Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[N:16]1([C:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=3)[CH2:4][CH:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C1CCNC1
Reactant: N#Cc1ccc(N2CCC(=O)CC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: N#Cc1ccc(N2CC=C(N3CCCC3)CC2)cc1

Procedure:
A solution of 24 g (0.1199 mol) of the compound of (B), 15 ml (12.78 g/0.1796 mol) of pyrrolidine, 240 mg of p-toluenesulfonic acid, and 100 ml of benzene is stirred at reflux with the azeotropic removal of water for 6 hours. After cooling, the resulting precipitate is collected and triturated with ethyl ether to afford 20 (66%) of title compound: m.p. 126°-129° C.; IR (KBr) 2200, 1635, and 1600 cm-1 ; NMR (CDCl3) δ7.48 (d, 2H), 6.7 (d, 2H), 4.3-4.1 (m, 1H) 3.95-3.45 (m, 4H), 3.2-2.85 (m, 4H) 2.65-2.25 (m, 2H), and 1.95-1.75 (m, 4H).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([NH:28][C@@H:29]2[C:35](=[O:36])[N:34]([CH2:37][C:38]([O:40]C(C)(C)C)=[O:39])[C:33]3[CH:45]=[CH:46][CH:47]=[CH:48][C:32]=3[S:31][CH2:30]2)[C:23]([O:25]CC)=[O:24])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.Br.C(O)(=O)C.C(OCC)C>C(O)(=O)C>[C:23]([C@@H:22]([NH:28][C@@H:29]1[C:35](=[O:36])[N:34]([CH2:37][C:38]([OH:40])=[O:39])[C:33]2[CH:45]=[CH:46][CH:47]=[CH:48][C:32]=2[S:31][CH2:30]1)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)([OH:25])=[O:24]
Reactant: CCOC(=O)[C@H](CCCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C(O)CN1C(=O)[C@@H](N[C@@H](CCCCCC2CCNCC2)C(=O)O)CSc2ccccc21
Reaction time: 1.5 h
Yield: 70.3 %

Procedure:
In 1 ml of acetic acid is dissolved 0.9 g of tert-butyl 3(R)-[6-(1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylhexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, and 2 ml of 30% hydrogen bromide-acetic acid solution is added to the solution, followed by allowing the mixture to stand at room temperature for 1.5 hours. Ethyl ether (200 ml) is added to the reaction solution, which is then allowed to stand. The supernatant liquid is decanted, and the precipitate is dissolved in 30 ml of 1N aqueous sodium hydroxide solution, followed by allowing the solution to stand at room temperature for 30 minutes. The solution is neutralized by adding 3 ml of acetic acid, and purified by MCI-gel chromatography (water:methanol=1:2). The eluent is concentrated under reduced pressure, and the residue is lyophilized to give 0.43 g of 3(R)-[1(S)-carboxy-6-(4-piperidyl)hexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:13]=1.[Br:14]Br.O>C(O)(=O)C>[Br:14][CH:8]1[C:7](=[O:12])[C:6]2[CH:13]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[S:11][CH2:10][CH2:9]1
Reactant: O=C1CCCSc2ccc(F)cc21
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2cc(F)ccc2SCCC1Br
Reaction time: 4 h

