Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[N:6]=[C:5]2[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(N(CC)CC)C.[OH:32][C@H:33]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:34](O)=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[N:6]=[C:5]2[N:19]1[CH2:20][CH2:21][N:22]([C:34](=[O:35])[C@H:33]([OH:32])[CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:23][CH2:24]1
Reactant: CC(C)(C)C[C@@H](O)C(=O)O
Reactant: Oc1ccccc1-c1nc(N2CCNCC2)c2cc(F)ccc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C[C@@H](O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)CC1
Reaction time: 3 h
Yield: 86.9 %

Procedure:
To a solution of 2-(6-fluoro-4-(piperazin-1-yl)quinazolin-2-yl)phenol (200 mg, 0.61 mmol) in CH2Cl2 (5 mL) was added triethylamine (170 μL, 1.22 mmol) followed by the addition of (R)-2-hydroxy-4,4-dimethylpentanoic acid (116 mg, 0.79 mmol), then HATU (301 mg, 0.79 mmol). An additional 3 mL of CH2Cl2 was added, and the reaction was stirred for 3 h. After quenching with water, the mixture was extracted twice with CH2Cl2. The organic phase was dried over MgSO4 and concentrated. Purification via silica gel chromatography using 0-10% EtOAc in 50:50 CH2Cl2:hexanes yielded (R)-1-(4-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4,4-dimethylpentan-1-one (240 mg, 86%). m/z: M+1 obs=453.5; tR=3.19 minutes; 1H NMR (400 MHz, DMSO-d6) d 8.46 (m, 1H), 8.01 (m, 1H), 7.84 (m, 2H), 7.40 (m, 1H), 6.96 (m, 2H), 4.89 (d, J=7.1 Hz, 1H), 4.45 (m, 1H), 3.97 (m, 4H), 3.76 (m, 4H), 1.56 (m, 1H), 1.42 (m, 1H), 0.97 (s, 9H) ppm.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[N:4]=[CH:5][NH:6][CH:7]=1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[CH3:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.[Cl-].[NH4+]>[CH3:20][C:12]1[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=1[N:6]1[CH:7]=[C:3]([C:2]([F:9])([F:8])[F:1])[N:4]=[CH:5]1
Reactant: FC(F)(F)c1c[nH]cn1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1-n1cnc(C(F)(F)F)c1
Temperature: 85 °C

Procedure:
A mixture of 4-(trifluoromethyl)-1H-imidazole (198 mg, 1.46 mmol), 1-fluoro-2-methyl-4-nitrobenzene (216 mg, 1.53 mmol) and potassium carbonate (402 mg, 2.91 mmol) in acetonitrile (1.5 mL) was heated to 85° C. for 24 hours. The mixture was diluted with water and saturated ammonium chloride and was extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0-50% ethyl acetate in heptane), gave 1-(2-methyl-4-nitrophenyl)-4-(trifluoromethyl)-1H-imidazole. 1H NMR (500 MHz, CDCl3, δ): 8.30 (d, J=2.44 Hz, 1H), 8.21-8.25 (m, 1H), 7.70 (s, 1H), 7.45-7.49 (m, 2H), 2.38 (s, 3H).
Reaction SMILES: C[O-].[Na+].Cl[CH2:5][C:6]12OC(=O)C(=O)[N:7]1[CH2:8][CH2:9][C:10]1[C:15]2=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=1.C[CH2:24][O:25]C(C)=O.O>CO>[CH2:16]([C:13]1[CH:14]=[C:15]2[C:10]([CH2:9][CH2:8][N:7]=[C:6]2[CH2:5][O:25][CH3:24])=[CH:11][CH:12]=1)[CH3:17]
Reactant: CCOC(C)=O
Reactant: CCc1ccc2c(c1)C1(CCl)OC(=O)C(=O)N1CC2
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCc1ccc2c(c1)C(COC)=NCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium methoxide (9.46 g) was added to a suspension of 10b-(chloromethyl)-9-ethyl-6,10b-dihydro-5H-[1,3]oxazolo[2,3-a]isoquinoline-2,3-dione (14.0 mL) in MeOH (140 mL) under ice-cooling. The mixture was stirred at room temperature for 0.5 hours and then heated under reflux for 3 hours. EtOAc and water were added to the mixture, followed by filtration. The organic layer of the filtrate was collected, washed with saturated brine, and dried over magnesium sulfate. Activated carbon and silica gel were added thereto, followed by filtration. The filtrate was concentrated under reduced pressure to obtain 7-ethyl-1-(methoxymethyl)-3,4-dihydroisoquinoline (4.75 g).
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[Cl:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:17]#[CH:18])[CH:16]=1>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:10][C:11]1[CH:16]=[C:15]([C:17]#[C:18][C:2]2[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=2)[CH:14]=[N:13][CH:12]=1
Reactant: Cc1ccc(N)c(Br)n1
Reactant: C#Cc1cncc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(N)c(C#Cc2cncc(Cl)c2)n1
Yield: 72.5 %

