Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:23])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:26][N:27]1[CH2:32][CH2:31][CH2:30][C@H:29]([C:33]2[N:37]3[CH:38]=[C:39]([O:42][C@H:43]4[C:52]5[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=5)[C@@H:46]([NH2:53])[CH2:45][CH2:44]4)[CH:40]=[CH:41][C:36]3=[N:35][N:34]=2)[CH2:28]1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:53][C@@H:46]2[C:47]3[C:52](=[CH:51][CH:50]=[CH:49][CH:48]=3)[C@H:43]([O:42][C:39]3[CH:40]=[CH:41][C:36]4[N:37]([C:33]([C@H:29]5[CH2:30][CH2:31][CH2:32][N:27]([CH3:26])[CH2:28]5)=[N:34][N:35]=4)[CH:38]=3)[CH2:44][CH2:45]2)=[O:23])[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:9]=1)([CH3:14])([CH3:15])[CH3:13]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CN1CCC[C@H](c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@H]5CCCN(C)C5)n4c3)c3ccccc32)cc1
Yield: 74 %

Procedure:
An orange-brown solution (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 243 mg, 0.600 mmol), Intermediate 88e (151 mg, 0.400 mmol) and DIPEA (0.122 mL, 0.700 mmol) in dry dioxane (5 mL) was stirred at 65° C. for 15 h. The cooled solution was concentrated in vacuo, redissolved in MeOH (2 mL), applied to an SCX-2 cartridge (10 g) and washed with MeOH (50 mL). The product was eluted with 2M NH3 in MeOH (30 mL); concentration in vacuo left a brown solid. FCC, using 2-7% [2M NH3 in MeOH] in DCM, gave the title compound as a pale yellow solid (188 mg, 74%). LCMS (Method 5): Rt 3.63 min, m/z 633 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.55 (1H, qd, J 11.9, 5.3), 1.68-1.79 (2H, m), 1.83-2.03 (4H, m), 2.06-2.14 (2H, m), 2.22 (1H, t, J 10.9), 2.22 (3H, s), 2.36 (3H, s), 2.83 (1H, br d, J 10.9), 3.01 (1H, ddd, J 11.1, 3.6, 1.6), 3.54 (1H, tt, J 11.1, 3.7), 4.83 (1H, td, J 8.4, 5.5), 5.57 (1H, t, J 4.5), 6.33 (1H, s), 7.09 (1H, d, J 8.5), 7.15 (1H, dd, J 9.8, 2.0), 7.27-7.42 (8H, m), 7.68 (1H, d, J 9.9), 8.03 (1H, s), 8.32 (1H, d, J 2.0).
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([CH3:13])([CH3:12])[C:9](Cl)=[O:10].[CH3:19][C:20]1([CH3:28])[CH2:25][C@H:24]([CH3:26])[CH2:23][C@H:22]([OH:27])[CH2:21]1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([CH3:13])([CH3:12])[C:9]([O:27][C@H:22]1[CH2:23][C@@H:24]([CH3:26])[CH2:25][C:20]([CH3:28])([CH3:19])[CH2:21]1)=[O:10]
Reactant: C[C@@H]1C[C@H](O)CC(C)(C)C1
Reactant: Cc1ccc(C)c(OCCCC(C)(C)C(=O)Cl)c1
Solvent: Cc1ccccc1
Product: Cc1ccc(C)c(OCCCC(C)(C)C(=O)O[C@H]2C[C@@H](C)CC(C)(C)C2)c1

Procedure:
25 g of 2-(3-(2,5-dimethylphenoxy)propyl)-2-methylpropionyl chloride are added to 14 g of (cis) 3,3,5-trimethylcyclohexanol dissolved in 100 ml of toluene. The mixture is refluxed for three hours and then evaporated to dryness. The evaporation residue is chromatographed on a silica column with chloroform. The title product is obtained in the amorphous state and in thin layer chromatography gives a single spot under the above conditions; the characteristic bands of its IR spectrum run in KBr are as follows: 3000-2850 cm-1, group of fine bands; 1730 cm-1, strong band for the carbonyl.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][N:3]=1.Cl[CH2:13][C:14](=O)[CH3:15].[OH-].[Na+]>CO>[CH3:15][C:14]1[N:1]=[C:2]2[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][N:3]2[CH:13]=1
Reactant: COC(=O)c1ccnc(N)c1
Reactant: CC(=O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccn2cc(C)nc2c1

