Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl.Cl[CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.C(N(CC)CC)C>CN(C=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(Nc2ncccn2)cc1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(N(Cc2cccnc2)c2ncccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
Under an argon atmosphere, N-(4-bromophenyl)pyrimidin-2-amine (200 mg) was added to a suspension of sodium hydride (48 mg) in anhydrous DMF (8 ml), and the resulting mixture was stirred at room temperature for 30 minutes. The reaction solution was cooled to 0° C., and 3-chloromethylpyridine hydrochloride (600 mg) and triethylamine (1.00 ml) were added thereto, followed by stirring the resulting mixture at room temperature for 2 hours. Saturated brine was added to the reaction solution and the resulting mixture was extracted 3 times with ethyl acetate. Organic layers were washed 3 times with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent:ethyl acetate/hexane=3/1) to obtain N-(4-bromophenyl)-N-((pyridin-3-yl)methyl)pyrimidin-2-amine (232 mg). NMR (H1, CDCl3): δ 5.23 (2H, s), 6.65 (1H, t, J=4.6 Hz), 7.08-7.12 (2H, m), 7.20 (1H, dd, J=7.8, 4.9 Hz), 7.46-7.50 (2H, m), 7.59-7.61 (1H, m), 8.35 (2H, d, J=4.6 Hz), 8.49 (1H, dd, J=4.9, 1.5 Hz), 8.54 (1H, d, J=2.2 Hz)
Reaction SMILES: Cl[CH:2]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:14].[CH:15]([Mg]Cl)=[CH2:16].CN1C(=O)N(C)CCC1.[Cl-].[NH4+]>C1COCC1>[CH:15]([C:4]12[O:14][CH:3]1[CH2:2][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)=[CH2:16]
Reactant: C=C[Mg]Cl
Reactant: O=C1CCCCCCCCCCC1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: C=CC12CCCCCCCCCCC1O2
Temperature: 50 °C
Yield: 82.6 %

Procedure:
A four-neck flask equipped with a thermometer, stirrer and condenser tube was charged with 100 g (0.46 mol) of 2-chlorocyclododecanone and 122 g of tetrahydrofuran, and at −10 to 0° C., a THF solution of vinylmagnesium chloride (0.82 mol) was added dropwise. The mixture was allowed to stand for reaction for 30 minutes, and 420 g (3.27 mol) of N,N′-dimethylpropyleneurea (DMPU) was added. The mixture was heated to 50° C. and allowed to stand for reaction for 1 hour, and saturated ammonium chloride aqueous solution was added dropwise for inactivation. The reaction mixture was subjected to extraction with hexane, and the solvent was recovered. The residue was distilled to obtain 1-vinyl-13-oxabicyclo[10.1.0]tridecane (80 g, 0.38 mol, chemical purity 98%, cis form:trans form=88:12). The yield was 82%.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[CH:14]=[C:15]([C:19]3[CH:20]=[C:21]([C:29]([CH3:33])([CH3:32])[C:30]#[N:31])[CH:22]=[C:23]4[C:28]=3[N:27]=[CH:26][CH:25]=[CH:24]4)[CH:16]=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)(=O)=O.[H-].[Na+].[F:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41]Br)=[CH:39][CH:38]=1>CN(C=O)C.[NH4+].[Cl-]>[F:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][N:11]([CH2:12][C:13]2[CH:14]=[C:15]([C:19]3[CH:20]=[C:21]([C:29]([CH3:33])([CH3:32])[C:30]#[N:31])[CH:22]=[C:23]4[C:28]=3[N:27]=[CH:26][CH:25]=[CH:24]4)[CH:16]=[CH:17][CH:18]=2)[C:8]2[CH:9]=[CH:10][C:5]([S:2][CH3:1])=[CH:6][CH:7]=2)=[CH:39][CH:38]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(C)(C#N)c1cc(-c2cccc(CNc3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CSc1ccc(N(Cc2ccc(F)cc2)Cc2cccc(-c3cc(C(C)(C)C#N)cc4cccnc34)c2)cc1
Reaction time: 0.17 h

