Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=2)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:36][CH2:37][C@H:38]([NH:46][S:47]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)(=[O:49])=[O:48])[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[C:42]([O:41][C:39](=[O:40])[C@@H:38]([NH:46][S:47]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)(=[O:49])=[O:48])[CH2:37][NH:36][C:20](=[O:22])[C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH2:13][C:11]2[N:10]=[CH:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:12]=2)=[CH:24][CH:23]=1)([CH3:45])([CH3:43])[CH3:44]
Reactant: O=C(O)c1ccc(OCCc2cn(Cc3ccccc3)cn2)cc1
Reactant: CC(C)(C)OC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(OCCc2cn(Cc3ccccc3)cn2)cc1)NS(=O)(=O)c1ccccc1

Procedure:
A stirred mixture of 3-6 (147 mg, 0.46 mmol), HOBT (94 mg, 0.61 mmol), 2-1 (154 mg, 0.46 mmol), NMM (100 μL, 0.91 mmol), and DMF (1.2 mL) at 0° C. was treated with EDC (118 mg, 0.61 mmol) followed by removal of the cooling bath. The reaction pH was adjusted to 8 by addition of more NMM. After 20 h the reaction mixture was concentrated and the residue purified by to a flash chromatography column (silica, 9/0.5/0.5 CH2Cl2 /CH3OH/AcOH) to give 3-7 as a yellow solid after azeotropic removal of residual AcOH with toluene. Rf 0.48 (silica, 9/0.5/0.5 CH2Cl2 /CH3OH/AcOH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[N:11]3[N:17]=[CH:18][C:19](I)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21]([C:23]1[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=1)#[CH:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[N:11]3[N:17]=[CH:18][C:19]([C:22]#[C:21][C:23]4[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCCc1cc(-c2ccc(Cl)cc2)nc2c(I)cnn12
Reactant: C#Cc1ccc(N)nc1
Product: CCCc1cc(-c2ccc(Cl)cc2)nc2c(C#Cc3ccc(N)nc3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-iodo-7-propyl-pyrazolo[1,5-a]pyrimidine (99 mg, 0.25 mmol) and 5-ethynyl-pyridin-2-ylamine (example D.1) (30 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (48 mg, 50%). MS (ISP) 388.4 [(M+H)+]; mp 215-217° C.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[C:5]([C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=1.[H-].[Na+].[C:18](OCC)(=[O:22])[CH:19]([CH3:21])[CH3:20].Cl>O1CCOCC1>[F:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[C:5]([C:13](=[O:15])[CH2:14][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)C
Reactant: CC(=O)c1ccc(F)c2ccc(F)cc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)C(=O)CC(=O)c1ccc(F)c2ccc(F)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
1-(4,7-difluoronaphth-1-yl)-ethanone (0.150 g, 0.72 mmol) was dissolved in dry dioxane (1 mL) and cooled to 0° C. Sodium hydride (0.145 g, 3.6 mmol, 60 wt. % dispersion) was added and the reaction mixture was stirred for 1 hour at room temperature. Ethyl isobutyrate (1.0 mL, 7.2 mmol) was added in one portion and the solution was heated to reflux for 15 minutes. After cooling to room temperature, the reaction mixture was poured onto 10% aqueous hydrochloric acid and extracted with methylene chloride. The organic layer was dried over sodium sulfate and purified by column chromatography to give 1-(4,7-difluoronaphth-1-yl)-4-methylpentane-1,3-dione (0.120 g, 72%).
Reaction SMILES: [K+].[K+].[C:3]12([C:13]#[C:14][C:15]3[CH:16]=[C:17]([C:24]([O-:26])=[O:25])[CH:18]=[C:19]([CH:23]=3)[C:20]([O-:22])=[O:21])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2>O>[C:3]12([C:13]#[C:14][C:15]3[CH:16]=[C:17]([C:24]([OH:26])=[O:25])[CH:18]=[C:19]([CH:23]=3)[C:20]([OH:22])=[O:21])[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:9]([CH2:11]3)[CH2:10]1)[CH2:12]2
Reactant: O=C([O-])c1cc(C#CC23CC4CC(CC(C4)C2)C3)cc(C(=O)[O-])c1
Agent: [K+]
Solvent: O
Product: O=C(O)c1cc(C#CC23CC4CC(CC(C4)C2)C3)cc(C(=O)O)c1
Yield: 99.6 %