Procedure:
Following the same procedure as described in Example 1, (2-bromo-6-methyl-pyridin-3-yl)amine (150 mg, 0.80 mmol) reacted with (PPh3)2PdCl2 (28 mg, 40 μmol), Cul (8 mg, 40 μmol) and 3-chloro-5-ethynyl-pyridine (165 mg, 1.20 mmol) in triethylamine (5 ml). The crude residue was purified by flash chromatography (hexane/ethyl acetate 7:3) to yield 141 mg (0.58 mmol, 72%) of (2-(5-chloro-pyridin-3-ylethynyl)-6-methyl-pyridin-3-yl)amine as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH:27]([CH3:29])[CH3:28])[O:23][CH2:22][C:21]2[N:16]3[C@H:17]([CH3:31])[C:18](=[O:30])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[NH:8]1[CH2:9][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH:27]([CH3:28])[CH3:29])[O:23][CH2:22][C:21]2[N:16]3[C@H:17]([CH3:31])[C:18](=[O:30])[NH:19][N:20]=2)[CH2:11]1
Reactant: CC(C)c1cc2c(cc1NC1CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)[C@H]1C)CO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1cc2c(cc1NC1CNC1)N1C(=NNC(=O)[C@H]1C)CO2

Procedure:
A solution of 3-(7-isopropyl-4(R)-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (Enantiomer 1, SFC (Table 1, Method 11) Rt=2.948 min.; 0.33 g, 0.77 mmol) in DCM (8 mL) and TFA (2 mL) was stirred at ambient temperature for 2 h. The solvent was removed in vacuo to give 6-(azetidin-3-ylamino)-7-isopropyl-4(R)-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid as a pale yellow solid (Example #57-1, Enantiomer 1, SFC (Table 1, Method 11) Rt=3.79 min, 0.31 g, 92%). LC/MS (Table 1, Method 5) Rt=1.676 min.; MS m/z: 330 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([C:44](=[O:46])[CH3:45])[CH2:14][C:15]2[CH:20]=[C:19]([O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([C:31](=[O:43])[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=3)[CH:26]=[CH:25]4)[N:18]=[CH:17][N:16]=2)[CH2:9]1)=O)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O.N>CO.C(Cl)Cl>[F:42][C:39]([F:40])([F:41])[C:35]1[CH:34]=[C:33]([NH:32][C:31]([N:27]2[C:28]3[C:24](=[CH:23][C:22]([O:21][C:19]4[CH:20]=[C:15]([CH2:14][N:13]([C:44](=[O:46])[CH3:45])[CH:10]5[CH2:11][CH2:12][NH:8][CH2:9]5)[N:16]=[CH:17][N:18]=4)=[CH:30][CH:29]=3)[CH:25]=[CH:26]2)=[O:43])[CH:38]=[CH:37][CH:36]=1
Reactant: CC(=O)N(Cc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1)C1CCN(C(=O)OC(C)(C)C)C1
Agent: N
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N(Cc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1)C1CCNC1

Procedure:
(±)-3-(Acetyl-{6-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-ylmethyl}-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester (30 mg, 0.056 mmol) is stirred in a solution of DCM (2 mL) and TFA (0.5 mL) overnight. After removal of the solvents, the residue is quenched with saturated aqueous sodium bicarbonate. The mixture is extracted with EtOAc (3×). The combined organic layers are washed with water and brine and the organic layer is dried with Na2SO4, filtered, and condensed. The residue is then separated by FCC (0-10%, 2 mol NH3 in MeOH/DCM) to provide the title compound. MS (ESI) m/z 538.9 (M+1).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([CH2:13][O:14][CH3:15])[O:10][C:9]2=[O:16])=[CH:4][CH:3]=1.[CH:17]12[CH2:23][CH:20]([CH2:21][CH2:22]1)[CH:19]=[CH:18]2.N1CCCCC1.CN(C)C=O>C(OCC)(=O)C.CC(O)=O.CC(O)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].C(O)=O>[CH:17]12[CH2:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][CH:18]2[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([CH2:13][O:14][CH3:15])[O:10][C:9]2=[O:16])=[CH:4][CH:3]=1
Reactant: C1=CC2CCC1C2
Reactant: COCC1CN(c2ccc(I)cc2)C(=O)O1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCC1CN(c2ccc(C3CC4CCC3C4)cc2)C(=O)O1

