Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[CH2:7]([O:14][C:15]1[CH:30]=[C:19]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[C:18]([NH2:31])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C(C)=CC=CC=1C.Br[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>CN(C=O)C.C(OCC)(=O)C>[C:42]([CH2:41][NH:31][C:18]1[C:19](=[CH:30][C:15]([O:14][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:16][CH:17]=1)[C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Nc1ccc(OCc2ccccc2)cc1C(=O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CNc1ccc(OCc2ccccc2)cc1C(=O)OCc1ccccc1
Yield: 76.8 %

Procedure:
A solution of saturated sodium bicarbonate (1.0 liter) was placed in a 4 liter Ehrlenmeyer flask along with 1.0 liter of ethyl acetate. The biphasic mixture was stirred at a rate that insured mixing and 5-benzyloxyanthranilic acid, benzyl ester, hydrochloride (50.0 g, 135 mmol) was added portionwise to the stirred mixture. After addition was complete, the mixture was stirred an additional 15 minutes. The layers were partitioned in a separatory funnel and the aqueous layer was extracted with ethyl acetate (500 mL). The combined organics were dried over MgSO4, filtered, and concentrated in vacuo to yield the free base, which was dissolved in anhydrous DMF (700 mL) under an atmosphere of argon. 2,6-lutidine (20.0 mL, 172 mmol) was added to the solution followed by the addition of t-butyl bromoacetate (29.0 mL, 196 mmol). The reaction mixture was stirred at 70° C. under an atmosphere of argon for 48 hours. The DMF was removed on a rotary evaporator under high vacuum and the crude product residue was partitioned between ethyl acetate (1.0 liter) and water (500 mL). The organic layer was washed with saturated NaCl (250 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to yield crude product as a light brown solid. The product was recrystallized from 7% ethyl acetate/hexanes to yield N-(carbo-t-butoxymethyl)-5-benzyloxyanthranilic acid, benzyl ester (46.4 g, 79% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>O1CCOCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][CH:11]([NH:10][C:2]2[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=2)[CH2:12][CH2:13]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: Cc1cc(C)nc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(C)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 130 °C
Reaction time: 5 h
Yield: 50.7 %

Procedure:
To a mixture of 2-chloro-4,6-dimethylpyrimidine (5.00 g, 0.035 mol), 4-amino-1-Boc-piperidine (7.023 g, 0.035 mol), sodium tert-butoxide (5.055 g, 0.53 mol) in dioxane (120 mL) was added under an argon atmosphere palladium(II) acetate (0.630 g, 0.003 mol) and 2-(dicyclohexylphospino)biphenyl (1.966 g, 0.006 mmol). The reaction mixture was stirred for 5 hours at 130° C. It was diluted with ethyl acetate (400 mL) and washed with aqueous sodium carbonate (1M, 200 mL), water (200 mL) and brine (150 mL). The combined aqueous layers were extracted with ethyl acetate (400 mL) and the combined organic layers were dried over sodium sulfate. Concentration and purification by chromatography (SiO2, n-heptane/ethyl acetate=2:1 to 1:1) afforded the title compound (5.44 g, 51%) as an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Br.[CH:11]([C:13]1[CH:21]=[C:17]([C:18]([OH:20])=[O:19])[C:16]([OH:22])=[CH:15][CH:14]=1)=[O:12].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][O:22][C:16]1[CH:15]=[CH:14][C:13]([CH:11]=[O:12])=[CH:21][C:17]=1[C:18]([O:20][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[F:1])=[O:19]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccc(F)cc2F)c(C(=O)OCc2ccc(F)cc2F)c1
Yield: 95.6 %

Procedure:
2,4-Difluorobenzyl bromide (0.77 mL, 6 mmol, 1 eq) was added dropwise to a stirred solution of 5-formylsalicylic acid (1 g, 6 mmol, 1 eq) and cesium carbonate (5.87 g, 18 mmol, 3 eq) in N,N-dimethylformamide (30 mL). The reaction mixture was diluted with ethyl acetate (50 mL) and the organic solution washed with water (50 mL), saturated aqueous sodium bicarbonate (2×50 mL) and brine (50 mL), then dried over sodium sulfate and evaporated in vacuo to give the product as a white powder (1.2 g, 50%). 1H NMR (CDCl3) δ9.91 (s, 1H, O═C—H), 5.37 (s, 2H, CH2Ar), 5.25 (s, 2H, CH2Ar).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4]
Reactant: Nc1c(F)cc(I)cc1Cl
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1c(F)cc(-c2ccccc2)cc1Cl
Temperature: 100 °C