Procedure:
Next, 7.6 g of the 5-(1-adamantylethynyl)isophthalic acid dipotassium salt obtained above (19 mmol) was dissolved in 20 mL of ion-exchange water and filtered to remove insoluble matter. Then, 5 mol/L hydrochloric acid was added to a resulting filtrate with agitating so as to have pH of 1. Solid precipitate was collected by filtration, then washed with 50 mL of ion-exchange water and dried under reduced pressure, thus obtaining 6.1 g of 5-(1-adamantylethynyl)isophthalic acid (18.9 mmol; yield: 99.5%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:18]=[CH:17][C:11]([CH:12]=[C:13]([CH3:16])[C:14]#[N:15])=[C:10]([N+:19]([O-])=O)[CH:9]=2)[CH:3]=1.O.O.[Sn](Cl)[Cl:25].[ClH:27].C(=O)([O-])O.[Na+]>C(O)C.C(OCC)(=O)C.O1CCOCC1>[ClH:25].[ClH:27].[NH2:15][C:14]1[C:13]([CH3:16])=[CH:12][C:11]2[C:10](=[CH:9][C:8]([C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=3)=[CH:18][CH:17]=2)[N:19]=1
Reactant: CC(C#N)=Cc1ccc(-c2cc(C)ccn2)cc1[N+](=O)[O-]
Reactant: Cl[Sn]Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccnc(-c2ccc3cc(C)c(N)nc3c2)c1

Procedure:
To a suspension of 2-(4-(4-methylpyridin-2-yl)-2-nitrobenzylidene)-propionitrile (221 mg) in ethanol (30 ml) was added tin (II) chloride dihydrate (1.25 g), and the mixture was refluxed for 30 minutes. Then to the solution was added hydrochloric acid (12N, 5 ml), and the mixture was refluxed for 6 hours. After cooling, the reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 25 g, 10% methanol in dichloromethane). The compound obtained was dissolved in ethyl acetate, and a solution of hydrogen chloride in 1,4-dioxane (4N, 1 ml) was added. The precipitate was collected by filtration and dried to give 2-amino-3-methyl-7-(4-methylpyridin-2-yl)quinoline dihydrochloride (57 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[N:7]=1.Cl.[NH2:12][C@H:13]([CH2:17][CH3:18])[C:14]([NH2:16])=[O:15].CCN(C(C)C)C(C)C.O>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:12][C@H:13]([CH2:17][CH3:18])[C:14]([NH2:16])=[O:15])[CH:5]=[N:4][C:3]=1[C:9]#[N:10]
Reactant: CC[C@@H](N)C(N)=O
Reactant: N#Cc1ncc(Cl)nc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@@H](Nc1cnc(C#N)c(Cl)n1)C(N)=O
Yield: 97.7 %

Procedure:
A solution of 3,5-dichloropyrazine-2-carbonitrile (628 mg, 3.60 mmol), 2-(R)-amino-butanamide hydrochloride (500 mg, 3.60 mmol) and DIEA (1.60 mL, 9.20 mmol) in DMF (10 mL) was stirred at room temperature for 4 h. Water and EtOAc were added. Organic phase was separated, washed with water, dried over Na2SO4, concentrated in vacuo to give (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)butanamide (843 mg) as a semi-solid.
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH2:16]([C:18]1[N:19]=[N+:20]([O-:33])[C:21]2[C:30]([N:31]=1)=[CH:29][C:28]1[CH2:27][N:26]([CH3:32])[CH2:25][CH2:24][C:23]=1[CH:22]=2)[CH3:17].C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[CH2:16]([C:18]1[N:19]=[N+:20]([O-:33])[C:21]2[C:30]([N+:31]=1[O-:4])=[CH:29][C:28]1[CH2:27][N:26]([CH3:32])[CH2:25][CH2:24][C:23]=1[CH:22]=2)[CH3:17]
Reactant: CCc1nc2cc3c(cc2[n+]([O-])n1)CCN(C)C3
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CN(C)CC3
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 17.1 %

