Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[O:9][C:5]=2[CH:4]=1.[BH4-].[Na+].C(O)(=O)C>O1CCCC1>[CH2:8]([NH:7][C:6]1[CH:11]=[C:12]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[OH:9])[CH3:10]
Reactant: COc1cc2oc(C)nc2cc1CC=C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCNc1cc(CC=C(C)C)c(OC)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
231 mg of 6-methoxy-2-methyl-5-(3-methyl-2-butenyl)benzoxazole was dissolved in 5 ml of tetrahydrofuran under nitrogen atmosphere. Thereafter, 0.4 ml of a tetrahydrofuran solution containing 0.12 g of sodium borohydride and 0.1 ml of acetic acid was added to the reaction solution over 20 minutes, and the obtained mixture was stirred at room temperature overnight. The reaction solution was concentrated under a reduced pressure. A saturated ammonium chloride aqueous solution was added to the residue, followed by extraction with methylene chloride. The extract was washed with a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), so as to obtain 80 mg of 2-ethylamino-5-methoxy-4-(3-methyl-2-butenyl)phenol containing a product whose structure was unknown. This compound was directly used in the following reaction without further purification.
Reaction SMILES: [CH3:1][CH:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][CH:7]=1)[CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32].O>CSC.CN(C=O)C>[CH3:1][CH:2]([S:5][C:6]1[CH:7]=[CH:8][C:9]([S:12][CH2:20][CH2:21][N:22]2[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]2=[O:32])=[CH:10][CH:11]=1)[CH2:3][CH3:4]
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: CCC(C)Sc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CSC
Product: CCC(C)Sc1ccc(SCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-(1-methylpropylthio)benzenethiol (8.79 g, 44.3 mmol) in 25 ml of DMS is added, under N2, potassium carbonate (7.05 g, 51.0 mmol) followed by dropwise addition of N-(bromoethyl)-phthalimide (12.94 g, 51.0 mmol) in 30 ml of DMF. The mixture is stirred at RT overnight. Water is then added and the aqueous phase is extracted with ether. The combined organic layers are washed with 5% sodium hydroxide, with water and with brine, dried and the solvent removed to give N-{2-[4-(1-methylpropylthio)-phenylthio]ethyl}phthalimide. Following the procedures of Example 13, the above phthalimide (2.12 g, 5.7 mmol is reacted with hydrazine hydrate (0.28 ml, 5.7 mmol) to give 2-[4-(1-methylpropylthio)phenylthio ethylamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](C#N)=[N:6][CH:7]=1.C[Mg]Br.[CH2:13]1[CH2:17][O:16]CC1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:17](=[O:16])[CH3:13])=[N:6][CH:7]=1
Reactant: C1CCOC1
Reactant: N#Cc1ncc(Br)cn1
Agent: C[Mg]Br
Product: CC(=O)c1ncc(Br)cn1
Temperature: -78 °C
Reaction time: 3.5 h
Yield: 61 %

Procedure:
To a solution of 5-bromopyrimidine-2-carbonitrile (221 mg, 1.2 mmol) in THF (10 ml) was added methylmagnesium bromide (3.0 ml, 4.20 mmol, 1.4 molar, THF) at −78° C. under nitrogen. The solution was stirred at −78° C. for 3.5 hours, and then quenched with satd aq NH4Cl, and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and concentrated. The reaction was purified by column chromatography on silica gel (petroleum ether: EtOAc=1:0 to 0:1) to afford 1-(5-bromopyrimidin-2-yl)ethanone (1.55 mg, 61% yield). 1H NMR (CDCl3 500 MHz): δ 9.00 (s, 2H), 2.80 (s, 3H).
Reaction SMILES: [C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]I)#[N:2].[Br:16][C:17]1[N:22]=[C:21]([O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:20]=[CH:19][CH:18]=1>>[C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:29]1[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][O:23][C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([Br:16])[N:22]=2)[CH2:27][CH2:28]1)#[N:2]
Reactant: Brc1cccc(OCCN2CCNCC2)n1
Reactant: CC(C)C(C#N)(CCCI)c1cccs1
Product: CC(C)C(C#N)(CCCN1CCN(CCOc2cccc(Br)n2)CC1)c1cccs1

