Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:29])=[N:27][CH:28]=1>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:22][C:23]2[CH:28]=[N:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[N:3]=1
Reactant: Cc1ccc(CCl)cn1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
To a solution of 3-iodo-4-nitro-1H-indazole (3.0 g, 10.4 mmol) in DMF (25 mL) was added potassium carbonate (2.87 g, 20.8 mmol) at ambient temperature. After 15 minutes, 5-(chloromethyl)-2-methylpyridine hydrochloride (2.03 g, 11.4 mmol) was added. The mixture was allowed to stir at ambient temperature for 18 hours. The mixture was concentrated under reduced pressure and diluted with ice-water (300 mL). The precipitated solids were collected by filtration and washed with water to provide 3-iodo-1-((6-methylpyridin-3-yl)methyl)-4-nitro-1H-indazole (3.77 g, 92% yield).
Reaction SMILES: [CH:1]([CH:3]1[CH2:5][C:4]1([C:10]([O:12][CH3:13])=[O:11])[C:6]([O:8][CH3:9])=[O:7])=[CH2:2].C(O)[C:15]1[O:19][CH:18]=[CH:17][CH:16]=1>>[CH:1]([CH:3]1[CH2:5][C:4]1([C:10]([O:12][CH2:13][C:18]1[O:19][CH:15]=[CH:16][CH:17]=1)=[O:11])[C:6]([O:8][CH3:9])=[O:7])=[CH2:2]
Reactant: C=CC1CC1(C(=O)OC)C(=O)OC
Reactant: OCc1ccco1
Product: C=CC1CC1(C(=O)OC)C(=O)OCc1ccco1
Yield: 34.6 %

Procedure:
A transalcoholysis reaction was carried out in a manner similar to that described for Example II using dimethyl 2-vinylcyclopropane-1,1-dicarboxylate (92 g; 0.5 mol) and furfuryl alcohol (24.5 g; 0.25 mol). When essentially all of the furfuryl alcohol was consumed, the reaction mixture was dissolved in ethyl ether and washed with aqueous potassium hydroxide (5%). The ether portion was dried over MgSO4, filtered and vacuum distilled to obtain 21.63 g crude methyl (2-furyl)methyl 2-vinylcyclopropane-1,1-dicarboxylate. B.p. 91°-97° C. at 0.015 mm Hg. The distilled product (M.p. 58°-64° C.) was first recrystallized from methanol and then from a mixture of petroleum ether and methanol to obtain high purity methyl (2-furyl)methyl 2-vinylcyclopropane-1,1-dicarboxylate (translucent crystals melting at 67.5°-68.5° C.). The infrared spectra and nuclear magnetic resonance spectra were consistent with the desired product. Similar results are obtained when (5-methyl-2-furyl)carbinol, (5-allyl-3-furyl)carbinol and 5-hydroxymethyl-2,2'-difuryl methane are substituted for the furfuryl alcohol in the above reaction and all of these products are useful in insecticidal formulations.
Reaction SMILES: [CH:1]([C:4]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:12]=[C:11]([CH:18]([CH3:20])[CH3:19])[C:5]=1[CH2:6][S:7]([NH2:10])(=[O:9])=[O:8])([CH3:3])[CH3:2].[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:25]=1[CH2:33][C:34](Cl)=[O:35])([CH3:23])[CH3:22].CCN(CC)CC>C1COCC1>[CH3:32][CH:30]([C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH:21]([CH3:22])[CH3:23])[C:25]=1[CH2:33][C:34]([NH:10][S:7]([CH2:6][C:5]1[C:11]([CH:18]([CH3:20])[CH3:19])=[CH:12][C:13]([CH:15]([CH3:17])[CH3:16])=[CH:14][C:4]=1[CH:1]([CH3:3])[CH3:2])(=[O:9])=[O:8])=[O:35])[CH3:31]
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)Cl
Reactant: CC(C)c1cc(C(C)C)c(CS(N)(=O)=O)c(C(C)C)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)c1cc(C(C)C)c(CS(=O)(=O)NC(=O)Cc2c(C(C)C)cccc2C(C)C)c(C(C)C)c1
Yield: 12.1 %

