Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12.[H-].[Na+].Cl[CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[Br:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:7]=12
Reactant: Brc1nccc2cc[nH]c12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2ccnc(Br)c21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83.9 %

Procedure:
To a stirred solution of 7-bromo-1H-pyrrolo[2,3-c]pyridine (0.2 g, 1.02 mmol) in DMF (5 mL), cooled to 0° C., was added sodium hydride (46.7 mg, 1.17 mmol). After 10 min the mixture was warmed to 25° C. After 20 min the mixture was recooled to 0° C. and (2-(chloromethoxy)ethyl)trimethylsilane (186 mg, 1.12 mmol) added drop-wise. After 5 min the mixture was warmed to 25° C. After 20 min the mixture was partitioned between ethyl acetate and water. The organic phase was washed with water then concentrated in vacuo. Purification by chromatography (silica, 12 g Analogix column, 0-8% ethyl acetate in hexanes) gave 7-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine (0.28 g, 84%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[CH3:12].[C:17]([O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][C:2]2[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=2[CH2:4][CH2:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][N:7]2[CH3:12])=[O:26])=[CH:23][CH:22]=1)(=[O:19])[CH3:18]
Reactant: CN1CCCCC1CCc1ccccc1N
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C(=O)Nc2ccccc2CCC2CCCCN2C)cc1

Procedure:
Reaction of 2-(o-aminophenethyl)-1-methylpiperidine with p-acetoxybenzoyl chloride in pyridine according to Example 1 provides 4-acetoxy-2'-[2-(1-methyl-2-piperidyl)-ethyl]benzanilide. Analytically pure product is obtained by crystallization from isopropyl ether, m.p. 88°-108° C. (corr.). The broad melting point of the analytically pure material is due to polymorphism.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:9]([CH:11]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:10]>ClCCl>[C:1]([C:22]1[CH:23]=[C:18]([CH2:17][CH:11]([CH2:9][CH3:10])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:19]=[CH:20][C:21]=1[O:24][CH3:25])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C(CC)Cc1ccc(OC)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(CC)Cc1ccc(OC)c(C(C)=O)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
Under stirring and cooling with ice, acetyl chloride (1.00 mL, 14.1 mmol) wad added dropwise to a suspension of aluminum chloride (III) (1.78 g, 13.3 mmol) in dichloromethane (30 mL), and then the mixture was stirred for 30 minutes. Next, a solution of ethyl 2-ethyl-3-(4-methoxyphenyl)propanoate (2.10 g, 8.89 mmol) in dichloromethane (10 mL) was added dropwise. After stirring for 1 hour under cooling with ice, the mixture was allowed to stand overnight at room temperature. The reaction mixture was poured in ice water, the dichloro-methane layer was separated. and the aqueous layer was extracted with dichloromethane. The organic layers were combined and washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (eluent n-hexane:ethyl acetate=6:1 v/v) to afford 1.21 g (49%) of the title compound as a yellow oily product.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Br[CH2:14][C:15]#[N:16]>>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][N:7]1[CH2:8][CH2:9][N:10]([CH2:14][C:15]#[N:16])[CH2:11][CH2:12]1
Reactant: C1COC(CN2CCNCC2)C1
Reactant: N#CCBr
Product: N#CCN1CCN(CC2CCCO2)CC1

Procedure:
The title compound is synthesized by coupling of 1-(Tetrahydro-furan-2-ylmethyl)-piperazine (commercially available from CHESS GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a white solid; ES-MS: M+=210.2.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:8]2[O:13][CH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][C:10](=[O:19])[C:9]=2[CH:20]=1)([CH3:4])([CH3:3])[CH3:2].BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([C:21]([CH3:22])([CH3:24])[CH3:23])[C:8]2[O:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:10](=[O:19])[C:9]=2[CH:20]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CC(=O)c2cc(C(C)(C)C)cc(C(C)(C)C)c2O1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(=O)c2cc(C(C)(C)C)cc(C(C)(C)C)c2o1

