Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[C:17]([NH2:23])[N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:24]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:20]([N:19]1[C:15]([C:13]2[N:14]=[C:7]3[C:6]4[CH:24]=[C:2]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH:3]=[CH:4][C:5]=4[O:11][CH2:10][CH2:9][N:8]3[CH:12]=2)=[N:16][C:17]([NH2:23])=[N:18]1)([CH3:22])[CH3:21]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)n1nc(N)nc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1nc(N)nc1-c1cn2c(n1)-c1cc(-c3ccccc3)ccc1OCC2
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 16 %

Procedure:
A mixture of 5-(10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-amine (0.5 mmol), phenylboronic acid (200 mg, 0.75 mmol), Cs2CO3 (490 mg, 1.5 mmol) was stirred in dioxane and water (5:1, 3.0 mL) followed by the addition of Pd(dppf)Cl2 (30 mg). The reaction mixture was bubbled with N2 gas for 10 min, the reaction tube was sealed, and the contents were stirred at 130° C. under microwave irradiation for 30 min. The mixture was filtered through celite and the filtrate was concentrated and purified with prep-HPLC to give 556 (31 mg, 18%). 1H-NMR (DMSO, 400 MHz): δ 8.68 (s, 1H), 8.16 (s, 1H), 7.64-7.68 (m, 3H), 7.38-7.50 (m, 2H), 7.34-7.37 (m, 1H), 7.17 (d, J=8.4 Hz, 2H), 5.49-5.55 (m, 1H), 4.54-4.60 (m, 4H), 1.46 (d, J=6.8 Hz, 6H)
Reaction SMILES: CS([O:5][C:6]1[C:28](=[O:29])[N:10]2[CH2:11][C@@H:12]([O:26][CH3:27])[CH2:13][CH2:14][C@@H:15]([N:16]([C:19](=[O:25])[C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH2:17][CH3:18])[C:9]2=[N:8][C:7]=1[C:30]([NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)=[O:31])(=O)=O.[OH-].[Na+].Cl>CC(O)C>[CH2:17]([N:16]([C@@H:15]1[CH2:14][CH2:13][C@H:12]([O:26][CH3:27])[CH2:11][N:10]2[C:28](=[O:29])[C:6]([OH:5])=[C:7]([C:30]([NH:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)=[O:31])[N:8]=[C:9]12)[C:19](=[O:25])[C:20]([N:22]([CH3:23])[CH3:24])=[O:21])[CH3:18]
Reactant: CCN(C(=O)C(=O)N(C)C)[C@@H]1CC[C@H](OC)Cn2c1nc(C(=O)NCc1ccc(F)cc1)c(OS(C)(=O)=O)c2=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCN(C(=O)C(=O)N(C)C)[C@@H]1CC[C@H](OC)Cn2c1nc(C(=O)NCc1ccc(F)cc1)c(O)c2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (7S,10R)-10-[[(dimethylamino)(oxo)acetyl](ethyl)amino]-2-{[(4-fluorobenzyl)amino]carbonyl}-7-methoxy-4-oxo-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-3-yl methanesulfonate (1 g, 1.72 mmol) in 2-propanol (17 mL) was added 2M NaOH (2.58 mL, 5.16 mmol). The resulting mixture was stirred at ambient temperature for 30 minutes, quenched with HCl (1M, 5.16 mL, 5.16 mmol), and extracted with EtOAc (3×). Three additional reactions on the same scale were performed in parallel. The combined organic layers from all four reactions were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by reverse phase HPLC (C18 Sunfire column) using a water/acetonitrile mobile phase gradient containing 0.5% TFA or by precipitation from water to provide N-ethyl-N-((7S,10R)-2-{[(4-fluorobenzyl)amino]carbonyl}-3-hydroxy-7-methoxy-4-oxo-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-10-yl)-N′,N′-dimethylethanediamide. LC-MS: 504.5 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.O.Cl.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:16]1[CH2:17][CH2:18][NH:13][CH2:14][CH:15]=1
Reactant: O=C1CCNCC1
Reactant: Fc1cccc2cc[nH]c12
Agent: Cl
Solvent: O
Product: Fc1cccc2c(C3=CCNCC3)c[nH]c12
Yield: 65.6 %