Procedure:
To solution of 2-(8-{3-[(4-Methanesulfonyl-phenylamino)-methyl]-phenyl}-quinolin-6-yl)-2-methyl-propionitrile from EXAMPLE 36 (Step 1) (1.0 eq) in DMF (0.2M) was added NaH (60% dispersion in oil; 4.0 eq). The resulting mixture was stirred for 10 min then 4-fluorobenzyl bromide (3.0 eq) was added. The mixture was stirred for 12 h, poured in saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 4:1) afforded the desired compound as a foam.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11](OC(=NC(C)C)NC(C)C)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCCC1>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)N=C(NC(C)C)OCc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A neat solution of 18.6 mL (15 g, 118.8 mmol) of 1,3-diisopropylcarbodiimide and 60 mg (0.6 mmol) of cuprous chloride was placed under a blanket of argon and then cooled to 0° C. in an ice bath. To this reaction mixture was added dropwise (via syringe) 12.9 mL (13.5 g, 124.7 mmol) of benzyl alcohol. The resultant green reaction mixture was allowed to stir at 0° C. overnight, filtered through celite (rinsing with hexane) and the filtrate then Kugelrohr distilled (105° C., 2 mm Hg) to give 2-benzyl-1,3-diisopropyl isourea as a clear, colorless oil. To a solution of 650 mg (4.7 mmol) of 4-hydroxybenzoic acid in 20 mL of tetrahydrofuran was added 1.1 g (4.7 mmol) of 2-benzyl-1,3-diisopropyl isourea. The reaction mixture was allowed to stir at ambient temperature overnight, filtered (rinsing with tetrahydrofuran) and then concentrated in vacuo. Purification by flash chromatography (silica, 3 25% ethyl acetate in hexane) gave the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:11]=[CH:12]/[C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[BH4-].[Na+].Cl>N1C=CC=CC=1.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(/C=C/C#N)cc1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(CCC#N)cc1OC
Temperature: 25 °C
Yield: 80.9 %

Procedure:
To a solution of 1 g (5.3 mmoles) of (2E)-3-(3,4-dimethoxyphenyl)prop-2-enenitrile in 9.3 mL of pyridine and 2.8 mL of methanol there is added, little by little, 0.24 g of NaBH4 (6.3 mmol, 1.2 eq.). The reaction mixture is heated at reflux for 9 hours. After cooling to ambient temperature, the reaction mixture is added to a solution of 9 mL of hydrochloric acid 37% in 24 g of ice. The solution is extracted twice with dichloromethane. The organic phases are collected and the solvent is evaporated off under reduced pressure to yield 0.82 g of a red-brown oil which crystallises.
Reaction SMILES: [BH4-].[Na+].O.[C:4]([O:8][C:9]([N:11]1[CH2:15][CH:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:13][CH:12]1[CH:24]=[CH:25][N+:26]([O-:28])=[O:27])=[O:10])([CH3:7])([CH3:6])[CH3:5]>C1COCC1>[C:4]([O:8][C:9]([N:11]1[CH2:15][CH:14]([O:16][Si:17]([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18])[CH2:13][CH:12]1[CH2:24][CH2:25][N+:26]([O-:28])=[O:27])=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1C=C[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1CC[N+](=O)[O-]
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
A 1 L round-bottomed flask was charged with NaBH4 (3.2 g, 84.5 mmol) in THF (300 mL) and then cooled to −20° C. Water (50 mL) was added to the reaction mixture followed by the dropwise addition of 2 (6.3 g, 16.9 mmol) in THF (50 mL) over 1 h. After an additional 30 min, the cold reaction mixture was quenched by the careful addition of 1M HCl (60 mL). The reaction mixture was then diluted with EtOAc. The organic phase was washed successively with 1M HCl and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was chromatographed by flash silica gel chromatography (4:1 hexanes/EtOAc) to afford 5.9 g (93%) of 3. 1H NMR (CDCl3, 300 MHz), mixture of rotomers: δ4.48 (m, 1H), 4.32 (m, 1H), 4.08 (m, 1H), 3.55 (m, 0.4H), 3.38 (m, 0.6H), 3.28 (app dd, J=11.7, 4.2 Hz, 1H), 2.32 (m, 1H), 2.18 (m, 1H), 2.04 (m, 2H), 1.67 (m, 1H), 1.45 (s, 9H), 0.85 (s, 9H), 0.05 (s, 6H) ppm.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4](=[N:8][O:9][CH2:10][C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12])[C:5]([OH:7])=[O:6].[NH2:20][C:21]([NH2:23])=[S:22].C([O-])(=O)C.[Na+]>O1CCCC1.O>[NH2:23][C:21]1[S:22][CH:2]=[C:3]([C:4](=[N:8][O:9][CH2:10][C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12])[C:5]([OH:7])=[O:6])[N:20]=1
Reactant: NC(N)=S
Reactant: O=C(CON=C(C(=O)O)C(=O)CBr)OCC(Cl)(Cl)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(C(=NOCC(=O)OCC(Cl)(Cl)Cl)C(=O)O)cs1
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 18.6 %

