Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:10](Br)=[CH:9][N:8]=[C:7]([Cl:12])[N:6]=1)[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:12][C:7]1[N:8]=[CH:9][C:10]2[C:2]([CH3:3])=[CH:1][NH:4][C:5]=2[N:6]=1
Reactant: C=CCNc1nc(Cl)ncc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1c[nH]c2nc(Cl)ncc12
Temperature: 100 °C
Yield: 40 %

Procedure:
A mixture of Allyl-(5-bromo-2-chloro-pyrimidin-4-yl)-amine (1 g, 4 mmol), palladium(II) acetate, (90 mg, 0.40 mmol), triphenylphosphine (211 mg, 0.80 mmol) and triethylamine (1.1 mL, 8.0 mmol) in DMF (10 mL) is heated at 100° C. overnight. After cooling to room temperature the reaction mixture is diluted with ethyl acetate and washed with brine. The organic phase is dried (anhydrous Na2SO4) and the solvent is evaporated. The crude product is purified by flash chromatography (gradient elution EtOAC:Heptanes 0:0 to 1:1) on silicagel to afford 2-Chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine as a white solid (40%).
Reaction SMILES: [C:1]1([C:7]2[S:11][CH:10]=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:21])=[C:17]([CH:20]=1)[CH:18]=O>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:21])=[C:17]([CH2:18][C:10]2[S:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][N:9]=2)[CH:20]=1
Reactant: c1ccc(-c2cncs2)cc1
Reactant: O=Cc1cc(Br)ccc1Cl
Product: Clc1ccc(Br)cc1Cc1ncc(-c2ccccc2)s1

Procedure:
A solution of thiazole (10.0 g), iodobenzene (2.63 ml), tetrakis(triphenylphosphine)palladium (0) (1.36 g) and potassium acetate (3.46 g) in N,N-dimethylacetamide (100 ml) was stirred under heating at 100° C. overnight. The solvent was evaporated under reduced pressure, and added to the residue was ethyl acetate. The mixture was washed successively with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-90:10) to give 5-phenylthiazole (1.50 g) as a pale yellow solid. APCI-Mass m/Z 162 (M+H). (2) The above 5-phenylthiazole and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 100 to give 5-bromo-2-chloro-1-(5-phenyl-2-thiazolylmethyl)benzene as a yellow solid. APCI-Mass m/Z 364/366 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:23]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH2:19][CH2:20][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C:10]1=2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c([nH]c3ccccc23)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(Cc3ccccc3)c3ccccc23)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole(2.96 g, 10.9 mmol) in dry DMF (15 ml) was added dropwise to a slurry of sodium hydride (60% dispersion in oil/479 mg, 12.0 mmol) in dry DMF (15 ml) maintained under nitrogen at room temperature. After stirring for 45 minutes at room temperature benzyl bromide (1.3 ml, 10.9 mmol) was added dropwise. The reaction was stirred for a further 2 hours, diluted with ethyl acetate (75 ml), washed with brine (2×80 ml) and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chromatography on silica gel with ethyl acetate-hexane (2:7) as eluant. (3.68 g, 92%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:26][N:27]([CH3:43])[C:28]1[CH:37]=[C:36]2[C:31]([C:32]([CH3:42])=[CH:33][C:34](=[O:41])[N:35]2[CH2:38][CH:39]=O)=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:39][CH2:38][N:35]4[C:36]5[C:31](=[CH:30][CH:29]=[C:28]([N:27]([CH3:43])[CH3:26])[CH:37]=5)[C:32]([CH3:42])=[CH:33][C:34]4=[O:41])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: Cc1cc(=O)n(CC=O)c2cc(N(C)C)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(N(C)C)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
To 2 mL of a chloroform solution containing 0.21 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 0.15 g of (7-dimethylamino-4-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde, 10 μL of acetic acid and 0.20 g of sodium triacetoxyborohydride were added, and stirred at room temperature overnight. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; ethyl acetate: 8 mol/L ammonia/methanol=50:1], to give 0.14 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-dimethylamino-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a pale yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][NH:5][C:6]1[S:7][C:8](=[CH:12][C:13]2[N:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][C:17](C#N)=[C:16]3[O:25][CH:26]([CH3:28])[CH3:27])[C:9](=[O:11])[N:10]=1.C(O[Na])(C)=O.C(OC1C=CN=C2C=1N=C(C=C1SC(NC3CC3C3C=CC=CC=3)=NC1=O)C=C2)(C)C>CC(O)=O>[Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][NH:5][C:6]1[S:7][C:8](=[CH:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([O:25][CH:26]([CH3:28])[CH3:27])[CH:17]=[CH:18][N:19]=3)[N:14]=2)[C:9](=[O:11])[N:10]=1
Reactant: CC(C)Oc1c(C#N)cnc2ccc(C=C3SC(NCc4ccccc4Cl)=NC3=O)nc12
Agent: CC(=O)O[Na]
Agent: CC(C)Oc1ccnc2ccc(C=C3SC(NC4CC4c4ccccc4)=NC3=O)nc12
Solvent: CC(=O)O
Product: CC(C)Oc1ccnc2ccc(C=C3SC(NCc4ccccc4Cl)=NC3=O)nc12
Temperature: 100 °C
Yield: 44.7 %