Procedure:
A solution of 2,4,6 - triisopropylbenzylsulfonamide (100 mg, 0.33 mmol), 2,6-diisopropylphenylacetyl chloride (75 mg, 0.34 mmol), and Et3N (47 μL, 0.34 mmol) in 10 mL THF was stirred at room temperature overnight. The solvent was evaporated and the residue was distributed between ethyl acetate and 0.1N HCl, the organic layer was washed with brine, dried, and evaporated. The pure product (20 mg, 12%) was isolated by column chromatography (4:1 hexane:EtOAc), m/e=499; NMR (CDCl3):δ 7.05-7.4 (m, 5H), 4.25 (s, 2H), 3.95 (s, 2H), 3.45-3.6 (m, 1H), 3.0-3.15 (m, 2H), 2.85-3.0 (m, 2H), 1.05-1.4 (m, 30H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[N:50]1[CH:55]=[CH:54][C:53]([N:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)=[CH:52][CH:51]=1>>[CH3:47][O:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][N:8]([CH2:7][C:6]2[CH:48]=[CH:49][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:31]=[CH:32][C:33]([C:34]([N:59]6[CH2:60][CH2:61][N:56]([C:53]7[CH:54]=[CH:55][N:50]=[CH:51][CH:52]=7)[CH2:57][CH2:58]6)=[O:35])=[CH:37][CH:38]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:45][CH:44]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCN(c5ccncc5)CC4)cc3)cn2)cc1
Yield: 119.1 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (80.0 mg, 0.121 mmol) obtained in Step A in Example 1-D-19 and 1-(4-pyridyl)piperazine (29.7 mg, 0.182 mmol) instead of 3-(aminomethyl)pyridine, amidation was carried out in the same manner as Step B in Example 1-D-19, to obtain a crude product of {4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-phenyl}-(4-pyridin-4-yl-piperazin-1-yl)-methanone as a brown solid (116 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-265) as a yellow powder (47.4 mg, 69%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[CH:11]([Si:14](Cl)([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])([CH3:13])[CH3:12]>C1COCC1.CCCCCC.C(OCC)C>[CH:11]([Si:14]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[N:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)([CH3:13])[CH3:12]
Reactant: c1cc[nH]c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cccc1
Yield: 91.9 %

Procedure:
To a solution of pyrrole (33.54 g) in THF (700 ml) at -78° C. under nitrogen was added a solution of 2.5M n-butyl lithium(200 ml) in hexane. After one hour triisopropylsilyl chloride (98 g) was added. After 24 hours the reaction was diluted with diethyl ether, washed with water, dried over sodium sulfate, filtered and evaporated to a tan oil which was distilled at 115°-119° C. (0.2 mm Hg) to give 102.6 g of a colorless mobile liquid. 1H NMR is consistent with proposed structure.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH:4]([O:33][CH2:34][CH3:35])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][N:14]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])=[O:16])=[CH:8][CH:7]=1.[Li+].[OH-]>O1CCCC1>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[NH:17][C:15](=[O:16])[N:14]([CH2:13][CH2:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH:4]([O:33][CH2:34][CH3:35])[C:3]([OH:36])=[O:2])=[CH:11][CH:10]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCN(CCc1ccc(CC(OCC)C(=O)OC)cc1)C(=O)Nc1ccc(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCN(CCc1ccc(CC(OCC)C(=O)O)cc1)C(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 94 h
Yield: 61.6 %

Procedure:
A solution of 3-(4-{2-[3-(2,4-difluoro-phenyl)-1-heptyl-ureido]-ethyl}-phenyl)-2-ethoxy-propionic acid methyl ester (44 mg, 0.087 mmol) and 1 M LiOH (0.26 mmol, 0.26 mL) in tetrahydrofuran (2 mL) was allowed to stir at room temperature for 94 hours. The solution was quenched by the addition of 2 N HCL until the solution had a pH<2. After dilution with twice its volume in water, the aqueous layer was extracted with diethyl ether (2×). The organic layers were combined, washed with 2 M HCl (2×), dried over anhydrous sodium sulfate, and concentrated to a crude oil. The oil was chromatographed on silica gel (15% methanol/methylene chloride) to give 3-(4-{2-[3-(2,4-difluoro-phenyl)-1-heptyl-ureido]-ethyl}-phenyl)-2-ethoxy-propionic acid as a white waxy-solid (26.3 mg, 62%).
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[F:25][C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:14]2[C:15]3[CH2:16][CH2:17][NH:8][CH2:9][C:10]=3[N:11]=[CH:12][N:13]=2)=[CH:24][CH:23]=1
Reactant: Fc1ccc(Nc2ncnc3c2CCN(Cc2ccccc2)C3)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Fc1ccc(Nc2ncnc3c2CCNC3)cc1
Reaction time: 24 h
Yield: 101.3 %

