Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][C:7](=[O:16])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[Si]([I:28])(C)(C)C>C(Cl)Cl>[I:28][N:6]1[C:7](=[O:16])[CH2:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: O=C1Cc2ccccc2-c2ccccc2N1
Reactant: C[Si](C)(C)I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1Cc2ccccc2-c2ccccc2N1I
Temperature: 7.5 °C

Procedure:
A solution of 5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1.0 g, 4.77 mmol) (Example 7-A) and Et3N (2.66 ml, 19.12 mmol) were stirred for 5.0 minutes at −15° C. in CH2Cl2 and treated with TMSI (1.36 ml, 9.54 mmol). After stirring for 15 minutes 12 (1.81 g, 7.16 mmol) was added in a single portion and the reaction allowed to warm to 5-10° C. over 3 h. The reaction was quenched with sat. Na2SO3, diluted with CH2Cl2 and separated. The organics were washed with Na2SO3 and NaHSO3 and dried over MgSO4. After filtration, the organics were concentrated to approximately 20 ml and diluted with an additional 20 ml of hexanes. The title compound was isolated as a tan precipitate by filtration.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38]S(CC1C=CC=CC=1)(=O)=O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:49][C:50]1[CH:51]=[C:52]([S:57](Cl)(=[O:59])=[O:58])[CH:53]=[C:54]([Cl:56])[CH:55]=1>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:57]([C:52]1[CH:51]=[C:50]([Cl:49])[CH:55]=[C:54]([Cl:56])[CH:53]=1)(=[O:59])=[O:58])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)c3cc(Cl)cc(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 60 %

Procedure:
To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step 6, Example 1) was added 3,5-dichlorobenzenesulfonyl chloride according to the procedure in Example 1 Step 7 to generate the product in 60% yield.
Reaction SMILES: CC(C)=CCC/C(/C)=C/CC/C(/C)=C/CN1C(=O)C2C=CC=C(O)C=2N[C:19]2[C:18]([OH:30])=[CH:17][C:16]([OH:31])=CC1=2.C([O:38][C:39](=[O:41])[CH3:40])(=O)C.CCOC(C)=O.O>N1C=CC=CC=1>[CH3:19][C:18]([CH2:17][C:16]([CH2:40][C:39]([OH:38])=[O:41])=[O:31])=[O:30]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CN1C(=O)c2cccc(O)c2Nc2c(O)cc(O)cc21
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)CC(=O)O
Reaction time: 1 h

Procedure:
BU-4664L (20 rag) was stirred with acetic anhydride (1.0 ml) in anhydrous pyridine (1.5 ml) for 18 hours at room temperature. To the reaction mixture, EtOAc and water (20 ml each) were added and stirred for one hour. After washing with water (20 ml portions) twice, the organic layer was concentrated to give a yellow solid. The residue was purified by preparative TLC (SiO2, CH2Cl2 -MeOH 20:1) followed by Sephadex LH-20 chromatography using CH2Cl2 -MeOH (4:6) as a developing solvent to give triacetate BU-4664L (2, 13 mg), m.p. >200° C. (dec.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].[CH:13]1([NH:19]C2CCCCC2)[CH2:18]CCC[CH2:14]1.S(=O)(=O)(O)[O-:27].[K+].NN>CO>[NH2:19][C@@H:13]([CH3:18])[C:14]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[C:10]([OH:12])=[O:11])=[O:27]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: O=S(=O)([O-])O
Reactant: C1CCC(NC2CCCCC2)CC1
Agent: NN
Agent: [K+]
Solvent: CO
Product: C[C@H](N)C(=O)N1c2ccccc2C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(S)-2,3-Dihydro-1-[(S)-2-(1,3-dihydro-1,3-dioxo-2H-isoindo]-2-yl)-1-oxopropyl]-1H-indole-2-carboxylic acid, dicyclohexylamine (20.4 g.) was treated with 5% aqueous potassium bisulfate solution (300 ml.), and the free acid that formed was extracted three times with methylene chloride (combined extracts 450 ml.). The combined extracts were washed with saline twice, then dried over anhydrous sodium sulfate. Evaporation of the methylene chloride on a rotary evaporator under reduced pressure, then in high vacuum gave an amorphous solid which was dissolved in methanol (200 ml.). Hydrazine (95%, 1.43 g.) was added to the methanol solution. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 24 hr., then chilled in an ice-salt mixture for 3 hr. A precipitate (phthalhydrazide, 4.06 g.) was collected on a filter, and washed with methanol. The combined filtrate and washings were evaporated on a rotary evaporator under reduced pressure, then in vacuo to give a solid residue. The residue was triturated with methylene chloride (ca. 250 ml.) and filtered. The filter residue was washed with methylene chloride several times and dried in vacuo. The crude product was dissolved in water (ca. 50 ml.) at room temperature, and filtered. The filter residue was washed with water. The combined filtrate and washings were evaporated carefully on a rotary evaporator under reduced pressure to give a solid residue which was dried over phosphorous pentoxide in vacuo to give the title product (6.31 g.), [α]D25 =-140.85 (c=1.44%, water). The analytical sample which was obtained by recrystallizations from methanol melted at 171°-172° (when the melting point was determined with rapid heating, the compound melted at 206.5°-209°), [α]D25 =-161.17° (c=1.065%, EtOH).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[CH3:5][N:6]([CH3:14])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.C(O)(=O)C.C([BH3-])#N.[Na+].C1COCC1>CO>[CH:2]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([N:6]([CH3:14])[CH3:5])=[CH:8][CH:9]=1)([CH3:4])[CH3:1]
Reactant: CN(C)c1ccc(N)cc1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)Nc1ccc(N(C)C)cc1
Reaction time: 8 h
Yield: 106.5 %

