Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].[CH:10]1[C:23]2[C:22](=O)[C:21](=O)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1.C(O)(=O)C>CO>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[N:9]=[C:21]1[C:22](=[N:8]2)[C:23]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]1=2
Reactant: Nc1cccc(N)c1N
Reactant: O=C1C(=O)c2ccccc2-c2ccccc21
Solvent: CO
Solvent: CC(=O)O
Product: Nc1cccc2nc3c4ccccc4c4ccccc4c3nc12

Procedure:
10.1 g (82 mmol) of 1,2,3-triaminobenzene and 4.6 g (70 mmol) of 9,10-phenanthrenequinone were placed in a four-necked flask, to which 350 g of a solvent of acetic acid and methanol at 1:1 was added for dissolution, followed by reaction at a reaction temperature of 70° C. for 2 hours. After the reaction, the solvent was removed and the resulting product was washed with methanol to obtain the intended product.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11])=O)(C)(C)C.[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1O)[C:17]([O:19][CH3:20])=[O:18].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[O:11][CH2:10][C@@H:9]([NH2:8])[CH3:12])[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC[C@H](C)N)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 45.2 %

Procedure:
To a cooled (0° C.) solution of (S)-2-(N-tert-butoxycarbonylamino)-1-propanol (1.05 g, 5.99 mmol), methyl 3-chloro-4-hydroxybenzoate (1.12 g, 6.00 mmol), and Ph3P (2.36 g, 9.00 mmol) in THF (20 mL) was added diisopropyl azodicarboxylate (DIAD) (1.77 mL, 8.99 mmol), and the resulting mixture was heated under reflux for 2 days. The solution was evaporated off and the residue was dissolved in CH2Cl2 (20 mL) and TFA (10 mL). The resulting mixture was stirred at room temp for 1.5 hr. The solution was concentrated in vacuo, and the residue was dissolved in CHCl3. The mixture was extracted with H2O, and the aqueous layer was made basic by the addition of sat. NaHCO3. This basic aqueous layer was extracted with CHCl3. The extract was washed with brine, dried over Na2SO4 and evaporated to give 660 mg (2 steps, 32%) methyl (S)-3-chloro-4-(2-amino-1-propoxy)benzoate as a colorless oil. 1H-NMR (CDCl3) δ 1.21 (d, 3 H, J=6.4 Hz), 3.41–3.48 (m, 1 H), 3.77–3.81 (m, 1 H), 3.89 (s, 3 H), 3.98–4.01 (m, 1 H), 6.91–6.94 (m, 1 H), 7.90–7.93 (m, 1 H), 8.05–8.06 (m, 1 H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([N:11]([CH3:32])[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[N:7]=[CH:8][C:9]=2[N:10]=1.[Cl:33][CH2:34][C:35](Cl)=[O:36].C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[Cl:33][CH2:34][C:35]([NH:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([N:11]([CH3:32])[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:27])[CH3:28])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[N:7]=[CH:8][C:9]=2[N:10]=1)=[O:36]
Reactant: O=C(Cl)CCl
Reactant: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(N)sc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(NC(=O)CCl)sc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)(methyl)amino]phenyl}-3-(1-cyano-1-methylethyl)benzamide (800 mg, 1.80 mmol) produced in Example D5(i) in N,N-dimethylacetamide (15 mL) was added chloroacetyl chloride (356 μL, 4.50 mmol), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (60 mL), and the mixture was extracted with ethyl acetate (60 mL, 10 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=60/40→30/70), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give the title compound (823 mg, 88%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:32])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:23][C@H:22]([CH2:24][O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][O:27]4)[C@@H:14]([O:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][O:17]4)[C@@H:12]3O)[C:6]=2[N:7]=1.C(N(S(F)(F)[F:39])CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.N1C=CC=CC=1>[NH2:1][C:2]1[N:3]=[C:4]([Cl:32])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:23][C@H:22]([CH2:24][O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][O:27]4)[C@@H:14]([O:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][O:17]4)[C@H:12]3[F:39])[C:6]=2[N:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: Nc1nc(Cl)c2ccn([C@@H]3O[C@H](COC4CCCCO4)[C@@H](OC4CCCCO4)[C@@H]3O)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Nc1nc(Cl)c2ccn([C@@H]3O[C@H](COC4CCCCO4)[C@@H](OC4CCCCO4)[C@H]3F)c2n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of the compound from Step G (0.24 g, 0.51 mmol) in CH2Cl2 (5 mL) and pyridine (0.8 mL) at −60° C. was added diethylaminosulfur trifluoride (DAST; 0.27 mL) dropwise under Ar. The solution was stirred at −60° C. for 0.5 h, at 0° C. overnight and at room temperature for 3 h. The mixture was diluted with CH2Cl2 (25 mL) and poured into saturated aqueous NaHCO3 (15 mL). The organic layer was washed with water (10 mL), dried (Na2SO4) and evaporated. The residue was purified on a silica gel column with a solvent system of hexanes/EtOAc: 5/1 to give the title compound (45 mg) as a pale yellow foam.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1Cl)([O-:3])=[O:2].[C:14]([NH:16][C:17]([NH:22][CH3:23])=[N:18][CH2:19][CH2:20][SH:21])#[N:15]>C(O)C>[C:14]([NH:16][C:17]([NH:22][CH3:23])=[N:18][CH2:19][CH2:20][S:21][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])#[N:15]
Reactant: CNC(=NCCS)NC#N
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCO
Product: CNC(=NCCSc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])NC#N