Procedure:
H2O2 (70%, 2.4 mL, ca. 25 mmol) was added dropwise to a stirred solution of TFAA (3.5 mL, 25 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C., added to a solution of 1-oxide 260 (590 mg, 2.4 mmol) and TFA (0.96 mL, 12.2 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 20° C. for 4 h, diluted with dilute aqueous NH3 solution (80 mL) and extracted with DCM (4×150 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (2-5%) of MeOH/DCM, to give 1,4-dioxide 261 (107 mg, 17%) as a yellow solid: mp 124-128° C.; 1H NMR δ 8.23 (s, 1H, H-10), 8.18 (s, 1H, H-5), 3.83 (s, 2H, H-6), 3.15-3.24 (m, 4H, CH2, H-8), 2.78 (t, J=6.0 Hz, 2H, H-9), 2.51 (s, 3H, NCH3), 1.43 (t, J=7.5 Hz, 3H, CH3); 13C NMR δ 149.3, 145.5, 136.5, 135.3, 129.3, 120.5, 116.3, 58.1, 51.9, 45.8, 29.6, 23.9, 9.3; MS (APCI) m/z 261 (MH+, 100%). Anal. calcd for C13H16N4O2.¼CH2Cl2: C, 56.5; H, 5.9; N, 19.9. Found: C, 56.6; H, 5.9; N, 19.7%.
Reaction SMILES: C1(C(=C)CS(C2C=CC=CC=2)(=O)=O)C=CC=CC=1.ClCC(C1C=CC=C(Cl)N=1)=C.[C:30]1(S([O-])=O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Na+].[Cl:40][C:41]1[N:46]=[C:45]([C:47](=[CH2:58])[CH2:48][S:49](C2C=CC=CC=2)(=[O:51])=[O:50])[CH:44]=[CH:43][CH:42]=1>>[Cl:40][C:41]1[N:46]=[C:45]([C:47](=[CH2:58])[C:48](=[S:49](=[O:51])=[O:50])[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:44]=[CH:43][CH:42]=1
Reactant: O=S([O-])c1ccccc1
Reactant: C=C(CS(=O)(=O)c1ccccc1)c1cccc(Cl)n1
Agent: C=C(CCl)c1cccc(Cl)n1
Agent: C=C(CS(=O)(=O)c1ccccc1)c1ccccc1
Agent: [Na+]
Product: C=C(C(c1ccccc1)=S(=O)=O)c1cccc(Cl)n1

Procedure:
In a similar manner to the preparation of 2-phenyl-1-phenylsulphonyl-2-propene, this mixture (7 g, 0.02 moles as 1-chloro-2-(6-chloro-2-pyridyl)-2-propene) is treated with sodium benzenesulphinate to obtain, after treatment, 2-(6-chloro-2-pyridyl)-1-phenylsulphonyl-2-propene (4.3 g, 73%). Mp=135° C.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[CH:4]=[N:3][CH:2]=1.[I:10]N1C(=O)CCC1=O.C(#N)C>O>[I:10][C:9]1[C:5]2[CH:4]=[N:3][CH:2]=[N:1][C:6]=2[NH:7][CH:8]=1
Reactant: c1ncc2cc[nH]c2n1
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CC#N
Product: Ic1c[nH]c2ncncc12
Reaction time: 3 h
Yield: 85 %

Procedure:
In a 250 mL round-bottomed flask, 7H-pyrrolo[2,3-d]pyrimidine (4.34 g, 36.4 mmol, Eq: 1.00) and N-iodosuccinimide (8.61 g, 38.3 mmol, Eq: 1.05) were combined with acetonitrile (60 ml) to give a light brown suspension. The reaction mixture was stirred for 3 h. The reaction mixture was poured into 100 mL H2O and extracted with EtOAc (3×50 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was triturated with diethyl ether (2×25 mL) to give 5-iodo-7H-pyrrolo[2,3-d]pyrimidine (7.58 g, 85%) as orange solid.
Reaction SMILES: [NH4+].[CH3:2][O:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:14]#[N:15])=[CH:8][CH:7]=1>[Ni].CO>[CH3:2][O:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:14][NH2:15])=[CH:10][CH:11]=1
Reactant: COCOc1ccc(CC(C#N)c2cccnc2)cc1
Agent: [Ni]
Agent: [NH4+]
Solvent: CO
Product: COCOc1ccc(CC(CN)c2cccnc2)cc1
Reaction time: 64 h
Yield: 85.3 %