Procedure:
To a mixture of 2-(2-chloro-benzylamino)-thiazol-4-one (38.5 mg, 0.16 mmol) (see Example 2), AcONa (160 mg, 1.95 mmol), molecular sieves, and 8-isopropoxy-[1,5]naphthyridine-2-carbaldehyde (38.9 mg, 0.18 mmol) (see Example 20) in a sealed tube was added AcOH (0.3 mL). The reaction mixture was heated to 100° C. (oil bath) for 5 hrs. The reaction mixture was then cooled to r.t. and triturated with water. The solid was collected by filtration and washed with water. The solid was collected by filtration and washed with water, acetone and ether to give 2-(2-chloro-benzylamino)-5-(8-isopropoxy-[1,5]naphthyridin-2-ylmethylene)-thiazol-4-one as a brown solid (31.4 mg, 44.7%). HR-ES (+) m/e calcd for C22H19ClN4O2S (M+H)+ 439.0990. found 439.0987.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:15]3[C@@H:14]4[CH2:16][C@@H:13]4[CH2:12][C:11]=3[C:10]([C:17]([OH:19])=[O:18])=[N:9]2)[CH:3]=1.[H-].[Na+].C[C:23]([N:25](C)C)=O>C(OCC)(=O)C.CO.[C-]#N.[Zn+2].[C-]#N>[C:23]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:15]3[C@@H:14]4[CH2:16][C@@H:13]4[CH2:12][C:11]=3[C:10]([C:17]([OH:19])=[O:18])=[N:9]2)[CH:3]=1)#[N:25]
Reactant: O=C(O)c1nn(-c2cc(Br)ccn2)c2c1C[C@H]1C[C@@H]21
Reactant: CC(=O)N(C)C
Agent: [C-]#N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: N#Cc1ccnc(-n2nc(C(=O)O)c3c2[C@@H]2C[C@@H]2C3)c1
Reaction time: 0.08 h

Procedure:
(1aR,5aR)-2-(4-Bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid (1.00 g, 3.12 mmol) was dissolved in DMA (10 mL). 60 wt % sodium hydride (0.125 g, 3.12 mmol) was added and the mixture was stirred vigorously for 5 min. Nitrogen was bubbled through the mixture for 10 min. Zinc(II) cyanide (0.734 g, 6.25 mmol) and palladium tetrakistriphenylphosphine (0.180 g, 0.156 mmol) were added. The reaction was microwaved at 120° C. for 1 h. The reaction was diluted with ethyl acetate (20 mL) and methanol (5 mL), filtered, then concentrated. The residue was purified by HPLC to give the title compound (0.557 g) as a white solid. LCMS m/z=267.2 [M+H]+.
Reaction SMILES: C(C(C(C(O)=O)O)O)(O)=O.[CH3:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:34][CH2:35][C:36]2[O:37][C:38]3[CH:44]=[CH:43][C:42]([Br:45])=[CH:41][C:39]=3[CH:40]=2)(=O)=O)=CC=1>C(#N)C.C1(C)C=CC=CC=1>[Br:45][C:42]1[CH:43]=[CH:44][C:38]2[O:37][C:36]([CH2:35][CH2:34][N:13]3[CH2:14][CH2:15][CH2:16][C@H:12]3[CH3:11])=[CH:40][C:39]=2[CH:41]=1
Reactant: C[C@@H]1CCCN1
Reactant: Cc1ccc(S(=O)(=O)OCCc2cc3cc(Br)ccc3o2)cc1
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: C[C@@H]1CCCN1CCc1cc2cc(Br)ccc2o1
Temperature: 60 °C
Yield: 60.8 %