Procedure:
In order to characterise this product a solution of 2,4-dinitrochlorobenzene (7.7 g) in 95% ethanol (50 ml) was added to a solution of N-cyano-N'-methyl-N"-(2-mercaptoethyl)guanidine (6.0 g) in 95% ethanol. The mixture was refluxed for one hour and cooled. The resulting crystalline solid (7.73 g) was collected and was triturated with a large volume of ether and was recrystallised from acetonitrile to afford N-cyano-N'-methyl-N"-[S-(2,4-dinitrophenyl)-2-mercaptoethyl]-guanidine, m.p. 210°-211° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[CH2:4][N:5]=[N+:6]=[N-:7].Cl[C:14](=[CH2:17])[C:15]#[N:16]>O>[C:15]([C:14]1[N:7]=[N:6][N:5]([CH2:4][C:3]2[C:2]([F:1])=[CH:11][CH:10]=[CH:9][C:8]=2[F:12])[CH:17]=1)#[N:16]
Reactant: C=C(Cl)C#N
Reactant: [N-]=[N+]=NCc1c(F)cccc1F
Solvent: O
Product: N#Cc1cn(Cc2c(F)cccc2F)nn1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of 2,6-difluorobenzyl azide (34.2 g), 2-chloroacrylonitrile (26.6 g) and water (125 ml) is stirred at about 80° C. for 24 hours. Excess 2-chloroacrylonitrile is distilled off by raising the external temperature to about 130° C. The mixture is cooled to about 95° C. and the product is crystallized by seeding. After cooling to about 40° C., the suspension is treated with cyclohexane (50 -ml) and brought to about 20° C., and stirred for about 2 hours. The product is isolated by filtration, washed with cyclohexane (75 ml) and then with water and dried in vacuo at about 60° C. Yield: 43.13 g=98%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7](#[N:10])[CH:8]=[CH2:9]>C(N(CC)CC)C>[NH2:10][CH2:7][CH2:8][CH2:9][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C=CC#N
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Product: NCCCN1CCOCC1
Reaction time: 5 h

Procedure:
One mole of morpholine is reacted with 1.1 moles of acrylonitrile, added at about 28° C. with about 0.05 moles of a basic triamine, such as triethylamine, as a catalyst. The reaction is exothermic. After stirring for about 5 hours, the reaction mixture is distilled free of unreacted acrylonitrile. The resulting acrylonitrile adduct is reduced to the amine at 100° C. -150° C. under 1000 psig hydrogen using a copper catalyst. The resulting product is distilled to purity.
Reaction SMILES: [NH3:1].[CH3:2][C:3]([CH3:12])([CH3:11])[CH2:4][CH2:5][CH2:6][S:7](Cl)(=[O:9])=[O:8]>O1CCCC1>[CH3:2][C:3]([CH3:12])([CH3:11])[CH2:4][CH2:5][CH2:6][S:7]([NH2:1])(=[O:9])=[O:8]
Reactant: CC(C)(C)CCCS(=O)(=O)Cl
Reactant: N
Solvent: C1CCOC1
Product: CC(C)(C)CCCS(N)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Anhydrous ammonia gas was passed into a solution of 4,4-dimethylpentane sulphonyl chloride (1.85 g) in dry tetrahydrofuran (5 ml) at 5-10° C. until saturation. The resulting suspension was stirred at room temperature for 18 hours and then evaporated under reduced pressure. The residue was partitioned between ethyl acetate (20 ml) and 2N aqueous hydrochloric acid (20 ml). The organic phase was separated, washed (brine 20 ml), dried (Na2SO4) and evaporated. Column chromatography on silica eluting with dichloromethane:methanol 98:2 gave 4,4-dimethylpentane sulphonic acid amide as an off-white solid (0.72 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[C:17]([O:21][C:22](=[O:26])[CH:23](Br)[CH3:24])([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O>[C:17]([O:21][C:22](=[O:26])[CH:23]([O:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1)[CH3:24])([CH3:20])([CH3:19])[CH3:18]
Reactant: N#Cc1ccc(O)cc1F
Reactant: CC(Br)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(Oc1ccc(C#N)c(F)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 93.1 %

