Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH2:13])=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:8]=1)#N.[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])C=[CH:18][C:17]=1B(O)O.[CH:27]1([CH:33]=O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([CH:33]2[NH:13][C:6]3[CH:5]=[CH:4][C:3]([C:1]4[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][C:20]=4[O:22][CH3:23])=[CH:8][C:7]=3[S:9](=[O:11])(=[O:10])[NH:12]2)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: N#Cc1ccc(N)c(S(N)(=O)=O)c1
Reactant: O=CC1CCCCC1
Reactant: COc1ccc(B(O)O)c(OC)c1
Product: COc1ccc(-c2ccc3c(c2)S(=O)(=O)NC(C2CCCCC2)N3)c(OC)c1

Procedure:
5-Iodo-2-aminobenzenesulfonamide (see compound 37) was transformed by Method H (using 2,4-dimethoxyphenylboronic acid) and Method G (using cyclohexanecarboxaldehyde). M.p. 208–213° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:63])([CH3:62])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=2)[C:47]1=[O:61])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:63])([CH3:62])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=2)[C:47]1=[O:61])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2ccc([N+](=O)[O-])cc2)C1=O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccc([N+](=O)[O-])cc2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.3 %

Procedure:
A solution containing the product from Example 2C (0.074 g, 0.138 mmol) in THF (1.5 mL) was treated with the product from Example 124A (0.051 g, 0.152 mmol), DEPBT (0.062 g, 0.207 mmol), and N,N-diisopropylethylamine (0.120 mL, 0.691 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by 0-5% methanol in ethyl acetate to give the title compound (0.066 g, 56% yield).
Reaction SMILES: Cl[Si](C)(C)C.BrCCBr.I[CH:11]1[CH2:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[F:18][C:19]1[C:24](I)=[N:23][CH:22]=[CH:21][N:20]=1>CC(N(C)C)=O.[Zn].[Cu]I>[F:18][C:19]1[C:24]([CH:11]2[CH2:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:23][CH:22]=[CH:21][N:20]=1
Reactant: IC1CCCOCC1
Reactant: Fc1nccnc1I
Agent: [Cu]I
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: CC(=O)N(C)C
Solvent: BrCCBr
Product: Fc1nccnc1C1CCCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of chlorotrimethylsilane (0.11 mL, 0.87 mmol) and 1,2 dibromoethane (0.075 mL, 0.87 mmol) was added slowly to a stirred mixture of zinc dust (0.71 g, 10.9 mmol) in DMA (2 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred for 15 min before a solution of 4-iodooxepane (1.97 g, 8.71 mmol) in DMA (5 mL) was added dropwise via syringe. The reaction mixture was stirred at room temperature for an additional 30 min before being warmed to 60° C. for 15 min. The reaction mixture was cooled to room temperature and added directly via syringe to a stirred mixture of 2-fluoro-3-iodopyrazine (1.39 g, 6.23 mmol), copper(i) iodide (0.12 g, 0.62 mmol), and dichloro(1,1-bis(diphenylphosphinoferrocene))palladium(ii) (0.25 g, 0.31 mmol) in DMA (8 mL) under an argon atmosphere. The reaction mixture was stirred at 80° C. for 3 h. The reaction mixture was cooled to room temperature, quenched with sat. ammonium chloride, and extracted with EtOAc. The organic layer was separated, washed with sat. sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography to give 2-fluoro-3-(oxepan-4-yl)pyrazine. [M+1]=197.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]3[S:17][CH:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:4][C:3]=1[NH2:18].O1CCN(CCNC(C2SC3C(OC4C=CC(N[C:47]([NH:49][C:50](=[O:58])[CH2:51][C:52]5[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=5)=[S:48])=CC=4F)=NC=NC=3C=2)=O)CC1>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]3[S:17][CH:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:4][C:3]=1[NH:18][C:47]([NH:49][C:50](=[O:58])[CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)=[S:48]
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3cc(C(=O)NCCN4CCOCC4)sc23)c(F)c1
Reactant: Nc1ccc(Oc2ncnc3ccsc23)cc1Cl
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3ccsc23)cc1Cl
Yield: 9 %