Procedure:
(2R)-2-Methylpyrrolidine tartrate (0.70 g, 3.0 mmol) and potassium carbonate (0.82 g, 6.0 mmol) were combined in acetonitrile (12 mL). The slurry was heated at 60° C. for 1 hour, treated with the product from Example 4B (790 mg, 2.0 mmol). The mixture was heated at about 60° C. for 6 hours, cooled to 25° C., and diluted with toluene (30 mL). The mixture was washed with 5% NaHCO3 (40 mL×2) and extracted with H2O: N-methylpyrrolidinone: MSA (methanesulfonic acid)=70:20:10 (30 mL). The aqueous solution was adjusted to pH about 12 with 50% NaOH and extracted with IPAC (45 mL). The organic phase was washed with 5% NaHCO3 (50 mL×3), water (50 mL, 2×), dried over MgSO4, filtered, and the filtrate was concentrated to dryness to provide 375 mg (60%) of the title compound. MS (esi): 308, 310 (M+H)+; 1H-NMR (CDCl3) δ 7.58 (1H, d, J=1.7 Hz), 7.27 (2H, m), 6.38 (1H, s), 3.20 (2 H, m), 2.95 (2H, m), 2.43 (1H, m), 2.28 (1H, m), 2.19 (1H, q, J=8.8 Hz), 1.95 (1 H, m), 1.75 (2H, m), 1.42 (1H, m), 1.13 (3H, d, J=6.2 Hz); 13C-NMR (CDCl3) δ 158.8, 152.9,130.6, 125.7, 122.6, 115.2,111.9, 101.8, 60.0, 53.9, 51.9, 32.9, 28.4, 22.0, 19.3.
Reaction SMILES: [CH:1]([C@H:4]1[C:9]([O:10]C)=[N:8][C@@:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(C)[C:6]([O:20][CH3:21])=[N:5]1)([CH3:3])[CH3:2].Cl.[CH2:23](OCC)C>>[CH:1]([C@@:4]1([CH3:23])[C:9](=[O:10])[NH:8][C@H:7]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:6]([O:20][CH3:21])=[N:5]1)([CH3:2])[CH3:3]
Reactant: COC1=N[C@](C)(Cc2ccccc2)C(OC)=N[C@H]1C(C)C
Reactant: CCOCC
Agent: Cl
Product: COC1=N[C@@](C)(C(C)C)C(=O)N[C@@H]1Cc1ccccc1
Reaction time: 2 h
Yield: 69 %

Procedure:
1.44 g of (2S,5R)-2,5-dihydro-2-isopropyl-3,6-dimethoxy-5-benzyl-5-methylpyrazine in 30 ml of diethyl ether were treated at room temperature with 25 ml of 0.2N HCl in diethyl ether. After 2 h, the mixture was evaporated in vacuo. Distillation of the residue gave 0.94 g (69%) of crude (2S,5R)-2,5-dihydro-2-isopropyl-6-methoxy-5-benzyl-methyl-pyrazin-3-one, boiling point 170° C./0.005 Torr.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([NH:15][C:16]([NH:18][NH2:19])=[O:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.[C:21](=N)(N)[CH3:22].C([O-])(=O)C.[Na+]>O(CCOC)CCOC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([N:15]3[C:21]([CH3:22])=[N:19][NH:18][C:16]3=[O:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCN(NC(=O)NN)CC2)cc1
Reactant: CC(=N)N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCOCCOC
Product: COc1ccc(N2CCN(n3c(C)n[nH]c3=O)CC2)cc1
Temperature: 130 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
A mixture of 13 parts of N-[4-(4-methoxyphenyl)-1-piperazinyl]hydrazinecarboxamide, 14.2 parts of ethanimidamide hydrochloride, 12.3 parts of sodium acetate and 95 parts of 1,1'-oxybis[2-methoxyethane] is stirred for 3 hours at 130° C. The reaction mixture is poured onto water and the product is extracted twice with dichloromethane. The combined extracts are dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone, yielding 5.1 parts (35%) of 2,4-dihydro-4-[4-(4-methoxyphenyl)-1-piperazinyl]-5-methyl-3H-1,2,4-triazol-3-one; mp. 264.3° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]#[CH:21])[CH2:15][C:14]3=[O:22])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCN(CC)CC>CN(C=O)C.[Cu]I>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]#[C:21][C:35]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:25]4[CH:24]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:15][C:14]3=[O:22])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: C#CCN1CCN(Cc2ccc3c(N)ncnc3c2)C(=O)C1
Reactant: Brc1ccccc1-c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncnc2cc(CN3CCN(CC#Cc4ccccc4-c4ccccc4)CC3=O)ccc12
Temperature: 80 °C
Yield: 5.3 %