Procedure:
7-Fluoro-2,3,4,5-tetrahydro-1-benzothiepin-5-one (1 equivalent) was also dissolved in glacial acetic acid and stirring continued at room temperature. Bromine (2.5 equivalents) was added dropwise and stirring continued at room temperature for 4 hours. Water was added to the reaction mixture was then extracted with 2×25 ml ethyl acetate. The combined ethyl acetate extracts were washed with water, saturated sodium bicarbonate, and water. The combined extract was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a solid which was recrystallized from the ethyl acetate/hexane 1:1 v/v to afford 4-bromo-7-fluoro-2,3,4,5-tetrahydro-1-benzothiepin-5-one: 1H NMR (CDCl3) δ 7.55 (dd, 1H, J=2.7, 9.0 Hz), 7.44 (dd, 1H, J=8.7, 5.1 Hz), 7.11 (Apparent dt, 1H, J=2.7, 4.8 Hz), 5.34 (dd, 1H, J=5.7, 10.2 Hz), 3.20-2.50 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].Cl[C:19]1[N:26]=[CH:25][CH:24]=[CH:23][C:20]=1[C:21]#[N:22].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:21]([C:20]1[C:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH3:17])=[N:26][CH:25]=[CH:24][CH:23]=1)#[N:22]
Reactant: N#Cc1cccnc1Cl
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCCC1Cc1c[nH]c2ccc(Nc3ncccc3C#N)cc12
Temperature: 110 °C
Yield: 32 %

Procedure:
(R)-5-Amino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole and 2-chloronicotinonitrile were used. Sodium carbonate were used as base. N,N-dimethylformamide was used as solvent, and the reaction was heated at 110° C. for 20 hours. Column chromatography afforded the title compound (32%) as an orange amorphous solid: Rf =0.4 in 9:1:0.1 [methylene chloride/methanol/ammonium hydroxide]; 13C NMR (CDCl3) δ157.7, 152.7, 141.7, 134.2, 129.8, 128.1, 123.1, 122.2, 118.7, 116.8, 113.6, 113.2, 111.5, 102.2, 66.6, 57.5, 40.8, 31.5, 30.0, 21.9; FAB HRMS calculated for [C20H21N5.H]332.2073, found 332.1871.
Reaction SMILES: [F:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]#[C:10][CH2:11][CH2:12][NH:13][CH3:14])[CH:6]=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:17]=1[C:18](Cl)=[O:19]>>[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:17]=1[C:18]([N:13]([CH2:12][CH2:11][C:10]#[C:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][F:1])[N:8]=1)[CH3:14])=[O:19]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: CNCCC#Cc1cccc(CF)n1
Product: CN(CCC#Cc1cccc(CF)n1)C(=O)c1c(Cl)cccc1Cl
Yield: 5.4 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from 4-(6-(fluoromethyl)pyridin-2-yl)-N-methylbut-3-yn-1-amine (180 mg, 0.93 mmol) and 2,6-dichlorobenzoyl chloride (255 mg, 1.22 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 18.5 mg of 2,6-dichloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-N-methylbenzamide as a yellow oil (Yield: 5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.I[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:17]
Reactant: CCOC(=O)CI
Reactant: OCCc1ccc(Cl)cc1
Agent: [Ag+]
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=S(=O)([O-])C(F)(F)F
Product: CCOC(=O)COCCc1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 78.1, 2-(4-chloro-phenyl)-ethanol was reacted with ethyl iodoacetate in the presence of silver trifluoromethanesulfonate and 2,6-di-tert-butylpyridin to give [2-(4-chloro-phenyl)-ethoxy]-acetic acid ethyl ester as colorless liquid. MS: m/e=243.2 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[C:4]([Cl:12])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](I)[CH3:20].O>CN(C)C=O>[CH2:19]([O:9][C:8]([C:7]1[C:2]([Cl:1])=[N:3][C:4]([Cl:12])=[CH:5][C:6]=1[CH3:11])=[O:10])[CH3:20]
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C)cc(Cl)nc1Cl
Reaction time: 18 h
Yield: 98.7 %