Procedure:
Beginning with 2.0 gm (14.8 mMol) 7-fluoro-1H-indole and 4.6 gm (30.0 mMol) 4-piperidone hydrochloride monohydrate, 2.1 gm (66%) of the title compound were recovered as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:15]([O:22][C:23]1[C:28](F)=[CH:27][C:26]([Cl:30])=[CH:25][N:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN1C(=O)CCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:28]2[C:23]([O:22][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:24][CH:25]=[C:26]([Cl:30])[CH:27]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: Fc1cc(Cl)cnc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)cnc2OCc2ccccc2)C1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 51.2 %

Procedure:
To 3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (0.35 g, 2.0 mmol) in NMP (3 mL) was added 60% NaH in mineral oil (0.08 g, 2.0 mmol). After 20 min at rt, the reaction was heated to 50° C. for 20 min, cooled to rt and the title compound from step A (0.40 g, 1.7 mmol) in NMP (1 mL) was added. The reaction was then heated in a microwave reactor at 145° C. for 1 h, cooled to rt, poured into H2O and extracted with EtOAc (2×). The combined organics were washed with brine and dried. Silica gel chromatography (2-15% EtOAc in hexanes) gave 0.34 g (51% yield) of the title compound as a white solid. 1H NMR (CDCl3): 7.74 (d, J=2.1 Hz, 1H), 7.46 (d, J=7.0 Hz, 2H), 7.39-7.30 (m, 3H), 6.77 (d, J=2.1 Hz, 1H), 5.42 (s, 2H), 4.87-4.82 (m, 1H), 4.26 (dd, J=10.5, 6.4 Hz, 2H), 4.05 (dd, J=10.3, 4.2 Hz, 2H), 1.44 (s, 9H).
Reaction SMILES: [C:1](=O)(O)[O-:2].[Na+].C=O.[C:8]1([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CS(C)=O>[C:15]([O:17][CH3:18])(=[O:16])[CH:14]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:1][OH:2]
Reactant: COC(=O)Cc1ccccc1
Reactant: O=C([O-])O
Agent: C=O
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(CO)c1ccccc1
Reaction time: 1.5 h
Yield: 80 %

Procedure:
A three necked one-liter flask equipped with a drying tube, a thermometer and a stopper was flame-dried, cooled and then charged with sodium bicarbonate (2.1 g; 0.025 mole), paraformaldehyde (34.74 g; 1.1 mole) and 300 mL of dimethylsulfoxide (DMSO). The air in the flask was purged with dry nitrogen and methyl phenylacetate (150:18 g; 1 mole) was added in one portion. Residual ester was washed into the flask using dry DMSO (5 mL). The slurry was then stirred magnetically (initial temperature 22°-23° C.) and the temperature rose slowly over one hour to 33° C. The temperature remained at about 32°-33° C. for 1.5 hrs. at which time the reaction liquid was almost a clear solution. The temperature was then raised to 45°-46° C. over 30 min. and kept at this temperature for 12 hrs. The solution was then allowed to cool and left at room temperature for 9 hrs. The reaction mixture was clear and essentially colorless with only a small amount of a white solid appearing at the bottom of the flask. NMR analysis of the solution indicated approximately an 80% yield of methyl tropate.
Reaction SMILES: [N:1]#[C:2]Br.[C:4]1([CH:10]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][NH:14][CH2:13][CH2:12][NH:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[C:4]1([CH:10]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]([C:2]#[N:1])[CH2:13][CH2:12][NH:11]2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: N#CBr
Reactant: c1ccc(C2NCCNCc3ccccc32)cc1
Solvent: CO
Product: N#CN1CCNC(c2ccccc2)c2ccccc2C1
Reaction time: 3 h
Yield: 35.7 %