Procedure:
2-Fluoro-4-hydroxybenzonitrile (1 g, 7.29 mmol) was dissolved in N,N-dimethyl-formamide (20 mL) and stirred with potassium carbonate (1.1 g, 8.0 mmol) at rt for 2 h. (±) 2-Bromopropionic acid tert-butyl ester (1.67 g, 8.0 mmol) was added and the reaction was stirred at rt for 72 hours. The reaction was quenched into dilute aqueous hydrochloric acid and extracted 2× with ethyl acetate. The pooled organics were dried (Na2SO4) and adsorbed onto silica gel, followed by purification by flash column chromatography (20% ethyl acetate/hexane) to afford 1.8 g colorless oil (93% yield).
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][CH2:15][C@:16]2([O:24][C:25](=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29])[C:17](=[O:20])[CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:33])[C:9]([C@@H:10]([CH3:31])[CH2:11]2)=[CH:8][C:7](=[O:32])[CH2:6][CH2:5]1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>>[C:34]([O:19][CH2:18][C:17](=[O:20])[C@:16]1([O:24][C:25](=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29])[C@:21]2([CH3:23])[C@H:13]([C@H:12]3[C@H:3]([C@@H:2]([OH:1])[CH2:22]2)[C@:4]2([CH3:33])[C:9](=[CH:8][C:7](=[O:32])[CH2:6][CH2:5]2)[C@@H:10]([CH3:31])[CH2:11]3)[CH2:14][CH2:15]1)(=[O:36])[CH3:35]
Reactant: CCCCC(=O)O[C@]1(C(=O)CO)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Reactant: CC(=O)OC(C)=O
Product: CCCCC(=O)O[C@]1(C(=O)COC(C)=O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C

Procedure:
Analogously to Example 9, 1.0 g of 11β,21-dihydroxy-6α-methyl-17-valeryloxy-4-pregnene-3,20-dione is reacted with acetic anhydride, worked up, and purified, thus isolating 980 mg of 21-acetoxy-11β-hydroxy-6α-methyl-17-valeryloxy-4-pregnene-3,20-dione.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](OCC)=[C:4]([F:11])[CH:3]=1.BrC[CH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:14]2[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]2)=[C:4]([F:11])[CH:3]=1
Reactant: CCCC1CCC(CBr)CC1
Reactant: CCOc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCC1CCC(c2ccc(Br)cc2F)CC1
Yield: 67.3 %

Procedure:
Under a nitrogen atmosphere, a mixture of 4-bromo-2-fluoro-1-phenol (52) (10.8 g, 56.58 mmol), 1-(bromomethyl)-4-propylcyclohexane (60) (12.4 g, 56.58 mmol) and potassium carbonate (15.6 g, 112.9 mmol) was agitated at 80° C. for 5 hours in 100 mL of DMF. The reaction mixture was quenched with 100 mL of water, and extracted with 60 mL of toluene three times. Combined organic layers were washed with a 2N sodium hydroxide aqueous solution, water and saturated brine, and then dried over magnesium sulfate, and a solvent was distilled off by an evaporator. The residue was purified by silica gel column chromatography, and thus 4-bromo-2-fluoro-1-(4-propylcyclohexyl)benzene (61) (11.4 g, yield 61.2%) was obtained.
Reaction SMILES: [OH-].[K+].[N+]([C:6]1[CH:7]=[C:8]([O:14][CH3:15])[CH:9]=[CH:10][C:11]=1[C:12]#[N:13])([O-])=O.[C:16]([O:20][CH3:21])(=[O:19])[CH2:17][SH:18]>O>[NH2:13][C:12]1[C:11]2[CH:10]=[CH:9][C:8]([O:14][CH3:15])=[CH:7][C:6]=2[S:18][C:17]=1[C:16]([O:20][CH3:21])=[O:19]
Reactant: COc1ccc(C#N)c([N+](=O)[O-])c1
Reactant: COC(=O)CS
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1sc2cc(OC)ccc2c1N
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 54.1 %

