Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][NH:9][C:10](=[O:41])[CH2:11][CH:12]([C:17](=[O:40])[NH:18][C@H:19]1[CH2:37][C:36]2=[CH:38][N:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=32)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:21][C:20]1=[O:39])[CH2:13][CH:14]([CH3:16])[CH3:15])C1C=CC=CC=1.[H][H]>C(O)C.O1CCCC1.[Pd]>[OH:8][NH:9][C:10](=[O:41])[CH2:11][CH:12]([C:17](=[O:40])[NH:18][C@H:19]1[CH2:37][C:36]2=[CH:38][N:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=32)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:21][C:20]1=[O:39])[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)CC(CC(=O)NOCc1ccccc1)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCCNC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)CC(CC(=O)NO)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCCNC1=O
Reaction time: 3 h

Procedure:
To a solution of the more polar stereoisomer of (11S)-N-benzyloxy-5-methyl-3-(10-oxo-1,9-diazatricyclo-[11.6.1.014,19 ]eicosa-13(20),14(19),15,17-tetraen-11-ylcarbamoyl)hexanamide (90 mg) in ethanol/tetrahydrofuran (350 mL; 2:1) was added 10% palladium on charcoal (30 mg). The material was stirred with a constant stream of hydrogen gas bubbling through it. After 3 hours TLC (10% CH3OH/CH2Cl2) showed the reaction was complete. The material was filtered through a bed of celite (3×) and concentrated under reduced pressure to an almost dry residue. Methylene chloride (15 mL) was added and the material was again concentrated under reduced pressure until almost dried and then repeated. To the residue was added 3-4 drops of methanol followed by methylene chloride (15 mL). The material was stirred with cooling (ice bath) and ether (5 mL) and then hexane (2 mL) was added. A crystalline material slowly emerged and was collected by filtration to yield 50 mg of the more polar stereoisomer of (11S)-N-hydroxy-5-methyl-3-(10-oxo-1,9-diazatricyclo[11.6.1.014,19 ]eicosa-13(20),14(19),15,17-tetraen-11-ylcarbamoyl)hexanamide, m.p. 197°-201° C., [α]D23 =-85.1° (3.5 mg/1.0 mL DMSO).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]1[CH:15]=[CH:14][S:13][CH:12]=1.[C:16](Cl)(=[O:18])[CH3:17]>ClCCl>[S:13]1[CH:14]=[CH:15][C:11]([CH2:10][NH:9][C:16](=[O:18])[CH3:17])=[CH:12]1
Reactant: CC(=O)Cl
Reactant: NCc1ccsc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCc1ccsc1
Temperature: -5 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
Triethylamine (0.46 g, 4.4 mmol) was added dropwise to a stirred suspension of 3-(aminomethyl)thiophene hydrochloride (0.6 g, 4 mmol) in dry dichloromethane (20 ml) maintained under nitrogen at -5° C. After 15 minutes acetyl chloride (0.31 g, 4 mmol) was added dropwise to the solution which was then stirred for 3 hours at -5° C. After this time the reaction mixture was washed sequentially with dilute HCl (50 ml, 0.5M) and dilute NaOH (50 ml, 0.5 m). The organic layer was separated, dried with magnesium sulphate, and the solvent removed in vacuo to yield the crude product which was recrystallised from hexane to give N-(3-thienylmethyl)acetamide (0.52 g, 85%) M.p. 46°-47° C. (Found: C, 53.5; H, 6.2; N. 8.7, S, 20.4. Calculated for C7H9NOS: C, 54.2; H, 5.8, N, 9.0; S, 20.7 (%); IR (Nujol): 3250, 1650 cm-1 ; EI m/e Intensity (%): 155 (37, M+), 112 (55, C4H3S.CH2NH+), 97 (29, C4H3S.CH2+). 83 (12, C4H3S); δH(CDCl3) 7.00-7.29 (3H, m), 6.26 (1H, br,s), 4.41 (2H, d), 1.93 (3H, s); δC(CDCl3): 23.1, 38.7, 122.2, 126.3, 127.3, 139.8, 170.0 ppm.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([OH:26])=O)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:26])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: C1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21)N1CCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 28.2 %

