH:70][C:71]3[O:75][N:74]=[C:73]([N:76](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:72]=3[CH:91]=2)[CH:67]=1>C(OCC)C>[NH2:76][C:73]1[C:72]2[CH:91]=[C:68]([C:66]3[CH:67]=[C:62]([Cl:61])[CH:63]=[CH:64][C:65]=3[O:92][C:93]3[C:94]([Cl:109])=[CH:95][C:96]([S:100]([NH:101][C:102]4[N:103]=[CH:104][S:105][CH:106]=4)(=[O:107])=[O:108])=[C:97]([F:99])[CH:98]=3)[CH:69]=[CH:70][C:71]=2[O:75][N:74]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1noc2ccc(-c3cc(Cl)ccc3Oc3cc(F)c(S(=O)(=O)Nc4cscn4)cc3Cl)cc12
Agent: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3ccc4onc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c4c3)cc2F)c(OC)c1
Solvent: CCOCC
Product: Nc1noc2ccc(-c3cc(Cl)ccc3Oc3cc(F)c(S(=O)(=O)Nc4cscn4)cc3Cl)cc12
Yield: 83 %

Procedure:
Following the procedure as described in EXAMPLE 44, making non-critical variations to replace di-tert-butyl [5-(5-chloro-2-{4-[(2,4-dimethoxybenzyl)(1,2,4-thiadiazol-5-yl)sulfamoyl]-2,5-difluorophenoxy}phenyl)-1,2-benzoxazol-3-yl]imidodicarbonate with di-tert-butyl (5-{5-chloro-2-[2-chloro-5-fluoro-4-(1,3-thiazol-4-ylsulfamoyl)phenoxy]phenyl}-1,2-benzoxazol-3-yl)imidodicarbonate, 4-(2-(3-aminobenzo[d]isoxazol-5-yl)-4-chlorophenoxy)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide was obtained as an off-white solid in 83% yield (0.230 g) after trituration in diethyl ether (10 mL): 1H NMR (300 MHz, DMSO-d6) δ11.36 (s, 1H), 8.86-8.84 (m, 1H), 7.97 (s, 1H), 7.81 (d, J=7.1 Hz, 1H), 7.65-7.59 (m, 2H), 7.54 (dd, J=8.6, 2.0 Hz, 1H), 7.42 (d, J=8.7 Hz, 1H), 7.31 (d, J=8.7 Hz, 1H), 7.03-7.00 (m, 1H), 6.95 (d, J=10.8 Hz, 1H), 6.45 (br s, 2H); MS (ES+) m/z 550.7 (M+1), 552.7 (M+1).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][C@H:17]1[C@H:22]([OH:23])[CH2:21][CH2:20][CH2:19][O:18]1.[H-].[Na+].[CH2:26](Br)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].O>CN(C)C=O>[CH2:41]([O:23][C@@H:22]1[CH2:21][CH2:20][CH2:19][O:18][C@H:17]1[CH2:16][O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][OH:7])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH3:26]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: O[C@@H]1CCCO[C@H]1COCCCCCCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCCCO[C@@H]1CCCO[C@H]1COCCCCCCCO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.652 g of dl-trans-2-[7-(tetrahydropyran-2-yloxy)heptyloxymethyl]tetrahydropyran-3-ol (prepared as described in Preparation 54) in 5 ml of dimethylformamide was added dropwise at room temperature to a suspension of 0.24 g of sodium hydride (as a 55% w/w dispersion in mineral oil) in 5 ml of dimethylformamide. The reaction mixture was stirred at room temperature for 30 minutes, after which it was heated on an oil bath kept at 60° C. for a further 30 minutes. At the end of this time, 1.83 g of hexadecyl bromide were added at room temperature, after which the mixture was heated on an oil bath kept at 60° C. for 30 minutes, whilst stirring. The mixture was then cooled, and 0.24 g of sodium hydride (as a 55% w/w dispersion in mineral oil) was added to it at room temperature. The mixture was then heated on an oil bath kept at 60° C. for 30 minutes. The reaction mixture was allowed to cool to room temperature and a further 1.83 g of hexadecyl bromide was added to it. The reaction mixture was then heated on an oil bath kept at 60° C. for 30 minutes, whilst stirring, after which it was cooled and poured into water and then extracted three times with methylene chloride. The combined extracts were dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. 40 ml of methanol and 0.5 ml of concentrated hydrochloric acid were added to a solution of the oil residue (5.74 g) dissolved in 15 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 30 minutes. The solvent was then removed by distillation under reduced pressure, and the residue was diluted with water and then extracted twice with diethyl ether. The combined extracts were washed with a saturated aqueous solution of sodium bicarbonate and with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The oily residue (5.14 g) was subjected to column chromatography through 90 g of silica gel. 2.123 g of the title compound were obtained, as a viscous oil, from those fractions eluted with a 2:1 by volume mixture of hexane and ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[CH:15]1([CH2:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[N:25]=[N:26][C:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:28][CH:29]=2)=[O:23])[CH2:17][CH2:16]1>>[CH:15]1([CH2:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[N:25]=[N:26][C:27]([N:30]3[CH2:31][CH2:32][N:33]([C:6](=[O:7])[C:5]4[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=4[C:11]([F:14])([F:13])[F:12])[CH2:34][CH2:35]3)=[CH:28][CH:29]=2)=[O:23])[CH2:17][CH2:16]1