Procedure:
A mixture of 2,6-dichlor-4-methylpyridin-3-carboxylic acid (100 g, 485 mmol) and potassium carbonate (100 g, 728 mmol) in dimethylformamide (1.25 I) is stirred for 30 h at RT before ethyl iodide (59.5 ml, 728 mmol) is added and stirring is continued for 18 h. After completion of the reaction, water is added and the mixture is extracted with ethyl acetate (3×). The combined organic layers are washed with water (2×) and brine (1×), dried over magnesium sulphate and evaporated to dryness to yield 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid ethyl ester (112 g), which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][C:3]=1[CH3:29].C(N(CC)C(C)C)(C)C.[Cl:39][C:40]1[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:41]=1[C:42](Cl)=[O:43]>C(Cl)Cl>[CH2:25]([O:24][C:22]([C:19]1[N:11]2[C:10]([CH2:9][N:8]([C:6](=[O:7])[C:5]3[CH:27]=[CH:28][C:2]([NH:1][C:42](=[O:43])[C:41]4[CH:45]=[CH:46][C:47]([Cl:49])=[CH:48][C:40]=4[Cl:39])=[C:3]([CH3:29])[CH:4]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12]2)=[CH:21][CH:20]=1)=[O:23])[CH3:26]
Reactant: CCOC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(N)c(C)c1)C2
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(NC(=O)c3ccc(Cl)cc3Cl)c(C)c1)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.4 %

Procedure:
To a solution of 0.30 g of ethyl 10,11-di-hydro-10-(4-amino-3-methylbenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylate in 20 ml of methylene chloride is added 0.15 g of N,N-diisopropylethylamine and 0.24 g of 2,4-dichlorobenzoyl chloride. The reaction mixture is stirred at room temperature for 18 hours and washed with water, saturated NaHCO3 and dried with Na2SO4. The organic layer is passed through a pad of hydrous magnesium silicate. Hexane is added to the filtrate at the boil to give 0.24 g of solid, m.p. 174°-184° C.
Reaction SMILES: ClC1N=CC=C2C=CNC=12.[F:11][C:12]1[CH:13]=[C:14]([NH:29][C:30]([NH:32][C:33](=[O:41])[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[S:31])[CH:15]=[CH:16][C:17]=1[O:18][C:19]1[N:20]=[CH:21][CH:22]=[C:23]2[CH:27]=[CH:26][N:25]([CH3:28])[C:24]=12.C(Br)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.CI>>[CH2:28]([N:25]1[C:24]2=[C:19]([O:18][C:17]3[CH:16]=[CH:15][C:14]([NH:29][C:30]([NH:32][C:33](=[O:41])[CH2:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[S:31])=[CH:13][C:12]=3[F:11])[N:20]=[CH:21][CH:22]=[C:23]2[CH:27]=[CH:26]1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: BrCc1ccccc1
Reactant: Cn1ccc2ccnc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c21
Agent: Clc1nccc2cc[nH]c12
Solvent: CI
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2nccc3ccn(Cc4ccccc4)c23)c(F)c1

Procedure:
Starting from the compound 259 and following the procedures described above for the synthesis of compound 262b (scheme 60, step 4, example 219) but using benzyl bromide in step 1 instead of methyl iodide, title compound 262c was obtained. 1H NMR (DMSO-d6) δ (ppm): 12.36 (s, 1H), 11.76(s, 1H), 7.78(m, 1H,), 7.58(t, 1H, J1=J2=2.7 Hz), 7.50(d, 1H, J=5.7 Hz), 7.34(m, 5H), 7.30-7.221(m, 5H), 7.15(dd, 1H, J1=8.1 Hz, J2=0.4 Hz), 7.10(t, 1H), 6.60(d, 1H, J=2.9 Hz), 5.68(s, 2H), 3.82(s, 2H). MS (m/z): 511.2(M+H) (found).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:9][C:10]=2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[N:5]=[CH:4][N:3]=1.[ClH:27].[Cl:28][C:29]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:30]=1[NH2:31].Cl>C(O)(C)C>[ClH:1].[ClH:28].[ClH:27].[Cl:28][C:29]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:30]=1[NH:31][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)=[CH:9][C:10]=2[N:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]2)[N:5]=[CH:4][N:3]=1
Reactant: COc1ccc(Cl)c(N)c1
Reactant: CN1CCN(c2cc(OCCN3CCCC3)cc3ncnc(Cl)c23)CC1
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(Cl)c(Nc2ncnc3cc(OCCN4CCCC4)cc(N4CCN(C)CC4)c23)c1