Procedure:
An appropriate amount of Raney nickel was suspended in 30 ml of saturated solution of ammonium and methanol, followed by addition of 5.75 g of 3-(4-methoxymethyloxyphenyl)-2-(3-pyridyl)propionitrile, and stirred for 64 hours under hydrogen atmosphere of 15 atm. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue obtained was subjected to chromatography on a silica gel column, which was then eluted with aqueous ammonia-methanol-chloroform (1:10:100 v/v), and from the eluted fraction was obtained 4.98 g of 3-(4-methoxymethyloxyphenyl)-2-(3-pyridyl)propylamine.
Reaction SMILES: CC(C)([O-])C.[Na+].[CH:7]([C:10]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([CH3:19])[CH3:18])[C:11]=1[NH2:12])([CH3:9])[CH3:8].Br[C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[CH:28][CH:27]=[CH:26]2>C1(C)C=CC=CC=1>[CH:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:10]([CH:7]([CH3:9])[CH3:8])[C:11]=1[NH:12][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[CH:28][CH:27]=[CH:26]2)([CH3:19])[CH3:18]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: Brc1cccc2cccnc12
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1Nc1cccc2cccnc12
Yield: 38 %

Procedure:
Charge a round bottomed flask equipped with a reflux condenser with tris(dibenzylidene acetone)dipalladium(0)(Pd2(dba)3) (0.090 mmol, Aldrich), racemic 2,2′-bis(diphenylphosphine)-1,1′-binaphthyl (rac-BINAP) (0.207 mmol; Fluka division of Aldrich), and sodium tertiary-butoxide (NaOtBu) (4.05 mmol; Aldrich) in toluene (15 mL). To the resulting suspension add 2,6-diisopropylaniline (2.88 mmol) and 8-bromoquinoline (2.88 mmol), and then heat the resulting mixture under reflux overnight. Pump down the reaction mixture to dryness under vacuum, and purify the resulting crude residue by column chromatography on silica gel eluting with 9:1 pentane:diethyl ether (C5H12:Et2O) to give purified (1) in 38% yield.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([O:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]([F:14])([F:15])[F:16])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:19])[CH3:18]
Reactant: COC(=O)c1cc(C(F)(F)F)c(C)cc1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1cc(C(F)(F)F)c(C)cc1OC(C)=O
Reaction time: 2 h

Procedure:
Methyl 2-hydroxy-4-methyl-5-(trifluoromethyl)benzoate (may be prepared as described in Description 45; 1.37 g, 5.85 mmol) was dissolved in pyridine (70 ml) and acetic anhydride (1.34 ml, 14.18 mmol) was added. The solution was stirred for 2 hours then the solvent was removed in vacuo to give oil. The oil was purified by column chromatography (SiO2, 3:1 cyclohexane/ethyl acetate) to yield the title compound as a gum. 1.53 g.
Reaction SMILES: [ClH:1].FC(F)(F)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.BrC1C=CC=CC=1[C:27]([F:30])([F:29])[F:28]>>[ClH:1].[Cl:1][C:4]1[CH:9]=[CH:8][C:7]([C:27]([F:30])([F:29])[F:28])=[CH:6][C:5]=1[NH:10][CH2:11][CH:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1
Reactant: FC(F)(F)c1ccccc1Br
Reactant: FC(F)(F)c1ccccc1NCC1CCNCC1
Agent: Cl
Product: FC(F)(F)c1ccc(Cl)c(NCC2CCNCC2)c1
Yield: 47 %

Procedure:
The synthesis of intermediate 1s is conducted starting with 1-bromo-2-trifluoromethyl-benzene following the operating mode for the synthesis of 1r (white solid, total yield 47%). TLC silica gel 60 F 254 Merck, CH2Cl2-MeOH—NH4OH: 90:9:1, Rf=0.23.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[CH3:28][N:29]1[CH:33]=[C:32]([S:34](Cl)(=[O:36])=[O:35])[N:31]=[CH:30]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][S:34]([C:32]5[N:31]=[CH:30][N:29]([CH3:28])[CH:33]=5)(=[O:36])=[O:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Agent: Cl
Product: Cn1cnc(S(=O)(=O)N[C@H]2CC[C@H](CCN3CCN(c4cccc5c4OCO5)CC3)CC2)c1