Procedure:
Acetone (30 mL, 408 mmol) is added to a mixture of N',N'-dimethyl-benzene-1,4-diamine (27.2 g, 200 mmol), acetic acid (glacial, 13.8 mL, 241 mmol), methanol (500 mL), and sodium cyanoborohydride in THF (1M, 440 mL, 440 mmol) and allowed to stir overnight under nitrogen. After concentrating in vacuo to a residue, the reaction mixture is partitioned between ethyl acetate and aqueous sodium carbonate. The layers are separated and the aqueous layer is extracted twice with ethyl acetate. The organic layers are combined, extracted with saturated brine, dried over anhydrous potassium carbonate, and concentrated in vacuo to afford the title compound as an oil (38.0 g, 213 mmol) of sufficient purity for the next step. 1H NMR (300 MHz, CDCl3) δ=1.18 (d, J=6.28 Hz, 6H); 2.82 (s, 6H); 3.04 (b, 1H), 3.47-3.59 (m, 1H); 6.59 (d, J=9.0 Hz, 2H); 6.73 (d, J=9.0 Hz, 2H). TLC Rf -0.3 (20:80 ethyl acetate: n-hexane).
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH3:12][C:13]1[C:14]2[N:15]([N:19]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH2:28])[CH:23]=3)[N:21]=2)[CH:16]=[CH:17][N:18]=1.C(N(CC)C(C)C)(C)C>C(O)C>[CH3:12][C:13]1[C:14]2[N:15]([N:19]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]4[C:2]([CH3:11])=[C:3]([C:5]5[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:28]=[C:24]4[CH:23]=3)[N:21]=2)[CH:16]=[CH:17][N:18]=1
Reactant: Cc1nccn2nc(-c3ccnc(N)c3)nc12
Reactant: CC(Br)C(=O)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1nccn2nc(-c3ccn4c(C)c(-c5ccccc5)nc4c3)nc12
Temperature: 80 °C
Yield: 18 %

Procedure:
2-Bromopropiophenone (0.034 ml, 0.221 mmol) was added to a solution of 4-(8-methyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)pyridin-2-amine (0.025 g, 0.111 mmol) in Ethanol (2.2 ml) and the mixture was heated at 80° C. for 40 hours. LC/MS analysis of the reaction mixture indicates reaction approximately 40% complete. The reaction mixture was transferred to a microwave reaction tube and N,N-diisopropylethylamine (0.059 ml, 0.332 mmol) was added. The reaction mixture was heated at 110° C. under standard microwave conditions for 2 hours. LC/MS analysis indicates reaction completion. The reaction mixture was concentrated in vacuo. The crude product was purified by flash chromatography (silica gel; 30-100% EtOAc/hexanes) to afford a tan solid (0.007 g, 0.020 mmol, 18.05% yield). 1H NMR (400 MHz, METHANOL-d4) δ 8.76 (d, J=4.5 Hz, 1H), 8.51 (s, 1H), 8.42 (d, J=6.5 Hz, 1H), 8.08 (d, J=4.5 Hz, 1H), 7.90 (dd, J=7.2, 1.6 Hz, 1H), 7.82-7.75 (m, 2H), 7.52 (t, J=7.5 Hz, 2H), 7.42 (s, 1H), 2.97 (s, 3H), 2.73 (s, 3H), LC/MS: (Method 2) Anal. Calcd. for [M+H]+C20H17N6: 341.15. Found: 341.07.
Reaction SMILES: [C:1]([OH:14])(=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[CH3:15]O>S(=O)(=O)(O)O>[C:1]([O:14][CH3:15])(=[O:13])[C:2]1[CH:3]=[C:4]([O:5][CH3:6])[C:7]([OH:8])=[C:9]([O:10][CH3:11])[CH:12]=1
Reactant: CO
Reactant: COc1cc(C(=O)O)cc(OC)c1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(OC)c(O)c(OC)c1