Procedure:
To a solution of 4-bromo-2-(2,2,2-trichloroethoxycarbonylmethoxyimino)-3-oxobutyric acid (20 g) in tetrahydrofuran (50 ml) was added a solution of thiourea (3.9 g) and sodium acetate (4.2 g) in water (50 ml), and the mixture was stirred at 40° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure to half of the original volume, which was adjusted to pH 7.5 with a saturated aqueous sodium bicarbonate and then washed with ethyl acetate. After the aqueous solution was further adjusted to pH 2.0 with 10% hydrochloric acid, the water was removed by decantation. The residual substance was dissolved in tetrahydrofuran (200 ml), followed by drying over magnesium sulfate. Removal of the solvent gave an oil, which was triturated with diisopropyl ether to give 2-(2-aminothiazol-4-yl)-2-(2,2,2-trichloroethoxycarbonylmethoxyimino)acetic acid (syn isomer) (3.5 g).
Reaction SMILES: C([NH:5][S:6]([C:9]1[C:14]([NH:15][CH3:16])=[CH:13][CH:12]=[CH:11][N:10]=1)(=[O:8])=[O:7])(C)(C)C.FC(F)(F)C(O)=O.C(OCC)(=O)C>CCCCCC>[CH3:16][NH:15][C:14]1[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: CNc1cccnc1S(=O)(=O)NC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CNc1cccnc1S(N)(=O)=O
Yield: 89.5 %

Procedure:
A mixture of 3.50 g of N-tert-butyl-3-methylamino-2-pyridinesulfonamide and 20 ml of trifluoroacetic acid was reacted at about 50° C. for 2 hours. Thereafter, the reaction product was distilled off under a reduced pressure to obtain a residue. Ethyl acetate and n-hexane were added thereto. The resulting crystals were filtered to obtain 2.41 g of 3-methylamino 2-pyridinesulfonamide. This compound had the following NMR values.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.Cl.[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[O:31][N:30]=[C:29]([C:32](O)=[O:33])[CH:28]=2)[CH2:22][CH2:21]1>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:32]([C:29]3[CH:28]=[C:27]([CH2:26][N:23]4[CH2:22][CH2:21][O:20][CH2:25][CH2:24]4)[O:31][N:30]=3)=[O:33])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1cc(CN2CCOCC2)on1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Agent: Cl
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(CN2CCOCC2)on1
Yield: 16.9 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(morpholinomethyl)isoxazole-3-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg, 0.690 mmol) and 5-(morpholinomethyl)isoxazole-3-carboxylic acid hydrochloride (206 mg, 0.828 mmol). The product was purified by reverse phase Flash-chromatography. Yield 16.9%. 1H-NMR (400 MHz; MeOD): δ 1.26 (d, 3H), 2.47-2.56 (m, 4H), 3.65-3.71 (m, 4H), 3.75 (d, 2H), 4.28-4.44 (m, 2H), 4.53-4.63 (m, 1H), 6.59 (t, 1H), 6.77 (d, 1H), 7.71 (d, 1H), 7.78 (dd, 1H), 7.88 (dd, 1H), 8.08 (dd, 1H).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[C:19](SC)[NH:20][C:21](=[O:22])[C:16]=4[C:15]([CH3:25])=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(O)(=O)C>COCCOC.C(OCC)(=O)C.CO.[Ni]>[F:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[CH:19][NH:20][C:21](=[O:22])[C:16]=4[C:15]([CH3:25])=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CSc1nc2c(c(C)cn2Cc2ccc(C(=O)c3ccc(F)cc3)cc2)c(=O)[nH]1
Agent: [Ni]
Solvent: CO
Solvent: CC(=O)O
Solvent: COCCOC
Product: Cc1cn(Cc2ccc(C(=O)c3ccc(F)cc3)cc2)c2nc[nH]c(=O)c12
Yield: 77 %