Procedure:
The title compound was synthesized in accordance with Example 75 from 4-cyano-4-(2-thienyl)-5-methylhexyl iodide and 1-[2-(6-bromo-2-pyridyloxy)ethyl]piperazine. The physico-chemical data of the compound was as below.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][NH:8][C:9](=[O:12])[C:10]=2[N:11]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][C:16]=1[CH3:24].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[CH3:24][C:16]1[CH:17]=[C:18]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]=[CH:7][NH:8][C:9](=[O:12])[C:10]=3[N:11]=2)[CH:19]=[CH:20][C:15]=1[O:14][CH3:13]
Reactant: COc1ccc(B(O)O)cc1C
Reactant: O=c1[nH]cnc2ccc(Cl)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ccc3nc[nH]c(=O)c3n2)cc1C
Temperature: 25 °C
Yield: 76.8 %

Procedure:
To a solution of 6-chloro-pyrido[3,2-d]pyrimidin-4(3H)one (1.94 mmole) in 1,4-dioxane (40 ml) and water (20 ml) was added 4-methoxy-3-methylphenyl boronic acid (2.33 mmole), potassium carbonate (4.85 mmole) and tetrakis(triphenylphosphine)palladium(0) (0.097 mmole). The reaction mixture was refluxed for two hours, cooled to room temperature and the solvents were evaporated in vacuo. The residue was adsorbed on silica and purified by silica gel column chromatography (the mobile phase being a methanol/dichloromethane mixture in a ratio of 3:97), affording the title compound as a pure white powder (398 mg, yield 77%) which was characterized by its mass spectrum as follows: MS (m/z): 268 ([M+H]+, 100).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=1[CH2:28][CH3:29])[CH2:10][C:9]2([CH3:31])[CH3:30])=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH2:28]([C:17]1[CH:18]=[CH:19][C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:21][C:16]=1[CH:11]1[CH2:10][C:9]([CH3:31])([CH3:30])[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12]1)[CH3:29]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cc(N3CCOCC3)ccc1CC)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc(N2CCOCC2)cc1C1CC(C)(C)c2cc(C(=O)O)ccc2N1
Temperature: 60 °C
Reaction time: 12 h
Yield: 90.5 %

Procedure:
To a stirred mixture solution of 2-(2-ethyl-5-morpholin-4-yl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.6 g, 1.4 mmol) in methanol (10 mL) and tetrahydrofuran (20 mL) was added 30% sodium hydroxide in water (10 mL). The reaction mixture was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(2-ethyl-5-morpholin-4-yl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.5 g, 89%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=395.2.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][C:23]=3[O:32][CH3:33])[CH2:14][CH2:13]2)=[O:11])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:47]([CH3:49])[CH3:48]>CN(C)C=O.C(OCC)(=O)C>[CH:47]([N:37]1[CH2:36][CH2:35][CH:34]([CH:9]([C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][C:23]=3[O:32][CH3:33])[CH2:14][CH2:13]2)=[O:11])[CH2:39][CH2:38]1)([CH3:49])[CH3:48]
Reactant: CC(C)I
Reactant: COc1ccc2ccccc2c1CCCCN1CCN(C(=O)C(c2ccc(F)cc2)C2CCNCC2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2ccccc2c1CCCCN1CCN(C(=O)C(c2ccc(F)cc2)C2CCN(C(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.20 g of 4-(1-(4-Fluorophenyl)-2-{4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazin-1-yl}-2-oxoethyl)piperidine hydrochloride obtained in Example 11(5) was dissolved in 2 ml of dimethylformamide, and 93 mg of potassium carbonate and 41 μl of 2-iodopropane were added, followed by stirring at room temperature overnight. The reaction solution was diluted with ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (Chromatorex NH, hexane:ethyl acetate=4:1) to give 0.15 g of 1-isopropyl-4-(1-(4-fluorophenyl)-2-{4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazin-1-yl}-2-oxoethyl)piperidine as an oil.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([NH2:7])[C:4]([Cl:8])=[CH:3][CH:2]=1.[O-:9][C:10]#[N:11].[K+]>O.C(O)(=O)C>[Cl:8][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[NH:7][C:10]([NH2:11])=[O:9]
Reactant: Nc1ccccc1Cl
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1ccccc1Cl
Temperature: 15 °C
Yield: 70.4 %

