Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][C:24](=[O:32])[CH2:25][NH:26][CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[C:19]([O:23][C:24](=[O:32])[CH2:25][N:26]([C:16](=[O:18])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31]1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)CNC1CCCC1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=O)OC(C)(C)C)C1CCCC1
Temperature: 25 °C
Yield: 85.3 %

Procedure:
To a solution of N-benzyloxycarbonyl-L-valine (50.0 g) and N-cyclopentylglycine t-butyl ester (39.8 g) in dichloromethane (1.3 liter), stirred under nitrogen and cooled in an ice bath to 0°-5° C., was added triethylamine (44.5 g) then bis(2-oxo-3-oxazolidinyl)phosphinic chloride (56.0 g) at 0° C. The stirred mixture was allowed to warm to room temperature overnight before it was evaporated. After the residue was partitioned between water (1 liter) and ethyl acetate (1 liter), the ethyl acetate solution was washed (1N hydrochloric acid (twice), water, saturated sodium bicarbonate, brine), dried (MgSO4) and evaporated. The residue was purified by flash chromatography, eluting with ethyl acetate:dichloromethane (0:100, 5:95, 10:90 and 25:75, successively). A first, mixed fraction was rechromatographed and the product obtained combined with the product obtained from the first chromatography to afford the ester (73.4 g, 85%); TLC, Rf =0.30, ethyl acetate:dichloromethane (5:95); MS, m/e=433 (M+1), 377, 325, 269, 234, 286, 162, 144 91(base).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[S:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.[CH2:26]1[O:38][C:37]2[CH:36]=[C:35]3[C:30]([CH2:31][CH2:32][NH:33][CH2:34]3)=[CH:29][C:28]=2[O:27]1>C(#N)C>[CH3:25][O:24][C:18]1[CH:17]=[C:16]([CH:7]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:33]2[CH2:32][CH2:31][C:30]3[CH:29]=[C:28]4[O:27][CH2:26][O:38][C:37]4=[CH:36][C:35]=3[CH2:34]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(C(CCCCCBr)Sc2ccc(C)cc2)cc1OC
Reactant: c1c2c(cc3c1OCO3)CNCC2
Solvent: CC#N
Product: COc1ccc(C(CCCCCN2CCc3cc4c(cc3C2)OCO4)Sc2ccc(C)cc2)cc1OC
Yield: 91.7 %

Procedure:
The procedure of Example 46 is repeated using 3.67 g of 4-[6-bromo-1-[(4-methylphenyl)thio]hexyl]-1,2-dimethoxybenzene in 40 mL of acetonitrile and 2.65 g of 6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline. This affords 4.13 g of the desired product as a yellow gum.
Reaction SMILES: [F:1][C:2]([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)([C:10]([F:13])([F:12])[F:11])[C:3]([F:9])([F:8])[C:4]([F:7])([F:6])[F:5].[Cl:21]N1C(=O)CCC1=O>C(#N)C>[Cl:21][C:16]1[CH:15]=[C:14]([C:2]([F:1])([C:10]([F:11])([F:12])[F:13])[C:3]([F:9])([F:8])[C:4]([F:7])([F:6])[F:5])[CH:19]=[CH:18][C:17]=1[NH2:20]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1ccc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1
Solvent: CC#N
Product: Nc1ccc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1Cl

Procedure:
4-(1,2,2,3,3,3-Hexafluoro-1-trifluoromethylpropyl)phenylamine (prepared as described in EP 1,006,102) (175.8 g, 565 mmol) was dissolved in acetonitrile (1000 ml) and N-chloro-succinimide (“NCS”) (76.2 g, 570.7 mmol) was added. The reaction mixture was heated to reflux for 90 minutes. The reaction mixture was concentrated, the residue suspended in diethyl ether and the solids removed via filtration. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (eluent: cyclohexane/dichloromethane 9:1) to give 2-chloro-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)phenylamine. The same procedure was repeated using N-bromosuccinimide (“NBS”) (100.5 g, 565 mmol) as reagent. This time the residue was purified by column chromatography on silica gel (eluent:cyclohexane/dichloromethane 2:1) to give 2-bromo-6-chloro-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)phenylamine (143.3 g, 59.7% yield). 1H NMR (400 MHz, CDCl3): 7.70 (s, 1H), 7.42 (s, 1H), 4.82 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N([Br:37])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][Br:37]
Reactant: Cc1cc([N+](=O)[O-])ccc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(Br)c(CBr)c1
Temperature: 25 °C
Yield: 73 %