Procedure:
2-Fluoro-4-iodo-6-chloroaniline (8.0 g, 36.0 mmol) is dissolved in DMF (110 mL) and treated with 2.8 equivalents of phenylboronic acid (10.0 g, 82 mmol), and a catalytic amount of tetrakistriphenylphosphine palladium(0) (3.0 g, 2.6 mmol) as a solution in DMF (20 mL). Sodium carbonate (30 mL of 2 M aqueous solution) is added and the reaction mixture stirred and heated to 100° C. for 24 hours. After cooling to room temperature most of the DMF is removed by rotary evaporator under high vacuum. The residual brown oil is partitioned between Et2O (300 mL) and water (150 mL). The organic layer is washed with brine, dried (MgSO4) and concentrated by rotary evaporator. The residual oil is purified by flash chromatography (9:1 hexanes/EtOAc) to give 2-fluoro-4-phenyl-6-chloroaniline (m.p. 105–107° C.).
Reaction SMILES: [CH2:1]([C:3]1[CH2:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].NC1C=CC=CC=1.C(CC(OCC)=O)(=O)CC.C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[C:51]2[N:55]([C:56]3[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][CH:57]=3)[N:54]=[N:53][N:52]=2)=[CH:41][CH:40]=1>CN1C(=O)CCC1.O>[CH2:1]([C:3]1[CH:12]=[C:11]([O:13][CH2:38][C:39]2[CH:40]=[CH:41][C:42]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[C:51]3[N:55]([C:56]4[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][CH:57]=4)[N:54]=[N:53][N:52]=3)=[CH:43][CH:44]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(-n2nnnc2-c2ccccc2-c2ccc(CBr)cc2)cc1
Reactant: CCC1=Nc2ccccc2C(=O)C1
Agent: CCOC(=O)CC(=O)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Nc1ccccc1
Solvent: CN1CCCC1=O
Product: CCc1cc(OCc2ccc(-c3ccccc3-c3nnnn3-c3ccc([N+](=O)[O-])cc3)cc2)c2ccccc2n1
Temperature: 80 °C
Yield: 28.4 %

Procedure:
A mixture of 2-ethyl-4-quinolone (1.9 g; 11 mmol), (prepared using a similar procedure to that described in Org. Syn., Coll., Vol. III, p. 374 and p. 593 from aniline and ethyl propionylacetate), and potassium carbonate (2.28 g; 16 mmol) in NMP (75 ml) was heated at 60° C. for 20 minutes with stirring. Compound E (5.2 g; 10 mmol) was added and the reaction mixture heated at 80° C. for 90 minutes. The mixture was allowed to cool to ambient temperature and water (150 ml) was added. The resultant precipitate was collected by filtration, dried at 60° C., then recrystallised from toluene to give 2-ethyl-4-[(2'-(1-(4-nitrophenyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline (A) (1.5 g) as a solid, m.p. 204°-206° C.; NMR (CDCl3): 1.42(3H, t), 3.0(2H, q), 5.23(2H, s), 6.67(2H, d), 6.75(1H, s), 6.85(2H, d), 7.25(2H, d), 7.43(1H, d), 7.55(1H, t), 7.70(3H, m) 7.90(3H, d), 8.05(1H, d), 8.20(1H, d).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[NH2:7])=[N+:2]=[N-:3].[CH:12]1[CH:17]=[CH:16][C:15]([O:18][C:19](OC2C=CC=CC=2)=[N:20][C:21]#[N:22])=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[N:1]([C:4]1[CH:5]=[C:6]([NH:7][C:19](=[N:20][C:21]#[N:22])[O:18][C:15]2[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=2)[CH:8]=[C:9]([Cl:11])[CH:10]=1)=[N+:2]=[N-:3]
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: [N-]=[N+]=Nc1cc(N)cc(Cl)c1
Solvent: ClC(Cl)Cl
Product: N#CN=C(Nc1cc(Cl)cc(N=[N+]=[N-])c1)Oc1ccccc1
Yield: 61.8 %