Procedure:
Using an analogous procedure to that described in Example 5, 4chloro-5-(4-methylpiperazin-1-yl)-7-(2-pyrrolidin-1-ylethoxy)quinazoline (0.11 g) was reacted with 2-chloro-5-methoxyaniline hydrochloride (0.064 g) in the presence of a 6M solution of hydrogen chloride in isopropanol (0.05 ml) to give the title compound, as a trihydrochloride salt (0.092 g), a portion of which was converted into the free base using an analogous procedure to that described in Example 3. The free base gave the following characterising data: NMR Spectrum: (CDCl3) 1.8–1.9 (m, 4H), 2.32 (s, 3H), 2.48 (m, 2H), 2.65 (br s, 4H), 2.82 (d, 2H), 2.98 (m, 4H), 3.2 (d, 2H), 3.82 (s, 3H), 4.25 (m, 2H), 6.65 (m, 1H), 6.95 (m, 1H), 7.3 (d, 1H), 8.02 (d, 1H), 8.52 (s, 1H); Mass Spectrum: M+H+ 497 and 499.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[C:4]([NH:6][C:7](=[N:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1)SC)#[N:5]>>[C:4]([NH:6][C:7]([NH:3][CH2:1][CH3:2])=[N:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1)#[N:5]
Reactant: CCN
Reactant: CSC(=NCCSCc1cnccn1)NC#N
Product: CCNC(=NCCSCc1cnccn1)NC#N

Procedure:
Anhydrous ethylamine is reacted with N-cyano-N'-[2-(2-pyrazinylmethylthio)ethyl]-S-methylisothiourea by the procedure of Example 4 to give N-cyano-N'-ethyl-N"-[2-(2-pyrazinylmethylthio)ethyl]guanidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[CH2:10][C@@H:9]1[C@H:19]1[O:23][C:22]([CH3:25])([CH3:24])[N:21]([C:26](=[O:28])[CH3:27])[C@H:20]1[CH2:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:10][C@@H:9]1[C@H:19]1[O:23][C:22]([CH3:24])([CH3:25])[N:21]([C:26](=[O:28])[CH3:27])[C@H:20]1[CH2:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@@H](OCC=C(C)C)CN2C(=O)OC(C)(C)C)OC1(C)C
Agent: [Pd]
Solvent: CO
Product: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@@H](OCCC(C)C)CN2C(=O)OC(C)(C)C)OC1(C)C
Yield: 76 %