Procedure:
A mixture of 1-bromo-2-methyl-4-nitrobenzene (15 g, 79 mmol), benzoyl peroxide (2 g, 8 mmol) and NBS (17 g, 95 mmol) in CCl4 (150 mL) was stirred at reflux overnight. The mixture was cooled to room temperature and filtered, the filtrate was washed with water twice, dried over Na2SO4 and concentrated to give 1-bromo-2-(bromomethyl)-4-nitrobenzene as light yellow oil (17 g, 69%). 1H NMR: 400 MHz CDCl3 δ 8.37-8.34 (m, 1H), 8.05-8.02 (m, 1H), 7.77-7.75 (m, 1H), 3.87 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:16][N:17]([CH3:36])[CH:18]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:33]=[C:32]([CH2:34][OH:35])[O:31][N:30]=3)=[CH:25][CH:24]=2)[CH2:19]1>CN(C=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:35][CH2:34][C:32]2[O:31][N:30]=[C:29]([C:26]3[CH:25]=[CH:24][C:23]([N:20]4[CH2:21][CH2:22][CH:18]([N:17]([CH3:36])[CH3:16])[CH2:19]4)=[CH:28][CH:27]=3)[N:33]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CN(C)C1CCN(c2ccc(-c3noc(CO)n3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C1CCN(c2ccc(-c3noc(COCc4ccc(F)cc4)n3)cc2)C1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
4-Fluorobenzyl bromide (18.9 mg) and potassium carbonate (27.6 mg) were added to a mixture of {3-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl][1,2,4]oxadiazol-5-yl}methanol (28.8 mg) and DMF (0.3 ml). The reaction mixture was stirred at 60° C. for 3 h, filtered and purified by preparative HPLC. The product with the molecular weight of 396.20 (C22H25FN4O2) was obtained in this way; MS (ESI): 397.27 (M+H+).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[F:12][C:13]1[N:14]=[CH:15][C:16]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1cc(Br)oc1C
Reactant: OB(O)c1ccc(F)nc1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(-c2ccc(F)nc2)oc1C
Yield: 89.5 %

Procedure:
A mixture of methyl 5-bromo-2-methyl-3-furancarboxylate (2.6 g), 2-fluoropyridine-5-boronic acid (2.1 g), tetrakis(triphenylphosphine)palladium(0) (0.7 g), 2N aqueous sodium carbonate solution (15 mL) and 1,2-dimethoxyethane (20 mL) was stirred under reflux overnight under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (2.5 g, 87%) as a white solid.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.[CH3:17][O-:18].[Na+].O>CO>[CH3:17][O:18][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1
Reactant: C[O-]
Reactant: COC(=O)c1nc(Cl)sc1-c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1nc(OC)sc1-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 15.7 %

Procedure:
Under a static N2 atm, a stirred solution of the compound of Example 2 (8.14 g, 32 mol) in 100 ml of methanol was treated dropwise with 7.6 g of 25% sodium methoxide in methanol. After stirring at ambient temperature for 24 hr, the mixture was added to H2O and extracted twice with ether. The ether layer was washed with H2O, dried over MgSO4 and concentrated in vacuo to yield a white solid which was recrystallized from methylcyclohexane to yield 5.5 g of methyl 2-methoxy-5-phenyl-4-thiazolecarboxylate as a white solid, m.p. 86°-88° C., yield 70%.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42][C:43]1[N:44]=NC(C)=CC=1)[CH2:4][CH2:3]2.ClC1N=[C:55]([S:57][CH3:58])[CH:54]=[CH:53][N:52]=1.C(O)(C(F)(F)F)=O>>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42][C:43]1[N:44]=[C:55]([S:57][CH3:58])[CH:54]=[CH:53][N:52]=1)[CH2:4][CH2:3]2
Reactant: CSc1ccnc(Cl)n1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCNc3ccc(C)nn3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)[C@@H]1CC[C@]2(NCCNc3nccc(SC)n3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 14 %