Procedure:
A solution of 20.3 g (0.363 mol) of potassium hydroxide in 100 ml of water is added to a mixture of 36.3 g (0.204 mol) of 3-nitro-4-cyanoanisole and 26 g (0.245 mol) of methyl thioglycolate in 400 ml of N,N-d-methylformamide, the temperature being maintained at 0° C. The mixture is left stirring at 0° C. for 20 min and is then poured into a mixture of water and ice. The precipitate is then filtered off, rinsed with water and dried. The product is dissolved in a mixture of dichloromethane and tetrahydrofuran, the organic phase is then dried over sodium sulphate and concentrated under reduced pressure and the residue is triturated in dichloromethane. 26.2 g of product are thus obtained in the form of a light-beige powder.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[O:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:43]([O:45][C:46](=[O:68])[C@@:47]([OH:67])([CH3:66])[CH2:48][N:49]([CH2:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[C:62]([Cl:64])[CH:61]=[CH:60][C:59]=2[F:65])=[CH:54][CH:53]=1)[NH2:50])[CH3:44]>CN(C=O)C>[CH2:43]([O:45][C:46](=[O:68])[C@@:47]([OH:67])([CH3:66])[CH2:48][N:49]([CH2:51][C:52]1[CH:53]=[CH:54][C:55]([C:58]2[CH:63]=[C:62]([Cl:64])[CH:61]=[CH:60][C:59]=2[F:65])=[CH:56][CH:57]=1)[NH:50][C:7]([C:5]1[O:4][N:3]=[C:2]([OH:1])[CH:6]=1)=[O:9])[CH3:44]
Reactant: O=C(O)c1cc(O)no1
Reactant: CCOC(=O)[C@](C)(O)CN(N)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@](C)(O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(O)no1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-Hydroxyisoxazole-5-carboxylic acid (132 mg, 1.0 mmol) and HATU (389 mg, 1.0 mmol) were combined in DMF (3.7 mL), and the resulting mixture was stirred for 10 minutes at room temperature. DIPEA (343 μL, 2.0 mmol) and (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-hydrazino]-2-hydroxy-2-methyl-propionic acid ethyl ester (300 mg, 0.8 mmol) were added and the resulting mixture was stirred for 30 minutes. LC/MS showed desired product. The mixture was the evaporated under reduced pressure to yield the title compound (210 mg, 100% purity). MS m/z [M+H]+ calc'd for C23H23ClFN3O6, 492.13; found 492.2.
Reaction SMILES: CCCCCC.[H-].C([Al+]CC(C)C)C(C)C.[Cl:17][C:18]1[C:23]([C:24]#N)=[CH:22][CH:21]=[CH:20][N:19]=1.Cl.[O:27]1CCCC1>>[Cl:17][C:18]1[C:23]([CH:24]=[O:27])=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: N#Cc1cccnc1Cl
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Product: O=Cc1cccnc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
200 ml of a 1.02 M hexane solution of diisobutylaluminum hydride were added to a solution of 16.7 g of 2-chloro-3-cyanopyridine in 200 ml of tetrahydrofuran at a temperature of -30° to 20° C. over a period of 30 minutes, after which the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, hydrochloric acid was added to the reaction mixture at 0° C., and then the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium carbonate and with a saturated aqueous solution of sodium chloride, in that order, and then dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 6:1 to 5:1 by volume as the eluent, to give 7.0 g of the title compound having Rf=0.50 (on silica gel thin layer chromatography using a 2:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [NH2:1][C:2](=O)[C@@H:3]([NH:19][C:20]([C:22]1([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[CH:12]=2)=[CH:7][CH:6]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>ClCCl>[C:2]([C@@H:3]([NH:19][C:20]([C:22]1([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[CH:12]=2)=[CH:7][CH:6]=1)#[N:1]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3cccc(C#N)c3)cc2)C(N)=O)CCOCC1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(-c3cccc(C#N)c3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.6 %

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(3′-cyanobiphenyl-4-yl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 8, step (i), 316 mg) in dichloromethane (8 mL) was treated with Burgess' reagent (306 mg) and the mixture was stirred at room temperature for 18 h. The solvent was partially evaporated and the solution was purified by chromatography on silica using ethyl acetate/isohexane and then ethyl acetate as eluent to afford the sub-titled compound as a white solid (282 mg).
Reaction SMILES: [C:1]([CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)#[N:2].Cl.C(N(CC)CC)C.[N-:25]=[N+:26]=[N-:27].[Na+]>C1(C)C=CC=CC=1>[NH:25]1[C:1]([CH2:3][N:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)=[N:2][N:27]=[N:26]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCN(CC#N)CC1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(Cc2nnn[nH]2)CC1
Temperature: 80 °C
Yield: 61.6 %