Procedure:
A solution of 6.87 g (63 mmol) of cyanogen bromide in 15 mL of methanol was added to a solution of 15 g (63 mmol) of 1,2,3,4,5,6-hexahydro-1-phenyl-2,5-benzodiazocine in 110 mL of methanol at 0°. The reaction was allowed to come to room temperature and stirred 3 hours. The reaction was stripped and the residue partitioned between ethyl acetate and water made slightly acidic with 6N HCl. The aqueous layer was made basic, extracted into ethyl acetate, dried, stripped and chromatographed on ten times its weight of silica gel, eluting with 1:9 ethyl acetate/dichloromethane. There was obtained 5.93 g of 6-phenyl-3,4,5,6-tetrahydro2,5-benzodiazocine-2(1H)-carbonitrile, mp 134°-135° from dichloromethane/ether/hexane.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:16][CH2:15][CH2:14][C@:13]([CH2:23][C:24]([CH3:26])=[CH2:25])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:36])C=1>C(Cl)Cl.C(OC)(C)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:16][CH2:15][CH2:14][C@:13]([CH2:23][C:24]3([CH3:26])[CH2:25][O:36]3)([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1
Reactant: C=C(C)C[C@]1(c2ccccc2)CCCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: C[C@@H](c1ccc(Br)cc1)N1CCC[C@](CC2(C)CO2)(c2ccccc2)OC1=O
Yield: 90 %

Procedure:
To a solution of (S)-3-((S)-1-(4-bromophenyl)ethyl)-7-(2-methylallyl)-7-phenyl-1,3-oxazepan-2-one (300 mg, 0.7 mmol) in dry CH2Cl2 (20 mL) was added m-CPBA (605 mg, 3.5 mmol) at room temperature. The reaction mixture was stirred until the starting material was completed. The mixture was diluted with (CH3)3COCH3 (30 mL), washed by 30% Na2S2O3, and NaHCO3 (aq.) for three times, dried over Na2SO4, filtered, and concentrated to give (7S)-3-((S)-1-(4-bromophenyl)ethyl)-7-((2-methyloxiran-2-yl)methyl)-7-phenyl-1,3-oxazepan-2-one (280 mg, 90%), which was used directly for the next step without further purification.
Reaction SMILES: C(OC([CH:6]1[CH2:11][C:10]([C:18]#[N:19])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][CH2:8][C:7]1=[O:20])=O)C.Cl>C(O)(=O)C.O.[Na+].[Cl-]>[O:20]=[C:7]1[CH2:8][CH2:9][C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([C:18]#[N:19])[CH2:11][CH2:6]1
Reactant: CCOC(=O)C1CC(C#N)(c2ccccc2)CCC1=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#CC1(c2ccccc2)CCC(=O)CC1
Temperature: 2.5 °C
Reaction time: 3.5 h

Procedure:
The title compound of step 1 (70.8 g, 261 mmol) in a mixture of acetic acid (810 mL) and concentrated hydrochloric acid (354 mL) was heated to boiling for 3.5 h under DC control. The mixture was then cooled to 0 to 5° C., diluted with water (1 L), saturated with NaCl and extracted cold with ethyl acetate (3×300 mL). The ethyl acetate phase was washed with water and concentrated to low volume in a vacuum. The solid residue was dissolved once again in ethyl acetate, washed with NaHCO3 solution and concentrated until dry.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4][C@@H:5]([C:7]([OH:9])=[O:8])[NH2:6].C([O-])([O-])=O.[K+].[K+]>Cl[Cu].O>[NH:6]1[C:10]2[C:3](=[CH:2][CH:13]=[CH:12][CH:11]=2)[CH2:4][C@H:5]1[C:7]([OH:9])=[O:8]