Procedure:
A mixture of 3.32 parts of 6,8-di-t-butyl-2,3-dihydro-4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester and 1.84 parts of N-bromosuccinimide was refluxed in 150 parts of carbon tetrachloride for six hours. The solution was cooled and then washed with water. The carbon tetrachloride extract was dried and the solvent was removed by evaporation. The resulting brown residue was crystallised from light petroleum (b.p. 40°-60°C) to give 1.69 parts of 6,8-di-t-butyl-4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester, m.p. 130°-131.5°C. The ester was hydrolysed to the sodium salt using the process of Example 5.
Reaction SMILES: [CH3:1][C@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[O:31])[CH:25]=[CH:26][C:27]=1[F:28].Cl>CN(C)C1C=CN=CC=1.ClCCl>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:31])[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Reactant: CC1(C)C2CC[C@@]1(C)C(=O)CC2=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@@]1(C)C(=O)C(C(=O)Nc1ccc(F)c(Cl)c1)C2=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice-cooled solution of (1R)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (25 mL) was added a solution of 3-chloro-4-fluorophenyl isocyanate (0.34 g, 2.0 mmole) in dry dichloromethane (5 mL). The resulting reaction mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature. It was then stirred at 30° C. for seven hours. The resulting mixture was treated with 2N aqueous HCl (30 mL) and the layers were separated. The aqueous layer was extracted with two additional portions of dichloromethane (50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The desired product was isolated by chromatography on silica gel (10% ethyl acetate/hexane) and recrystallized from 95% ethanol to yield the title compound as a light orange solid (0.39 g, 56% yield), mp=89–91° C.; MS (−) ESI m/z=352 (M−H)−; [α]D25=+24.0° (c=1, EtOH).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[H-].[Na+].[CH3:13][O:14][C:15](=O)[O:16]C.Cl>O1CCCC1>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:15](=[O:16])[O:14][CH3:13])[N:7]=1
Reactant: COC(=O)OC
Reactant: COc1cc(C)nc(N)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Nc1nc(C)cc(OC)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a suspension of 50 g of 2-amino-4-methoxy-6-methylpyrimidine in 1000 ml of tetrahydrofuran was added portionwise, under a nitrogen atmosphere, 42.8 g of 50% sodium hydride while cooling the reaction flask in an ice-water bath. After stirring one hour at 25° C., 58.5 g of dimethylcarbonate was added dropwise at 5° to 25° C. The suspension was stirred about 16 hours at ambient temperature, then 80 ml of concentrated hydrochloric acid was added dropwise while maintaining a reaction temperature of 20° to 25° C. with external ice-bath cooling. The suspension was stirred 0.5 hour, filtered, and the filtrate was dried over sodium sulfate and then concentrated in vacuo. The residue was recrystallized from hexane to yield 54 g of the title compound, m.p. 89°-92.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=O)=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: Cc1cccc(N)n1
Product: COc1ccc(CCNc2cccc(C)n2)cc1

Procedure:
Similarly prepared from 4-methoxyphenyl acetic acid and 2-amino-6-picoline.
Reaction SMILES: [C:1]([N:5]=[N:6][C:7](Cl)([CH3:17])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11])([CH3:4])([CH3:3])[CH3:2].CCCCC.[C:24]1([Mg]Br)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CCOCC>[C:1]([N:5]=[N:6][C:7]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:17])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCOC(=O)CCC(C)(Cl)N=NC(C)(C)C
Reactant: Br[Mg]c1ccccc1
Solvent: CCCCC
Solvent: CCOCC
Product: CCCCOC(=O)CCC(C)(N=NC(C)(C)C)c1ccccc1
Yield: 66 %

Procedure:
To a clean, dry, 500 ml, 4-neck round bottom flask equipped with a mechanical stirrer, thermometer, condenser with drying tube and under a nitrogen atmosphere was added a solution of 70 grams (0.253 moles) of n-butyl 4-t-butylazo-4-chlorovalerate (prepared as in Example XX) in 200 ml. of pentane and the solution cooled to 5° C. With rapid stirring 86.6 ml. (0.26 moles) of a 3 molar solution of phenylmagnesium bromide in ether was added from a dropping funnel over 1/2 hour holding the reaction temperature at 10°-15° C with an ice bath. After the addition was complete, the reaction was stirred for an additional 45 minutes at 15° C. Ice chips were then added to the stirred reaction until the excess phenylmagnesium bromide was destroyed. The reaction mixture was then stirred into 200 ml. of 5% HCl until the magnesium salts dissolved. The pentane layer was separated, washed with 5% HCl, water, dried over anhydrous sodium sulfate, filtered and the pentane evaporated to leave 53 grams (66% yield) of product.
Reaction SMILES: [CH3:1][C:2]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[O:16][CH2:15][CH2:14][NH:13][CH2:12]2)=[CH:7][CH:6]=1.[C:22]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH2:23][C:24]([CH3:26])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(O)(=O)C>[C:29]([O:28][C:22](=[O:27])[CH2:23][CH:24]([N:13]1[CH2:14][CH2:15][O:16][CH:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][C:3]3[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:2]=3[CH3:1])=[CH:10][CH:9]=2)[CH2:12]1)[CH3:26])([CH3:32])([CH3:31])[CH3:30]
Reactant: Cc1cccc(Oc2ccc(C3CNCCO3)cc2)c1C
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1cccc(Oc2ccc(C3CN(C(C)CC(=O)OC(C)(C)C)CCO3)cc2)c1C