Procedure:
O-chloroaniline (50 g) was added in water (400 g) and acetic acid (200 g), followed by cooling to 15° C. Then, a solution of potassium cyanate (63.6 g) and water (300 g) was added dropwise at not more than 15° C. over 40 minutes. The mixture was heated to 30° C., filtered and then washed with cold water to obtain a white crystal. This crystal was recrystallized from a solution of ethanol (350 g) and water (100 g) to obtain 47.1 g of o-chlorophenylurea as a white needle crystal.
Reaction SMILES: Cl.CN.[CH2:4]([N:6](CC)CC)C.Br[C:12]1[N:16]([C@H:17]2[O:29][C@@H:28]([CH2:30][O:31]C(=O)C)[C@H:23]([O:24]C(=O)C)[C@@H:18]2[O:19]C(=O)C)[C:15]2[CH:35]=[C:36]([Cl:40])[C:37]([Cl:39])=[CH:38][C:14]=2[N:13]=1.C(O)C>CN(C=O)C>[Cl:39][C:37]1[C:36]([Cl:40])=[CH:35][C:15]2[N:16]([C@H:17]3[O:29][C@@H:28]([CH2:30][OH:31])[C@H:23]([OH:24])[C@@H:18]3[OH:19])[C:12]([NH:6][CH3:4])=[N:13][C:14]=2[CH:38]=1
Reactant: CCN(CC)CC
Reactant: CC(=O)OC[C@@H]1O[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: CNc1nc2cc(Cl)c(Cl)cc2n1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Methylamine hydrochloride (3.0 g, 45 mmol), triethylamine (3 mL), and 2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole (0.6 g, 1.1 mmol) were combined with absolute ethanol (25 mL) and stirred at 80° C. for 24 h. The reaction mixture was separated between saturated sodium bicarbonate (50 mL) and ethyl acetate (150 mL). The organic layer was dried with sodium sulfate, concentrated and absorbed onto silica gel (15 g). This material was dry loaded onto a silica gel column (5 cm×10 cm, 230-400 mesh) with 1:10 methanol:dichloromethane. The main product came off the column as a white solid (0.22 g, 0.62 mmol, 54%) m.p. 238-240° C.; [a]20D=(−) 15.2 (c=0.5 DMF).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:12])[CH:3]=1.[N+](=[CH2:15])=[N-]>C(OCC)(=O)C.C(OCC)C>[CH3:15][O:7][C:6](=[O:8])[C:5]1[C:9]([CH3:11])=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[Cl:12]
Reactant: C=[N+]=[N-]
Reactant: Cc1cc(Br)cc(Cl)c1C(=O)O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C)cc(Br)cc1Cl
Reaction time: 1 h
Yield: 113 %

Procedure:
4-Bromo-2-chloro-6-methylbenzoic acid (1.10 g, 4.41 mmol) was dissolved in ethyl acetate (15 mL). A solution of diazomethane in diethyl ether was added until the yellow colour persisted. After fifteen minutes the reaction was quenched with acetic acid. After one hour, the mixture was washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated to provide the title compound as a yellow oil (1.31 g, 113%). 1H NMR CDCl3: 7.43 (s, 1H), 7.31 (s, 1H), 3.94 (s, 3H), 2.33 (s, 3H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([N:24]([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26])[C:11]1[S:12][CH:13]=[C:14]([CH:16]=[N:17][S:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[Si:1]([O:8][CH2:9][CH:10]([N:24]([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[S:25]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)(=[O:26])=[O:27])[C:11]1[S:12][CH:13]=[C:14]([CH2:16][NH:17][S:18]([C:20]([CH3:22])([CH3:23])[CH3:21])=[O:19])[CH:15]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)CCN(C(CO[Si](C)(C)C(C)(C)C)c1cc(C=NS(=O)C(C)(C)C)cs1)S(=O)(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCN(C(CO[Si](C)(C)C(C)(C)C)c1cc(CNS(=O)C(C)(C)C)cs1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-[2-{[tert-butyl(dimethyl)silyl]oxy}-1-(4-{[(tert-butylsulfinyl)imino]methyl}thiophen-2-yl)ethyl]-N-(3-methylbutyl)benzenesulfonamide (146 mg, 0.244 mmol) was dissolved in 2.4 mL MeOH at −78° C. Sodium borohydride (11.99 mg, 0.317 mmol) was added and the mixture was then warmed to room temperature and stirred for 1 hour. The reaction was quenched slowly with saturated NaHCO3, after which DCM was added and the phases separated with a phase extractor. The DCM was removed under reduced pressure.
Reaction SMILES: [C:1]([O:4][CH:5]=[CH2:6])(=[O:3])[CH3:2].[CH3:7]OCCOCCO>CCCCCC>[C:1]([O:4][CH:5]=[CH2:6])(=[O:3])[CH3:2].[C:1]([O:4][CH3:5])(=[O:3])[CH:2]=[CH2:7]
Reactant: COCCOCCO
Solvent: C=COC(C)=O
Solvent: CCCCCC
Product: C=CC(=O)OC
Yield: 5.4 %