Procedure:
The title compound, white solid (23 mg, 59.3%), MS (ISP) m/z=476.1 [(M+H)+], was prepared in accordance with the general method of example 66 from N-trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 μmol) and 1-methyl-1H-imidazole-4-sulfonyl chloride.
Reaction SMILES: [C:1]([C:5]1[CH:40]=[CH:39][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:19]=[C:20]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([NH:33][CH3:34])=[C:29]([N+:35]([O-])=O)[CH:28]=4)[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=3)[C:13]=2[CH3:38])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)C.[H][H]>[Pd].C(OCC)(=O)C>[NH2:35][C:29]1[CH:28]=[C:27]([NH:26][C:20]2[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=[C:18]([C:14]3[C:13]([CH3:38])=[C:12]([NH:11][C:9](=[O:10])[C:8]4[CH:39]=[CH:40][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][CH:7]=4)[CH:17]=[CH:16][CH:15]=3)[N:19]=2)[CH:32]=[CH:31][C:30]=1[NH:33][CH3:34]
Reactant: CNc1ccc(Nc2nc(-c3cccc(NC(=O)c4ccc(C(C)(C)C)cc4)c3C)cn(C)c2=O)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNc1ccc(Nc2nc(-c3cccc(NC(=O)c4ccc(C(C)(C)C)cc4)c3C)cn(C)c2=O)cc1N
Yield: 85.1 %

Procedure:
A mixture of 4-tert-butyl-N-{2-methyl-3-[4-methyl-6-(4-methylamino-3-nitro-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide (3) (500 mg), 10% palladium-on-carbon (100 mg), ethanol (50 mL), and ethyl acetate (100 mL) was hydrogenated at room temperature and 40 psi hydrogen for 16 hr. The mixture was filtered through a celite pad, washing with ethyl acetate (2×100 mL). The combined filtrates were evaporated to give N-{3-[6-(3-amino-4-methylamino-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide (4) as a yellow solid (402 mg), m/z 512.08 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([OH:29])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([OH:29])[CH2:24][CH2:25][N:26]([C:13]([C:9]3[CH:10]=[N:11][O:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[O:15])[CH2:27][CH2:28]2)=[CH:19][CH:18]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(O)(c3ccc(Cl)cc3)CC2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 4-(4-chlorophenyl)-4-hydroxypiperidine (12.7 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (8.2 mg). Calcd for C22H21ClN2O3: 396.1241, found 396.1239.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[C@@H:7]([NH:10][C:11](=[O:23])[C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1Cl)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC(C(F)(F)F)=CC=1C(O)=O.N[C@@H](CC)C(OC(C)(C)C)=O.[CH2:50]([NH2:57])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1.[Cl-].[NH4+].[Cu].[Cu]Br>[C:1]([O:5][C:6](=[O:24])[C@@H:7]([NH:10][C:11](=[O:23])[C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[NH:57][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@H](NC(=O)c1cc(C(F)(F)F)ccc1Cl)C(=O)OC(C)(C)C
Reactant: NCc1ccccc1
Agent: [Cu]
Agent: [Cu]Br
Agent: CC[C@H](N)C(=O)OC(C)(C)C
Product: CC[C@H](NC(=O)c1cc(C(F)(F)F)ccc1NCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 160 °C

Procedure:
To a solution of (S)-2-(2-chloro-5-trifluoromethyl-benzoylamino)-butyric acid tert-butyl ester (prepared from 2-chloro5-trifluoromethylbenzoic acid and (S)-2-aminobutyric acid, tert butyl ester in a procedure similar to that described in method F) (3 g) and benzylamine (1.1 ml) in N-methylpyrrolidine (40 ml) was added potassium carbonate (1.6 g), copper (30 mg) and copper (I) bromide (15 mg). The mixture was heated at 160° C. for 3 hours then cooled to room temp. and diluted with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate and the organic solution dried (magnesium sulfate), filtered and concentrated. The residue was purified on silica gel, eluting with 15% ethyl acetate/hexane. The sub-titled product was obtained as a white solid (950 mg, 27%). 1H NMR (400 MHz, CDCl3) δ 1.04 (3H, t), 1.50 (9H, s), 2.86 (1H, m), 2.02 (1H, m), 4.50 (2H, d), 4.65 (1H, m), 6.69 (2H, m), 7.21-7.70 (7H, m), 8.42 (1H, m) ppm; MS ES (−) 435.32 (M−H).
Reaction SMILES: [CH3:1][CH:2]([CH:4]([C:12]([O:14]C(C1C=CC=C(OC2C=CC=CC=2)C=1)C#N)=[O:13])[C:5]1[CH:6]=[CH:7][C:8]([Cl:11])=[CH:9][CH:10]=1)[CH3:3]>C(O)C.[Pt]=O>[Cl:11][C:8]1[CH:7]=[CH:6][C:5]([C@H:4]([CH:2]([CH3:3])[CH3:1])[C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1
Reactant: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Agent: O=[Pt]
Solvent: CCO
Product: CC(C)[C@H](C(=O)O)c1ccc(Cl)cc1