Procedure:
To a stirred suspension of 1.50 g (6.66 mmol) of the title compound from Step A above in 25 mL of anhydrous toluene was added 1.38 g (10.0 mol) of triethylamine hydrochloride followed by 0.65 g (10 mmol) of sodium azide. The resulting mixture was heated to 80° C. for 12 h then cooled to ambient temperature. All volatiles were removed in vacuo, and the residue suspended in 5 mL of brine and 1.0 N aqueous hydrogen chloride solution was added until pH of ˜4 was achieved. The aqueous phase was extracted with chloroform and the combined organics were dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography eluting with a 0-100% acetone in hexanes gradient to afford the title compound (i-18) as white solid (1.1 g, 63%). 1H-NMR (500 MHz, DMSO-d) δ 3.82 (s, 2H), 3.29 (br s, 4H), 2.38-2.34 (m, 4H), 1.36 (s, 9H). LC-MS: m/z (ES) 269.0 (MH)+.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:11][C@H:10]([NH:12][C:13]2[C:14]3[CH:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:15]=3[N:16]=[C:17]([NH:19][C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)[N:18]=2)[CH2:9]1)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:7][C@H:8]1[CH2:9][C@H:10]([NH:12][C:13]2[C:14]3[CH:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:15]=3[N:16]=[C:17]([NH:19][C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)[N:18]=2)[CH2:11]1
Reactant: Cn1cc(Nc2nc(N[C@H]3C[C@H](NC(=O)OC(C)(C)C)C3)c3ccn(COCC[Si](C)(C)C)c3n2)cn1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1cc(Nc2nc(N[C@H]3C[C@H](N)C3)c3ccn(COCC[Si](C)(C)C)c3n2)cn1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 93.1 %

Procedure:
To tert-butyl((trans)-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)carbamate (115 mg, 0.218 mmol) in DCM (5 mL) was added 4 N HCl in 1,4-dioxane (0.3 mL, 1.2 mmol). The reaction was allowed to stir at rt for 3.5 hrs and then quenched with saturated aqueous NaHCO3 (2 mL). DCM (10 mL) was added and the DCM extract was dried over MgSO4, filtered and concentrated to afford the title compound (87 mg, 93% yield) as a tan foam.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>C1COCC1>[C:18]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: OCCCCc1cccs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCCCCc1cccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude product from Step A was dissolved in 100 ml of THF and the mixture was cooled in an ice-water bath. Triethylamine (7.5 ml, 54 mmol) was added followed by dropwise addition of 3.8 ml of acetyl chloride (54 mmol). The mixture was allowed to stir overnight at ambient temperature. The solution was filtered and concentrated on a rotary evaporator. The residue was partitioned between ethyl acetate and dilute, cold 1N HCl. The organic phase was washed with saturated NaHCO3 solution, brine and then dried (Na2SO4). Evaporation of the solvent left 10.48 g of the desired acetate (98%) the solvent left 10.48 g of the desired acetate (98%) as a light yellow oil. 1H-NMR (CDCl3)δ7.2-6.6 (3H, m); 2.9 (2H, t); 2.45 (2H, t); 2.15 (3H, s); 2.0 (4H, m).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=1.[C:14](=O)([O:18]CC)[O:15][CH2:16][CH3:17]>O1CCCC1>[CH2:16]([O:15][C:14](=[O:18])[CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[N:8]=1)[CH3:17]
Reactant: Cc1cccc(Cl)n1
Reactant: CCOC(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cccc(Cl)n1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 28.1 %

Procedure:
n-Butyl lithium (23% in hexane, 13.2 mL, 47.3 mmol) was added dropwise to a cold solution (−70° C.) of 2-chloro-6-methyl-pyridine (5.0 g, 39.4 mmol) in tetrahydrofuran (30 mL) and stirred for 30 min at −70° C. Diethyl carbonate (5.75 mL, 47.3 mmol) was added slowly and the reaction mixture stirred for 30 min at −70° C. before warning to room temperature and stirring for a further 1 h. The reaction mixture was quenched into saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate, filtered and concentrated to yield the crude compound which was purified by column chromatography over silica gel (100-200 mesh), using 9% ethyl acetate in petroleum ether as eluent, to afford (6-chloro-pyridin-2-yl)-acetic acid ethyl ester (2.21 g, 28%) as an oil.