Procedure:
7-[4-(4-Fluorobenzoyl)benzyl]-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (775 mg) was dissolved in a mixture of DME (100 ml), ethyl acetate (100 ml) and methanol (80 ml). After addition of acetic acid (2.5 ml), Raney nickel was added. After confirming disapperance of the starting compound, the catalyst was filtered off. The solvent was then distilled off under reduced pressure. The residue was pulverized with ether, and the crystalline powder was collected by filtration, rinsed with ether, and dried to provide the title compound (529 mg).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]1[CH:30]=[CH:29][C:14]([CH2:15][CH:16]2[C:25]3[CH:24]=[C:23]4[O:26][CH2:27][O:28][C:22]4=[CH:21][C:20]=3[CH2:19][CH2:18][NH:17]2)=[CH:13][CH:12]=1.[C:31]([O:35][C:36](N1CCC2C=C3OCOC3=CC=2C1CC1C=CC(Br)=CC=1)=[O:37])([CH3:34])([CH3:33])[CH3:32].COC1C=CN=CC=1B(O)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CC(O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:31]([O:35][C:36]([N:17]1[CH2:18][CH2:19][C:20]2[CH:21]=[C:22]3[O:28][CH2:27][O:26][C:23]3=[CH:24][C:25]=2[CH:16]1[CH2:15][C:14]1[CH:13]=[CH:12][C:11]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[O:4][CH3:3])=[CH:30][CH:29]=1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCc2cc3c(cc2C1Cc1ccc(Br)cc1)OCO3
Reactant: COc1ccncc1-c1ccc(CC2NCCc3cc4c(cc32)OCO4)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccncc1B(O)O
Solvent: CC(C)O
Product: COc1ccncc1-c1ccc(CC2c3cc4c(cc3CCN2C(=O)OC(C)(C)C)OCO4)cc1

Procedure:
The synthesis of 5-[4-(4-methoxypyridin-3-yl)benzyl]-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline dihydrochloride salt 45 is shown in Scheme-12. Reaction of compound 38 with 4-methoxypyridine-3-boronic acid 19 in the presence of Palladium (II) acetate, triphenylphosphine, and Na2CO3 in anhydrous 2-propanol yielded 5-[4-(4-methoxypyridin-3-yl)benzyl]-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isoquinoline-6-carboxylic acid tert-butyl ester 43 which was treated with trifluoroacetic acid in dichloromethane to get 5-[4-(4-methoxypyridin-3-yl)benzyl]-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline trifluoro acetate salt 44. Compound 44 was treated by 37% HCl, 1N NaOH followed by 2M HCl/Ether in MeOH-Ether to obtain 45.
Reaction SMILES: [O:1]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:19]([N:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][N:13]([C:19]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:24])[CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:1][CH2:2][CH2:3]1)=[O:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C1COCCOCCNCCOCCOCCN1
Product: CC(C)(C)C(=O)N1CCOCCOCCN(C(=O)C(C)(C)C)CCOCCOCC1

Procedure:
Analogously to Example 2 from 1,7,10,16-tetraoxa-4,13-diazacyclooctadecane and pivalyl chloride.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[O:12]1[C:14]2([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH2:13][C:14]3([OH:12])[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(O)(Cn2nc(I)c3c(N)ncnc32)CC1
Temperature: 60 °C
Reaction time: 18 h
Yield: 42.4 %