Procedure:
7-Benzyl-N-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (0.64 g, 1.9 mmol) was dissolved in methanol (25 mL) and palladium hydroxide was added (0.5 g, 20% wt). The mixture was shaken on a Parr Shaker under H2(g) atmosphere (60 PSI) for 1 day. The mixture was filtered through celite and evaporated to give 0.47 g of material as grey crystals (quant.), which was used as such for the next step.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C@@H:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][C@:20]2([CH3:36])[C:32]([O:34][CH3:35])=[O:33])(=[O:17])=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([S:15]([NH:18][C@@H:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:21][C@:20]2([CH3:36])[C:32]([O:34][CH3:35])=[O:33])(=[O:16])=[O:17])=[CH:13][CH:14]=1
Reactant: COC(=O)[C@@]1(C)CN(C(=O)OC(C)(C)C)CC[C@H]1NS(=O)(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@@]1(C)CN(C(=O)OC(C)(C)C)CC[C@H]1NS(=O)(=O)c1ccc(O)cc1
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
(3S,4R)-1-tert-Butyl 3-methyl 4-(4-(benzyloxy)phenylsulfonamido)-3-methylpiperidine-1,3-dicarboxylate (4.659 g, 8.09 mmol) was taken up in methanol (30 mL) and combined with Pearlman's catalyst (501 mg). The heterogeneous mixture was stirred under a hydrogen atmosphere for 0.5 h, and then filtered through celite and concentrated to give (3S,4R)-1-tert-butyl 3-methyl 4-(4-hydroxyphenylsulfonamido)-3-methylpiperidine-1,3-dicarboxylate (3.754 g, 7.73 mmol, 96%) as a colorless solid. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.16 (s, 3H) 1.24 (s, 9H) 1.37-1.48 (m, 10H) 1.68-1.77 (m, 2H) 2.54 (d, J=15.41 Hz, 1 H) 2.82 (td, J=13.20, 2.65 Hz, 1H) 3.27 (ddd, J=12.25, 8.59, 3.92 Hz, 1H) 4.00 (ddd, J=13.58, 2.53, 2.34 Hz, 1H) 4.33 (d, J=13.89 Hz, 1H) 6.85-6.89 (m, 2H) 7.67-7.72 (m, 2H).
Reaction SMILES: [C@@H:1]1([NH:11][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]3[CH:25]=[C:24]([N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[CH:23]=[CH:22][C:21]=3[NH:32][C:33]([C:35]3[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=3)[C:38](O)=[O:39])=[O:34])[CH:15]=2)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:44][NH:45][CH2:46][CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1.CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1.O>[CH3:44][N:45]([CH2:46][CH2:47][CH2:48][N:49]1[CH2:50][CH2:51][O:52][CH2:53][CH2:54]1)[C:38](=[O:39])[C:37]1[CH:41]=[CH:42][CH:43]=[C:35]([C:33]([NH:32][C:21]2[CH:22]=[CH:23][C:24]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:25][C:20]=2[C:16]2[CH:15]=[C:14]([C:12](=[O:13])[NH:11][C@@H:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:4][CH2:3][CH2:2]3)[CH:19]=[CH:18][N:17]=2)=[O:34])[CH:36]=1
Reactant: CNCCCN1CCOCC1
Reactant: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CN(CCCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
A solution of 3-((2-(4-(((S)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzoic acid (150 mg, 0.26 mmol, 1.00 equiv) in dichloromethane (3 mL), N-methyl-3-morpholinopropan-1-amine (42 mg, 0.27 mmol, 1.00 equiv), EDC.HCl (75 mg, 0.39 mmol, 1.50 equiv), 4-dimethylaminopyridine (48 mg, 0.39 mmol, 1.50 equiv). The resulting solution was stirred for 2 h at 25° C. The resulting solution was diluted with 3 mL of water. The resulting solution was extracted with 2×5 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 1×5 mL of water and 2×5 mL of Brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (120 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (24% CH3CN up to 34% in 6 min); Detector, Waters2545 UvDector 254&220 nm. 97 mg product was obtained. This resulted in 97 mg (35%) of (S)—N1-methyl-N1-(3-morpholinopropyl)-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide. Example 126 as a yellow solid. (ES, m/z): 715 [M+H]+(400 MHz, CD3OD, ppm): 8.91 (s, 1H), 8.73 (d, J=8.8 Hz, 1H), 8.41 (s, 1H), 8.14˜8.09 (m, 3H), 7.873˜7.857 (m, 1H), 7.753˜7.69 (m, 3H), 7.27 (d, J=7.2 Hz, 1H), 7.19˜7.13 (m, 3H), 5.40 (d, J=6.4 Hz, 1H), 4.18 (s, 2H), 3.90˜3.50 (m, 9H), 3.46˜3.17 (m, 5H), 3.07 (s, 3H), 2.89˜2.78 (s, 2H), 2.26˜2.03 (m, 8H), 1.98˜1.81 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:26][C@H:25]2[C@@H:15]([CH2:16][C:17]3[C:27]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]2=4)[NH:19][CH:18]=3)[N:14]([CH3:28])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)#[N:30]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:26][C@H:25]2[C@@H:15]([CH2:16][C:17]3[C:27]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]2=4)[NH:19][CH:18]=3)[N:14]([C:28]#[N:30])[CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CBr
Reactant: CN1C[C@@H](NC(=O)OCc2ccccc2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Solvent: ClC(Cl)Cl
Product: N#CN1C[C@@H](NC(=O)OCc2ccccc2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21