Procedure:
Starting from the amine 172 and following the procedure described above for the synthesis of compound 26a (scheme 4, example 22), title compound 173 was obtained in 9% yield. 1H NMR (400 MHz, DMSO-d6 ppm: 12.35(s, 1H), 11.89(s, 1H), 8.72 (s, 1H), 8.48(d, J=5.6 Hz, 1H), 8.04(d, J=8.8 Hz, 1H), 7.69(d, J=2.8 Hz, 1H), 7.68(d, J=5.6 Hz, 1H), 7.40(dd, J=2.8 and 8.8 Hz, 1H), 7.36-7.30(m, 4H), 7.30-7.24(m, 1H), 3.84 (s, 2H). LRMS (M+1) (100%).
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[NH:6][C:5]1=[O:15])=[N+:2]=[N-:3].[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[CH:17]=[CH2:18].C(O)(C)(C)C.[K]>O1CCCC1.C(O)(C)(C)C.O1CCCC1>[N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]([CH2:18][CH2:17][C:16]([O:20][CH2:21][CH3:22])=[O:19])[C:5]1=[O:15])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC1CCc2ccccc2NC1=O
Reactant: C=CC(=O)OCC
Agent: [K]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CCOC(=O)CCN1C(=O)C(N=[N+]=[N-])CCc2ccccc21

Procedure:
A solution of 3-azido-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one [prepared as described by Watthey et al., J. Med. Chem., 28, p. 1511-15156 (1985)] in tetrahydrofuran/tert-butanol was cooled to 0° C. and treated with ethyl acrylate and 1N tert-butanol, potassium salt/tetrahydrofuran according to the procedure of Example 40 part (a) affording 3-azido-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-propanoic acid, ethyl ester as a syrup. TLC (ethyl ether:hexane, 1:1) Rf =0.45.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:32]#[C:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:23][C@H:22]([O:24][CH2:25]C2C=CC=CC=2)[CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].ClC1[N:44]=[CH:43][CH:42]=[CH:41][N:40]=1.C(#N)C.FC(F)(F)C(O)=O>O>[CH3:36][C:34]([CH3:35])([CH3:37])[C:33]#[C:32][C:7]1[S:6][C:5]([C:3]([OH:2])=[O:4])=[C:9]([N:10]([C:11]([C@H:13]2[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]2)=[O:12])[C@H:20]2[CH2:21][C@H:22]([O:24][C:25]3[N:44]=[CH:43][CH:42]=[CH:41][N:40]=3)[CH2:23]2)[CH:8]=1
Reactant: Clc1ncccn1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1C[C@H](OCc2ccccc2)C1
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C#Cc1cc(N(C(=O)[C@H]2CC[C@H](C)CC2)[C@H]2C[C@H](Oc3ncccn3)C2)c(C(=O)O)s1

Procedure:
The title compound was synthesized in a manner analogous to Example 20, using 3-[(trans-3-benzyloxy-cyclobutyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester in place of 3-[(cis-3-benzyloxy-cyclobutyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester and 2-chloro-pyrimidine in place of 3-fluoro-pyridine: MS (m/z): 493.8 [M−H]−; HPLC retention time: 3.53 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:7]([CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:20])=[C:15]([CH3:26])[CH:14]=2)=[O:11])[CH:8]=1)#[N:2].Cl.[NH2:36][OH:37].[C:38](=[O:41])([O-])[O-:39].[Cs+].[Cs+].[C:44](=O)([O-])[O-].[Na+].[Na+]>CO.O>[OH:37][NH:36][C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:7]([CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:20])=[C:15]([CH3:26])[CH:14]=2)=[O:11])[CH:8]=1)=[NH:2].[C:38]([O-:39])(=[O:41])[CH3:44]
Reactant: Cc1cc(NC(=O)Cc2cc(C#N)ccc2OCc2ccccc2)ccc1C(=O)N1CCCC1
Reactant: NO
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Cs+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)[O-]
Product: Cc1cc(NC(=O)Cc2cc(C(=N)NO)ccc2OCc2ccccc2)ccc1C(=O)N1CCCC1
Temperature: 0 °C