Procedure:
A mixture of 15 parts of methyl 2-amino-4-pyridinecarboxylate, 13.75 parts of 1-chloro-2-propanone and 160 parts of absolute methanol was stirred and refluxed for 18 hours. The reaction mixture was treated with a sodium hydroxide solution 1N in methanol. The solvent was evaporated in vacuo and the residue was dissolved in trichloromethane. The solution was filtered and the filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 9.7 parts of methyl 2-methylimidazo[1,2-a]pyridine-7-carboxylate; mp. 149.1° C. (intermediate 12).
Reaction SMILES: [CH:1]1([CH2:4][C:5]([NH:13][C:14]([C:16]2[CH:21]=[C:20]([O:22][C@@H:23]([CH3:28])[C:24]([F:27])([F:26])[F:25])[C:19](Br)=[CH:18][N:17]=2)=[O:15])([CH3:12])[C:6]2[N:10]=[C:9]([CH3:11])[O:8][N:7]=2)[CH2:3][CH2:2]1.[CH:30]1(B(O)O)[CH2:32][CH2:31]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(OC(=O)C)C>[CH:1]1([CH2:4][C:5]([NH:13][C:14]([C:16]2[CH:21]=[C:20]([O:22][C@@H:23]([CH3:28])[C:24]([F:27])([F:26])[F:25])[C:19]([CH:30]3[CH2:32][CH2:31]3)=[CH:18][N:17]=2)=[O:15])([CH3:12])[C:6]2[N:10]=[C:9]([CH3:11])[O:8][N:7]=2)[CH2:3][CH2:2]1
Reactant: OB(O)C1CC1
Reactant: Cc1nc(C(C)(CC2CC2)NC(=O)c2cc(O[C@@H](C)C(F)(F)F)c(Br)cn2)no1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1nc(C(C)(CC2CC2)NC(=O)c2cc(O[C@@H](C)C(F)(F)F)c(C3CC3)cn2)no1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 5-Bromo-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid [2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide (Example 100c, 160 mg, 0.335 mmol) in toluene (4.8 mL) were added cyclopropylboronic acid (43.2 mg, 0.503 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (12.3 mg, 17 μmol) and 2M aqueous solution sodium carbonate (335 μL, 0.670 mmol). Reaction was stirred at 80° C. for 18 hours. The reaction mixture was diluted with ethylacetate and extracted with water. The organic layer was dried on sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the mixture of epimers (151 mg, 100%). The mixture of epimers was separated by preparative chiral HPLC (Chiralpak AD, isopropanol/heptane) and the title compound was the first epimer collected and isolated as colorless oil; MS (ESI, m/z): 439.7 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>CN(C=O)C.CO>[N:15]1([C:2]2[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=2)[C:7]([O:9][CH3:10])=[O:8])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: C1COCCN1
Reactant: COC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 2.0 g (9.28 mmol) product from Step A and 1.6 mL (18.6 mmol) morpholine in 20 mL DMF was heated to 90° C. for 6 hours. After the mixture had cooled to room temperature, the DMF was stripped off in vacuo. The crude material was then redissolved in methanol and stirred with 20 g Amberlyst-A26® for about 20 minutes. The mixture was then stripped of solvent and used without further purification in the next step. Rf 0.20 in 40% EtOAc/hexane, visualized by UV and visible light.
Reaction SMILES: O[C:2]1[CH:14]=[C:5]2[N:6]=[CH:7][C:8]3[CH:13]=[CH:12][CH:11]=[N:10][C:9]=3[N:4]2[N:3]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=2[N:4]2[N:3]=[CH:2][CH:14]=[C:5]2[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc2ncc3cccnc3n2n1
Product: Clc1nc2ccnn2c2ncccc12