Procedure:
Syringic acid was esterified by the Fischer Method using concentrated sulfuric acid as catalyst and a large excess of methanol to give a nearly quantitative yield of methyl syringate, m.p. 104°-106° C. after recrystallization from isopropanol and hexane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5][NH2:6])[CH3:2].[ClH:8].[OH2:9]>>[Cl:8][C:5](=[N:6][OH:9])[C:4]([O:3][CH2:1][CH3:2])=[O:7]
Reactant: CCOC(=O)CN
Reactant: O
Reactant: Cl
Product: CCOC(=O)C(Cl)=NO

Procedure:
Ethyl chlorohydroxyiminoacetate (ECHA) can be produced from glycine ethyl ester hydrochloride by the in-situ generation of nitrosyl chloride gas from aqueous sodium nitrite and HCl. In particular, Glycine ethyl ester.HCl is dissolved in water. To this is added concentrated HCl solution (32%) and the reaction mixture is cooled to <10° C. HCl gas is then bubbled into the reaction mixture. An aqueous solution of sodium nitrite is dosed into the reactor while maintaining the temperature at <10° C. HCl gas is bubbled into the reactor again followed by a second portion of aqueous sodium nitrite. Finally, the product is purified from the reaction mixture by any appropriate means known to those of skill in the art. For example, the reaction mixture is stirred for a further period and then extracted with a water immiscible solvent (dichloroethane, chloroform, carbon tetrachloride) at room temperature to remove the product from the reaction mixture. The organic extracts are dried with a drying agent and the solvent is flashed off. An oily residue remains, which crystallizes on cooling. The crystals are filtered and washed with a suitable solvent to obtain a purified ECHA.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:18]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[C:3]=12.[H-].[Na+].F[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N+:40]([O-:42])=[O:41]>O1CCOCC1>[C:14]([OH:17])(=[O:41])[CH3:15].[C:14]([OH:17])(=[O:41])[CH3:15].[CH3:30][N:27]1[CH2:26][CH2:25][N:24]([C@@H:21]2[CH2:22][CH2:23][C@H:18]([N:8]3[C:4]4=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]4[C:10]([C:11]4[CH:16]=[CH:15][C:14]([O:17][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=5[N+:40]([O-:42])=[O:41])=[CH:13][CH:12]=4)=[N:9]3)[CH2:19][CH2:20]2)[CH2:29][CH2:28]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CN1CCN(C2CCC(n3nc(-c4ccc(O)cc4)c4c(N)ncnc43)CC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccccc5[N+](=O)[O-])cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 26.3 %

Procedure:
A mixture of 4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenol (0.200 g, 0.491 mmol, 1 equiv) and 60% sodium hydride (0.020 g, 0.49 mmol, 1 equiv) in dioxane (4.9 mL) was stirred at ambient temperature for 20 minutes. 2-Fluoronitrobenzene (0.06 mL, 0.6 mmol, 1.1 equiv) was added and the reaction mixture was heated at 100° C. for 3 h. Additional sodium hydride (0.010 g, 0.24 mmol, 0.5 equiv) and 2-fluoronitrobenzene (0.02 mL, 0.2 mmol, 0.4 equiv) were added and the reaction mixture was heated at 100° C. for 3 h. The reaction mixture was allowed to cool to room temperature and the resulting solid was removed by filtration with the aid of CH2Cl2 (10 mL) and EtOAc (10 mL). The filtrate was concentrated to afford a yellow semi-solid which was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 10%-60% acetonitrile-0.1M ammonium acetate over 20 min, 21 mL/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to afford cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-[4-(2-nitrophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate salt as a white solid (0.023 g, 0.043 mmol): 1H NMR (d6 DMSO, 400 MHz): δ H 8.23 (1H, s), 8.10 (1H, d, J=8.2 Hz), 7.68-7.73 (3H, m), 7.33-7.40 (1H, m), 7.31 (1H, d, J=7.3 Hz), 7.24 (2H, d, J=8.7 Hz), 4.76-4.82 (1H, m), 2.26-2.51 (1H, m), 2.24 (3H, s), 2.17-2.21 (2H, m), 2.05 (6H, s), 1.56-1.71 (4H, m); RP-HPLC (Delta Pak C18, 5 μm, 300 Å, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 20 min, 1 mL/min) Rt 13.09 min.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:13]([C:15]1[CH:16]=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1)#[N:14]>>[C:13]([C:15]1[CH:16]=[C:17]([S:21]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1)#[N:14]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cccc(C#N)c2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 3-cyanobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (39.4 mg) with purity >90%. MS (pos) m/z 352.3.
Reaction SMILES: [Li+].[OH-].[CH3:3][N:4]([CH3:26])[S:5]([C:8]1[CH:9]=[CH:10][C:11]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([CH:17]=1)[C:13]([O:15]C)=[O:14])(=[O:7])=[O:6].Cl>O1CCCC1.O.C(OCC)(=O)C>[CH3:3][N:4]([CH3:26])[S:5]([C:8]1[CH:9]=[CH:10][C:11]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([CH:17]=1)[C:13]([OH:15])=[O:14])(=[O:6])=[O:7]
Reactant: COC(=O)c1cc(S(=O)(=O)N(C)C)ccc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)c1ccc(OCc2ccccc2)c(C(=O)O)c1
Temperature: 50 °C