Procedure:
A mixture of 2-[4-(2,3-dimethyl-phenoxy)-phenyl]-morpholine (1.00 g; 3.13 mmol), tert-butyl acetoacetate (2.07 mL; 12.5 mmol), sodium triacetoxyborohydride (1.86 g; 8.75 mmol), and a drop of acetic acid, in 1,2-dichloroethane (20 mL) was stirred overnight, at RT. The resulting mixture was treated with 5% aqueous NaHCO3 and extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered, concentrated in vacuo, and purified by column chromatography (SiO2, Et2O/hexanes 1:3) to afford 3-{2-[4-(2,3-dimethyl-phenoxy)-phenyl]-morpholin-4-yl}-butyric acid tert-butyl ester (1.17 g
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11](/[C:14](/[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2F)=[N:15]/[OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>O1CCOCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(/C(=N/O)c2cc(F)ccc2F)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2noc3ccc(F)cc23)CC1
Yield: 85.2 %

Procedure:
4-{(2,5-Difluoro-phenyl)-[(E)-hydroxyimino]-methyl}-piperazine-1-carboxylic acid tert-butyl ester (28.3 g, 82.9 mmol) was suspended in 200 ml dioxane and stirred together with 300 ml 30% KOH in water for 16 hours at reflux. The reaction mixture was cooled and extracted two times with dichloromethane. The organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash-chromatography on silica gel with hexane:ethyl acetate (95:5 to 40:60) to give 22.7 g (85%) of the product as a white solid. MS (m/e): 322.2 (M−H+).
Reaction SMILES: [CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)C(OC(C)(C)C)=O.[F:45][C:46]1[CH:47]=[C:48]([CH:52]=[CH:53][CH:54]=1)[C:49](Cl)=[O:50]>>[CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:12]([CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:26][CH2:27]2)[CH2:11]1)[C:49]([C:48]1[CH:52]=[CH:53][CH:54]=[C:46]([F:45])[CH:47]=1)=[O:50]
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](N(C)C(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Reactant: O=C(Cl)c1cccc(F)c1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](N(C)C(=O)c3cccc(F)c3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(R)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 29, Step H in Step A and 3-fluorobenzoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [CH3:1][Li].[CH3:3][CH:4]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6](=O)[CH2:5]1>C(OCC)C>[CH3:3][C:4]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]([CH3:1])[CH:5]=1
Reactant: CC1CC(=O)C2=C1CCCC2
Reactant: [Li]C
Solvent: CCOCC
Product: CC1=CC(C)C2=C1CCCC2
Reaction time: 1 h
Yield: 45.7 %

Procedure:
Methyl lithium (96 mL, 1.5M, 0.144 mol) was added dropwise to a solution of 4,5,6,7-tetrahydro-1-methyl-indan-3-one (17.7 g, 0.118 mol) in 50 mL of diethyl ether under an argon atmosphere whereupon the reaction mixture was refluxed for 18 hours. The mixture was hydrolyzed, and extracted with diethyl ether. The ether extracts were dried over anhydrous MgSO4 and filtered. To the ether solution 0.5 mL of 6M HCl was added and the solution was stirred for one hour. After this time period the ether solution was washed with water, dried over anhydrous MgSO4, filtered, and concentrated. Distillation at reduced pressure afforded 8.0 g (45 percent) of product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].Cl[C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:23]([CH3:25])[CH3:24])=[C:16]([NH:26][C:27]2[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=2)[N:15]=1.O>CN(C=O)C>[CH:23]([N:20]1[CH:19]=[N:18][C:17]2[C:21]1=[N:22][C:14]([O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[N:15][C:16]=2[NH:26][C:27]1[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=1)([CH3:25])[CH3:24]
Reactant: CC(C)n1cnc2c(Nc3cnn(C)c3)nc(Cl)nc21
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1cnc2c(Nc3cnn(C)c3)nc(Oc3cccc([N+](=O)[O-])c3)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.4 %