Procedure:
Stir a solution of (2R,4R)-2-[(4S,5S)-3-acetyl-4-(3,5-difluoro-benzyl)-2,2-dimethyl-oxazolidin-5-yl]-4-(3-methyl-but-2-enyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester and 10% palladium on carbon (0.02 g) in methanol (5 mL) under one atmosphere of hydrogen gas for 18 hours. Filter and evaporate to give the desired compound as a foam (0.081 g, 76%).
Reaction SMILES: [CH:1]1([CH:4]([N:6]2[CH:11]=[C:10]([C:12]3[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=3)[C:9](OC)=[C:8]([C:20]#[N:21])[C:7]2=[O:22])[CH3:5])[CH2:3][CH2:2]1.O.[NH2:24][NH2:25]>C(O)C>[NH2:21][C:20]1[C:8]2[C:7](=[O:22])[N:6]([CH:4]([CH:1]3[CH2:3][CH2:2]3)[CH3:5])[CH:11]=[C:10]([C:12]3[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=3)[C:9]=2[NH:25][N:24]=1
Reactant: NN
Reactant: COc1c(-c2ccn(C)n2)cn(C(C)C2CC2)c(=O)c1C#N
Solvent: O
Solvent: CCO
Product: CC(C1CC1)n1cc(-c2ccn(C)n2)c2[nH]nc(N)c2c1=O
Temperature: 90 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
A mixture of 1-(1-cyclopropylethyl)-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step C of Example 163 (22 mg), hydrazine monohydrate (18 mg) and ethanol (2 mL) was stirred at 90° C. for 1 hr. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate). The residue was crystallized from ethyl acetate/hexane to give the title compound (13 mg).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[CH2:10][CH2:11][C@H:12]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([NH:28][NH2:29])(=O)[CH3:26]>O1CCCC1>[CH2:1]([O:8][C:9](=[O:24])[CH2:10][CH2:11][C@H:12]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:13]1[O:15][C:25]([CH3:26])=[N:28][N:29]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)NN
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Solvent: C1CCOC1
Product: Cc1nnc([C@H](CCC(=O)OCc2ccccc2)NC(=O)OC(C)(C)C)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
674 mg (2 mmol) of (S)-5-(benzyloxy)-2-(tert-butoxycarbonylamino)-5-oxopentanoic acid (Boc-Glu (OBzl)-OH) and 148 mg (2 mmol) of acetohydrazide were added with 5 ml of tetrahydrofuran, added with 356 mg of N,N-carbonyl diimidazole and stirred at room temperature overnight. The solvent was distilled away, and the resultant was purified using purified purification step A to obtain a crude purified substance of (4S)-4-(N′-acetylhydrazinecarbonyl)-4-{[(tert-butoxy)carbonyl]amino}butanoic acid benzyl ester. The obtained crude purified substance was dissolved in 2 ml of methylene chloride, which was added with 72 mg of Burgess reagent and stirred at room temperature overnight. Another 72 mg of Burgess reagent was added and stirred for two days. After distilling the solvent away, purification was carried out using purification step A to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]([CH3:16])[C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[C:4]([CH3:17])[CH:3]=1.[Cl-].[CH:19]1([Zn+])[CH2:21][CH2:20]1>C1COCC1.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>[C:10]([Si:7]([O:6][C:5]1[C:14]([CH3:16])=[CH:15][C:2]([CH:19]2[CH2:21][CH2:20]2)=[CH:3][C:4]=1[CH3:17])([CH3:9])[CH3:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: [Zn+]C1CC1
Reactant: Cc1cc(Br)cc(C)c1O[Si](C)(C)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1cc(C2CC2)cc(C)c1O[Si](C)(C)C(C)(C)C
Temperature: 80 °C
Yield: 63.1 %