Procedure:
75 g. of hydroxypyrazolo[1,5-a]pyrido[3,2-e]pyrimidine are refluxed in 200 ml. of phosphorus oxychloride for 12 hours with stirring. The excess phosphorus oxychloride is removed in vacuo and the remaining oil poured onto ice. The aqueous solution is neutralized with sodium hydroxide and evaporated in vacuo to about 100 ml. The product, 5-chloropyrazolo[1,5-a]pyrido[3,2-e]pyrimidine, crystallizes and is filtered off, yield: 60 g. (73%); m.p. 159.8° (ethyl acetate).
Reaction SMILES: [N:1]#N.[C:3]([OH:9])([C:5]([F:8])([F:7])[F:6])=[O:4]>C(Cl)Cl>[C:3]([OH:9])([C:5]([F:8])([F:7])[F:6])=[O:4].[C:3](#[N:1])[CH3:5].[C:3]([OH:9])([C:5]([F:8])([F:7])[F:6])=[O:4]
Reactant: N#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To N2 (0.033 g, 0.058 mmol) in DCM (0.20 mL) was added TFA (0.067 mL, 0.86 mmol). The reaction was stirred for 1 h at room temperature and then concentrated in vacuo. The residue was Purified by reverse phase chromatography: 5% (2 column volumes), 5-100% (10 column volumes) 0.1% TFA/acetonitrile//0.1% TFA/water) to provide Example 16 as a TFA salt.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@H:5]3[C@@H:21]([C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C:2]124)[CH2:20][CH2:19][C@@:18]1([CH3:29])[C@H:6]3[CH2:7][CH2:8][C@@H:9]1[C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].[NH2:30][CH2:31][CH2:32][C:33]1C2C(=CC=CC=2)NC=1.C(O)CCC>COC(C)(C)C>[OH:1][C@:2]12[CH2:26][C@@H:25]([OH:27])[CH2:24][CH2:23][C@:22]1([CH3:28])[C@@H:21]1[C@H:5]([C@H:6]3[C@:18]([CH3:29])([CH2:19][CH2:20]1)[C@@H:9]([C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[CH2:8][CH2:7]3)[CH2:4][C@H:3]2[NH:30][CH2:31][CH2:32][CH3:33]
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@@H]4OC45C[C@@H](O)CC[C@]5(C)[C@H]3CC[C@]12C
Solvent: CCCCO
Solvent: COC(C)(C)C
Product: CCCN[C@@H]1C[C@H]2[C@@H]3CC[C@H]([C@H](C)CCCC(C)C)[C@@]3(C)CC[C@@H]2[C@@]2(C)CC[C@H](O)C[C@]12O
Temperature: 25 °C
Yield: 71.5 %

Procedure:
5,6α-epoxicholestan-3β-ol (8.9 g, 22.1 mmol, 1 eq) and tryptamine (7.1 g, 44.1 mmol, 2 eq) were charged in a round-bottomed flask equipped with a magnetic stirrer bar. 1-Butanol (70 ml, 5 vol) was added and the mixture heated to reflux for 40 h. The reaction mixture was cooled at r.t., diluted with methyl-tertbutyl-ether (5 vol) and washed with water (5 vol) and with brine (5 vol). The organic layer was passed through a silica pad (40 g) eluted with methyl-tertbutyl-ether (3 vol) then 10% Methanol/ethyl acetate (60 vol). Fractions of interest were pooled and the solvent was removed under reduced pressure to give 5α-Hydroxy-6β-(3-propylamino)-cholestan-3β-ol as a white solid (7.3 g, 59%). In same conditions, use of ethanol as solvent (40 vol) and Ca(OTf)2 as catalyst gave a 21% yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[O:8])[CH:2]=1.[H-].[Na+].[CH3:20]I.O>CN(C)C=O>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[CH:9]([CH3:20])[C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:8]
Reactant: CI
Reactant: O=C(Cc1ccc(Cl)cc1Cl)c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C(=O)c1cccnc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
28 g of 2,4-dichlorobenzyl 3-pyridyl ketone are dissolved in 800 ml of dimethylformamide and treated portionwise at 0° with 5.5 g of sodium hydride (50% dispersion in oil). After 2 hours at room temperature, 14.9 g of methyl iodide are added and the mixture is stirred at room temperature for an additional 3 hours. Then the mixture is poured into water and extracted with diethyl ether, and the organic phase is washed and dried over anhydrous sodium sulfate and subsequently concentrated. The product is purified by chromatography on silica gel with n-hexane/ethyl acetate (1:2) to yield 2-(2,4-dichlorophenyl)-1-(3-pyridyl)-1-propanone as an oil.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([O:25][CH3:26])=[C:8]([O:23][CH3:24])[CH:9]=2)[N:4]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(O)C>ClCCl>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:25][CH3:26])=[C:8]([O:23][CH3:24])[CH:9]=3)[N:4]=[C:3]([CH2:2][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[N:12]=2)[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: COc1ccc(-c2nc(CCl)nc3cc(OC)c(OC)cc23)cc1OC
Reactant: C1CCNCC1
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(-c2nc(CN3CCCCC3)nc3cc(OC)c(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.6 %