Procedure:
To a suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (510 mg, 1.4 mmol) in CH2Cl2 (9 mL) were added pyrrolidine (174 μL, 2.1 mmol), diisopropylethylamine (DIPEA) (366 μL, 2.1 mmol) and 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (798 mg, 2.1 mmol). The solution obtained was stirred at room temperature for 90 min then diluted with CH2Cl2. The organic phase was washed with aqueous NaHCO3, passed over a phase separator and concentrated in vacuo. The resultant residue was purified using chromatography (silica gel, gradient 0 to 70% ethyl acetate/isohexane) followed by a second chromatography purification (silica gel, gradient 0 to 25% dichloromethane/ether) yielding Compound 45 as a solid (165 mg).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:11])[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+].[Br:23]Br.O>C(Cl)Cl>[CH2:1]([NH:8][C:9](=[O:10])[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:23][C:16]1[CH:15]=[CH:14][NH:13][N:12]=1
Reactant: c1cn[nH]c1
Reactant: BrBr
Agent: O=C(O)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Brc1cc[nH]n1
Reaction time: 6 h

Procedure:
To a solution of pyrazole benzyl carbamate (115.0 mg, 0.38 mmol), prepared in step A, in 6 mL of CH2Cl2 at room temperature was added solid potassium carbonate in one portion. A solution of bromine was added dropwise to the stirred mixture. After 6 h, 30 mL of H2O was added, and the mixture was extracted with CH2Cl2 (30 mL×3). The combined organic extracts were washed with a 10% Na2S2O3 aqueous solution (20 mL), a saturated NaHCO3 aqueous solution (20 mL) and brine (20 mL), and dried with Na2SO4. Evaporation of solvent gave a slightly yellow oil, which was purified by preparative TLC (CH2Cl2-MeOH=20:1). The silica was extracted with CH2Cl2 and methanol, the extracts were filtered and concentrated under reduced pressure to afford an oil, which was further dried on high vacuum, yielding 134.2 mg (93%) of the bromo-pyrazole benzyl carbamate (MH+=381).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:11][C:12]2[C:17]([F:18])=[CH:16][C:15]([NH:19][C:20](=[O:22])[CH3:21])=[CH:14][C:13]=2[F:23])[NH:4][CH:3]=1.C([Li])CCC.[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>C1COCC1>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:11][C:12]2[C:17]([F:18])=[CH:16][C:15]([NH:19][C:20](=[O:22])[CH3:21])=[CH:14][C:13]=2[F:23])[N:4]([S:35]([C:32]2[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=2)(=[O:37])=[O:36])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)Nc1cc(F)c(Oc2ccnc3[nH]cc(Br)c23)c(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(F)c(Oc2ccnc3c2c(Br)cn3S(=O)(=O)c2ccc(C)cc2)c(F)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
1.37 g (3.58 mmol) of N-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}acetamide are dissolved in 200 ml of THF and cooled to −78° C. 1.6 ml (4.0 mmol) of a 2.5M n-butyllithium solution are added dropwise, and the mixture is stirred for 15 min. 752 mg (3.94 mmol) of p-toluenesulfonyl chloride as a solution in 7.5 ml of THF are then added dropwise. The reaction solution is allowed to warm to RT and stirred for one hour. The mixture is then partitioned between ethyl acetate and 0.1N aqueous sodium hydroxide solution. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is removed under reduced pressure. The product is purified by column chromatography on silica gel (mobile phase: dichloromethane/acetone 20:1 to 10:1).
Reaction SMILES: [Li][CH2:2]CCC.CCCCCC.[Br:12][C:13]1[C:14](=O)[CH2:15][CH2:16][C:17]2([CH2:27][CH2:28][CH2:29][CH3:30])[C:25]=1[C:24]1[C:19](=[CH:20][C:21]([OH:26])=[CH:22][CH:23]=1)[CH2:18]2>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Br:12][C:13]1[C:14](=[CH2:2])[CH2:15][CH2:16][C:17]2([CH2:27][CH2:28][CH2:29][CH3:30])[C:25]=1[C:24]1[C:19](=[CH:20][C:21]([OH:26])=[CH:22][CH:23]=1)[CH2:18]2
Reactant: CCCCC12CCC(=O)C(Br)=C1c1ccc(O)cc1C2
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C1CCC2(CCCC)Cc3cc(O)ccc3C2=C1Br
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A suspension of methyltriphenylphosphonium bromide (373 mg, 1.04 mmol) in anhydrous tetrahydrofuran (2 mL) was cooled in an ice bath and stirred under a nitrogen atmosphere while 2.5 N nBuLi in hexane (0.36 mL, 0.90 mmol) was added by syringe. The mixture was stirred at 0° C. for 10 minutes to complete formation of the methylenetriphenylphosporane reagent. A solution of 4-bromo-9a-butyl-7-hydroxy-1,2,9,9a-tetrahydro-fluoren-3-one (50 mg, 0.15 mmol) in tetrahydrofuran (1 mL) was added to the reaction mixture and the ice bath was removed. The resulting mixture was stirred at room temperature for 3.2 hours, then at 50° C. for 1.5 hour, and finally at room temperature for an additional 17 hours. The mixture was partitioned between saturated aqueous NH4Cl (5 mL) and EtOAc (9 mL). The organic phase was acidified with 2N HCl (0.2 mL), washed with brine (4 mL), dried over MgSO4, filtered, and evaporated under vacuum to an oil (90. mg). The crude product was purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate using 3:1 hexanes-EtOAc as developing solvent. The UV visible band at Rf 0.50-0.63 was eluted with EtOAc. The eluant was concentrated under vacuum to a residue which was lyophilized from benzene to afford 4-bromo-9a-butyl-3-methylene-2,3,9,9a-tetrahydro-1H-fluoren-7-ol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](O)=[O:24])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].O[N:27]=[C:28]([NH2:32])[CH:29]([CH3:31])[CH3:30]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][CH:11]([C:23]3[O:24][N:32]=[C:28]([CH:29]([CH3:31])[CH3:30])[N:27]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC(C)C(N)=NO
Reactant: Cc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1C
Product: Cc1ccc(C2CC(c3nc(C(C)C)no3)CN(C(=O)N3CCOCC3)C2)cc1C