Procedure:
A mixture of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.86 g, 0.0033 mol), tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (0.7 g, 0.0033 mol) and cesium carbonate (1.1 g, 0.0033 mol) in anhydrous N,N-dimethylformamide (30 mL) was stirred at 60° C. for 18 hours. The solvent was removed under reduced pressure. The residue was partitioned between water and dichloromethane (200 mL). The organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was triturated with dichloromethane, and the solid was filtered to give tert-butyl 4-[(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl]-4-hydroxy-1-piperidinecarboxylate (0.66 g, 0.0014 mol). RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 8.7 min.
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[CH3:12])[CH2:3][CH2:4][CH3:5].[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:23])=[C:18]([CH:22]=1)[C:19](Cl)=[O:20]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CS(C)=O.CO>[CH2:2]([N:6]1[C:10]([CH3:11])=[CH:9][S:8]/[C:7]/1=[CH:12]\[C:19]([C:18]1[CH:22]=[C:14]([F:13])[CH:15]=[CH:16][C:17]=1[CH3:23])=[O:20])[CH2:3][CH2:4][CH3:5]
Reactant: Cc1ccc(F)cc1C(=O)Cl
Reactant: CCCC[n+]1c(C)csc1C
Agent: CN(C)c1ccncc1
Agent: [I-]
Solvent: CS(C)=O
Solvent: CO
Solvent: ClCCl
Product: CCCCN1C(C)=CS/C1=C\C(=O)c1cc(F)ccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial a solution of 3-butyl-2,4-dimethylthiazol-3-ium iodide (47.92 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL) was added, followed by the addition of DMAP (49.24 mg, 0.40 mmol) dissolved in CH2Cl2 (0.8 mL). Then, to the solution was added 5-fluoro-2-methylbenzoyl chloride (27.6 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL). The vial was capped and shaken overnight at room temperature. The residue was dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.92 (t, 3 H) 1.28-1.41 (m, 2 H) 1.57-1.68 (m, 2 H) 2.28-2.31 (m, 3 H) 2.33-2.36 (m, 3 H) 3.92-4.03 (m, 2 H) 6.09-6.15 (m, 1 H) 6.54-6.59 (m, 1 H) 7.05-7.14 (m, 1 H) 7.19-7.27 (m, 2 H);); MS (ESI) positive ion 306 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=2)[C:5]2[CH:18]=[CH:19][C:20]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][C:4]=2[O:3]1.O1CCCC1.[H][H]>CO.[C].[Pd]>[NH2:15][C:11]1[CH:10]=[C:9]([N:6]2[C:5]3[CH:18]=[CH:19][C:20]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][C:4]=3[O:3][C:2]([CH3:1])([CH3:27])[C:7]2=[O:8])[CH:14]=[CH:13][CH:12]=1
Reactant: [H][H]
Reactant: CC1(C)Oc2cc(NS(C)(=O)=O)ccc2N(c2cccc([N+](=O)[O-])c2)C1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)Oc2cc(NS(C)(=O)=O)ccc2N(c2cccc(N)c2)C1=O

Procedure:
To a solution of N-[2,2-dimethyl-4-(3-nitrophenyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide (compound obtained in Example 146; 240 mg) in methanol (5 mL)-tetrahydrofuran (5 mL) was added 10% palladium-carbon (100 mg), and the mixture was stirred at room temperature under atmospheric pressure of hydrogen for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give N-[4-(3-aminophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-methanesulfonamide as a colorless powder.
Reaction SMILES: [Si]([O:8][C:9]1[C:17]([CH2:18]/[CH:19]=[C:20](\[CH3:32])/[CH:21]([CH2:28][CH2:29][CH2:30][Br:31])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]([O:33][CH3:34])[C:15]([CH3:35])=[C:14]2[C:10]=1[C:11](=[O:36])[O:12][CH2:13]2)(C(C)(C)C)(C)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOCC>[OH:8][C:9]1[C:17]([CH2:18]/[CH:19]=[C:20](\[CH3:32])/[CH:21]([CH2:28][CH2:29][CH2:30][Br:31])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]([O:33][CH3:34])[C:15]([CH3:35])=[C:14]2[C:10]=1[C:11](=[O:36])[O:12][CH2:13]2
Reactant: CCOC(=O)CC(CCCBr)/C(C)=C/Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)CC(CCCBr)/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62.2 %