Procedure:
A solution of 29.5 g (79 mM) of 8α-benzyloxycarbonylamino-6-methylergoline obtained from step (a) and 25 g (236 mM) cyanobromide in 600 ml chloroform is stirred for 65 hours at room temperature and finally concentrated on a rotary evaporator to give the heading compound which is dried in a high vacuum.
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[C:4]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH2:24]([O:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([Br:1])=[CH:3][C:4]=1[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1cc(O)c(C2CCCCC2)cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(OCc2ccccc2)c(C2CCCCC2)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
To a solution of 4-bromo-2-cyclohexyl-5-nitro-phenol (1.19 g, 4.0 mmol) and Cs2CO3 (1.54 g, 4.72 mmol) in DMF (10 mL) was added benzyl bromide (1.02 g, 707 μL, 6.0 mmol) dropwise. The reaction mixture was stirred at room temperature under an inert atmosphere for 2 h. The reaction was quenched with water and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography using 5% EtOAc/hexane gradient gave 1-(benzyloxy)-4-bromo-2-cyclohexyl-5-nitrobenzene (1.35 g, 87%). 1H NMR (400 MHz, CDCl3) δ 7.42 (s, 1H), 7.39 (s, 1H), 7.36-7.25 (m, 5H), 5.06 (s, 2H), 2.99-2.93 (m, 1H), 1.79 (d, J=11.5 Hz, 4H), 1.70 (d, J=13.4 Hz, 1H), 1.39-1.14 (m, 5H)
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:18][CH3:19])(=[O:17])[CH:14]([CH3:16])[CH3:15].Br[CH2:21][CH2:22][Cl:23].Cl>O.O1CCCC1>[Cl:23][CH2:22][CH2:21][C:14]([CH3:16])([CH3:15])[C:13]([O:18][CH3:19])=[O:17]
Reactant: ClCCBr
Reactant: COC(=O)C(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: COC(=O)C(C)(C)CCCl
Temperature: -70 °C
Reaction time: 0.33 h
Yield: 75.8 %

Procedure:
The reaction vessel was dried and, under an argon atmosphere, 75.9 grams (0.75 mole) of diisopropylamine and 450 ml of tetrahydrofuran was added. The stirred solution was cooled to -70° C. and 48.0 grams (0.75 mole-484 ml of 1.5 molar in hexane) of n-butyl lithium was added. Upon completion of addition the reaction mixture stirred for 20 minutes and, at -70° C., 68.9 grams (0.675 mole) of methyl isobutyrate was added dropwise. Upon completion of addition the reaction mixture stirred for an additional 20 minutes and, at -70° C., 108.0 grams (0.75 mole) of 1-bromo-2-chloroethane was added dropwise. The reaction mixture was allowed to warm to ambient temperature where it stirred for 16 hours. After this time 500 ml of water, then 85 ml of concentrated hydrochloric acid, were added dropwise to the reaction mixture. Upon completion of addition the reaction mixture stirred for an additional five minutes. The organic layer was separated and washed with 150 ml of aqueous 10% hydrochloric acid. The combined aqueous layers were washed with 150 ml of methylene chloride. The combined organic layers were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was distilled under reduced pressure to give 84.2 grams of methyl 4-chloro-2,2-dimethylbutanoate; b.p. 80°-84° C./15 mm.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][C:8]=2[C:9]=1[C:10](O)=[O:11])[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:24])=O>>[CH2:1]([C:5]1[O:6][C:7]2[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][C:8]=2[C:9]=1[C:10]([Cl:24])=[O:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)O
Reactant: O=S(Cl)Cl
Product: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)Cl
Temperature: 22.5 °C
Reaction time: 3 h