Procedure:
One hundred grams of the hexane--vinyl acetate--methyl acry azeotrope and 50 grams of diethylene glycol methyl ether were charged to the vapor-liquid equilibrium still and refluxed for five hours. Analysis gave a vapor composition of 78.3% hexane, 16.3% vinyl acetate and 5.4% methyl acrylate and a liquid composition of 59.7% hexane, 27.5% vinyl acetate and 12.8% methyl acrylate. This indicates a relative volatility of hexane to vinyl acetate of 2.2, of hexane to methyl acrylate of 3.2 and of vinyl acetate to methyl acrylate of 1.4.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11]3=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:23]=[CH:24][N:10]3[N:9]=2)[CH:5]=[N:6][CH:7]=1.N1C=CC=CC=1.Cl[C:38](=[O:45])[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].O>C(Cl)Cl>[CH2:15]([NH:14][C:12]1[C:11]2=[C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:23]=[CH:24][N:10]2[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:38](=[O:45])[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:7]=[N:6][CH:5]=2)[N:13]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)CC(=O)Cl
Reactant: Nc1cncc(-c2nc(NCc3ccccc3)c3c(-c4ccccc4)ccn3n2)c1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)CC(=O)Nc1cncc(-c2nc(NCc3ccccc3)c3c(-c4ccccc4)ccn3n2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 62.2 %

Procedure:
2-(5-Aminopyridin-3-yl)-N-benzyl-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (0.500 g, 1.27 mmol) was dissolved in CH2Cl2 (10 mL) and pyridine (0.103 mL, 1.27 mmol) was added, followed by the addition of ethyl 3-chloro-3-oxopropanoate (0.192 g, 1.27 mmol). The reaction mixture was stirred at room temperature for 14 h. Water (10 mL) was added to the reaction mixture followed by addition of CH2Cl2 (10×4 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using CombiFlash (REDISEP®, silica gel, 24 g, 3% methanol in CH2Cl2) to afford ethyl 3-((5-(4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-yl)amino)-3-oxopropanoate (0.400 g, 62.0%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (t, J=7.2 Hz, 3H), 3.54 (s, 2H), 4.15 (q, J=7.2 Hz, 2H), 4.82 (d, J=5.6 Hz, 2H), 6.66 (t, J=5.6 Hz, 1H), 6.81 (d, J=2.8 Hz, 1H), 7.27-7.55 (m, 10H), 7.91 (d, J=2.8 Hz, 1H), 8.81 (d, J=2.4 Hz, 1H), 8.87 (dd, J=2.4 Hz, J=1.6 Hz, 1H), 9.09 (d, J=1.6 Hz, 1H), 10.52 (s, 1H). LCMS Condition B-49: retention time 1.91 min, [M+1]=507.2. HPLC Condition B-32: retention time 10.36 min, Purity 98.80%.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:12]([NH:14][C@H:15]([C:23]([NH:25][C@@H:26]([C:44]([NH:46][C@H:47]([C:63]([O:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:64])[CH2:48][C:49]1[CH:54]=[CH:53][C:52]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[CH:51][CH:50]=1)=[O:45])[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:43])[NH:32][S:33]([C:36]1[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=1)(=[O:35])=[O:34])=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:80][C:81]([O:84][C:85]([NH:87][C@H:88]([C:93]([OH:95])=O)[CH2:89][C:90]([NH2:92])=[O:91])=[O:86])([CH3:83])[CH3:82].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:87]([C:85]([O:84][C:81]([CH3:80])([CH3:82])[CH3:83])=[O:86])[C@H:88]([C:93]([NH:1][C@H:2]([C:12]([NH:14][C@H:15]([C:23]([NH:25][C@@H:26]([C:44]([NH:46][C@H:47]([C:63]([O:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:64])[CH2:48][C:49]1[CH:50]=[CH:51][C:52]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[CH:53][CH:54]=1)=[O:45])[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:43])[NH:32][S:33]([C:36]1[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=1)(=[O:34])=[O:35])=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:95])[CH2:89][C:90](=[O:91])[NH2:92]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](COCc2ccccc2)NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](COCc2ccccc2)NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)OCc2ccccc2)cc1