Procedure:
A mixture of 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazoline (2.0 g), piperidine (2.27 g) and ethanol (40 ml)-dichloromethane (10 ml) was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and dichloromethane (50 ml) was added to the residue. The dichloromethane layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform-ethyl acetate (1/1, v/v) gave 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-piperidinomethylquinazoline (1.46 g, 65%) which was then recrystallized from ethyl acetate-hexane. Colorless needles. mp. 130°-132° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.O=S(Cl)Cl.[CH3:11][NH:12][C:13]1[C:14]([I:27])=[C:15]([C:24]([Cl:26])=[O:25])[C:16]([I:23])=[C:17]([C:21]=1[I:22])[C:18]([Cl:20])=[O:19]>CC(N(C)C)=O>[CH3:1][O:2][CH2:3][C:4]([N:12]([C:13]1[C:21]([I:22])=[C:17]([C:18]([Cl:20])=[O:19])[C:16]([I:23])=[C:15]([C:14]=1[I:27])[C:24]([Cl:26])=[O:25])[CH3:11])=[O:6]
Reactant: CNc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Reactant: COCC(=O)O
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: COCC(=O)N(C)c1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Reaction time: 0.5 h

Procedure:
30 ml. (400 mmol) of methoxyacetic acid is dissolved in 100 ml. of DMA, cooled to 0° C., and 29 ml. (400 mmol) of SOCl2 is added dropwise. The mixture is stirred for 30 minutes at this temperature, a solution of 61 g. (100 mmol) of 5-methylamino-2,4,6-triiodoisophthalic acid dichloride in 200 ml. of DMA is added dropwise thereto, and the reaction solution is stirred for 20 hours at room temperature. Then, the solution is stirred into 4 l. of water, the precipitate is vacuum-filtered, dissolved in 2 l. of ethyl acetate, successively extracted with respectively 250 ml. of saturated bicarbonate solution, saturated sodium chloride solution, and water; the ethyl acetate phase is dried over Na2SO4 and evaporated. Yield: 61.4 g. (90 mmol)=90% of theory.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>C1(C)C=CC=CC=1>[C:24]1([O:23][C:21](=[O:22])[N:12]([CH2:11][C:8]2[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][CH:9]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCCCc1ccc(CNCCCCCCO)cc1
Solvent: Cc1ccccc1
Product: CCCCc1ccc(CN(CCCCCCO)C(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.1 %