Procedure:
7 g (22.48 mmol) of 2-butyl-5-methanesulfonamidobenzofuran-3-carboxylic acid are dissolved in 50 g of thionyl chloride and stirred for 3 hours at 20-25° C. and then refluxed for 30 minutes (79° C.). The reaction medium is then concentrated to dryness under reduced pressure and the residue (8.8 g) is taken up in 46.2 g of anhydrous DCE (total mass=55 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH3:19])[N:10]=[C:9]2[CH:20]([NH:22][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][N:27]3COCC[Si](C)(C)C)[CH3:21])[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:42][CH2:43][N:44]([CH3:46])[CH3:45].Cl.OC1C=C(N2C(=O)C3C(=CC=CC=3C)N=C2C(NC2N=CN=C3C=2N=CN3)C)C=CC=1>CO>[CH3:45][N:44]([CH3:46])[CH2:43][CH2:42][O:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH3:19])[N:10]=[C:9]2[CH:20]([NH:22][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][NH:27]3)[CH3:21])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCCl
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(O)c3)c(=O)c12
Agent: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cnc34)n(-c3cccc(O)c3)c(=O)c12
Agent: Cl
Solvent: CO
Product: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cnc34)n(-c3cccc(OCCN(C)C)c3)c(=O)c12

Procedure:
Compound 126 (300 mg, 0.54 mmol) was treated with 2-chloro ethyl dimethylamine hydrochloride salt, at 90° C. for 17 hrs, using the procedure described above for compound 127. The resulting compound was then treated with 4N HCl, in MeOH, using the procedure described for compound 121 (step D). Compound 129 was obtained. m/z=485 (M+H). The structure of compound 129 is shown below.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]#[C:20][CH2:21][CH2:22][NH:23]C(=O)OCC1C=CC=CC=1)[CH:13]=[CH:12]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO.[Pd]>[Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:13]=[CH:12]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc(C#CCCNC(=O)OCc3ccccc3)ccc2c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(CCCCN)ccc2c1
Reaction time: 6 h
Yield: 62.8 %

Procedure:
A suspension of crude 29 (900 mg) and 10% Pd/C (400 mg) in MeOH (50 mL) was subject to hydrogenation conditions (1 atm) for 6 h at room temperature. The reaction mixture was filtered through a plug of diatomaceous earth and the plug was washed with MeOH. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel, 80:18:2 CHCl3/CH3OH/NH4OH) to afford amine 77 (405 mg, 27% over two steps) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.62 (t, J=8.9, 2H), 7.52 (br s, 1H), 7.26 (dd, J=8.4, 1.7 Hz, 1H), 7.15 (d, J=2.2 Hz, 1H), 7.04 (dd, J=8.8, 2.5 Hz, 1H), 3.03-2.37 (br s, 1H), 2.74 (t, J=7.5 Hz, 2H), 1.78-1.65 (m, 2H), 1.58-1.47 (m, 2H), 1.01 (s, 9H), 0.23 (s, 6H).
Reaction SMILES: C[Al](C)C.[NH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C([O:14][C:15]([C:17]1[C:21]([NH2:22])=[C:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[N:19]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[N:18]=1)=O)C>C(Cl)(Cl)Cl>[N:6]1([NH:5][C:15]([C:17]2[C:21]([NH2:22])=[C:20]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[N:19]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])[N:18]=2)=[O:14])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1N
Reactant: NN1CCOCC1
Agent: C[Al](C)C
Solvent: ClC(Cl)Cl
Product: Nc1c(C(=O)NN2CCOCC2)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trimethylaluminum (2M solution in toluene, 625 microliters, 1.25 mmol) is added to a solution of 4-aminomorpholine (121 microliters, 1.25 mmol) in CHCl3 (3 ml) at room temperature. The reaction mixture was stirred for 1 h, then 4-amino-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (I-2A-1a, 188 mg, 0.5 mmol) was added in one portion. The reaction mixture was stirred at 45° C. for 4h, cooled to room temperature, and quenched with 1 M HCl (1 ml) (CAREFUL: gas evolution). The pH of the solution was adjusted to ˜13 using 25% KOH, at which point all solids went into solution. The aqueous solution was extracted with EtOAc (2×) and the combined organic solution was washed with saturated aqueous brine, dried, and concentrated under vacuum to give the product I-10A-1a as an amorphous solid (208 mg): MS 432.0 (M+1)+; 1H NMR (400 MHz, CDCl3) δ 7.44–7.32 (m, 4H), 7.28–7.23 (m, 2H), 7.13–7.09 (m, 2H), 3.86 (m, 4H), 2.95 (m, 4H).