Procedure:
Chart B, Step B-1. To a stirred solution of 3-azido-5-chloroaniline (A-4, 0.706 g, 4.18 mmol) in 6 mL of chloroform, is added diphenyl cyanocarbonimidate (0.997 g, 4.18 mmol). The solvent is allowed to evaporate at a temperature of 75° C. overnight. The resulting solid is triturated with ether and filtered. The solid is recrystallized from ethyl acetate/hexane to afford 0.808 g of N-(3-azido-5-chlorophenyl)-N'-cyanocarbamimidic acid, phenyl ester. (B-1) Mp 193°-194° C. (dec); IR (mull) 3084, 2954, 2925, 2210, 2117, 2104, 1652, 1608, 1581, 1500, 1449, 1438, 1405, 1222, 1197, 1002, 892 cm-1 ; 1H NMR (DMSO) δ10.9 (bs, 1 H), 7.45-7.20 (bm, 8 H), 7.07 (bs, 1 H); 13C NMR (DMSO) δ151.3, 141.5, 138.6, 134.0, 129.8, 126.4, 120.8, 119.4, 116.2, 112.8, 112.5; Analysis calculated for C14H9ClN6O: C, 53.77; H, 2.90; N, 26.87; Cl, 11.34. Found: C, 53.39; H, 2.71; N, 26.54; Cl, 11.32.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]2O)=[CH:4][CH:3]=1.BrC1C=CC(O[C@@H]2CCCC[C@H]2O)=CC=1.[CH3:31][CH:32]([S:34]([NH2:37])(=[O:36])=[O:35])[CH3:33]>>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]2[NH:37][S:34]([CH:32]([CH3:33])[CH3:31])(=[O:36])=[O:35])=[CH:4][CH:3]=1
Reactant: CC(C)S(N)(=O)=O
Reactant: O[C@H]1CCCC[C@@H]1Oc1ccc(Br)cc1
Agent: O[C@@H]1CCCC[C@H]1Oc1ccc(Br)cc1
Product: CC(C)S(=O)(=O)N[C@H]1CCCC[C@H]1Oc1ccc(Br)cc1

Procedure:
The title compound of Step 7 was prepared according to the general procedure for the synthesis of cis-N-[2-(4-bromophenoxy)cyclopentyl]propane-2-sulfonamide in Example 5, except that (1S,2R)-2-(4-bromophenoxy)cyclohexanamine was used in place of cis-2-(4-bromophenoxy)cyclopentan-amine, and the product purification was carried out using a gradient of 0% to 1% methanol in dichloromethane. N-[(1S,2R)-2-(4-bromophenoxy)cyclohexyl]propane-2-sulfonamide was obtained as a white foam. Yield: 1.67 g, 4.44 mmol, 75%. 1H NMR (400 MHz, CDCl3) δ 1.36 (d, J=6.9 Hz, 3H), 1.37 (d, J=6.9 Hz, 3H), 1.37-1.48 (m, 4H), 1.77-1.88 (m, 3H), 2.06 (m, 1H), 3.12 (septet, J=6.8 Hz, 1H), 3.54 (m, 1H), 4.48 (d, J=9.5 Hz, 1H), 4.54 (m, 1H), 6.84 (d, J=9.0 Hz, 2H), 7.39 (d, J=9.0 Hz, 2H). The enantiomer of N-[(1S,2R)-2-(4-bromophenoxy)cyclohexyl]propane-2-sulfonamide was prepared using similar chemistry to that described above in this Step 7, but employing (1S,2S)-2-(4-bromophenoxy)cyclohexanol as starting material instead of (1R,2R)-2-(4-bromophenoxy)cyclohexanol. The absolute stereochemistry of the enantiomer of N-(1S,2R)-2-(4-bromophenoxy)cyclohexyl]propane-2-sulfonamide was established via X-ray crystallography.
Reaction SMILES: [N+:1](=[CH2:3])=[N-].[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]23[CH2:16][CH:15]2[C:14](=[O:17])N[C:12]3=[O:18])=[CH:7][CH:6]=1>CO>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]23[CH2:16][CH:15]2[C:14](=[O:17])[N:1]([CH3:3])[C:12]3=[O:18])=[CH:9][CH:10]=1
Reactant: C=[N+]=[N-]
Reactant: Nc1ccc(C23CC2C(=O)NC3=O)cc1
Solvent: CO
Product: CN1C(=O)C2CC2(c2ccc(N)cc2)C1=O
Reaction time: 16 h

