Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[CH3:10][C:11]1([CH3:20])[NH:17][C:16]([CH3:19])([CH3:18])[CH2:15][C:13](=[O:14])[CH2:12]1.C([Li])CCC.Cl>CCCCCC.CCOCC>[OH:8][CH:7]([CH:15]1[C:13](=[O:14])[CH2:12][C:11]([CH3:20])([CH3:10])[NH:17][C:16]1([CH3:19])[CH3:18])[C:4]1[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1ccc(C(O)C2C(=O)CC(C)(C)NC2(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 12g. of p-tolualdehyde, 15.5 g. of triacetone amine and 50 ml. of anhydrous ether was added dropwise 42.6g. of butyl lithium (as a 15% solution in n-hexane) at -50° to -60°C. under a nitrogen gas stream. After completion of the dropwise addition, the mixture was stirred at room temperature for 3 hours. Then, the reaction mixture was poured into 5% dilute hydrochloric acid with ice-cooling. The aqueous layer was separated and saturated with potassium carbonate. Then, the ether layer was separated and concentrated to yield crude crystalline mass. The mass was recrystallized from benzene to give the desired product as white crystals having a decomposition point of 160° - 161°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]([NH2:13])=[O:12])[CH2:7]1.[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21]N.Cl>O1CCCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]([NH:13][CH2:21][CH2:20][N:19]([CH3:23])[CH3:18])=[O:12])[CH2:7]1
Reactant: NC(=O)N1CCC(Oc2ccc(Cl)c(Cl)c2)C1
Reactant: CN(C)CCN
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)N1CCC(Oc2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Yield: 40.1 %

Procedure:
A stirred solution of 17.7 g (0.06 mole) of 3-(3,4-dichlorophenoxy)-1-pyrrolidinecarboxamide in 170 ml of tetrahydrofuran was treated by the rapid addition of 10.6 g (0.12 mole) of N,N-dimethylethylenediamine. The reaction was slightly exothermic and the mixture was stirred at ambient temperature over the weekend. Filtration removed some precipitated diamine hydrochloride, and the filtrate was concentrated in vacuo to give an oil, 23 g. The oil was treated with ethereal hydrogen chloride to give a granular solid which was recrystallized twice from acetone to give 4.6 g of pale green product, m.p. 143°-145° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[CH:18]=[C:17]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[O:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2.[OH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=O>>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[CH:18]=[C:17]([N:19]4[CH2:20][CH2:21][N:22]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][OH:26])[CH2:23][CH2:24]4)[O:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cc(N4CCNCC4)on3)ccc21
Reactant: O=CCCCCO
Product: CC1(C)CCC(C)(C)c2cc(-c3cc(N4CCN(CCCCCO)CC4)on3)ccc21

Procedure:
The preparation was carried out as already described via a reductive amination starting from 26 mg (0.05 mmol) of 1-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)isoxazol-5-yl]piperazine and 5 mg (0.05 mmol) of 5-hydroxypentanal. The product was purified by means of preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:21]=[C:20]2[C:10]([NH:11][CH:12]=[C:13]2[CH2:14][CH:15]([C:17]([OH:19])=[O:18])[NH2:16])=[CH:9][CH:8]=1.[CH3:22]O>>[CH3:22][O:18][C:17](=[O:19])[CH:15]([CH2:14][C:13]1[C:20]2[C:10](=[CH:9][CH:8]=[C:7]([O:6][CH3:5])[CH:21]=2)[NH:11][CH:12]=1)[NH2:16]
Reactant: COc1ccc2[nH]cc(CC(N)C(=O)O)c2c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C(N)Cc1c[nH]c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 73 %

Procedure:
Thionyl chloride (1.0 mL, 13.7 mmol) was added dropwise to a slurry of 5-methoxy-DL-tryptophan (2.0 g, 8.54 mmol) in anhydrous methanol (22 mL) at 0° C. under a nitrogen blanket. The resulting solution was warmed slowly to room temperature, stirred for 17 hours, then the solvent was removed under reduced pressure. The resulting residue was dissolved in water (20 mL), neutralized with saturated NaHCO3 (10 mL), and extracted twice with methylene chloride. The combined organic layers were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to provide 5-methoxy-DL-tryptophan methyl ester (Intermediate 4) as a light brown solid (1.55 g, 73%): 1H NMR (300 MHz, CDCl3): δ 7.93 (bs, 1H), 7.30-7.25 (m, 1H), 7.09-7.03 (m, 1H), 6.90-6.83 (m, 1H), 3.90-3.78 (m, 4H), 3.72 (s, 3H), 3.30-3.20 (m, 1H), 3.10-2.98 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([N+:27]([O-:29])=[O:28])=[C:21]([CH:26]=1)[C:22](=[O:25])[CH2:23]Br>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:23]=1[C:22](=[O:25])[C:21]1[CH:26]=[C:17]([Cl:16])[CH:18]=[CH:19][C:20]=1[N+:27]([O-:29])=[O:28]
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: O=C(CBr)c1cc(Cl)ccc1[N+](=O)[O-]
Product: CCOC(=O)n1c(C(=O)c2cc(Cl)ccc2[N+](=O)[O-])c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 5-chloro-2-nitrophenacyl bromide (Schofield, K.; and Simpson, J. C. E.; J. Chem. Soc., 1947, 1170-1174.). 1H-NMR (CDCl3) δ: 8.12 (1 H, d, J=1.8 Hz), 7.95 (1 H, d, J=8.4 Hz), 7.56-7.48 (3 H, m), 7.31 (1 H, dd, J=1.6, 8.4 Hz), 6.32 (2 H, br s), 3.99 (2 H, q, J=7.1 Hz), 1.09 (3 H, t, J=7.1 Hz).
Reaction SMILES: [CH:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2/[C:17](=[N:19]/[OH:20])/[NH2:18])(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CC[O:25][CH2:24][CH2:23]1.O.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>C(O)(=O)C>[C:24]([O:20]/[N:19]=[C:17](/[C@@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][N:11]1[S:8]([CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)(=[O:9])=[O:10])\[NH2:18])(=[O:25])[CH3:23]
Reactant: N/C(=N\O)[C@@H]1CCCCN1S(=O)(=O)CC1CCCCC1
Reactant: CN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)O/N=C(\N)[C@@H]1CCCCN1S(=O)(=O)CC1CCCCC1

Procedure:
The title compound was prepared by a similar method to Preparation 5 from (Z)-(2S)-1-[cyclohexylmethylsulfonyl]-N′2-hydroxy-2-piperidinecarboximidamide [see Preparation 28], acetic acid, N-methyl morpholine, hydroxybenzotriazole hydrate and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, to afford (Z)-(2S)-N′2-(acetyloxy)-1-[(cyclohexylmethyl)sulfonyl]-2-piperidinecarboximidamide as a colourless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C@@H:11]2[CH2:13][O:12]2)=[CH:7][CH:6]=1.[NH2:16][CH2:17][C@H:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]3[CH:37]=[CH:36][C:31]([C:32]([O:34]C)=[O:33])=[CH:30][CH:29]=3)[CH:24]=2)[O:19]1.[OH-].[Na+]>O1CCOCC1>[OH:12][C@H:11]([CH2:10][O:9][C:8]1[CH:14]=[CH:15][C:5]([CH2:4][CH2:3][O:2][CH3:1])=[CH:6][CH:7]=1)[CH2:13][NH:16][CH2:17][C@H:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]3[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:36][CH:37]=3)[CH:24]=2)[O:19]1
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)CC[C@H](CN)O3)cc1
Reactant: COCCc1ccc(OC[C@@H]2CO2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COCCc1ccc(OC[C@@H](O)CNC[C@H]2CCc3cc(-c4ccc(C(=O)O)cc4)ccc3O2)cc1
Temperature: 80 °C
Reaction time: 72 h
Yield: 10.5 %

Procedure:
To a solution of epoxide (Example 16, 0.25 mmol) in 2 mL of aqueous 1,4-dioxane (10% water) was added methyl 4-[(2R)-2-(aminomethyl)-3,4-dihydro-2H-chromen-6-yl]benzoate (40 mg, 0.13 mmol). The mixture was stirred at 80° C. for 72 hours and allowed to cool to room temperature. When ambient temperature was achieved, 1N aqueous sodium hydroxide (1 mL) was added to the solution at room temperature, and stirring continued for another 0.5 hour. The product was then purified by preparative HPLC (Gradient 0-70% Acetonitrile/0.1% aq. TFA) to obtain 6.7 mg of product (as a TFA salt). MH+492.4 (free base).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6](Cl)(=[O:9])[CH2:7][CH3:8].[Sn](Cl)(Cl)(Cl)Cl>C1C=CC=CC=1>[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:9])[CH2:7][CH3:8]
Reactant: c1ccsc1
Reactant: CCC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCC(=O)c1cccs1
Reaction time: 3 h
Yield: 71 %

Procedure:
The procedure for the Friedel-Crafts acylation of thiophene with propionyl chloride in the presence of tin tetrachloride is as follows. Tin tetrachloride (630 mg, 2.4 mmol) was added slowly to perfluorohexanes (FC-72, 3 mL) in a test tube (14 mm×105 mm) and then a mixed benzene solution (3 mL) of thiophene (168 mg, 2.0 mmol) and propionyl chloride (185 mg, 2.0 mmol) was slowly poured into the test tube. The tin tetrachloride layer in the bottom was stirred gently so as not to mix the three phases. which disappeared after 3 h. The benzene layer was decanted, washed with 10% HCl and H2O, dried over MgSO4, and concentrated. The residue was purified by short column chromatography (10 mm×40 mm) on silica gel with benzene to give 2-propionylthiophene in 71 % yield (200 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][O:35][CH:36]1[CH2:41][CH2:40][CH2:39][NH:38][CH2:37]1>>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:38]4[CH2:39][CH2:40][CH2:41][CH:36]([O:35][CH3:34])[CH2:37]4)[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: COC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N4CCCC(OC)C4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 3-methoxy-piperidine. ES-MS m/e (%): 484 (M+H+, 100).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[CH:17][CH:16]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:32]1([CH3:42])[C:33]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:35]=[CH:36][CH:37]=1>C(OCC)(=O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][S:38]([C:33]3[C:32]([CH3:42])=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:40])=[O:39])=[CH:19][CH:20]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)n1ncc(SCc2ccc(CCCCO)cc2)c(Cl)c1=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccccc1S(=O)(=O)OCCCCc1ccc(CSc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Reaction time: 2 h

Procedure:
To a 15 ml round bottom flask charged with 2-tert-butyl-4-chloro-5-(4-(4-hydroxybutyl)benzyl)thio-3(2H)-pyridazinone (0.15 g, 0.39 mmol) is added pyridine. Toluenesulfonyl chloride (88.9 mg, 0.42 mmol) is then added to it and the mixture stirred for 2 hours. The reaction mixture is diluted with ethyl acetate, washed with 5% copper sulfate solution and then with water and dried. After removing the solvent on the rotary evaporator the crude is purified by flash chromatography using ethyl acetate-hexanes as the eluting mixture.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:9]([C:10]([OH:12])=[O:11])[C:8]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1.CS(O[CH2:22][C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1)(=O)=O>>[CH3:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:9]([C:10]([O:12][CH2:22][C:23]3[NH:24][CH:25]=[CH:26][C:27]=3[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)=[O:11])[C:8]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: Cc1ccc(OC2C(C(=O)O)C2(C)C)cc1
Reactant: CS(=O)(=O)OCc1[nH]ccc1Cc1cccc(F)c1
Product: Cc1ccc(OC2C(C(=O)OCc3[nH]ccc3Cc3cccc(F)c3)C2(C)C)cc1

Procedure:
Following the procedure of Example 2, 3-(4-methylphenoxy)-2,2-dimethylcyclopropanecarboxylic acid is reacted with 3-(3-fluorobenzyl)-pyrrolylmethyl methanesulfonate to yield 3-(3-fluorobenzyl)-pyrrolylmethyl 3-(4-methylphenoxy)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[C:17]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[N:18][C:19]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:20][C:9]1=2)(=O)=O.[NH:31]1[CH:35]=[CH:34][N:33]=[CH:32]1>C1(C)C(C)=CC=CC=1>[N:31]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3[C:17]([N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[N:18][C:19]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:20][C:9]2=3)[CH:35]=[CH:34][N:33]=[CH:32]1
Reactant: CS(=O)(=O)OCCn1c2ccccc2c2c(N3CCCC3)nc(N3CCCC3)nc21
Reactant: c1c[nH]cn1
Solvent: Cc1ccccc1C
Product: c1ccc2c(c1)c1c(N3CCCC3)nc(N3CCCC3)nc1n2CCn1ccnc1

Procedure:
A mixture of 9-(2-methanesulfonyloxyethyl)-2,4-di-1-pyrrolidinyl-9H-pyrimido[4,5-b]indole (IX, EXAMPLE4, 0.64 g), imidazole (1.02 g) and xylene (15 mL) is heated at reflux for 3 hr. The xylene is then removed under reduced pressure, and the residue is partitioned between methylene chloride and aqueous sodium bicarbonate. The organic phase is washed with saline, dried over sodium sulfate and concentrated. Chromatography (silica gel, 4% methanol/methylene chloride) gives the title compound, mp=181°-183°; NMR (CDCl3) 7.88, 7.40, 7.14-7.09, 7.01-6.97, 6.82, 4.56-4.54, 4.44-4.42, 3.92, 3.63 and 1.99 δ.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([N:6]([CH3:15])[C:7](=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([NH2:18])[CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH3:15])[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[N:18][C:4]=2[CH:3]=1
Reactant: CN(C(=O)c1ccccc1)c1ccc(Br)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: Cn1c(-c2ccccc2)nc2cc(Br)ccc21
Yield: 87.1 %

Procedure:
7.8 g (26 mmol) of 4′-bromo-N-methyl-2′-aminobenzanilide was suspended in 50 mL of xylene. After the addition of 1.5 g (7.7 mmol) of p-toluenesulfonic acid monohydrate, the mixture was heat refluxed for 7 hours. After completion of the reaction, the mixture was filtered. The resulting solid was dissolved in methylene chloride, washed with a 10% potassium carbonate aqueous solution and a saturated sodium chloride solution, and dried over magnesium sulfate. The solvent was then evaporated under reduced pressure. An organic substance was also collected from the filtrate by the same washing method. The solid and the organic substance were purified by silica gel column chromatography to obtain 6.5 g of 5-bromo-1-methyl-2-phenyl-1H-benzimidazole as a white crystal (yield: 89%).
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9].I[CH2:22][CH2:23][CH2:24][C:25]([F:37])([F:36])[C:26]([F:35])([F:34])[C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29].O>O1CCCC1>[CH2:3]([C:10]([CH2:22][CH2:23][CH2:24][C:25]([F:36])([F:37])[C:26]([F:34])([F:35])[C:27]([F:32])([F:33])[C:28]([F:29])([F:31])[F:30])([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCI
Reactant: C=CCCCCCC(C(=O)OCC)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCCCCC(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.6 %

Procedure:
60% sodium hydride (0.54 g, 13.5 mmol) was added to a solution of diethyl 2-(6-heptenyl)malonate (3.0 g, 11.7 mmol) in tetrahydrofuran (30 ml) followed by stirring for 30 minutes at room temperature. 1-Iodo-4,4,5,5,6,6,7,7,7-nonafluoroheptane (5.45 g, 14.04 mmol) was added to the mixture followed by stirring for 12 hours at room temperature. After the reaction was completed, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/25) to give diethyl 2-(6-heptenyl)-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)malonate (6.14 g, quantitative) as a colorless oil.
Reaction SMILES: [BrH:1].[Br:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:11])=[C:7]([CH:10]=1)[CH2:8]O>>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:11])=[C:7]([CH:10]=1)[CH2:8][Br:1]
Reactant: OCc1cc(Br)ccc1Cl
Reactant: Br
Product: Clc1ccc(Br)cc1CBr
Temperature: 70 °C

Procedure:
An aqueous hydrobromide acid solution (2 M, 2 ml) was added to 5-bromo-2-chlorobenzyl alcohol (Aldrich Co., 1 g), and the mixture was stirred with heating at 70° C. for 1 hr. After completion of the reaction, the mixture was extracted three times with diethyl ether. The organic layer was dried and the solvent was evaporated under reduced pressure to give 5-bromo-2-chlorobenzylbromide (1.3 g).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([S:30](Cl)(=[O:32])=[O:31])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>CN(C)C=O>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([S:30]([N:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:9]2=[O:10])(=[O:31])=[O:32])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: O=c1[nH]c(-c2ccccc2)cc2ccccc12
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)n2c(-c3ccccc3)cc3ccccc3c2=O)cc1OC
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 46.7 %

Procedure:
A solution of 3-phenylisocarbostyril (0.1 g) in N,N-dimethylformamide (2 ml) was cooled to 0° C. under an inert atmosphere. Sodium hydride (0.019 g) was added and the resulting mixture stirred at 0° C. for 5 minutes. 3,4-Dimethoxybenzenesulphonylchloride (0.107 g) was added over a 3 minute period, with continued stirring at 0° C. for a further 15 minutes. The reaction mixture was warmed to room temperature and stirred for 24 hours. The DMF was evaporated under high vacuum and the residue partitioned between ethyl acetate (2×12 ml) and water (12 ml). The combined organic phases were dried over magnesium sulphate and concentrated in vacuo to yield a yellow oil. Purification using column chromatography eluting with 50% ethyl acetate in hexane yielded an oil which was crystallized from ethyl acetate/hexane to furnish the title compound as white crystals (0.089 g).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].[C:7]([OH:11])([CH3:10])([CH3:9])[CH3:8]>CCOCC>[C:7]([O:11][C:1](=[O:5])[C:2]([Cl:4])=[O:3])([CH3:10])([CH3:9])[CH3:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (12.4 μL. 0.1 mmol) and t-butyl alcohol (13.1 μL) were combined in ether (0.3 mL) under nitrogen at 0° C. The resulting mixture was stirred for 30 minutes at room temperature. The solvent was evaporated under vacuum to form chloro-oxo-acetic acid t-butyl ester, which was then dissolved in DCM (0.7 mL) and combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methylpentanoic acid ethyl ester (33.4 mg, 98 μmol). Et3N (43.6 μL,) at 0° C. was added and the resulting mixture was stirred for 30 minutes at room temperature. The solvent were evaporated and the residue was dissolved in 1:1 TFA:DCM and stirred for 1 hour. AcOH was added and the product was purified by preparative HPLC to yield the title compound (7 mg, purity 95%). MS m/z [M+H]+ calc'd for C23H27NO6, 414.18. found 414.4.
Reaction SMILES: [C:1]1([CH:7]([NH2:10])[C:8]#[CH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][CH2:12][CH2:13][N:14]=[C:15]=[O:16].C(N(CC)CC)C>C(Cl)Cl>[Cl:11][CH2:12][CH2:13][NH:14][C:15]([NH:10][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]#[CH:9])=[O:16]
Reactant: C#CC(N)c1ccccc1
Reactant: O=C=NCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CC(NC(=O)NCCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 180 mg of 1-phenyl-prop-2-ynylamine (Formula 28) in 5 mL of CH2Cl2 were added 0.1 mL of 2-chloroethyl isocyanate and 0.2 mL of triethylamine. After the mixture was stirred at room temperature for 2 hours, the solvent was removed. Column chromatography (50% ethyl acetate/hexane) gave 153 mg of 1-(2-chloro-ethyl)-3-(1-phenyl-prop-2-ynyl)-urea (Formula 29) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.46 (m, 1H), 3.45-3.49 (m, 2H), 3.52-3.54 (m, 2H), 5.40-5.41 (m, 1H), 5.55-5.57 (m, 1H), 5.74-5.76 (m, 1H), 7.27-7.35 (m, 3H), 7.48-7.50 (m, 2H).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:32])([CH3:31])[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[N:12]=[C:11]2[Sn](CCCC)(CCCC)CCCC)([CH3:4])([CH3:3])[CH3:2].[C:33]([NH:37][C:38]([C:40]1[C:48]2[C:43](=[N:44][CH:45]=[C:46](Br)[N:47]=2)[N:42]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[CH:41]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34]>CN(C=O)C.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.[Cu]I>[C:33]([NH:37][C:38]([C:40]1[C:48]2[C:43](=[N:44][CH:45]=[C:46]([C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[C:8]([C:7]([CH3:32])([CH3:31])[O:6][SiH2:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=4)[N:13]([CH3:17])[N:12]=3)[N:47]=2)[N:42]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[CH:41]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(C(C)(C)O[SiH2]C(C)(C)C)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cc(C(C)(C)O[SiH2]C(C)(C)C)ccc21
Temperature: 90 °C
Yield: 74 %

Procedure:
To a solution of 5-(tert-butyl-dimethyl-silanyloxymethyl)-1-methyl-3-tributylstannanyl-1H-indazole (265 mg, 0.47 mmol) and 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (100 mg, 0.23 mmol) in DMF (2 mL) were added Pd(PPh3)4 (14 mg, 0.012 mmol) and copper(I) iodide (9 mg, 0.047 mmol). The reaction mixture was heated at 90° C. for 1 h then cooled to room temperature, quenched with water and extracted with EtOAc (2×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated. The residue was absorbed on silica gel and chromatographed with 20% to 50% EtOAc/hexanes to isolate 106 mg (73%) of 2-[5-(tert-butyldimethyl-silanyloxymethyl)-1-methyl-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as a beige solid.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[C:12]2[O:13][CH2:14][C:15]3[S:19][C:18]([SH:20])=[N:17][C:16]=3[C:11]=2[CH:10]=[CH:9][CH:8]=1)C.Br[CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([CH:23]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[S:20][C:18]2[S:19][C:15]3[CH2:14][O:13][C:12]4[C:7]([O:6][CH2:5][C:4]([OH:3])=[O:21])=[CH:8][CH:9]=[CH:10][C:11]=4[C:16]=3[N:17]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)COc1cccc2c1OCc1sc(S)nc1-2
Reactant: BrC(c1ccccc1)c1ccccc1
Product: O=C(O)COc1cccc2c1OCc1sc(SC(c3ccccc3)c3ccccc3)nc1-2
Yield: 17 %

Procedure:
Using ethyl[(2-mercapto-4H-[1]benzopyrano[4,3-d]thiazol-6-yl)oxy]acetate and bromodiphenylmethane, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 17%.