Procedure:
The title compound was prepared following a similar procedure as described for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(6-methylpyridazin-3-ylamino)ethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 2-chloro-4-(methylthio)pyrimidine (0.016 g, 0.100 mmol) was used in place of 3-bromo-6-methylpyridazine. Iterative purification of the crude mixture by reverse phase preparative HPLC first using Prep HPLC Method 9 and then repurification by Prep HPLC Method 10 gave the title compound as a white glassy solid (12.0 mg, 14% yield) bis TFA salt. LCMS: m/e 697.5 (M+H)+, 2.30 min (method 11). 1H NMR (500 MHz, 1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 7.99-7.85 (m, 3H), 7.17 (d, J=8.2 Hz, 2H), 6.75-6.63 (m, 1H), 5.26 (d, J=4.6 Hz, 1H), 4.82 (s, 1H), 4.70 (br. s., 1H), 3.96 (s, 1H), 3.85 (br. s., 2H), 3.43-3.34 (m, 1H), 3.25 (br. s., 1H), 2.72 (br. s., 1H), 2.55 (s, 3H), 2.10 (dd, J=17.1, 6.4 Hz, 1H), 2.04 (d, J=15.3 Hz, 1H), 2.01-1.89 (m, 3H), 1.89-1.77 (m, 2H), 1.70 (s, 4H), 1.68-1.49 (m, 5H), 1.46 (d, J=7.3 Hz, 3H), 1.42-1.18 (m, 7H), 1.18-1.06 (m, 2H), 1.03 (s, 3H), 0.97 (s, 3H), 0.95 (s, 3H), 0.92 (s, 3H), 0.91 (br. s., 3H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].ClCCl.[CH2:9]([C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([CH2:26][OH:27])[CH2:22][CH2:21]2)[CH2:14][CH2:13]1)[CH2:10][CH3:11].Cl>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH3:1][S:2]([O:27][CH2:26][C@H:23]1[CH2:22][CH2:21][C@H:20]([CH2:19][CH2:18][C@H:15]2[CH2:16][CH2:17][C@H:12]([CH2:9][CH2:10][CH3:11])[CH2:13][CH2:14]2)[CH2:25][CH2:24]1)(=[O:4])=[O:3]
Reactant: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](CO)CC2)CC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](COS(C)(=O)=O)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methanesulfonyl chloride (15.0 mL) was added by titration under water-cooling conditions to dichloromethane solution (200 mL) of trans-4-(2-(trans-4-propylcyclohexyl)ethyl)cyclohexyl methanol (47.3 g), and then pyridine (17.0 mL) was also added by titration, with the temperature maintained. After being cooled down to room temperature, 4-(N,N-dimethylamino)pyridine (2.6 g) was added, and the resultant was stirred continuously at room temperature for 16 hours. After the reaction was halted by adding 3M hydrochloric acid to a reaction solution, an organic layer was separated and extracted from a water layer by using dichloromethane. The thus collected organic layer was washed by using 3M hydrochloric acid, water, a saturated sodium bicarbonate aqueous solution and brine in that order, and dried with anhydrous magnesium sulphate. Solvents were removed by distillation to obtain a slightly yellow solid. The thus obtained solid was purified by column chromatography (alumina, toluene) and also subjected to recrystallization (toluene/hexane), thereby obtaining a colourless scaly crystal of 51.5 g.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.F[C:12]1[CH:21]=[C:20]2[C:15]([C:16](=[O:22])[NH:17][CH:18]=[N:19]2)=[CH:14][CH:13]=1>C1COCC1>[N:8]1[CH:9]=[CH:10][C:5]([CH2:4][O:3][C:12]2[CH:21]=[C:20]3[C:15]([C:16](=[O:22])[NH:17][CH:18]=[N:19]3)=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=c1[nH]cnc2cc(F)ccc12
Reactant: OCc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]cnc2cc(OCc3ccncc3)ccc12
Temperature: 120 °C
Yield: 73.7 %