Procedure:
100 mg (0.29 mmol) of the compound from Example 130A and 46 mg (0.43 mmol) of N′-hydroxy-2-methylpropanimidamide were reacted according to the General Method 2. Yield: 107 mg (90% of theory)
Reaction SMILES: C([O:4][P:5]([CH2:11][O:12][CH2:13][C:14]([CH3:31])=[CH:15][CH2:16][C:17]1[C:18]([OH:30])=[C:19]2[C:23](=[C:24]([CH3:28])[C:25]=1[O:26][CH3:27])[CH2:22][O:21][C:20]2=[O:29])(=[O:10])[O:6]C(C)C)(C)C.N1C(C)=CC=CC=1C.C[Si](Br)(C)C>C(#N)C>[OH:30][C:18]1[C:17]([CH2:16][CH:15]=[C:14]([CH3:31])[CH2:13][O:12][CH2:11][P:5](=[O:4])([OH:10])[OH:6])=[C:25]([O:26][CH3:27])[C:24]([CH3:28])=[C:23]2[C:19]=1[C:20](=[O:29])[O:21][CH2:22]2
Reactant: COc1c(C)c2c(c(O)c1CC=C(C)COCP(=O)(OC(C)C)OC(C)C)C(=O)OC2
Agent: C[Si](C)(C)Br
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Product: COc1c(C)c2c(c(O)c1CC=C(C)COCP(=O)(O)O)C(=O)OC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of [4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonic acid diisopropyl ester (25 mg, 0.055 mmol) and 2,6-lutidine (0.18 mL, 1.65 mmol) in acetonitrile was added trimethylsilyl bromide (0.126 mL, 1.1 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred for 4 h. The reaction was quenched with methanol at 0° C., and the resulting mixture was concentrated. The residue was purified by preparative reverse-phase HPLC to afford, after removal of the solvent, [4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonic acid as an oil (17 mg, 83%); 1H NMR (300 MHz, CD3OD) δ 1.81 (s, 3H), 2.06 (s, 3H), 3.40 (d, J=6.6 Hz, 2H), 3.50 (d, 2H), 3.77 (s, 3H), 3.97 (s, 2H), 5.20 (s, 2H), 5.47 (t, J=6.6 Hz, 1H); MS (m/z) 371 [M−H]−.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](=[O:23])[CH:13]([OH:22])[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:30](Cl)(=[O:38])[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](=[O:23])[CH:13]([O:22][C:30]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:38])[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCC(O)C(=O)c1ccc(F)c2ccccc12
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)CCCC(OC(=O)Oc1ccccc1)C(=O)c1ccc(F)c2ccccc12
Yield: 100.5 %