Reactant: N[C@@H](Cc1ccccc1Br)C(=O)O
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)[C@@H]1Cc2ccccc2N1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
A flask was charged successively with 366 mg (1.5 mmol) (S)-2-bromophenylalanine, 217 mg (1.6 mmol) K2CO3, 3 mg (0.03 mmol) CuCl and 3.4 g H2O. The reactor was flushed with argon and then kept under a slow stream of argon. The reaction mixture was stirred and heated until 95° C. and kept at this temperature. Samples were taken regularly and analyzed by HPLC. After 2 hour full conversion of (S)-2-bromophenylalanine was found. The reaction mixture was cooled to 25° C. and analyzed by HPLC. The yield in solution of (S)-2,3-dihydro-1H-indole-2-carboxylic acid was 81.1%, ee>99%.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[NH2:12][CH:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15].S(=O)(=O)(O)O>O1CCOCC1>[C:1]([NH:12][CH:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(N)C(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)C(NC(=O)c1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
119 ml. (1.025 moles) of benzoyl chloride and 760 ml. of 2N. sodium hydroxide solution (1.52 moles) are simultaneously added to a mixture of 100 g. (0.854 mole) of DL-valine, 200 ml. of dioxane and 350 ml. of 2N. sodium hydroxide solution (0.7 mole) stirred at 0°-5° C., the additions being at rates such that the pH of the reaction mixture is always basic and the temperature does not exceed 5° C., the reaction being exothermic. The reaction mixture is allowed to warm to 20°-25° C., stirred at 20°-25° C. for 2 hours, cooled to 0° C. and acidified with about 40 ml. of concentrated sulfuric acid. The precipitate is collected by filtration, washed with water, air dried for 16 hours and dissolved in ethyl acetate. The ethyl acetate solution is decanted from some residual water, and petroleum ether is added to obtain a precipitate. The precipitate is subjected to high vacuum for 8 hours to remove some residual dioxane and obtain the product (165.81 g. (88%)), m.p. 125°-128° C. Lit.: 132° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[C:10]([Cl:17])=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH2:12]Br)=[O:8])=[CH:5][CH:4]=1.[C-:20]#[N:21].[K+].O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[C:10]([Cl:17])=[C:11]([CH2:12][C:20]#[N:21])[CH:14]=[CH:15][CH:16]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: [C-]#N
Reactant: COc1ccc(C(=O)c2cccc(CBr)c2Cl)cc1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(C(=O)c2cccc(CC#N)c2Cl)cc1
Yield: 97.6 %