Procedure:
A solution of 56 mg of bis-(triphenylphosphine)-palladium (II) diacetate, 0.5 g of (RS)-3-(4-iodophenyl)-5-methoxymethyl-oxazolidin-2-one, 0.16 g of bicyclo[2.2.1]hept-2-ene, 0.5 ml of piperidine, 1 ml of dimethylformamide and 0.15 ml of formic acid was stirred for 3 hours under an argon atmosphere. The reaction mixture was diluted with 50 ml of ethyl acetate and the separated precipitate was removed. The filtrate was extracted twice with 20 ml of water each time, the organic phase was dried over magnesium sulfate and the solvent was distilled off. The brown oil obtained was chromatographed on a 30-fold amount of silica gel with ethyl acetate/hexane (7:3), with 0.43 g of uniform product being obtained after crystallization in ethyl acetate/hexane while cooling. The racemic (1:1) diastereomer mixture melted at 83°-84°.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH3:12][CH:13]([OH:16])[C:14]#[CH:15].[OH-].[K+]>CCOCC>[S:1]([O:16][CH:13]([C:14]#[CH:15])[CH3:12])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: C#CC(C)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: C#CC(C)OS(=O)(=O)c1ccc(C)cc1
Reaction time: 1.5 h
Yield: 95 %

Procedure:
To a solution of tosyl chloride (0.5 mole) and commercial 3-butyn-2-ol (0.4 mole 40-50% aqueous solution) in ether (350 ml), potassium hydroxide (2.5 moles) is slowly added over a period of 15-30 minutes. The temperature is maintained at 0°-5° C. for the entire period and the reaction mixture is allowed to stand for 90 minutes. When the reaction is complete, the ether phase is washed and dried. Removal of the ether, in vacuo, yields crude 2-tosyloxy-3-butyne.
Reaction SMILES: Br.[NH:2]=[C:3]1[N:7]([CH2:8][C:9]#[CH:10])[C:6]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:5]=2[S:4]1.[Na].[ClH:18]>C(O)C>[ClH:18].[CH3:16][O:15][C:13]1[CH:12]=[CH:11][C:6]2[N:7]3[CH:8]=[C:9]([CH3:10])[N:2]=[C:3]3[S:4][C:5]=2[CH:14]=1
Reactant: C#CCn1c(=N)sc2cc(OC)ccc21
Agent: Br
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: COc1ccc2c(c1)sc1nc(C)cn12

Procedure:
In 100 ml of n-butanol was dissolved 5.0 g of 2-amino-6-methoxybenzothiazole. With heating at 100° C., 25.0 g of propargyl bromide was dropwise added to the solution over 2 hours. The mixture was heated for a further 2 hours. After completion of the reaction, the solvent was evaporated to dryness. After the residue was crystallized with acetone, the crystals were recrystallized from isopropyl alcohol to give 25.1 g of 2-imino-6-methoxy-3-propargylbenzothiazole hydrobromide. The hydrobromide, 24.0 g, was added to sodium ethoxideethanol solution(Na, 2.0 g) followed by refluxing for 1.5 hours. After the reaction mixture was evaporated to dryness, water and ethyl acetate were added to the residue followed by separation. The residue obtained from the ethyl acetate phase was dissolved in ethanol and reacted with hydrochloric acid to convert the same into the hydrochloride. Recrystallization from 95% ethanol gave 17.3 g of 7-methoxy-2-methylimidazo[2,1-b]benzothiazole hydrochloride. The hydrochloride, 17.0 g, was added to a mixture of 10 ml of phosphorus oxychloride and 180 ml of dry dimethylformamide. After stirring at room temperature for one hour, the mixture was heated at 60° C. for 7 hours. The reaction solution was evaporated to dryness and the residue was dissolved in water. The solution was alkalized with potassium carbonate and extracted with chloroform. From the chloroform phase, 14.2 g of 3-formyl-7-methoxy-2-methylimidazo[2,1-b]benzothiazole was obtained. The obtained formyl compound, 3.7 g, was suspended in methanol and treated with 1.0 g of sodium borohydride. The reaction mixture was evaporated to dryness, and the obtained residue was recrystallized from ethanol to give 3.5 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH3:18])[CH:12]=2)[CH2:6]1)=[O:4].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:23][C:22]3[CH:25]=[CH:26][CH:27]=[C:20]([F:19])[CH:21]=3)=[C:13]([CH3:18])[CH:12]=2)[CH2:6]1)=[O:4]
Reactant: Fc1cccc(CBr)c1
Reactant: COC(=O)C1CC(=O)N(c2ccc(O)c(C)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1CC(=O)N(c2ccc(OCc3cccc(F)c3)c(C)c2)C1