Procedure:
Using 2.20 g Boc-Ser(Bzl)-Phe-D-Arg(Tos)-Tyr(Bzl)-OBzl, 0.61 g Boc- Asn-OH, 0.51 g HONB and 0.58 g DCC, the desired product was obtained in exactly the same manner as in Example 1-(IV).
Reaction SMILES: Cl.[CH3:2][C:3]1([OH:7])[CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.[C:15]([C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:27]=1[OH:28])[C:22](O)=[O:23])([CH3:18])([CH3:17])[CH3:16].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:29]([C:26]1[CH:25]=[C:21]([C:22]([N:5]2[CH2:6][C:3]([OH:7])([CH3:2])[CH2:4]2)=[O:23])[CH:20]=[C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:27]=1[OH:28])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC1(O)CNC1
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(O)CN(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
3-Methyl-azetidin-3-ol hydrochloride (0,6 g, 4,84 mmoles) was suspended in tetrahydrofuran (50 ml) and Triethylamine (1,2 ml) was added. The mixture was stirred at room temperature (approximately 25° C.) for 30 minutes and 3,5-di-tert-butyl-4-hydroxy benzoic acid (1,26 g, 5,1 mmoles) was added in one portion, the mixture was cooled to 0° C. and subsequently a solution of dicyclohexylcarbodiimide (1 g, 4,84 mmoles) in tetrahydrofuran (27 ml) was added. The reaction mixture was then heated to reflux for 3,5 hours, cooled and the insoluble solid was filtered off. The filtrate was concentrated using a rotavapor, the remaining solid dissolved in ethyl acetate, washed with water, dried over magnesium sulfate, filtered and evaporated to dryness. The crude residue obtained is crystallized from diethyl ether to give 1,14 g (73% of theoretical yield) of (3,5-di-tert-butyl-4-hydroxy-phenyl)-(3-hydroxy-3-methyl-azetidin-1-yl)-methanone.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:10][C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:22](I)[CH3:23]>C1COCC1>[Cl:1][C:2]1[C:3]2[CH:10]([CH2:22][CH3:23])[C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1C(=O)Nc2ncnc(Cl)c21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
Add 4-chloro-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.5 g; 0.0029 mol; 1.0 equiv) in THF (20 mL) and cool to −78° C. under argon atmosphere. Add drop-wise lithium hexamethyl-disilazide (5.89 mL, 0.0059 mol; 2.0 equiv; 1 M in THF). Stir at −78° C. for 30 min. Add drop-wise ethyl iodide (0.48 mL; 0.0059 mol; 2.0 equiv) and allow the reaction temperature to come to 0° C. slowly. Stir for 4 h. Quench with saturated ammonium chloride aqueous and extract with EA. Evaporate the organic layer to get the title compound (0.24 g; 41.38%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([OH:22])([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[SH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1I.FC1C=C(O)C=CC=1[N+]([O-])=O.NC1C=CC(O)=CC=1F.CI>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[S:21][C:25]2[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:24]=2[F:23])([OH:22])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(F)ccc2S)CC1
Reactant: COc1ccc(I)c(F)c1
Agent: Nc1ccc(O)cc1F
Agent: O=[N+]([O-])c1ccc(O)cc1F
Solvent: CI
Product: COc1ccc(Sc2ccc(F)cc2C2(O)CCN(C(=O)OC(C)(C)C)CC2)c(F)c1

Procedure:
Prepared from 4-hydroxy-4-(2-mercapto-5-fluoro-phenyl)-piperidine-1-carboxylic acid tert-butyl ester and 2-fluoro-1-iodo-4-methoxy-benzene (prepared from 3-fluoro-4-nitro-phenol by reduction to 4-amino-3-fluoro-phenol as reported by Hogdson and Nicholson J. Chem. Soc. 1941, 645-646 followed by diazotization according to the general procedure by Tunney and Stille J. Org. Chem. 1987, 52, 748-753 followed by alkylation with methyl iodide according to the general procedure by Uozumi et al. J. Org. Chem. 1993, 58, 1945-1945).