Procedure:
A solution of of ethyl (E) 6-(4-tert-butyldimethylsilyloxy -1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl) -3-(3-bromopropyl)-4-methylhex-4-enoate (1.62 g) was dissolved in THF (25 ml), cooled to 0° C., and a solution of tetrabutylammonium fluoride trihydrate (919 mg) in THF (5 ml) was added. The reaction was stirred for 15 min, diluted with ether, washed water (2×), brine, and dried. The solvent was evaporated, and the resulting oil chromatographed on silica gel (15%-20% ethyl acetate in hexanes) to give ethyl (E) 6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl -3-oxoisobenzofuran -5-yl)-3-(3-bromopropyl)-4-methylhex -4-enoate (810 mg ) .
Reaction SMILES: C([O:9][C@H:10]1[C@@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@H:11]1[N:34]1[CH:41]=[CH:40][C:38](=S)[NH:37][C:35]1=[O:36])(=O)C1C=CC=CC=1.[NH3:42]>>[C@@H:11]1([N:34]2[CH:41]=[CH:40][C:38]([NH2:42])=[N:37][C:35]2=[O:36])[O:12][C@@H:13]([CH2:24][OH:25])[C@H:14]([OH:15])[C@@H:10]1[OH:9]
Reactant: N
Reactant: O=C(OC[C@@H]1O[C@@H](n2ccc(=S)[nH]c2=O)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Product: Nc1ccn([C@@H]2O[C@@H](CO)[C@H](O)[C@@H]2O)c(=O)n1
Temperature: 25 °C
Yield: 81 %

Procedure:
Compound 19 (3.68 g, 6.42 mmol) was treated with 200 ml of methanolic ammonia in a bomb at 100° C. for 18 hours. After cooling to room temperature, the solvent was evaporated to dryness and the residue dissolved in water (200 ml). The aqueous solution was extracted successively with CHCl3 and CCl4 (3×100 ml) to remove benzamide and methyl benzoate. The aqueous layer was treated with active charcoal, filtered through Celite®, evaporated to dryness and coevaporated with EtOH. The solid obtained was recrystallized from MeOH to give pure compound 20 (1.36 g, 81%) as white solid: m.p. 206°-207° C. (dec).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[OH:7][C@@H:8]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:13]=1)[CH2:9][C:10]#[N:11].N.CO.C(Cl)Cl>>[NH2:11][CH2:10][CH2:9][C@H:8]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:13]=1)[OH:7]
Reactant: N#CC[C@@H](O)c1cccc(OCCc2ccccc2)n1
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: ClCCl
Solvent: CO
Product: NCC[C@@H](O)c1cccc(OCCc2ccccc2)n1

Procedure:
LiAlH4 reduction of (R)-3-hydroxy-3-(6-phenethoxypyridin-2-yl)propanenitrile following the method described in Example 1 gave after flash chromatography purification (20%-30% 7N NH3/MeOH—CH2Cl2 gradient) Example 41 as a colorless oil. Yield (0.13 g, 21%); 1H NMR (400 MHz, DMSO-d6) δ 7.62 (t, J=8.0 Hz, 1H), 7.28-7.16 (m, 5H), 7.02 (d, J=8.0 Hz, 1H), 6.60 (d, J=8.0 Hz, 1H), 4.70-4.68 (m, 1H), 4.78 (t, J=7.2 Hz, 2H), 3.05 (t, J=7.2 Hz, 2H), 2.78 (t, J=6.8 Hz, 2H), 2.04-1.82 (m, 2H); RP-HPLC tR=7.83 min; ESI-MS m/z 273.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([Mg]Br)=[N:4][CH:5]=[CH:6][CH:7]=1.C1C[O:13][CH2:12]C1.CN(C=O)C>>[CH3:1][C:2]1[C:3]([CH:12]=[O:13])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: Cc1cccnc1[Mg]Br
Solvent: CN(C)C=O
Product: Cc1cccnc1C=O
Yield: 33 %

Procedure:
3-Methyl-pyridine-2-carbaldehyde (200 mg, 33.0%) was obtained from 0.25 M 3-methyl-2-pyridinylmagnesium bromide of THF solution (20 mL, 5 mmol) with DMF (0.773 mL, 10 mmol) at room temperature under argon.