Procedure:
In analogy to the alkylation described in Example 1d), the (RS)-1-(4-hydroxy-3-methyl-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester is reacted with 3-fluorobenzyl bromide in presence of potassium carbonate in DMF at 80° C. to yield the (RS)-1-[(4-(3-fluoro-benzyloxy)-3-methyl-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a light brown oil; MS: m/e=375 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:3]=1[O:4][C:5]1[C:6](O)=[N:7][C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:9][C:10]=1[CH3:11].O=P(Cl)(Cl)[Cl:27]>>[Cl:27][C:6]1[C:5]([O:4][C:3]2[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:2]=2[Cl:1])=[C:10]([CH3:11])[N:9]=[C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:7]=1
Reactant: COc1ccc(Cl)c(Oc2c(C)nc(N3CCOCC3)nc2O)c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(Cl)c(Oc2c(C)nc(N3CCOCC3)nc2Cl)c1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
1.72 g of 5-(2-chloro-5-methoxy-phenoxy)-6-methyl-2-(morpholin-4-yl)-pyrimidin-4-ol were mixed with 3.3 ml of POCl3. The reaction mixture was stirred at 120° C. for 2 hours, thereafter the excess reagent was distilled off. The residue was taken up in chloroform and washed with water, 1N NaOH and water. The organic phase was dried, concentrated and the residue was recrystallized from ether. There were obtained 1.48 g of 4-[4-chloro-5-(2-chloro-5-methoxy-phenoxy)-6-methyl-pyrimidin-2-yl]-morpholine, m.p. 134° C., MS: M=369.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([C:9](Cl)=[O:10])[CH2:2]2.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C>C1COCC1.ClCCl>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([C:9]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=3)=[CH:17][CH:18]=1)=[O:10])[CH2:2]2
Reactant: O=C(Cl)[C@H]1CN2CCC1CC2
Reactant: COC(=O)c1ccc(-c2ccc(N)cc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(NC(=O)[C@@H]3CN4CCC3CC4)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
679 mg (3.91 mmol) of (3R)-1-azabicyclo[2.2.2]octane-3-carbonyl chloride, 846 mg (3.73 mmol) methyl 4′-amino-1,1′-biphenyl-4-carboxylate, 963 mg (7.45 mmol) of N,N-diisopropylethylamine and 227 mg (1.86 mmol) of 4-N,N-dimethylaminopyridine are dissolved in 5 ml of THF and stirred at RT overnight and then at 50° C. overnight once again. The reaction mixture is taken up in dichloromethane and water, and the aqueous phase is extracted three times with dichloromethane. The crude product is purified by chromatography on silica gel 60 (mobile phase: dichloromethane/triethylamine 100:1→dichloromethane/methanol/triethylamine 50:50:1). The solvent is removed under reduced pressure. The product is taken up in 1N sodium hydroxide solution and extracted a total of three times with ethyl acetate. The organic phase is dried over magnesium sulfate and freed of solvent under reduced pressure. Finally, the last residues of solvent are removed under high vacuum. 50 mg (4% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9]=2[N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[N:4](S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.C1COCC1.CO.[Li+].[OH-]>O>[CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9]=2[N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13][CH2:12]2)[NH:4][CH:3]=1
Reactant: Cc1cn(S(=O)(=O)c2ccccc2)c2ncc(-c3ccccc3)c(N3CCN(C(=O)OC(C)(C)C)CC3)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1c[nH]c2ncc(-c3ccccc3)c(N3CCN(C(=O)OC(C)(C)C)CC3)c12
Temperature: 50 °C
Yield: 58.8 %