Procedure:
3-(4-Methoxybenzoyl)-2-chlorotoluene (4.55 g, 17.45 mmol) [prepared by the method described in Example 1(a)]was dissolved in benzene (150 ml), and the solution was purged with nitrogen. N-Bromosuccinimide (3.10 g, 1 eq.) and benzoyl peroxide (0.42 g, 0.1 eq.) were added and the reaction mixture was heated at reflux overnight. Since there was an appreciable amount of unreacted starting material still present in the reaction mixture, additional amounts of N-bromosuccinimide (1.55 g, 0.5 eq.) and benzoyl peroxide (0.21 g, 0.05 eq.) were added, and the heating was continued. After 3 h the reaction mixture was cooled to room temperature, and diluted with ether. The organic layer was separated, washed with water and brine, and dried over MgSO4. The solvent was removed in vacuo to give 7.6 g of an orange oil. Purification by flash chromatography (10/90 EtOAc/hexanes) gave 3-(4-methoxybenzoyl)-2-chlorobenzyl bromide as an oil that slowly crystallized to a solid (5.13 g, 87% yield). 1H NMR showed it was approximately 90% pure 3-(4-methoxybenzoyl)-2-chlorobenzyl bromide (4.97 g, 1 eq.) [prepared as described above] was added to a solution of KCN (1.05 g, 1.1 eq.) in dry DMSO (40 ml) under a nitrogen atmosphere. After 30 min the reaction mixture was poured into water (1 L) and the product was extracted into ethyl acetate. The organic extract was washed with water and brine, and dried over MgSO4. The solvent was evaporated in vacuo to give 2-[3-(4-methoxy-benzoyl)-2-chlorophenyl]acetonitrile (4.08 g, 98% yield) as an oil.
Reaction SMILES: [CH3:1][C:2]([NH2:11])([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[CH:5]=1)[CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]([CH3:22])=[CH2:21]>CN(C)C=O>[CH3:3][C:2]([NH:11][CH2:21][C:20]([CH3:22])=[CH2:19])([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[CH:5]=1)[CH3:1]
Reactant: C=C(C)CCl
Reactant: CC(C)(N)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)CNC(C)(C)c1cccc(Cl)c1
Temperature: 85 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
To 15 ml of N,N-dimethylformamide were added 2.6 g of 1-methyl-1-(3-chlorophenyl)ethylamine, 2.0 g of potassium carbonate and 2.1 g of 3-chloro-2-methylpropene, and the solution was then stirred at 85° C. for 1 hour. After potassium carbonate was removed by filtration, 100 ml of water were added, followed by extraction with toluene. The resultant extract was dried over anhydrous sodium sulfate, and then concentrated by an evaporator. Afterward, silica gel column chromatography was done to obtain 2.6 g of the desired amine.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[H-].[Na+].[NH2:8][C:9]1[C:18]2[C:13](=[C:14](F)[C:15]([N:19]3[C:27]4[CH2:26][C:25]([CH3:29])([CH3:28])[CH2:24][C:23](=[O:30])[C:22]=4[C:21]([CH3:31])=[CH:20]3)=[CH:16][CH:17]=2)[N:12]=[CH:11][N:10]=1>CN(C=O)C>[NH2:8][C:9]1[C:18]2[C:13](=[C:14]([NH:5][CH2:4][CH2:3][O:2][CH3:1])[C:15]([N:19]3[C:27]4[CH2:26][C:25]([CH3:28])([CH3:29])[CH2:24][C:23](=[O:30])[C:22]=4[C:21]([CH3:31])=[CH:20]3)=[CH:16][CH:17]=2)[N:12]=[CH:11][N:10]=1
Reactant: Cc1cn(-c2ccc3c(N)ncnc3c2F)c2c1C(=O)CC(C)(C)C2
Reactant: COCCN
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCNc1c(-n2cc(C)c3c2CC(C)(C)CC3=O)ccc2c(N)ncnc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In a small microwave vial with a stir bar, 2-Methoxy-ethylamine (0.1 mmol, 75 mg) is dissolved in 1 mL DMF. To this solution is added sodium hydride (60% suspension in mineral oil) (0.1 mmol, 4 mg) and the mixture is stirred at rt for 5 min. and then 1-(4-Amino-8-fluoro-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.044 mmol, 15 mg) is added. The reaction is sealed and placed in the microwave reactor where it is heated to 150° C. for 30 min. The reaction is cooled and quenched by pouring into 10 mL of Sat'd. NH4Cl aq. and extracted 3 times with 2 mL CH2Cl2. The combined organics are dried with Na2SO4, concentrated, and purified by silica gel chromatography on Biotage using a gradient of 0-50% MeOH in CH2Cl2. 1-[4-Amino-8-(2-methoxy-ethylamino)-quinazolin-7-yl]-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one is isolated (8 mg, LC/MS m/z=393 [M+H]+) as a tan powder.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([CH:18]([N:22]2C(=O)C3C(=CC=CC=3)C2=O)[CH:19]([CH3:21])[CH3:20])=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN>C(O)C>[CH2:1]([C:8]1[C:9]([CH:18]([NH2:22])[CH:19]([CH3:20])[CH3:21])=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(c1nc2ccccc2cc1Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Product: CC(C)C(N)c1nc2ccccc2cc1Cc1ccccc1
Temperature: 25 °C
Yield: 49.3 %