Procedure:
An approx. 0.3 molar solution of diazomethane is added dropwise at 0° C. to a solution of 202 mg of 1-(4-aminophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione in 10 ml of methanol. The reaction mixture is allowed to stand for 16 hours, concentrated, and partitioned twice between ethyl acetate and water. The organic phases are dried over magnesium sulfate, filtered and concentrated. The residue is crystallised from ethyl acetate/petroleum ether, affording the title compound which is identical with the title compound of Example 3(a).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[Si:21](OS(C(F)(F)F)(=O)=O)([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23]>C(Cl)Cl>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)Cc1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1
Temperature: 25 °C

Procedure:
To methyl 2-(4-hydroxyphenyl)acetate (E1) in CH2Cl2 at 0° C. was added 2,6-lutidine and TIPS-OTf. The ice bath was removed and the solution was allowed to warm to room temperature and stirred. After 4 h the solution was poured into NH4Cl(sat) and CH2Cl2 and the organic layer was further extracted with NH4Cl(sat). The organics were dried (Na2SO4) filtered and evaporated. Column chromatography (0-15% EtOAc/Hexanes) gave pure methyl-2-(4-(triisopropylsilyloxy)phenyl)acetate (E2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[CH2:16]>>[CH2:19]([O:18][C:14](=[O:17])[CH2:15][CH2:16][N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH:7]=[CH:8][C:9]1=[O:13])[CH3:20]
Reactant: COc1ccc2ccc(=O)[nH]c2c1
Reactant: C=CC(=O)OCC
Product: CCOC(=O)CCn1c(=O)ccc2ccc(OC)cc21
Yield: 100 %

Procedure:
The compound was obtained according to procedure H starting from 7-methoxy-2(1H)-quinolinone (614 mg, 3.5 mmol) and ethyl acrylate (0.4 mL). The crude brown oil (0.96 g; 100% yield) was used as such in the next step.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]=[CH:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([OH:64])[CH2:5][C:4]1=[O:65])[CH3:2].[H][H]>[Rh]>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH2:52][CH2:53][C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([OH:64])[CH2:5][C:4]1=[O:65])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC=Cc4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: [H][H]
Agent: [Rh]
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCCCc4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.6 %

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-cinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (37 mg in 2 ml ethanol) was added 4 mg of 5% rhodium on carbon catalyst. The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 1.5 hours, the mixture was filtered over Celite, concentrated and purified by preparative TLC on silica gel (ethyl acetate: hexane (1:2)+1% methanol) to give the title compound (19.5 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[C:13]([Cl:14])=[C:12]([C:15]([F:18])([F:17])[F:16])[N:11]([CH3:19])[N:10]=2)=[CH:4][C:3]=1[CH2:20][OH:21].C([O-])([O-])=O.[K+].[K+].Br[CH2:29][C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31]>CS(C)=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[C:13]([Cl:14])=[C:12]([C:15]([F:16])([F:17])[F:18])[N:11]([CH3:19])[N:10]=2)=[CH:4][C:3]=1[CH2:20][O:21][CH2:29][C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31]
Reactant: Cn1nc(-c2cc(CO)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)OC(=O)COCc1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1Cl
Temperature: 45 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
At 25° C., 1.7 g (5.0 mmole) 2-chloro-5-[4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-fluorobenzenemethanol, 0.8 g (5.5 mmole) K2CO3 and 0.7 mL (5.5 mmole) isopropyl bromoacetate were slurried in 15 mL DMSO. The mixture was stirred overnight at 45° C. The mixture was cooled, diluted with 100 mL cold water and extracted four times with ethyl acetate. The ethyl acetate extracts were washed with brine, dried over anhydrous MgSO4 and stripped in vacuo. The residue was purified chromatographically using 10% ethyl acetate in hexane as the eluent to give 0.9 g (41%) of ((2-chloro-5-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4-fluorophenyl)methoxy)acetic acid, 1-methylethyl ester as a white solid; mp 55° C.
Reaction SMILES: [O-]S(S([O-])=O)=O.[Na+].[Na+].[C:9]([C:11]1[CH:12]=[C:13]([N:20]([C:25]2[C:44]([CH:45]3[CH2:47][CH2:46]3)=[CH:43][C:28]3[C:29]([C:39]([NH:41][CH3:42])=[O:40])=[C:30]([C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)[O:31][C:27]=3[CH:26]=2)[S:21]([CH3:24])(=[O:23])=[O:22])[CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)#[N:10]>O.C1COCC1>[NH2:17][C:16]1[CH:15]=[CH:14][C:13]([N:20]([C:25]2[C:44]([CH:45]3[CH2:47][CH2:46]3)=[CH:43][C:28]3[C:29]([C:39]([NH:41][CH3:42])=[O:40])=[C:30]([C:32]4[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=4)[O:31][C:27]=3[CH:26]=2)[S:21]([CH3:24])(=[O:23])=[O:22])=[CH:12][C:11]=1[C:9]#[N:10]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C#N)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(C#N)c3)S(C)(=O)=O)c(C3CC3)cc12
Reaction time: 8 h
Yield: 74.3 %