Procedure:
To a solution of 3-nitro-phenol (143 mg, 1.03 mmol) in DMF (15 mL) was added sodium hydride (56 mg, 1.4 mmol) slowly and the mixture was stirred at rt for 30 min. 2-chloro-9-isopropyl-N-(1-methyl-1H-pyrazol-4-yl)-9H-purin-6-amine (200 mg, 0.69 mmol), as prepared in step 1 of Example 2, was added slowly. After the addition, the mixture was stirred at 110° C. overnight. The cooled reaction mixture was poured into water (100 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were dried over Na2SO4, concentrated and the residue was purified by flash column chromatography (MeOH:EtOAc=1:10) to give the title compound (50 mg, 18% yield) as light yellow oil.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12]([NH2:17])=[C:11]3[C:18]#[N:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>C1COCC1>[O:29]([C:27]([NH:17][C:12]1[NH:13][C:14]2[C:10]([C:11]=1[C:18]#[N:19])=[CH:9][C:8]([S:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH:16][CH:15]=2)=[O:28])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: N#Cc1c(N)[nH]c2ccc(Sc3ccccc3)cc12
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: N#Cc1c(NC(=O)Oc2ccccc2)[nH]c2ccc(Sc3ccccc3)cc12
Temperature: 25 °C
Yield: 49.6 %

Procedure:
A solution of 5-phenylsulphanyl-2-amino-1H-indole-3-carbonitrile (0.43 g; 1.62 mmol) [Amphethinile, U.S. Pat. No. 4,533,672] in THF (5 ml) and pyridine (0.17 ml; 2.1 mmol) under argon was cooled to 0° C. and treated dropwise with phenyl chloroformate (0.25 ml; 2.0 mmol). The mixture was allowed to warm to room temperature overnight. After dilution with CH2Cl2 the organic phase was washed with water, then brine and dried over MgSO4. The residue was purified by flash chromatography eluting with increasingly polar mixtures of Et2O/CH2Cl2 (5 to 10% Et2O) to give 2-phenoxycarbonylamino-5-phenylsulphanyl-1H-indole-3-carbonitrile as a beige solid (310 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:112])[CH2:7][N:8]([CH2:104][C:105](=[O:111])[O:106][C:107]([CH3:110])([CH3:109])[CH3:108])[C:9](=[O:103])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[C:12]1[CH2:16][N:17]([CH2:77][C:78]1[N:79]([CH2:83][C:84](=[O:102])[N:85]([CH2:94][C:95](=[O:101])[O:96][C:97]([CH3:100])([CH3:99])[CH3:98])[CH2:86][C:87](=[O:93])[O:88][C:89]([CH3:92])([CH3:91])[CH3:90])[CH:80]=[CH:81][N:82]=1)[CH2:18][CH2:19][CH2:20][CH2:21][C@@H:22]([C:41](=[O:76])[NH:42][CH2:43][CH2:44][CH2:45][CH2:46][C@@H:47]([C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[NH:48][C:49](=[O:68])[NH:50][C@H:51]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:52][CH2:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[NH:23]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>CN(C=O)C>[NH2:23][C@H:22]([C:41](=[O:76])[NH:42][CH2:43][CH2:44][CH2:45][CH2:46][C@@H:47]([C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[NH:48][C:49](=[O:68])[NH:50][C@H:51]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:52][CH2:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:77][C:78]1[N:79]([CH2:83][C:84]([N:85]([CH2:86][C:87]([O:88][C:89]([CH3:90])([CH3:91])[CH3:92])=[O:93])[CH2:94][C:95](=[O:101])[O:96][C:97]([CH3:98])([CH3:99])[CH3:100])=[O:102])[CH:80]=[CH:81][N:82]=1)[CH2:16][C:12]1[N:11]([CH2:10][C:9]([N:8]([CH2:104][C:105]([O:106][C:107]([CH3:109])([CH3:108])[CH3:110])=[O:111])[CH2:7][C:6](=[O:112])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:103])[CH:15]=[CH:14][N:13]=1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)[C@H](CCCCN(Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)[C@@H](N)CCCCN(Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
To a solution of the above product, (5S,12S,16S)-tri-tert-butyl 5-(4-(bis((1-(2-(bis(2-tert-butoxy-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)butyl)-1-(9H-fluoren-9-yl)-3,6,14-trioxo-2-oxa-4,7,13,15-tetraazaoctadecane-12,16,18-tricarboxylate in DMF (1.0 mL) was added piperidine (0.50 mL). The mixture was stirred at room temperature for 2 hrs. Solvent was evaporated under reduce pressure to afford a residue, which was purified by biotage eluting with 5% MeOH to 50% MeOH in DCM to afford (7S,14S,18S)-tri-tert-butyl 7-amino-1-(1-(2-(bis(2-tert-butoxy-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)-2-((1-(2-(bis(2-tert-butoxy-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)-8,16-dioxo-2,9,15,17-tetraazaicosane-14,18,20-tricarboxylate (40 mg, 25%) as a white solid. 1H NMR (400 MHz, CDCl3) 6.96 (s, 2H), 6.83 (d, 2H), 6.37 (brs, 1H), 6.33 (brs, 1H), 5.05 (s, 4H), 4.87 (brs, 2H), 4.27-4.24 (m, 2H), 4.18 (s, 4H), 4.10 (s, 4H), 3.88 (d, J=15.2 Hz, 2H), 3.62 (d, J=15.2 Hz, 2H), 3.14-3.12 (m, 1H), 2.30-1.24 (m, 83H); MS (ESI), 674.1 (M/2+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7][NH2:8].I.CS[C:16]1[NH:25][CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1>C(#N)C.C(O)(C(F)(F)F)=O>[N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:24][NH:25][C:16]=1[NH:8][CH2:7][CH2:6][O:5][C:4]1[CH:9]=[CH:10][CH:11]=[CH:12][C:3]=1[O:2][CH3:1]
Reactant: COc1ccccc1OCCN
Reactant: CSC1=Nc2ccccc2CN1
Agent: I
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1ccccc1OCCNC1=Nc2ccccc2CN1
Temperature: 80 °C
Yield: 61.4 %