Procedure:
Sodium hydride (0.72 g of a 60% suspension in mineral oil, 18 mmol) was added to a solution of 4-hydroxymethylpyridine (4 g, 36 mmol) in THF (30 ml) and the mixture heated at reflux for 15 minutes. 7-Fluoro-3,4-dihydroquinazolin-4-one (1 g, 6 mmol), (J. Chem. Soc. section B 1967, 449), was added, the THF was removed by evaporation, and the mixture was heated at 120° C. for 30 minutes. The mixture was allowed to cool, diluted with water (40 ml) and was adjusted to pH8 with concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water, then ether and dried under vacuum to give 7-(4-pyridylmethoxy)-3,4-dihydroquinazolin-4-one (1.12 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15]C(=O)OC(C)(C)C)[CH2:10]2)[CH:5]=[C:4]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]([S:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:24]=2)[CH:3]=1.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH2:15])[CH2:10]2)[CH:5]=[C:4]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]([S:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:24]=2)[CH:3]=1.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]
Reactant: COc1cnc2c(c1)c(-c1cc(Cl)nc(NC3CCCC(NC(=O)OC(C)(C)C)C3)c1)cn2S(=O)(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cnc2c(c1)c(-c1cc(Cl)nc(NC3CCCC(N)C3)c1)cn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of Example 261b (1.76 g, 2.88 mmol) in CH2Cl2 (30 mL) was treated with trifluoroacetic acid (3.32 mL, 43.1 mmol). The mixture is stirred at room temperature for 3 hours and concentrated to give 2.34 of the title compound as trifluoroacetic acid salts.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].Cl[CH2:13][C:14](=[O:16])[CH3:15]>>[O:16]=[C:14]([CH3:15])[CH2:13][S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1S
Reactant: CC(=O)CCl
Product: CC(=O)CSc1ccccc1CC(=O)O

Procedure:
Prepared according to the procedure described in Example 1, Step 1, using the following starting materials: 2-mercaptophenylacetic acid and chloroacetone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9](Cl)(=[O:11])=[O:10])=[CH:4][C:3]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[F-:20].[K+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([F:20])(=[O:11])=[O:10])=[CH:4][C:3]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)Cc1ccc(F)c(Oc2ccccc2)c1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=S(=O)(F)Cc1ccc(F)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.8 %

Procedure:
The sulfonyl chloride obtained in step 2 (2.0 g, 6.65 mmol) is diluted with acetonitrile (20 mL). The resultant solution is treated with potassium fluoride (1.93 g, 33.25 mmol) and tetrabutylamonium fluoride (0.208 g, 0.66 mmol), stirred at room temperature for one day, poured into water, and extracted with ethyl acetate. The organic extract is washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a residue. Flash chromatography of the residue on silica gel eluting with 15:85 ethyl acetate/hexanes gives (4-fluoro-3-phenoxyphenyl)methanesulfonyl fluoride (0.81 g, mp 59.5-61.5° C.) which is identified by NMR spectral analyses.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl[C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[N:12][N:13]2[S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[C:9]([C:25]2[O:26][C:27]([CH2:30][N:31]3[CH2:36][CH2:35][N:34]([CH:37]([CH3:39])[CH3:38])[CH2:33][CH2:32]3)=[CH:28][N:29]=2)[CH:8]=1.CC1(C)C(C)(C)OB([C:48]2[CH:56]=[CH:55][CH:54]=[C:53]3[C:49]=2[CH:50]=[CH:51][NH:52]3)O1>O.C(O)(C)C>[NH:52]1[C:53]2[C:49](=[C:48]([C:7]3[CH:15]=[C:14]4[C:10]([CH:11]=[N:12][N:13]4[S:16]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)(=[O:17])=[O:18])=[C:9]([C:25]4[O:26][C:27]([CH2:30][N:31]5[CH2:36][CH2:35][N:34]([CH:37]([CH3:38])[CH3:39])[CH2:33][CH2:32]5)=[CH:28][N:29]=4)[CH:8]=3)[CH:56]=[CH:55][CH:54]=2)[CH:50]=[CH:51]1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: CC(C)N1CCN(Cc2cnc(-c3cc(Cl)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)N1CCN(Cc2cnc(-c3cc(-c4cccc5[nH]ccc45)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
A solution of sodium bicarbonate (228.0 g) in water (2.7 L) was added to a suspension of 6-Chloro-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole (271.2 g) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (263.2 g, available from Apollo Scientific Limited) in isopropanol (2.7 L) stirred under nitrogen at ambient temperature. After degassing, via evacuation and flushing with nitrogen, 2′-(dimethylamino)-2-biphenylyl-palladium(II) chloride dinorbornylphosphine complex (29.83 g) was added. The mixture was degassed again and was then heated to 90±3° C. and held at this temperature for 2 hours. The mixture was cooled to 20±5° C. over 25 minutes and aged at this temperature overnight. The resultant suspension was filtered, washed with water (1.35 L) and then slurried with toluene (4×1.35 L). The solid was dried under vacuum at 50° C. to give the title compound as grey solid (302.7 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][C:15]=1[Cl:21]>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:15]1[CH:16]=[C:17]([NH2:18])[CH:19]=[CH:20][C:14]=1[C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Nc1ccc(Br)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Nc1ccc(-c2cccc([N+](=O)[O-])c2)c(Cl)c1
Yield: 32.2 %