Procedure:
A solution containing 1-(4-amino-quinazolin-7-ylmethyl)-4-prop-2-ynyl-piperazin-2-one (50 mg, 0.17 mmol), EXAMPLE 283, 2-bromobiphenyl (44 mg, 0.19 mmol), Et3N (69 mg, 0.68 mmol), (Ph3P)4PdCl2 (6 mg, 0.008 mmol), and CuI (1 mg, 0.005 mmol) in anhydrous DMF (2 mL) is warmed at 80° C. for 1 hours. The reaction mixture is cooled to 50° C. and the solvent is removed over 16 h under a stream of nitrogen. The crude residue is purified by flash silica gel chromatography (CH2Cl2 to 10% MeOH CH2Cl2) to afford a colorless gum which is triturated with ethyl alcohol to provide 4 mg (5%) of the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO) δ3.03 (s, 2H), 3.14 (m, 2H), 3.31 (m, 2H), 3.50 (s, 2H), 7.21-7.55 (m, 11H), 7.76 (br s, 2H), 8.18 (d, J=8.6 Hz, 1H), 8.36 (s, 1H) ppm; MS (ion spray): m/z 448 (M+H).
Reaction SMILES: [C:1]1([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]([CH2:21][CH2:22][C:23](O)=[O:24])[C:13]2=[O:26])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N.O1CCOCC1.O[N:35]1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>O.C1COCC1>[C:1]1([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]([CH2:21][CH2:22][C:23]([NH2:35])=[O:24])[C:13]2=[O:26])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)CCn1c(=O)n(Cc2cccc3ccccc23)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: C1COCCO1
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)CCn1c(=O)n(Cc2cccc3ccccc23)c2ccccc21
Reaction time: 20 h
Yield: 76.5 %

Procedure:
To the THF (1.0 mL) suspension of 3-(3-Naphthalen-1-ylmethyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propionic acid (50 mg, 0.14 mmol) at room temperature are added ammonia 0.5 M solution in dioxane (1.4 mL, 0.72 mmol) and 1-hydroxybenzotriazole (94 mg, 0.7 mmol). Then N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (118 mg, 0.61 mmol) is added in small portions. The reaction mixture is stirred for 20 hr and then water (5 mL) is added and the mixture is extracted with EtOAc (3×10 mL). The organic layers are combined, dried over MgSO4 and concentrated to give crude product. Purification by preparative TLC using 5% MeOH in CH2Cl2 affords 37 mg (74%) of 3-(3-Naphthalen-1-ylmethyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propionamide. LCMS (ESMS): m/z 346.12 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1.[C:16]([O:20][C:21]([N:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][C:27]([CH2:33][CH2:34]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:28][CH:29]=2)[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][C:27]([CH2:33][CH2:34][N:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:10][C:11]3=[O:15])=[CH:28][CH:29]=2)[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=c1cc(OCc2ccccn2)cc[nH]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3)cc1
Product: CC(C)(C)OC(=O)N1CCc2ccc(CCn3ccc(OCc4ccccn4)cc3=O)cc2C1

Procedure:
7-{2-[2-Oxo-4-(pyridin-2-ylmethoxy)-2H-pyridin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester is prepared following example 24.1 from 530 mg (2.23 mmol) 4-(pyridin-2-ylmethoxy)-1H-pyridin-2-one (preparation 22.4) and 1.06 g (2.45 mmol) 7-[2-(toluene-4-sulfonyloxy)-ethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (preparation 7).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:10]=[C:9]([CH:11]=[O:12])[S:8][C:6]=2[N:7]=1.[CH2:19]([C:21]1[NH:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1)[CH3:20].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:19]([C:21]1[N:22]([C:2]2[N:3]=[C:4]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:5]3[N:10]=[C:9]([CH:11]=[O:12])[S:8][C:6]=3[N:7]=2)[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1)[CH3:20]
Reactant: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: CCc1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)sc2n1
Temperature: 115 °C
Yield: 88.8 %