Procedure:
The optical purity of the acid moiety of fenvalerate A was determined as follows: Fenvalerate A was hydrogenated in ethanol using platinum oxide as a catalyst to obtain (S)-2-(4-chlorophenyl)isovaleric acid which was then converted to an acid chloride using thionyl chloride. The acid chloride was converted to the l-menthol ester with l-menthol. The ratio between the two resulting diastereomers was determined by gas chromatography, and the optical purity of the acid moiety was calculated.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][C@@H:13]([CH2:15][OH:16])[O:12][C:11](=[O:17])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Si:1]([O:8][C@H:9]1[CH2:10][C:11](=[O:17])[O:12][C@H:13]([CH:15]=[O:16])[CH2:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC(=O)O[C@H](CO)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC(=O)O[C@H](C=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.7 %

Procedure:
A mixture of (4R,6S)-4-(tert-butyldimethylsilyloxy)-6-(hydroxymethyl)-tetrahydropyran-2-one (8) (150 mg, 0.58 mmol) and Dess-Martin periodinane (380 mg, 0.86 mmol) in CH2Cl2 (15 mL) is stirred at ambient temperature for 3 hours. The mixture is diluted with t-BuMeO (20 mL), washed with saturated Na2S2O3 solution, saturated NaHCO3 solution, dried (MgSO4) and concentrated to give 130 mg (87%) of crude (2S,4R)-4-(tert-butyldimethylsilyloxy)-6-oxo-tetrahydro-2H-pyran-2-carbaldehyde (9) which is used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ: 9.82 (s, 1H), 5.09 (dd, J=11 Hz, J=4 Hz, 1H), 4.38 (m, 1H), 2.67 (d, J=4 Hz, 2H), 2.18−2.10 (m, 1H), 1.91−1.81 (m, 1H), 0.89 (s, 9H), 0.09, (s, 6H). 13C NMR (75 MHz, CDCl3) δ: 199.4, 168.0, 79.2, 62.9, 39.6, 31.4, 25.6, 17.9, −4.9. The hydrate form of (9) has following NMR spectra: 1H NMR (300 MHz, THF-d8) δ: 5.27 (d, J=6 Hz, 1H, OH), 5.19 (d, J=6 Hz, 1H, OH), 4.90−4.85 (m, 1H), 4.44−4.38 (m, 2H), 2.58 (dd, J=17 Hz, J=4 Hz, 1H), 2.44−2.36 (m, 1H), 1.92−1.87 (m, 2H), 0.91 (s, 9H), 0.10, (s, 6H). 13C NMR (75 MHz, THF-d8) δ: 168.7, 91.7, 79.0, 65.1, 40.3, 31.0, 26.2, 18.7, −4.8, −4.8.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:14]1[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([N:21]2[CH2:24][CH:23]([C:25]3[N:29]([CH3:30])[C:28]4[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=4[N:26]=3)[CH2:22]2)[CH:15]=1>CC(N(C)C)=O>[CH3:30][N:29]1[C:28]2[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=2[N:26]=[C:25]1[CH:23]1[CH2:24][N:21]([C:16]2[CH:15]=[C:14]([N:4]3[CH:3]=[C:2]([CH3:1])[CH:6]=[N:5]3)[N:19]=[C:18]([CH3:20])[N:17]=2)[CH2:22]1
Reactant: Cc1cn[nH]c1
Reactant: Cc1nc(Cl)cc(N2CC(c3nc4ccccc4n3C)C2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1cnn(-c2cc(N3CC(c4nc5ccccc5n4C)C3)nc(C)n2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-methylpyrazole (10.5 mg, 0.13 mmol) in DMA (0.65 mL) in a microwave vial was added Cs2CO3 (83 mg, 0.26 mmol) and the mixture was stirred at rt. After 15 min, Intermediate 3 (40 mg, 0.13 mmol) was added and the tube was capped, sealed, and heated at 150° C. for 3 h. The reaction was cooled to rt, filtered through a syringe filter and purified by reverse-phase preparative chromatography (5-50% acetonitrile/water+0.1% TFA) to give Example 2. 1H NMR: (500 MHz, CD3OD) δ 8.31 (m, 1H), 7.76 (m, 1H), 7.54 (m, 1H), 7.33 (m, 3H), 6.62 (s, 1H), 4.64 (m, 4H), 4.31 (m, 1H), 3.73 (s, 3H), 2.51 (s, 3H), 2.14 (s, 3H) ppm. MS: m/z=360.5 (M+H).