Reactant: O=C(NCCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Product: O=C(NCCCC1CC1)c1ccc(N2CCN(C(=O)c3ccc(F)cc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 4-fluoro-2-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-cyclopropylpropyl)amide, the title compound was obtained as a white powder (49% yield). 1H NMR (300 MHz, CDCl3) δ 8.04, 7.87, 7.45-7.3, 6.99, 4.09-3.98, 3.89-3.67, 3.49, 3.33, 1.75-1.66, 1.28, 0.69-0.62, 0.43-0.37, 0.04-0.03.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[C:33]([CH3:40])[CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>O1CCOCC1>[N:21]1([CH2:20][CH2:19][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5]([C:4]3[CH:3]=[C:2]([C:34]4[CH:35]=[CH:36][C:31]([F:30])=[CH:32][C:33]=4[CH3:40])[CH:29]=[CH:28][CH:27]=3)=[O:6])=[CH:9][CH:10]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(F)ccc1-c1cccc(C(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)c1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
3-Bromo-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-benzamide (600 mg, 1.31 mmol), 4-fluoro-2-methylphenyl boronic acid (271 mg, 1.98 mmol), cesium carbonate (730 mg, 2.24 mmol) and tetrakis triphenylphosphine palladium(0) (25 mg) in dioxane (10 ml) are heated to 100° C. under a nitrogen atmosphere for 16 hours. The mixture is cooled to room temperature then poured into ethyl acetate (100 ml). The organic layer is washed with water (100 ml), dried over anhydrous sodium sulfate and evaporated to dryness. The residue is then purified by column chromatography on silica gel to give 4′-fluoro-2′-methyl-biphenyl-3-carboxylic acid [4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-amide as pale purple needles (0.44 g). Mp: 95-7° C. 1H NMR 300 MHz (CDCl3) δ 8.35 (d, 1H, J=7.5 Hz), 7.85-8.1 (m, 5H), 7.75 (d, 1H, J=7.5 Hz), 7.5-7.63 (m, 4H), 7.2 (m, 1H), 6.9-7.05 (m, 2H), 6.85 (d, 1H, J=12 Hz), 4.3 (t, 2H), 3.75 (m, 4H), 2.98 (t, 2H), 2.6 (m, 4H), 2.3 (s, 3H).
Reaction SMILES: C(C1C=NC(C2C=CC([OH:23])=CC=2)=NC=1)CCCCCCCCC.C([C@H]1CC[C@H](C(O)=O)CC1)CCCC.[CH:38]1([N:44]=[C:45]=[N:46][CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>ClCCl>[CH:47]1([NH:46][C:45]([NH:44][CH:38]2[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]2)=[O:23])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: CCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
A solution of 35.4 g of 4-(5-decylpyrimidin-2-yl)phenol, 22.5 g of trans-4-pentylcyclohexanecarboxylic acid and 23.4 g of N,N'-dicyclohexylcarbodiimide in 600 ml of dichloromethane is stirred at 20° C. for 12 hours. The N,N'-dicyclohexylurea formed is filtered off, and the filtrate is chromatographed over 5 kg of silica gel using dichloromethane. The product-containing fraction gives 21.5 g of colorless crystals after recrystallization from n-hexane.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([O:30][CH3:31])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:5]=[C:4]([Cl:32])[N:3]=1.[CH3:33][O:34][C:35]1[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=1[NH2:37].CC(C)([O-])C.[K+]>C1COCC1>[Cl:32][C:4]1[N:3]=[C:2]([NH:37][C:36]2[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=2[O:34][CH3:33])[C:7]2[C:8]([O:30][CH3:31])=[N:9][N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:5]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(Cl)c12
Reactant: COc1ccccc1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccccc1Nc1nc(Cl)cc2c1c(OC)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
4,6-dichloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine (Intermediate 37B, 100 mg, 0.217 mmol), 2-methoxyaniline (26.0 μl, 0.217 mmol), t-butyl X-Phos palladacycle (5.97 mg, 8.69 μmol) were combined in a 5 ml microwave vial. The vial was evacuated and backfilled (3×) with N2 gas before adding THF (2.2 ml) and potassium t-butoxide (326 μl, 0.326 mmol). The reaction was allowed to stir at 80° C. for 2 hours. Room temperature was attained and the mixture was filtered through a celite frit and concentrated in vacuo while loading onto silica gel. Purifcation by MPLC 0-20% EtOAc/DCM gave 6-chloro-3-methoxy-N-(2-methoxyphenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-amine (52B). MS: [M+H]+ m/z 547.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([N:12]1[C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[C:14]([CH2:21][CH2:22][NH:23]C(=O)[O-])=[CH:13]1)(=[O:11])=[O:10].FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([N:12]1[C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[C:14]([CH2:21][CH2:22][NH2:23])=[CH:13]1)(=[O:11])=[O:10]
Reactant: O=C([O-])NCCc1cn(S(=O)(=O)c2ccc(F)cc2F)c2ccncc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCc1cn(S(=O)(=O)c2ccc(F)cc2F)c2ccncc12
Reaction time: 2 h

Procedure:
A solution of {2-{1-[(2,4-difluorophenyl)sulfonyl]-1H-pyrrolo[3,2-c]pyridin-3-yl}ethyl}carbamate in CH2Cl2 is treated with trifluoroacetic acid, stirred for 2 h and concentrated in vacuo. The resultant residue is purified by preparative reverse phase HPLC to afford the title product.