Procedure:
To a suspension of (4-bromo-2,6-dimethylphenoxy) tert-butyldimethylsilane (668 mg, 2.12 mmol) and tetrakis(triphenylphosphine)palladium (122 mg, 0.11 mmol) in THF (20 mL) was added cyclopropyl zinc chloride (28.0 mL, 11.2 mmol). The mixture was heated at 80° C. for 24 h and cooled to room temperature. The reaction was passed through a short pad of SiO2 to remove the catalyst and the solution was concentrated to oil. The resulting oil was diluted in EtOAc (100 mL), washed with brine (100 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=90:10) yielded 370 mg (63%) of tert-butyl(4-cyclopropyl-2,6-dimethylphenoxy)dimethylsilane. To tert-butyl(4-cyclopropyl-2,6-dimethylphenoxy)dimethylsilane (320 mg, 1.16 mmol) in THF (10 mL) was added a solution of tetrabutylammonium fluoride (5.0 mL, 1 M in THF, 5.0 mmol) and acetic acid (0.40 mL). The reaction was stirred at room temperature for 3 h and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=85:15) yielded 175 mg (93%) of 4-cyclopropyl-2,6-dimethylphenol as a light yellow oil.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[I-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C(C)C)C=CC=CC=1.[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[C@:37]12[CH2:46][O:45][C@@H:44]([CH:47]=O)[CH2:43][C@H:42]1[CH2:41][S:40][C:39]([NH:49][C:50](=[O:57])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[N:38]2>O1CCCC1.C(OCC)(=O)C>[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[C@:37]12[CH2:46][O:45][C@@H:44]([CH:47]=[C:2]([CH3:3])[CH3:1])[CH2:43][C@H:42]1[CH2:41][S:40][C:39]([NH:49][C:50](=[O:57])[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[N:38]2
Reactant: [Li]CCCC
Reactant: O=C[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Agent: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)=C[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (2.5 M in hexanes, 0.90 mL, 2.25 mmol) was added drop-wise to a suspension of triphenyl(propan-2-yl)phosphonium iodide (1.08 g, 2.50 mmol) in tetrahydrofuran (10 mL) at 0° C. The resulting solution was stirred and allowed to warm to room temperature for 30 minutes, whereupon it was cooled to 0° C. A solution of N-[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-formyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C23) (104 mg, 0.250 mmol) in tetrahydrofuran (1 mL) was added, and stirring was continued at 0° C. for 1 hour, then at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (20 mL), washed with saturated aqueous sodium bicarbonate solution (3×20 mL), washed with water (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 30% ethyl acetate in heptane) provided the product as a white solid. Yield: 42 mg, 95 μmol, 38%. LCMS m/z 443.3 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 11.8 (v br s, 1H), 8.24 (d, J=7.4 Hz, 2H), 7.38-7.55 (m, 4H), 6.85-6.97 (m, 2H), 5.27 (d, J=8 Hz, 1H), 4.31-4.40 (m, 1H), 4.19 (d, J=12.1 Hz, 1H), 3.80 (d, J=12.1 Hz, 1H), 3.13-3.22 (m, 1H), 2.98-3.06 (m, 1H), 2.59-2.68 (m, 1H), 2.00-2.13 (m, 1H), 1.75 (s, 6H), 1.59-1.67 (m, 1H).
Reaction SMILES: Cl.C([O:4][C:5](=[O:8])[CH2:6][NH2:7])C.[C:9]1([N:15]=[C:16]=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C1C=CC=CC=1>[C:9]1([NH:15][C:16]([NH:7][CH2:6][C:5]([OH:4])=[O:8])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)CN
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(O)CNC(=O)Nc1ccccc1
Reaction time: 5 h

Procedure:
7.0 g of glycine ethyl ester hydrochloride was suspended in 100 ml of benzene, and 10 ml of phenylisocyanate and 8 ml of triethylamine were added thereto. The mixture was stirred for 5 hours and benzene was distilled away. Ethyl acetate was added to the residue, washed with water and brine, and dried over anhydrous sodium sulfate. Ethyl acetate was distilled away and 100 ml of 1N aqueous solution of sodium hydroxide was added to the resulting residue. The solution was stirred at 50° C. for 2 hours. Insoluble substance was filtered off and the filtrate was acidified with concentrated hydrochloric acid. The precipitated crystals were collected by filtration and recrystallized from methanol/water to give 6.8 g of phenylcarbamoylglycine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=2)[NH:8][C:7]=1[CH3:21])=[O:5])[CH3:2].[Br:22]Br>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([Br:22])=[C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=2)[NH:8][C:7]=1[CH3:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1ccc2[nH]c(C)c(C(=O)OCC)c2c1
Reactant: BrBr
Solvent: CC(=O)O
Product: CCOC(=O)Cc1cc2c(C(=O)OCC)c(C)[nH]c2cc1Br
Reaction time: 0.17 h
Yield: 86.2 %

Procedure:
To a solution of 5-ethoxycarbonylmethyl-2-methyl-1H-indole-3-carboxylic acid ethyl ester (3 g, 10.4 mmol) in acetic acid (20 mL) is added bromine (1.65 g, 10.4 mmol) dropwise, and the reaction mixture is stirred for 10 minutes. The solution is then concentrated in vacuo and chromatographed with a gradient of hexane/ethyl acetate (5%-30%) within 30 minutes to afford a yellow solid (3.3 g, 86%). MS: 368, 370 (M+1)+.