Procedure:
To a mixture of ethyl 6-(4-fluoro-1-naphthyl)-5-hydroxy-6-oxohexanoate (19.0 g), pyridine (5.50 g) and tetrahydrofuran (100 ml) was added dropwise phenyl chlorocarbonate (10.8 g) with stirring under ice-cooling. After 16 hours of stirring at room temperature, the reaction mixture was concentrated, diluted with ethyl acetate (400 ml) and washed with water (200 ml). The organic layer was dried over anhydrous magnesium sulfate, and concentrated to give ethyl 6-(4-fluoro-1-naphthyl)-6-oxo-5-phenoxycarbonyloxyhexanoate as a yellow oil (26.3 g, 96%).
Reaction SMILES: [CH3:1][N:2]([C:9]1[CH:14]=[CH:13][C:12]([N:15]=O)=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:17](N1C=CN=C1)(N1C=CN=C1)=[S:18]>C(OCC)(=O)C.C(Cl)Cl.[Pd]>[CH3:1][N:2]([C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:17]=[S:18])=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)CN(C)c1ccc(N=O)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(C)c1ccc(N=C=S)cc1

Procedure:
A solution of 14.7 g (66 mmol) of ethyl N-methyl-N-(4-nitrosophenyl)glycinate in 200 mL of ethyl acetate was reduced (10% Pd/C, 50 psi H2) until uptake was complete, dried 1 hr (Na2SO4), filtered, concentrated, and dissolved in a solution of 12.5 g (70 mmol) of thiocarbonyldimidazole in 100 mL CH2Cl2 /300 ml toluene. When tlc showed only product (2 hr,Rf 0.6, CH2Cl2), the solution was washed with 2×100 mL of water, passed throug a silica plug to remove color, and recrystallized from hexane (300 mL) to give 13.6g (54 mmol, 82%) mp 90-91°. Anal. C12H14N2O2S (250): Calcd.: C,57.58; H,5.64; N,11.19; S,12.81. Found: C,57.63; H,5.59; N,11.17; S,12.49. MS(FD) m/z250. 1H NMR(CDCl3)δ: 7.10,d,2H,ArH; 6.58,d,2H,ArH; 4.18,q,2H,CH2 --O; 4.05,s,2H,CH2 --N; 3.07,s,3H,CH3 --N; 1.25,s,3H,CH3 --C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.BrC1C(=O)C2C(C=1C1C=CC=CC=1)=CC=C(O)C=2.O[CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:49][CH2:48]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:45][CH2:46][CH:47]4[CH2:48][CH2:49][N:50]([C:53]([O:55][C:56]([CH3:57])([CH3:59])[CH3:58])=[O:54])[CH2:51][CH2:52]4)=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccc3c(c2)C(=O)C(c2cccnc2)=C3c2cc(F)cc(F)c2)CC1
Reaction time: 13 h
Yield: 66 %

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 3-(3,5-difluorophenyl)-6-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one obtained in Step 1 of Example 64 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, t-butyl 4-(2-hydroxyethyl)piperidin-1-carboxylate (2.0 eq) instead of 4-(2-hydroxyethyl)morpholine, using 2 equivalents of PPh3 and DIAD, and being stirred for 13 h to provide the title compound (80 mg, 66%).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([N:12]3[C:16]([CH2:17][CH3:18])=[CH:15][C:14]([CH2:19][CH3:20])=[N:13]3)=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[OH:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[O:30][C:2]1[N:6]([CH3:7])[C:5]2[C:8]([N:12]3[C:16]([CH2:17][CH3:18])=[CH:15][C:14]([CH2:19][CH3:20])=[N:13]3)=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1
Reactant: Cc1cc(Cl)cc(Cl)c1O
Reactant: CCc1cc(CC)n(-c2cccc3nc(Cl)n(C)c23)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc(CC)n(-c2cccc3nc(Oc4c(C)cc(Cl)cc4Cl)n(C)c23)n1
Yield: 78.3 %

Procedure:
A suspension of 2-chloro-7-(3,5-diethyl-1H-pyrazol-1-yl)-1-methyl-1H-benzimidazole (92 mg, 0.318 mmol), 2,4-dichloro-6-methylphenol (114 mg, 0.643 mmol), potassium carbonate (89 mg, 0.643 mmol) in N,N-dimethylformamide (1.5 ml) was stirred at 90° C. for 5.5 days (2,4-dichloro-6-methylphenol and potassium carbonate were added in three equal portions each over 5.5 days). After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a 10-25% ethyl acetate/n-hexane gradient mixture to give 107 mg (0.249 mmol, 78.3%) of the title compound as an oil. The oil was crystallized from hexane to give 70 mg (51%) as a pale yellow crystal.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][CH:6]([C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:7]([CH3:9])=O)C.[C:20]1([NH:26][NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)(=O)C>C(O)C>[CH3:9][C:7]1[C:6]([CH2:5][C:4]([OH:3])=[O:19])=[C:10]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[N:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:27]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)CC(C(C)=O)C(=O)c1ccc(Cl)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1nn(-c2ccccc2)c(-c2ccc(Cl)cc2)c1CC(=O)O
Yield: 72.2 %