Procedure:
To a stirred solution of 7.26 g of 6-[[(4-butylphenyl)methyl]amino]-1-hexanol in 50 ml of toluene was added a solution of 2.16 g of phenyl chloroformate in 20 ml of toluene, with the immediate precipitation of a white solid. The resulting mixture was stirred at room temperature for 24 hours. The mixture was filtered, and the filter was washed with toluene. The combined filtrate and wash was evaporated in vacuo and gave a colorless oil. The oil was Kugelrohr distilled and gave 3.5 g of the desired product in 66% yield as a colorless oil, bp 180°-195° C./0.06 mm of mercury.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])/[CH:5]=[N:6]/[NH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])[CH3:2].[N+]([C:22]([CH2:49][CH2:50][CH2:51][CH3:52])=[CH:23][C:24]1[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:26][C:25]=1[C:37]([N:39]1[CH2:48][CH2:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40]1)=[O:38])([O-])=O>>[C:31]([O:30][C:28]([C:27]1[CH:35]=[CH:36][C:24]([C:23]2[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:18])=[N:6][N:7]([C:8]3[CH:17]=[CH:16][CH:15]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=3)[C:22]=2[CH2:49][CH2:50][CH2:51][CH3:52])=[C:25]([C:37]([N:39]2[CH2:48][CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40]2)=[O:38])[CH:26]=1)=[O:29])([CH3:32])([CH3:33])[CH3:34]
Reactant: CCCCC(=Cc1ccc(C(=O)OC(C)(C)C)cc1C(=O)N1CCc2ccccc2C1)[N+](=O)[O-]
Reactant: CCOC(=O)/C=N/Nc1cccc(C(=O)OC)c1
Product: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2CCc3ccccc3C2)c(C(=O)OCC)nn1-c1cccc(C(=O)OC)c1
Yield: 28.9 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 223E, (E)-methyl 3-(2-(2-ethoxy-2-oxoethylidene)hydrazinyl)benzoate (65 mg, 0.26 mmol) and tert-butyl 4-(2-nitrohex-1-enyl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (120 mg, 0.26 mmol) were converted to the title compound (50 mg, 29%). MS(ESI+) m/z 666.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[O:23]1[CH:27]=[CH:26][C:25]([NH2:28])=[N:24]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([NH:28][C:25]2[CH:26]=[CH:27][O:23][N:24]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Reactant: Nc1ccon1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)Nc2ccon2)cc1Cl
Reaction time: 2 h
Yield: 33.3 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (prepared as in Example 1, 93 mg, 0.27 mmol), isoxazol-3-ylamine (29 □L, 0.30 mmol) and N,N-diisopropylethylamine (141 μL, 0.81 mmol) were combined in acetonitrile (1.25 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (103 mg, 0.27 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 25% ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-N-isoxazol-3-yl-acetamide (37 mg, 33%) as a slightly yellow solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C17H18ClN3O5S [M+] 411.07, found 412 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.67 (m, 4 H, 2×CH2), 1.88 (m, 4 H, 2×CH2), 3.31 (s, 3 H, SO2CH3), 4.94 (m, 1 H, OCH), 7.07 (d, J=1.7 Hz, 1 H, Ar), 7.56 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.66 (d, Jm=1.5 Hz, 1 H, Ar), 8.20 (d, Jo=8.2 Hz, 1 H, Ar), 8.33 (d, J=1.7 Hz, 1 H, Ar), 9.40 (s, 1 H, NH).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]=[CH:10][C:9]([CH:12]([OH:15])[CH2:13]C)=[CH:8][CH:7]=2)=[CH:2]1.[CH:16]1[N:20]=[CH:19][N:18]([C:21](N2C=NC=C2)=[O:22])[CH:17]=1>C(#N)C>[N:18]1([C:21]([O:15][CH:12]([C:9]2[CH:10]=[N:11][C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)=[CH:7][CH:8]=2)[CH3:13])=[O:22])[CH:17]=[CH:16][N:20]=[CH:19]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCC(O)c1ccc(-c2ccoc2)nc1
Solvent: CC#N
Product: CC(OC(=O)n1ccnc1)c1ccc(-c2ccoc2)nc1