Procedure:
2-(2-Methoxy-phenoxy)-ethylamine (42 mg, 0.25 mmol) was added to a solution of 2-methylsulfanyl-3,4-dihydro-quinazoline hydroiodide (70 mg, 0.23 mmol) in acetonitrile (1 ml), and the mixture was heated overnight (80° C.) in a screw-capped vial. The title compound (42 mg, 62%) was then isolated from the reaction mixture by preparative, reverse-phase HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=O)=O)=[CH:9][CH:8]=1)[CH3:2].[Sn].Cl.C(Cl)Cl>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([SH:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Sn]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(S)cc1

Procedure:
To a mixture of (4-chlorosulfonyl-phenoxy)-acetic acid ethyl ester (0.98 g, 3.5 mmol) and tin powder (2.1 g) in ehtanol (4.4 mL) is added HCl in dioxane (1.0 M, 4.4 mL) under nitrogen. The mixture is heated to reflux for 2 hrs, it is poured into ice and methylene chloride and filtered. The layers are separated and extracted with methylene chloride, dried and concentrated. The crude product is used for next step without purification.
Reaction SMILES: [F:1][C:2]([F:10])(S(F)(=O)=O)C(O)=O.[OH:11][CH2:12][C@@H:13]([O:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])[CH3:14]>C(#N)C.[Cu]I>[F:1][CH:2]([F:10])[O:11][CH2:12][C@@H:13]([O:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])[CH3:14]
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(O[C@@H](C)CO)c1
Agent: [Cu]I
Solvent: CC#N
Product: COC(=O)c1cc(OCc2ccccc2)cc(O[C@@H](C)COC(F)F)c1
Temperature: 45 °C
Reaction time: 24 h

Procedure:
2,2-Difluoro-2-fluorosulfonyl-acetic acid (CAS no. 1717-59-5) (0.239 mL, 2.31 mmol) was added dropwise, with stirring, to a degassed mixture of methyl 3-[(2S)-1-hydroxypropan-2-yl]oxy-5-phenylmethoxy-benzoate (0.73 g, 2.31 mmol) and copper (I) iodide (88 mg, 0.46 mmol) in acetonitrile (10 mL) at 45° C. The reaction was stirred at 45° C. for 24 hours. The solvent was removed in vacuo and ethyl acetate (30 mL) added. The organics were washed with water (30 mL), brine (30 mL), dried (MgSO4), filtered and the solvent removed in vacuo. The residue was chromatographed on silica, eluting with a gradient of 0-30% ethyl acetate in isohexane, to give the desired compound (0.11 g).