Procedure:
11.5 grams 3-(p-chlorobenzoyl)-levulinic acid ethyl ester, 4.9 grams phenyl-hydrazine, 2.8 grams glacial acetic acid and 10 milliliters ethanol were mixed an the mixture was heated to the boiling temperature under reflux for 3.5 hours. The reaction mixture was evaporated and 100 milliliters benzene were added to the residue. The pH of the solution was adjusted to 3, followed by extraction with water. The benzene phase was evaporated and 30 milliliters ethanol and 20 milliliters 2n aqueous sodium hydroxide added to the residue. The mixture was heated to the boiling temperature under reflux for 1 hour, and thereafter worked up and the free acid recovered in accordance with a procedure analogous to that set out in Example (1b). 9.6 grams 3-methyl-1-phenyl-5-(p-chlorophenyl)pyrazol-4-acetic acid, melting at 174°-177° C., were obtained representing a yield of 72%.
Reaction SMILES: [C:1]1([CH:7]2[CH2:10][CH:9]([NH2:11])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)[O:19][CH2:18][CH2:17][CH:16]2[C:33]([O:35][CH2:36][CH3:37])=[O:34].Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CN(C)C1C=CN=CC=1.CCOC(C)=O>[Cl:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](=[O:29])[NH:11][CH:9]3[CH2:8][CH:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:10]3)=[CH:26][CH:25]=1)[O:19][CH2:18][CH2:17][CH:16]2[C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: NC1CC(c2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CC(c5ccccc5)C4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.6 %

Procedure:
To a solution of 3-phenylcyclobutanamine (0.101 g, 0.686 mmol) in DMF (2 ml) was added 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (0.129 g, 0.343 mmol), N,N-dimethylpyridin-4-amine (0.00838 g, 0.0686 mmol), and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.0789 g, 0.412 mmol), and the reaction was stirred for 16 hours at ambient temperature. The reaction was diluted with EtOAc and washed with 1M hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was on a Biotage SP1 system eluting with a 5-70% EtOAc in hexanes linear gradient to yield 86 mg of the title compound (49.5% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>ClCCl>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(Br)cc1)N1CCOCC1
Temperature: 0 °C

Procedure:
Morpholine (58.2 mg, 0.668 mmol) and triethylamine (116 μl, 0.835 mmol) were placed in a round-bottom flask with a stir bar. Dry dichloromethane (5870 μL) was then added and the solution cooled to 0° C. 4-bromobenzenesulfonyl chloride (150 mg, 0.556 mmol) was added and the reaction was allowed to warm to room temperature overnight. It was quenched with water and extracted in ethyl acetate. The organic layers were washed with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 4-[(4-bromophenyl)sulfonyl]morpholine as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:21][C:22]1[NH:26][C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[N:23]=1)[CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:39]1([S:45](Cl)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:21][C:22]1[N:26]([S:45]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:47])=[O:46])[C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[N:23]=1)[CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cccnc1CN(CCCCNC(=O)OC(C)(C)C)Cc1nc2ccccc2[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccnc1CN(CCCCNC(=O)OC(C)(C)C)Cc1nc2ccccc2n1S(=O)(=O)c1ccccc1
Yield: 70.3 %

Procedure:
To a solution of {4-[(1H-benzoimidazol-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester (0.215 g, 0.51 mmol) in CH2Cl2 (10 mL) was added Et3N (0.30 mL, 2.15 mmol) followed by benzenesulfonyl chloride (0.—ml, 1.02 mmol) and the resultant solution was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 (40 mL), washed with brine (3×10 mL), dried (Na2SO4), and concentrated. Purification of the crude material by column chromatography on silica gel (15:1 CH2Cl2-MeOH) provided 0.202 g (70%) of {4-[(1-Benzenesulfonyl-1H-benzoimidazol-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester as an orange-brown oil.