Procedure:
Synthesized using compound 48a (73.0 mg, 0.36 mmol), CDI (291 mg, 1.80 mmol) and acetonitrile (4 mL) according to Method E. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (1:1) as eluent. Green oil. Yield: 62 mg, 67%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=1.00 (t, J=7.4 Hz, 3H), 1.96-2.08 (m, 1H), 2.12-2.24 (m, 1H), 5.85 (t, J=7.1 Hz, 1H), 6.88 (dd, J=1.9, 0.6 Hz, 1H), 7.04-7.09 (m, 1H), 7.42 (t, J=1.4 Hz, 1H), 7.45-7.51 (m, 2H), 7.69 (dd, J=8.2, 2.2 Hz, 1H), 8.01-8.06 (m, 1H), 8.15 (s, 1H), 8.63 (d, J=2.2 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=9.7, 28.6, 79.8, 108.5, 117.0, 119.8, 126.5, 130.7, 131.8, 134.9, 136.9, 141.5, 144.0, 148.0, 148.3, 152.3; MS (ESI): m/z=298.27 [M+H]+.
Reaction SMILES: [N:1]([C@H:4]1[C@@H:9]([CH3:10])[CH2:8][N:7]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH:17][C:18](=[O:34])[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])[N:20]=2)[CH2:6][C@H:5]1[NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[N+:2]=[N-:3].C.[C:44]([C:46]1[CH:50]=[CH:49][S:48][CH:47]=1)#[CH:45].C(N(CC)CC)C>O1CCOCC1.[Cu]>[F:32][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([F:33])[C:26]=1[C:21]1[N:20]=[C:19]([C:18]([NH:17][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:11]=2[N:7]2[CH2:8][C@H:9]([CH3:10])[C@H:4]([N:1]3[CH:45]=[C:44]([C:46]4[CH:50]=[CH:49][S:48][CH:47]=4)[N:3]=[N:2]3)[C@H:5]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:6]2)=[O:34])[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: C#Cc1ccsc1
Reactant: C[C@H]1CN(c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N=[N+]=[N-]
Agent: [Cu]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C[C@H]1CN(c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1cc(-c2ccsc2)nn1
Temperature: 100 °C
Yield: 48 %

Procedure:
In a high pressure vial was added tert-butyl (3R,4S,5S)-4-azido-1-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-5-methylpiperidin-3-ylcarbamate (1.0 equiv.), copper in charcoal (0.4 equiv.), 3-ethynyl thiophene (5.0 equiv.) and triethylamine (1.0 equiv.), in dioxane (0.09 M) to give a black suspension. The pressure tube was sealed and the mixture was stirred with heating to 100° C. overnight. The reaction was cooled to RT, filtered through celite, concentrated to yield tert-butyl (3R,4S,5S)-1-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-5-methyl-4-(4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl)piperidin-3-ylcarbamate in 48% yield. LC/MS (m/z)=691.2 (MH+), Rt=0.98 min.
Reaction SMILES: [CH2:1]1[C@@H:3]2[C:4](=[O:22])[CH:5]=[C:6]3[C@:19]([CH3:20])([CH:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C:13](=[O:21])[CH2:12][CH2:11]2)[CH2:8][CH2:7]3.[Br:23]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:23][C@H:7]1[C:6]2[C@:19]([CH3:20])([CH:2]3[CH2:1][C@@H:3]3[C:4](=[O:22])[CH:5]=2)[C@@H:18]2[C@H:9]([C@H:10]3[C@@:14]([CH2:16][CH2:17]2)([CH3:15])[C:13](=[O:21])[CH2:12][CH2:11]3)[CH2:8]1
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)[C@H]5CC5[C@@]43C)[C@@H]1CCC2=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: C[C@]12CC[C@H]3[C@@H](C[C@@H](Br)C4=CC(=O)[C@H]5CC5[C@@]43C)[C@@H]1CCC2=O
Temperature: 25 °C
Yield: 70 %

Procedure:
A mixture of 1,2β-methylenandrost-4-ene-3,17-dione (2.44 g), N-bromosuccinimide (2.33 g), benzoyl peroxide (0.060 g), and carbon tetrachloride (200 ml) are heated to reflux for 4 hours. After cooling to room temperature the precipitate is filtered off, the residue washed with carbon tetrachloride and the combined filtrates evaporated in vacuo. The residue is chromatographed on silica gel using benzene/ethyl ether to give pure 6β-bromo-1,2β-methylenandrost-4-ene-3,17-dione (2.16 g, 70%).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32]([C:34]([NH:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:35])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32]([C:34]([NH:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:35])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)c1ccc2c(c1)nc(CCCC)n2Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCNC(=O)c1ccc2c(c1)nc(CCCC)n2Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5-n-butylaminocarbonyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid