Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[O:6][C@@H:5]2[C:7]([CH2:12][O:13][C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:8][C@@H:9]([CH:10]=[CH2:11])[C@@H:4]2[O:3]1.CC(C)=[O:36]>CC1(C)OO1>[CH3:1][C:2]1([CH3:33])[O:6][C@@H:5]2[C:7]([CH2:12][O:13][C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:8][C@@H:9]([C@H:10]3[CH2:11][O:36]3)[C@@H:4]2[O:3]1
Reactant: CC(C)=O
Reactant: C=C[C@@H]1C=C(COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]2OC(C)(C)O[C@@H]12
Agent: CC1(C)OO1
Product: CC1(C)O[C@H]2[C@H]([C@H]3CO3)C=C(COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2O1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
(3aS,4R,6aR)-2,2-dimethyl-6-(trityl oxymethyl)-4-vinyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxole (1-3) (1.4 g, 3.19 mmol, 1.0 equiv) was dissolved in a freshly prepared solution of DMDO (dimethyl dioxirane) in acetone (37.7 mL, 0.076 M, 0.9 equiv). The resulting mixture was stirred at 0° C. for 4 hours, then concentrated and purified via flash chromatography on silica gel column (ethyl acetate/hexanes) to yield (3aS,4S,6aR)-2,2-dimethyl-4-((S)-oxiran-2-yl)-6-(trityloxymethyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxole (1-5). 1H NMR (500 MHz, CDCl3) δ 7.21-7.47 (m, 15H), 5.83 (2 s, 1H), 4.99 (t, 1H, J=5 Hz), 4.63 (t, 1H, J=5 Hz), 3.86 (d, 1H, J=14 Hz), 3.67 (d, 1H, J=14 Hz), 2.85-2.97 (m, 2H), 2.77 (m, 1H), 2.60 (m, 1H), 1.35 (s, 3H), 1.32 (s, 3H).
Reaction SMILES: [Cl:1][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH3:20][CH2:21][N:22]([CH2:31][CH3:32])[CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]1>ClCCl.CO>[ClH:1].[CH3:32][CH2:31][N:22]([CH2:21][CH3:20])[CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:26]1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: CCN(CC)CCC1CCCNC1
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)CCC1CCCN(C(=O)N2c3ccccc3C(=O)Nc3cccnc32)C1
Product: Cl
Yield: 38 %

Procedure:
Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 3-[2-(methylethylmethylamino)ethyl]piperidine in a yield of 38% of theory. Colourless crystals, m.p. 196°-198° C. (D.), Rf 0.21 (Merck DC ready made TLC plates, silica gel 60 F254 ; eluant: dichloromethane/methanol/conc. ammonia 90/10/1, v/v/v).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:20])([F:19])[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8]2.Cl[CH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1>CN(C=O)C.C1COCC1.C(OCC)(=O)C>[F:20][C:4]([F:19])([F:3])[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1)[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8]2
Reactant: ClCc1nccs1
Reactant: CCOC(=O)c1cc2cc(C(F)(F)F)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(C(F)(F)F)ccc2n1Cc1nccs1
Temperature: 50 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
To a suspension of 87 mg (1.983 mmol) of sodium hydride (55%) in 10 mL of dry DMF, maintained under an inert atmosphere, are added dropwise, at room temperature, 340 mg (1.322 mmol) of ethyl 5-trifluoromethyl-1H-indole-2-carboxylate in 5 mL of dry DMF. The reaction mixture is stirred at 50° C. for 1 hour. A solution of 265 mg (1.983 mmol) of 2-(chloromethyl)thiazole, prepared according to the protocol described in the preceding step, in 10 mL of THF is then added dropwise, at 0° C. The reaction mixture is then stirred for 20 hours at room temperature, and then diluted with 100 mL of ethyl acetate. The aqueous phase is extracted with 30 mL of ethyl acetate. The combined organic phases are washed successively with saturated aqueous sodium hydrogen carbonate solution, with water, with saturated aqueous sodium chloride solution and then dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil is purified by chromatography on a column of silica, eluting with a mixture of heptane and ethyl acetate. 265 mg of the expected product are isolated in the form of a colourless oil.
Reaction SMILES: Cl.[OH:2]/[N:3]=[C:4](/[C:10]1[N:11]=[C:12]([NH:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:13][CH:14]=1)\[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:42][F:43]>CS(C)=O.C(Cl)Cl>[F:43][CH2:42][O:2]/[N:3]=[C:4](/[C:10]1[N:11]=[C:12]([NH:15][C:16]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:13][CH:14]=1)\[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: FCBr
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)/C(=N\OCF)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
Ethyl (Z)-2-hydroxyimino-2-(2-triphenylmethylaminothiazol-4-yl)acetate, hydrochloride salt (8.7 g) was stirred with potassium carbonate (15.35 g) in dimethyl sulphoxide (30 ml) under nitrogen at 21° . Bromofluoromethane (ca 3 g) was added. The nitrogen flow was stopped and the stirring continued for two hours. The mixture was poured into an ice-water mixture with stirring and the solid was collected by filtration and washed with water. The solid was dissolved in methylene chloride and the organic layer was separated and dried with magnesium sulphate. Evaporation gave a foam. This was dissolved in methylene chloride and pre-absorbed onto Kieselgel 60 (50 g). This was added to the top of a column of similar silica (125 g) set up in 10% ethyl acetate in cyclohexane. The column was eluted successively with 10%, 20% and 33% ethyl acetate in cyclohexane. After combination of appropriate fractions, evaporation gave the title compound (8.06 g) as a foam; λmax (EtOH) 302 nm (E1 cm1% 92), λinfl include 227.5 nm (E1 cm1% 546) and 259 nm (E1 cm1% 221), νmax (CHBr3) 3400 (NH), 1739 (ester) and 1533 cm-1 (C=N).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: Cc1cccc2sc(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc2sc(Sc3ccc4c(c3)CC[C@H]3N(C)C(=O)CC[C@]43C)nc12
Yield: 42.5 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4-methylbenzothiazole (84 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 66 mg (43%) of the title compound as an amorphous solid. mp 134°-142° FDMS: m/e =408. α[D]589 =+62.80 (c=0.74, chloroform).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.CS(Cl)(=O)=O.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:17]([NH:24][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: OCCCSc1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: c1ccc(CNCCCSc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 161.3 %

Procedure:
In 150 ml of methylene chloride were dissolved 5.22 g (30.8 mmol) of 4-(3-hydroxypropylthio)pyridine and 5.16 ml (37.0 mmol) of triiethylamine, methanesulfonyl chloride [2.86 ml (37.0 mmol)] was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried. Then the solvent was distilled off. 2.62 ml (24.0 mmol) of benzylamine was added to the residue, and the mixture was heated at 80° C. for 3 hours. After cooling, the mixture was purified by column chromatography (eluent: chloroform/methanol=25:1) to obtain 10 g of the desired compound (yield: 16.1%, yellow oil).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=2)[C:12]#[N:13])=[CH:4][CH:3]=1.[CH2:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH3:18]>CS(C)=O>[CH2:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=3)[C:12]#[N:13])=[CH:4][CH:3]=2)[CH2:21][CH2:20]1)[CH3:18]
Reactant: CCN1CCNCC1
Reactant: N#Cc1ccc(-c2ccc(F)cc2)[nH]c1=O
Solvent: CS(C)=O
Product: CCN1CCN(c2ccc(-c3ccc(C#N)c(=O)[nH]3)cc2)CC1

Procedure:
From 21.4 g. of 6-(p-fluorophenyl)-1,2-dihydro-2-oxonicotinonitrile and 22.8 g. of N-ethylpiperazine in 200 ml. of dimethyl sulfoxide, there is obtained 6-[p-(4-ethyl-1-piperazinyl)phenyl]-1,2-dihydro-2-oxonicotinonitrile; m.p. 283°-285° (dec.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[CH:12][C:11]=2[F:23])=[C:6]([F:24])[CH:5]=[CH:4][C:3]=1[OH:25].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].O>CC(C)=O>[Cl:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[CH:12][C:11]=2[F:23])=[C:6]([F:24])[CH:5]=[CH:4][C:3]=1[O:25][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1Cl
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
To a solution of 2-chloro-4-fluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenol (144 mg, 0.40 mmol, 1.0 eq) in acetone (3 mL) was added Cs2CO3 (193.5 mg, 0.59 mmol, 1.5 eq). The reaction mixture was stirred for 30 min, then ethyl 2-bromoacetate (79.3 mg, 0.48 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for 1 h and the resulting mixture poured into water and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered, and evaporated in vacuo. The residue obtained was purified by column chromatography (EtOAc:petroleum ether, 1:20 to 1:10) to give the title compound as an oil (155 mg, 87%).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:27])=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][C:6]1[C:7]([C:21](O)=[O:22])=[C:8]2[N:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:12]=[CH:11][CH:10]=[CH:9]2.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:21]([C:7]2[C:6]([CH2:5][C:4]3[CH:24]=[CH:25][CH:26]=[C:2]([F:1])[C:3]=3[CH3:27])=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[CH:12]3)=[O:22])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: Cc1c(F)cccc1Cc1c(C(=O)O)c2ccccn2c1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1c(F)cccc1Cc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccccn2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
To a solution of the crude compound obtained in step 4 (125 mg, 0.35 mmol), 1-tert-butoxycarbonyl-piperazine (67.9 mg, 0.37 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (73.4 mg, 0.38 mmol) and 1-hydroxybenzotriazole (61.3 mg, 0.40 mmol) in DMF (2 ml) was added N-methyl-morpholine (0.115 ml, 1.04 mmol). The mixture was stirred at room temperature overnight, then quenched with water and extracted with EA. The organic layer was separated, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (HEP/EA) to give 158 mg of the title compound.
Reaction SMILES: C(N1CCN(C2N=C(Br)C=C3C=CSC=23)CC1)C.[CH2:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:28]=[C:29]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([CH3:50])([CH3:49])[CH2:43][CH2:44][O:45]C(=O)C)=[CH:38][CH:37]=3)[CH:30]=[C:31]3[CH:35]=[CH:34][S:33][C:32]=23)[CH2:23][CH2:22]1)[CH3:20].[ClH:51]>C(OCC)(=O)C>[ClH:51].[ClH:51].[CH2:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:28]=[C:29]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([CH3:49])([CH3:50])[CH2:43][CH2:44][OH:45])=[CH:38][CH:37]=3)[CH:30]=[C:31]3[CH:35]=[CH:34][S:33][C:32]=23)[CH2:23][CH2:22]1)[CH3:20]
Reactant: CCN1CCN(c2nc(-c3ccc(C(C)(C)CCOC(C)=O)cc3)cc3ccsc23)CC1
Agent: CCN1CCN(c2nc(Br)cc3ccsc23)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCN1CCN(c2nc(-c3ccc(C(C)(C)CCO)cc3)cc3ccsc23)CC1
Reaction time: 2 h

Procedure:
The resulting compound and 7-(1-ethylpiperazin-4-yl)-5-bromothieno[2,3-c]pyridine (0.20 g) were reacted in the same manner as in Example 300-4, to give a reaction solution containing 7-(4-ethylpiperazin-1yl)-5-[4-(3-acetoxy-1,1-dimethylpropyl)phenyl]thieno[2,3-c]pyridine. Ethyl acetate and 2N hydrochloric acid were added to the reaction solution, and the resulting insoluble matters were filtered off. The aqueous layer was separated, while the organic layer was extracted with 2N hydrochloride acid. The aqueous layers were combined and washed with ethyl acetate twice. The pH of the resulting solution was adjusted to pH 10 by adding a 8N aqueous solution of sodium hydroxide thereto, and the solution was extracted with ethyl acetate twice. The extract was washed with brine, dried over magnesium sulfate, and the solvent was evaporated. Methanol (10 ml) was added to the resulting residue and dissolved, followed by the addition of a 8N aqueous solution of sodium hydroxide (0.75 ml). The resulting solution was left as it was at room temperature for 2 hr, and then the solvent was evaporated. Water was added to the resulting residue, and then the mixture was extracted with ethyl acetate thrice. The extract was washed with brine, dried over magnesium sulfate, and the solvent was evaporated. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate/n-hexane system), to give 0.16 g of the free compound of the title compound as a colorless viscous oil.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](Cl)=[O:5].[CH2:9](N(CC)CC)C.[Br:16][C:17]1[CH:23]=[C:22]([C:24](F)(F)F)[C:20]([NH2:21])=[C:19](Cl)[CH:18]=1.O>C(#N)C>[Br:16][C:17]1[CH:23]=[C:22]([CH3:24])[C:20]([NH:21][C:4](=[O:5])[CH2:3][C:2]([CH3:8])([CH3:7])[CH3:1])=[C:19]([CH3:9])[CH:18]=1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Nc1c(Cl)cc(Br)cc1C(F)(F)F
Solvent: O
Solvent: CC#N
Product: Cc1cc(Br)cc(C)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
3,3-dimethylbutanoyl chloride (3.37 g, 3.5 mL, 25 mmol) and triethylamine (2.53 g, 3.5 mL, 25 mmol) were added to a solution of 4-bromo-2-chloro-6-(trifluoromethyl)aniline (5.0 g, 25 mmol) in acetonitrile (30 mL). The reaction mixture was stirred at room temperature for 4 hours. Water was added to the mixture, and the precipitate formed collected to give the title compound as a powder (7.46 g, 100% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11](=[O:15])[C@@H:12]([CH3:14])[NH2:13])[CH3:9].C(N)C1C=CC=CC=1.[CH2:24]([O:34][CH2:35][CH2:36][C:37](Cl)=[O:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].COCCCCCCCCCCCC(Cl)=O>>[CH2:24]([O:34][CH2:35][CH2:36][C:37]([NH:13][C@@H:12]([C:11]([O:10][CH2:8][CH3:9])=[O:15])[CH3:14])=[O:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCOCCC(=O)Cl
Reactant: CCOC(=O)[C@@H](C)N
Agent: COCCCCCCCCCCCC(=O)Cl
Solvent: NCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCOCCC(=O)N[C@H](C)C(=O)OCC

Procedure:
The title compound is prepared by the method of Example 14 using an equivalent amount of D-alanine ethyl ester trifluoroacetate [the title product of Example 33] as a reactant instead of benzylamine, and using 3-decyloxypropanoyl chloride [the title product of Example 98] as a reactant instead of 12-methoxy-1-dodecanoyl chloride [the title product of Example 11].
Reaction SMILES: ClC1C=C(C(Cl)=O)C=C(Cl)C=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[C:29]([F:34])[CH:28]=1.[Cl:35][C:36]1[CH:37]=[C:38]([C:43]([N:45]=[C:46]=[S:47])=[O:44])[CH:39]=[C:40]([Cl:42])[CH:41]=1>C1(C)C=CC=CC=1.C(O)C>[Cl:35][C:36]1[CH:37]=[C:38]([C:43]([N:45]=[C:46]=[S:47])=[O:44])[CH:39]=[C:40]([Cl:42])[CH:41]=1.[Cl:35][C:36]1[CH:37]=[C:38]([CH:39]=[C:40]([Cl:42])[CH:41]=1)[C:43]([NH:45][C:46]([NH:31][C:30]1[CH:32]=[CH:33][C:27]([O:26][C:17]2[C:16]3[C:21](=[CH:22][C:23]([O:24][CH3:25])=[C:14]([O:13][CH3:12])[CH:15]=3)[N:20]=[CH:19][CH:18]=2)=[CH:28][C:29]=1[F:34])=[S:47])=[O:44]
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(Cl)c1cc(Cl)cc(Cl)c1
Agent: O=C(N=C=S)c1cc(Cl)cc(Cl)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cc(Cl)cc(Cl)c4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
3,5-Dichloro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3,5-dichloro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3,5-dichloro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (51 mg, yield 64%). Mass spectrometry value (ESI-MS, m/z): 547 (M++1)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].O>ClCCl>[CH3:16][S:17]([O:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)(=[O:19])=[O:18]
Reactant: OCc1ccncc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccncc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Pyridin-4-ylmethanol (4.0 g, 37 mmol) was dissolved in dichloromethane (50 mL), and triethylamine (11.21 g, 111 mmol) was added to the reaction mixture. The solution was cooled to 0° C. and methanesulfonyl chloride (MsCl) (6.3 g, 55.5 mmol) was added slowly. After the addition was complete, the reaction was stirred at 0° C. for 15 min and then stirred at room temperature for 2 hours. Water was slowly added and the solution was extracted with dichloromethane. The organic layer was washed with brine, and dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in methanol, and activated charcoal was added. After the mixture was stirred for 1 hour the mixture was filtered through a plug of celite and concentrated in vacuo to afford pyridine-4-ylmethyl methanesulfonate (49).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:32][C@H:33]([NH2:36])[CH2:34][CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(#N)C>[C@@H:33]([NH:36][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])[CH:19]=1)=[O:22])([CH2:34][CH3:35])[CH3:32]
Reactant: CC[C@H](C)N
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (50 mg, 0.11 mmol), (S)-butan-2-amine (9 mg, 0.12 mmol), and HATU (45 mg, 0.12 mmol). Then added acetonitrile (1 mL) followed by N,N-diisopropylethylamine (0.09 mL, 0.55 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water. The mixture was extracted with ethyl acetate (3×). The organic layers were combined, dried over Na2SO4, and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/heptanes (gradient: 0-50% EtOAc) to afford 40 mg (71%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-sec-butyl)-amide as a white solid. [M+Na]+=519.
Reaction SMILES: C[O:2][C:3](=[O:37])[C@H:4]([CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)[NH:5][C:6](=[O:26])[C@H:7]([C@H:22]([CH2:24][CH3:25])[CH3:23])[NH:8][S:9]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10].C1COCC1.[OH-].[K+].Cl>O.CO>[C:12]1([S:9]([NH:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:37])=[O:2])[CH2:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][CH:29]=2)=[O:26])[C@H:22]([CH2:24][CH3:25])[CH3:23])(=[O:11])=[O:10])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CC[C@H](C)[C@H](NS(=O)(=O)c1cccc2ccccc12)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC[C@H](C)[C@H](NS(=O)(=O)c1cccc2ccccc12)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 0 °C
Reaction time: 20 h
Yield: 98.3 %

Procedure:
To an ice-cooled mixture of N-(1-naphthylsulfonyl)-(L)-isoleucyl-(L)-tryptophan methyl ester (6.9 g) and THF (40 ml)-methanol (20 ml) was added dropwise a solution of KOH (1.5 g) in water (10 ml). After stirring at 0° C. for 20 hours, the reaction mixture was acidified with 1N HCl (35 ml) with ice-cooling, diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with brine and dried (MgSO4). The organic solvent was evaporated off to yield N-(1-naphthylsulfonyl)-(L)-isoleucyl-(L)-tryptophan (6.6 g, 98%) as crystals. Melting point: 167-168° C.