Procedure:
A solution of Na2S2O4 (7.24 g, 41.6 mmol) in water (70 mL) was added dropwise to a solution of 6-(N-(3-cyano-4-nitrophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (3.8 g, 6.93 mmol) in THF at room temperature under N2. The mixture was stirred overnight. H2O was added to the mixture and then extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4. After concentration, the crude residue was purified by chromatography on silica gel eluted with 0-20% EtOAC in DCM to give the desired product as a white solid (2.67 g, 74.3%). LCMS (m/z, ES+)=519 (M+H+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[O:6][CH2:7][C:8](=O)[CH2:9][NH:10][C:11]([C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[O:6][CH2:7][C:8]1[S:40][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:10][CH:9]=1
Reactant: COc1ccc(OCC(=O)CNC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1OC
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(OCc2cnc([C@@H]3CCCN3C(=O)OC(C)(C)C)s2)cc1OC
Temperature: 110 °C
Yield: 35 %

Procedure:
To a toluene (5 ml) solution of the compound (0.287 g) obtained in Example 19-(4), Lawesson's reagent (0.275 g) was added and the mixture was stirred at 110° C. for an hour. After reversion to room temperature, the reaction mixture was concentrated to give a crude product, which was further purified by silica gel chromatography (AcOEt/hexane) to give the titled compound (0.100 g, colorless amorphous.)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.Cl[C:11]1C(C)=NC(C)=NC=1>C1COCC1.CN1C(=O)CCC1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[Cl:1][C:2]1[N:7]=[C:6]([CH3:11])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Cc1ncc(Cl)c(C)n1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Cc1nc(Cl)ncc1Cl
Temperature: 25 °C

Procedure:
2,4,5-trichloropyrimidine (1.83 g, 10 mmol) was dissolved in THF:NMP (10:1, 100 mL) at room temperature and iron(III) acetylacetonate (0.71 g, 2.0 mmol) was added under N2. MgBrMe (3M, 12 mmol) was added drop-wise via syringe. The mixture was cooled to RT, progress was verified by LC-MS: typical results show product vs starting material vs 5-chloro-2,4-dimethylpyrimidine side product ˜2:2:1 ratio. The reaction was quenched with ice cold, saturated ammonium chloride (, 100 mL), extracted with ethyl acetate (100 mL), washed with brine (100 mL, ×2), dried over MgSO4, filtered and concentrated i. vac. The crude mixture was purified by silica gel chromatography (5% ethylacetate/hexane) to yield the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][C:10](=[CH:13][CH2:14][NH:15][C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][N:19]=3)=[O:17])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:32][CH2:33][CH3:34]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][C:10](=[CH:13][CH2:14][NH:15][C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH2:32][CH2:33][CH3:34])[N:19]=3)=[O:17])[CH2:9][CH2:8]2)=[CH:27][CH:28]=1
Reactant: O=C(NCC=C1CCN(Cc2ccc(F)cc2)CC1)c1n[nH]c2ccccc12
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCn1nc(C(=O)NCC=C2CCN(Cc3ccc(F)cc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
N-[2-(1-p-Fluorobenzyl-4-piperidylidene)ethyl]-1H-indazole-3-carboxamide (0.33 g) obtained in Example 9 was dissolved in DMF (5 ml), 60% sodium hydride (0.05 g) and 1-bromopropane (0.21 g) were successively added under ice-cooling, and the mixture was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate (50 ml), washed with water (20 ml×4), dried over anhydrous magnesium sulfate, and distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to give the title compound (0.15 g). Yield=41%.