Procedure:
tert-Butyl 4-(3-methyl-5-phenyl-1-(phenyl sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (0.9 g, 1.69 mmol) was placed in 1:1 THF:MeOH (10 mL). 3M LiOH (aq., 5.63 mL, 16.9 mmol) was added, and the reaction was heated to 50° C. for 1 hour. The reaction was then cooled, added to water and extracted with DCM. The organics were dried, filtered and concentrated to give the crude product which was purified (500:3 to 500:8 DCM:MeOH) to give tert-butyl 4-(3-methyl-5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (0.390 g, 58.8% yield).
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[NH2:19][C@H:20]([C:31]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:43][CH:44]([CH3:46])[CH3:45])=[O:40])[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:32])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:19][C@H:20]([C:31]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:43][CH:44]([CH3:45])[CH3:46])=[O:40])[C:35]([CH3:37])([CH3:38])[CH3:36])=[O:32])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:5]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
Z-Pro (2.18 g, 8.3 mmol) and Trp-Tle-Leu-OEt (prepared by catalytic hydrogenation of Z-Trp-Tle-Leu-OEt over palladium on charcoal) (3.47 g, 7.6 mmol), and NMM (0.92 mL) are dissolved in 35 mL DMF, cooled to 0° C., and treated with TBTU (2.66 g, 8.3 mmol). The reaction is stirred at 0° C. for 1 hour then removed from the ice bath and stirred at room temperature for 2 hours. The mixture is poured into 350 mL of a saturated solution of sodium bicarbonate which is then extracted with 350 mL of ethyl acetate. The combined organic extracts are washed with 350 mL of 1 M KHSO4, water and brine, and then dried over sodium sulfate. The solvents are removed and the residue chromatographed on silica gel (1.5% MeOH in chloroform) to give Z-Pro-Trp-Tle-Leu-OEt (Seq ID No: 7) (4.7 g). FABMS M+1 690
Reaction SMILES: [CH:1]1([CH:6]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:8][C:9]([F:45])([F:44])[C:10]1[CH:11]=[C:12]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:13][N:14]([C:31]1[N:32]=[N:33][N:34]([CH3:36])[N:35]=1)[C@H:15]1[CH2:21][CH2:20][CH2:19][NH:18][C:17]2[CH:22]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:24]([CH3:26])=[CH:25][C:16]1=2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl.C(Cl)Cl>[F:45][C:9]([F:8])([F:44])[C:10]1[CH:11]=[C:12]([CH:37]=[C:38]([C:40]([F:43])([F:41])[F:42])[CH:39]=1)[CH2:13][N:14]([C@H:15]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:17]2[CH:22]=[C:23]([C:27]([F:28])([F:29])[F:30])[C:24]([CH3:26])=[CH:25][C:16]1=2)[C:31]1[N:32]=[N:33][N:34]([CH3:36])[N:35]=1
Reactant: O=CC1CCCC1
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)N(CC1CCCC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reaction time: 1 h
Yield: 70.3 %

Procedure:
Add cyclopentanecarboxaldehyde (462 mg, 4.71 mmol) to a solution of (S)-(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)amine (520 mg, 0.941 mmol) in acetic acid (1 mL) and 1,2-dichloroethane (10 mL) at room temperature under nitrogen and stir for 1 h. Add sodium triacetoxy borohydride (998 mg, 4.71 mmol) and stir for 5 min. Dilute the mixture with methylene chloride (30 mL) and wash with saturated aqueous sodium bicarbonate solution (2×10 mL). Extract the combined aqueous washes with methylene chloride (20 mL) and wash the combined organic extracts with brined (20 mL) and dry over anhydrous sodium sulfate. Remove the solvents under reduced pressure and purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:2), to provide the title compound as a colorless oil (420 mg, 70%). APCI MS m/z 635 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:21]([N:23]3[CH2:28][CH2:27][S:26](=[O:30])(=[O:29])[CH2:25][CH2:24]3)=[O:22])[N:8]2[CH2:11][CH2:12][O:13][Si](C(C)(C)C)(C)C)=[CH:4][C:3]=1[O:31][CH:32]1[CH2:37][CH2:36][N:35]([CH:38]([CH3:40])[CH3:39])[CH2:34][CH2:33]1.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:21]([N:23]3[CH2:24][CH2:25][S:26](=[O:30])(=[O:29])[CH2:27][CH2:28]3)=[O:22])[N:8]2[CH2:11][CH2:12][OH:13])=[CH:4][C:3]=1[O:31][CH:32]1[CH2:37][CH2:36][N:35]([CH:38]([CH3:40])[CH3:39])[CH2:34][CH2:33]1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCS(=O)(=O)CC4)n(CCO[Si](C)(C)C(C)(C)C)c3cc2Br)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCS(=O)(=O)CC4)n(CCO)c3cc2Br)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
A mixture of [6-bromo-1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-methanone (130 mg, 1.0 eq.) and trifluoroacetic acid in dichloromethane was stirred for 1 h at room temperature and concentrated in vacuo. The crude mixture was partitioned between an aqueous solution of sodium hydroxide and dichloromethane. The aqueous layer was extracted with dichloromethane. Combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo, to yield 106 mg (99%) of the desired product as white foam. MS (m/e): 542.1 (M+H, 100%).