Procedure:
LiOH (20.56 mg, 0.86 mmol) was added to a stirred solution of methyl 5-[(dimethylamino) sulfonyl]-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 62; 300 mg, 0.86 mmol) in a mixture of tetrahydrofuran and water (3:1, 40 ml). The mixture was heated at 50° C. for 6 h, and then diluted with ethyl acetate (50 ml). 10% Aqueous HCl was added to the mixture to adjust pH to 2. The organic phase was isolated, washed with brine, dried over MgSO4, and concentrated to yield the title compound as a white solid. 230 mg.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]#[N:13])[CH:9]=2)[NH:4][CH2:3]1.CCN(C(C)C)C(C)C.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC#N>[C:12]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][CH2:3][C@@H:2]([NH:1][S:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:31])=[O:30])[CH2:11]2)#[N:13]
Reactant: N#Cc1ccc2c(c1)C[C@H](N)CN2
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)c1ccccc1)CN2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.4 %

Procedure:
To a suspension of 1F (103.9 mg, 0.6 mmol) in CH3CN (3 mL) at RT under argon was added DIPEA (0.11 mL, 0.66 mmol), followed by dropwise addition of benzene sulfonylchloride (0.08 mL, 0.63 mmol). The reaction mixture was stirred at RT for 1.5 h, then concentrated under reduced pressure. The residue was taken into EtOAc, washed with water, brine, dried (Na2SO4), and concentrated. The resulting residue was chromatographed (silica gel) eluting with EtOAc (30-50%) in hexane to give the title compound (170 mg, 90%). HPLC: 99% at 5.2 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient. (A=90% H2O−10% MeOH−0.1% H3PO4 and B=10% H2O−90% MeOH−0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm). MS (ES): m/z 314 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[CH:3]=1.[Li]CCCC.[Br:15][C:16]1[N:17]=[C:18]([CH:40]=[O:41])[N:19]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=1>C1COCC1>[Br:15][C:16]1[N:17]=[C:18]([CH:40]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[CH:3]=2)[OH:41])[N:19]([C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=1
Reactant: O=Cc1nc(Br)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cccc(C(O)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 77.6 %