Procedure:
This compound was prepared by General Method 14 (EXAMPLE 191) from 3-nitrobenzeneboronic acid (0.25 g, 1.5 mmol), 4-bromo-3-chloroaniline (0.21 g, 1.0 mmol), and (PPh3)4Pd (35 mg, 0.030 mmol) to afford 0.08 g (32%) of 2-chloro-4-amino-3′-nitrobiphenyl as an orange solid. Data for 2-chloro-4-amino-3′-nitrobiphenyl: 1H-NMR (400 MHz, acetone-d6) 8.29 (app t, J=2.0, 1H), 8.18 (dt, J=9.0, 1.2, 1H), 7.76 (dd, J=9.0, 1.2, 1H), 7.56 (t, J=8.0, 1H), 7.14 (d, J=8.2, 1H), 6.82 (d, J=2.2, 1H), 6.65 (dd, J=8.2, 2.2, 1H), 3.86 (br s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH:21](OCC)(OCC)OCC>C(O)C.Cl>[CH2:14]([N:13]1[C:3]2[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:11]=[CH:12][C:2]=2[N:1]=[CH:21]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)c1ccc(N)c(NCc2ccccc2)c1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc2ncn(Cc3ccccc3)c2c1
Temperature: 25 °C
Yield: 48.1 %

Procedure:
A solution of ethyl 4-amino-3-(benzylamino)benzoate (0.24 g, 0.89 mmol) and triethyl orthoformate (0.8 mL, 4.8 mmol) in ethanol (10 mL) and conc. HCl (7 drops) was heated to reflux for 24 hr. The solution was cooled to room temperature and concentrated, then diluted with ethyl acetate (100 mL) and washed with dilute aq. NaHCO3 (1×100 mL). Then organic layer was dried (MgSO4), filtered and then concentrated and the resulting residue was purified by flash chromatography (50% ethyl acetate/hexane then ethyl acetate) to provide 0.12 g (48%) of ethyl 3-benzyl-3H-benzo[d]imidazole-5-carboxylate as an off white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH2:14]([O:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26](Cl)=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=[N:29]2)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>O>[C:9]([O:8][C:7](=[O:13])[NH:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:26]1[C:25]2[C:30](=[CH:31][C:22]([O:21][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:23][CH:24]=2)[N:29]=[CH:28][C:27]=1[N+:32]([O-:34])=[O:33])([CH3:10])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 73.2 %

Procedure:
tert-Butyl N-(4-aminobutyl)carbamate (22.01 g, 116.9 mmol) was added to a solution of 7-benzyloxy-4-chloro-3-nitroquinoline (36.80 g, 116.9 mmol), prepared in Parts A-D of Example 1, in distilled water. The reaction was heated at 80° C. for 1.5 hours and then stirred at room temperature for four hours. The reaction was not complete, and triethylamine (16 mL, 115 mmol) was added. The reaction was stirred overnight at room temperature. A precipitate formed, which was isolated by filtration and washed with hexanes to provide 39.92 g of tert-butyl[4-(7-benzyloxy-3-nitroquinolin-4-ylamino)butyl]carbamate as a yellow solid.