Procedure:
To a solution of 1-(3-benzylquinolin-2-yl)-2-methylpropan-1-amine 14 (91 mg, 1 eq.) in ethanol (2 ml), was added hydrazine (10 μl, 1.5 eq). The reaction was stirred at room temperature for an hour but very little product was detected. It was heated to 40° C. for 3 h and the 27% starting material was detected. More hydrazine (10 μl, 1.5 eq) was added and the reaction mixture was stirred for another half hour. The precipitate was filtered through a PTFE filter and washed with more CH2Cl2. The filtrate was concentrated and the crude product was purified by flash chromatography to yield 31 mg of 1-(3-benzylquinolin-2-yl)-2-methylpropan-1-amine 15 as clear oil.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9](=O)=O.C(Cl)(Cl)Cl>CI>[OH:8][C:7]1[C:2](=[O:1])[N:3]([CH3:9])[CH:4]=[CH:5][CH:6]=1
Reactant: O=C=O
Reactant: Oc1cccnc1O
Solvent: ClC(Cl)Cl
Solvent: CI
Product: Cn1cccc(O)c1=O
Temperature: 140 °C

Procedure:
2,3-dihydroxypyridine (5.55 g) is suspended in methyl iodide (20 ml) in a sealed tube and heated for 24 hours at 140° C. The reaction is taken to be complete when a dark brown residue forms as a separate phase from the methyl iodide and the tube is then cooled in solid carbon dioxide and opened. The excess methyl iodide is poured off, distilled water (10 ml) is added to the brown residue, and sulphur dioxide gas is bubbled through the mixture until the aqueous phase becomes clear. The pH of the reaction mixture is adjusted to a value of 6 with 1M aqueous sodium carbonate and the resulting solution then saturated with ammonium sulphate and extracted with chloroform until the chloroform layer no longer gives a blue colouration when added to ferric chloride solution. The chloroform extracts are combined and dried over sodium sulphate. The solvent is then evaporated under vacuum and the resulting residue is crystallized from petroleum ether (b.p. 100°-120° C.) using activated charcoal to give 3-hydroxy-1-methylpyrid-2-one, m.p. 129°-131° C.; νmax (nujol) 1660, 3100 cm-1 ; δ(d6DMSO) 3.6(s, 3H), 6.1(t, 1H), 6.8(m, 2H), 7.3(s, 1H); M+ 125.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:36][C:37]([C@@H:39]2[CH2:48][C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH2:41][N:40]2C(OC(C)(C)C)=O)=[O:38])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]#[N:35])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:36][C:37]([C@@H:39]2[CH2:48][C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH2:41][NH:40]2)=[O:38])[C:10]([N:12]2[CH2:13][CH2:14][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]#[N:35])(=[O:26])=[O:27])[CH2:16][CH2:17]2)=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2NS(=O)(=O)c2ccccc2C#N)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccccc1S(=O)(=O)Nc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2)CC1
Reaction time: 0.5 h

Procedure:
The title compound was prepared according to the procedure described in Example 3 (Step b) using tert-butyl 3-(N-{(1R)-1-[(4-chlorophenyl)methyl]-2-[4-(2-{[(2-cyanophenyl}sulfonyl]amino}phenyl)piperidyl]-2-oxoethyl]carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Step a) (167 mg, 0.21 mmol) and 50% TFA in CH2Cl2 (10 mL). Purification by reverse phase preparative HPLC [Phenomenex; 5 μm 250×21.2 mm, 5% to 95% CH3CN (0.1% TFA) in H2O (0.1% TFA) over 30 min, then 100% CH3CN (0.1% TFA) for 2 min] provided the title compound (TFA salt) as a white foam (76 mg). MS (ESI, pos. ion) m/z: 682 (M+1); (ESI, neg. ion) m/z: 680 (M−1). Calc'd for C37H36ClN5O4S: 681.22.
Reaction SMILES: [Si:1]([N:8]1[C@@H:11]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:10]([C:32](=[O:40])[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:9]1=[O:41])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+].Cl>C1COCC1>[Si:1]([N:8]1[CH:11]([S:12][C:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:10]([CH:32]([OH:40])[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:9]1=[O:41])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](C(=O)Cc2ccccc2)[C@@H]1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)N1C(=O)C(C(O)Cc2ccccc2)C1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 95.5 %

Procedure:
trans 1-(t-butyldimethylsilyl)-3-phenylacetyl-4-tritylthio-2-azetidinone (28.8 g, 50 mmol) and NaBH4 (0.5 g, 0.25 mole) in THF (200 ml) were stirred at room temperature for 18 h. The mixture was poured onto ice-1 N HCl and extracted with CH2Cl2. The CH2Cl2 solution was washed with brine and dried (Na2SO4). It was evaporated to give an amorphous solid (27.7 g). A portion of the solid (23.0 g) was chromatographed on SiO2 and eluted with hexane: ether to give off-white solid (14.4 g) which was found to be a mixture of (1'R,3S,4R and 1'S,3R,4S) and (1'S,3S,4R and 1'R,3R,4S) isomers in the ratio of 1:1 (60%). 1Hmr (CDCl3) δ: 7-7.7 (20H, m), 4.37 (1/2H, d), 4.18 (1/2H, d), 3.3-3.8 (H, m), 3.45 (1/2H, dd), 3.1 (1/2H, dd), 2.7 (2H, m), 0.87 (9H, d) and 0.25 ppm (6H, s).