Procedure:
To a solution of 1-bromo-3-ethylbenzene (266 mg, 1.44 mmol) in 7 mL THF at −78° C., was added BuLi (1.6 M in hexanes, 0.99 mL, 1.58 mmol). The mixture was stirred at −78° C. for 10 min, then a solution of Intermediate 175.1 (600 mg, 1.44 mmol) in 3 mL THF was added. The mixture was stirred at −78° C. for 1 h, then was removed from the cooling bath and stirred 20 min. The reaction was quenched with sat. NH4Cl, then was diluted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 40% EtOAc/hexanes gradient) to afford 585 mg of Intermediate 175.2 as a colorless solid. LCMS (4 min gradient, 50 to 100% B, A=95% H2O/5% CH3CN/0.1% TFA, B=95% CH3CN/5% H2O/0.1% TFA) RT=3.65 min, 523.10 (M+H)+.
Reaction SMILES: [Mg].Cl[Si:3]([CH3:6])([CH3:5])[CH3:4].[F:7][C:8](F)([F:17])[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10]>O1CCCC1>[F:7][C:8]([F:17])=[C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[O:10][Si:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: C[Si](C)(C)Cl
Reactant: O=C(c1ccccc1)C(F)(F)F
Agent: [Mg]
Solvent: C1CCOC1
Product: C[Si](C)(C)OC(=C(F)F)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a dry 250 ml Schlenk flask the following compounds were added: magnesium turnings (1.45 g, 60 mmol), dry tetrahydrofuran (THF, 120 ml) and chlorotrimethylsilane (TMSCl, 13.0 g, 120 mmol). The flask was cooled to 0° C. 2,2,2-Trifluoroacetophenone (non-radioactive) 2a (5.2 g, 30 mmol) was added drop wise into the flask with a syringe. After addition of the 2,2,2-Trifluoroacetophenone, the reaction mixture was stirred for an additional 1 h. The completion of the reaction was monitored by 19F NMR spectroscopy. The solvent and excess TMSCl were removed under vacuum, and hexane (50 ml) was added to the residue. Solid impurities were removed by suction filtration, and the solvent was evaporated to yield 2,2-difluoro-1-phenyl-1-trimethylsiloxyethene 1a (6.8 g, 99% yield).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][C:17]#N)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].C(OP(OCC)OCC)C.O>CO>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH3:17])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(SC#N)cc(C(C)(C)C)c1O
Agent: CCOP(OCC)OCC
Solvent: O
Solvent: CO
Product: CSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
A mixture of 3,5-bis(1,1-dimethylethyl)-4-hydroxyphenylthiocyanate (238 g, 0.90 mole), triethylphosphite (225 g, 1.35 mole), water (200 g), and methanol (2000 ml) was stirred at reflux for two hours. Upon cooling, the mixture was concentrated in vacuo. The residue was triturated with water, and the solid was collected by filtration and air dried. Recrystallization from aqueous methanol gave the title compound, m.p. 69°-71°.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23].CCOC(C)=O>CN(C=O)C.[Cl-].[Na+].O>[CH3:25][O:24][C:22](=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1
Reactant: c1ccc(Nc2ccccn2)nc1
Reactant: COC(=O)CCCCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCCCCN(c1ccccn1)c1ccccn1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 24 %

Procedure:
NaH (112 mg, 2.92 mmol) was added to di-pyridin-2-yl-amine (500 mg, 2.92 mmol) in DMF (10 mL) at rt. After 10 min, KI (485 mg, 2.92 mmol) and methyl 6-bromohexanoate, I (0.464 mL, 2.92 mmol) were added, and the reaction mixture was stirred at 90° C. for 21 h. Brine (200 mL) and EtOAc (200 mL) were then added, the phases were separated, and the aqueous phase was extracted with EtOAc (100 mL). The organic phases were combined, dried over MgSO4, filtered, and subsequently evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using CH2Cl2/MeOH (100:0.5 to 100:1) as eluant to furnish II as a colourless oil (206 mg, 24%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH:20]([CH3:22])[CH3:21])[C:4]([N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[CH2:8][C@H:7]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5].[C:23]([O:27][C:28]([N:30]([CH3:36])[C@@H:31]([CH3:35])[C:32](O)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[C:23]([O:27][C:28]([N:30]([CH3:36])[C@@H:31]([CH3:35])[C:32]([NH:2][C@@H:3]([CH:20]([CH3:21])[CH3:22])[C:4]([N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[CH2:8][C@H:7]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: CCOC(=O)[C@@H]1Cc2cccnc2N1C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H]1Cc2cccnc2N1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a solution of (S)-ethyl 1-((S)-2-amino-3-methylbutanoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate hydrochloride (1.6 g, 4.88 mmol, Eq: 1.00) in DMF (20 mL) was added (S)-2-(tert-butoxycarbonyl(methyl)amino)propanoic acid (1.2 g, 5.9 mmol, Eq: 1.21) and HATU (2.2 g, 5.79 mmol, Eq: 1.19). Diisopropylethylamine (1.63 g, 2.2 mL, 12.6 mmol, Eq: 2.58) was then added and the resulting yellow solution was stirred at rt for 1 h. The reaction mixture was diluted with EtOAc (100 mL) and hexanes (50 mL) and washed with 0.1 M aqueous KHSO4, 0.1 M aqueous NaOH, and brine and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80 g, 0% to 20% EtOAc/(DCM:hexanes 1:1) then 20% to 40% EtOAc/(DCM:hexanes 1:1) after first spot has eluted) to give (S)-ethyl 1-((S)-2-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-3-methylbutanoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (1.9 g), m/z=477 (M+H).