Procedure:
A mixture of 5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine-2-carbaldehyde (1.0 g, 3.51 mmol), 2-ethylbenzimidazole (512 mg, 3.71 mmol), tris(dibenzylideneacetone)dipalladium (90 mg, 2.5 mol %), XPhos (158 mg, 10 mol %) and Cs2CO3 (1.6 g, 4.91 mmol) in dioxane (30 mL) was purged with argon then heated at 115° C. for 17 h. The reaction mixture was filtered through Celite® which was washed with hot dioxane, and the filtrated concentrated in vacuo. The resulting residue was triturated with Et2O and the resulting brown solid collected by filtration and dried in vacuo affording the title compound (1.23 g, 88%). 1H NMR (CDCl3, 400 MHz): δ 10.01 (1 H, s), 8.09-8.09 (1 H, m), 7.75-7.74 (1 H, m), 7.33-7.26 (2 H, m), 5.00-4.00 (4 H, brd s), 3.93 (4 H, t, J=4.72 Hz), 3.37 (2 H, q, J=7.45 Hz), 1.46 (3 H, t, J=7.45 Hz).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.Cl[C:31]([O:33][CH3:34])=[O:32].O>O1CCCC1.CCCCCC>[C:31]([C:21]1[N:20]([C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=[CH:23][N:22]=1)([O:33][CH3:34])=[O:32]
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2ccnc2)cc1
Reactant: COC(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.7 %

Procedure:
To a stirred solution of 12.4 g (40 mmol.) of 1-tritylimidazole in 250 mL of tetrahydrofuran, under argon, at 0° C. was added 20 mL (48 mmol.) of a solution of n-butyl-lithium in hexane. After the solution was allowed to warm to ambient temperature, it was stirred for 1 hour and then 3.4 mL (50 mmol.) of methyl chloroformate was added dropwise. The mixture was stirred for 20 hours at 25° C., 100 mL of water was added and then the mixture was concentrated in vacuo. The residue was extracted with ether. After the extracts were dried (MgSO4) and concentrated, the residue was chromatographed on 200 g of silica using 1:3 ethyl acetate: hexane, followed by 1:1 ethyl acetate: hexane, and finally ethyl acetate to give 3.2 g of colorless product.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=4)[N:21]=3)[CH:19]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:37][C:32]1[CH:31]=[C:30]([C:22]2[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[N:25]=[C:20]([N:18]3[CH:19]=[C:15]([C:12]4[CH:11]=[CH:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:14][CH:13]=4)[N:16]=[CH:17]3)[N:21]=2)[CH:35]=[CH:34][C:33]=1[Cl:36]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)cn2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.4 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-4-{1-[6-(3,4-dichloro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.08 g) in dichloromethane (2 mL) was added TFA (2 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (2.5 mL) and MeOH (2.5 mL) were added. The mixture was stirred at room temperature for 30 min, the precipitate was collected by filtration and washed with water. The crude product was further purified by crystallization (dichloromethane/heptane/MeOH) to yield the title compound as a white solid (0.058 g, 11%). MS (ISN) 512.3 [(M−H)−]; mp 334° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[C:46]=1[Cl:55]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[C:46]=3[Cl:55])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: FC(F)(F)c1cccc(CBr)c1Cl
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3cccc(C(F)(F)F)c3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2-chloro-3-(trifluoromethyl)b enzene and isolated as white solid. MS (m/e): 475.3 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=3[O:18][CH3:19])[C:5]2=[CH:4][N:3]=1.[NH2:20][C@H:21]1[CH2:26][CH2:25][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][C@@H:22]1O>>[F:17][C:15]1[CH:14]=[CH:13][C:12]([O:18][CH3:19])=[C:11]([C:10]2[C:5]3[C:6](=[N:7][C:2]([NH:20][CH:21]4[CH2:26][CH2:25][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][CH2:22]4)=[N:3][CH:4]=3)[NH:8][N:9]=2)[CH:16]=1
Reactant: CS(=O)(=O)N1CC[C@H](N)[C@@H](O)C1
Reactant: COc1ccc(F)cc1-c1n[nH]c2nc(Cl)ncc12
Product: COc1ccc(F)cc1-c1n[nH]c2nc(NC3CCN(S(C)(=O)=O)CC3)ncc12

Procedure:
The same procedure as described in Example 25 was used starting from 6-chloro-3-(5-fluoro-2-methoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidine, Example 24, (103 mg, 0.37 mmol), and (3S,4S)-4-amino-1-methanesulfonyl-piperidin-3-ol, (115 mg, 0.59 mmol), to give a yellow solid. 70 mg, 46%. MS (M+H)+, 437.