Procedure:
1.1 g (2.5 mmol) of 2-(5-cyano-2-benzyloxy-phenyl)-N-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-acetamide are dissolved in 100 ml of methanol and combined with a solution of 300 mg (5 mmol) of hydroxylamine hydrochloride in 2.0 ml of water. After the addition of 800 mg (2.5 mmol) of caesium carbonate and 300 mg (3.0 mmol) of sodium carbonate the reaction mixture is refluxed for 6 hours. After cooling and the addition of 0.5 l of ice water the crude product obtained is suction filtered and purified on silica gel, eluting first with methylene chloride and methylene chloride/ethanol (19:1), then with methylene chloride/ethanol (9:1+1% glacial acetic acid and 4:1+1% glacial acetic acid). The uniform fractions are combined and concentrated by evaporation.
Reaction SMILES: [CH2:1]([C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:5]=2[N:4]=1)[CH3:2].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH2:27]([O:26][C:24]([CH2:23][N:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[C:5]=2[N:4]=[C:3]1[CH2:1][CH3:2])=[O:25])[CH3:28]
Reactant: CCOC(=O)CBr
Reactant: CCc1nc2c(OCc3ccc(OC)cc3)cccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(CC)nc2c(OCc3ccc(OC)cc3)cccc21
Yield: 66.6 %

Procedure:
A solution of 2-ethyl-4-(4-methoxybenzyloxy)-1H-benzimidazole (282 mg), ethyl bromoacetate (184 mg) and potassium carbonate (414 mg) in dimethylformamide (3 ml) was stirred for 2 hours, and to the reaction mixture were added ethyl acetate and water. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash chromatography (ethyl acetate:n-hexane=1:2 to 2:1, v/v) to give 1-ethoxycarbonylmethyl-2-ethyl-4-(4-methoxybenzyloxy)-1H-benzimidazole (245 mg) as white powder.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([OH:13])[CH:10]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=1>>[C:1]1([C:7]2[N:12]=[C:11]([O:13][CH2:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=3)[CH:10]=[C:9]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Oc1cc(-c2ccccc2)nc(-c2ccccc2)n1
Product: O=C(O)c1ccc(COc2cc(-c3ccccc3)nc(-c3ccccc3)n2)cc1

Procedure:
The title compound was prepared from 2,6-diphenyl-pyrimidin-4-ol (which was obtained in Intermediate 4) and methyl 4-(bromomethyl)benzoate according to Method A and Method B; 1H NMR (DMSO-d6, 300 MHz) δ 5.62 (s, 2H), 7.25 (t, J=8.9 Hz, 2H), 7.49 (s, 1H), 7.50-7.70 (m, 12H); LC retention time 3.59 min; MS: m/z (ESI) 381 (M−H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[CH3:15][NH:16][CH3:17]>CO.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([N:16]([CH3:17])[CH3:15])(=[O:13])=[O:12]
Reactant: CNC
Reactant: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Solvent: O
Solvent: CO
Product: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)N(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
To a solution of 2-methyl-5-nitrobenzenesulfonyl chloride (5.0 g, 21.2 mmol) in 100 mL of methanol at 0° C. was added dimethylamine (5.3 mL of a 40% aqueous solution). The resulting reaction mixture was stirred at 0° C. for 10 min, during which time the product crashed out as white needles. The mixture was diluted with water and filtered, washing once with water. The needles were collected and dried in vacuo to provide 2-methyl-5-nitro(N,N-dimethyl)benzenesulfonamide (4.4 g, 85%), mp 72-74° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]([CH3:13])[C:7](=[O:14])[C:6]=2[CH:15]=1.[Cu][C:17]#[N:18]>N1C=CC=CC=1>[C:17]([C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]([CH3:13])[C:7](=[O:14])[C:6]=2[CH:15]=1)#[N:18]
Reactant: N#C[Cu]
Reactant: CN1CC(=O)Nc2ccc(Br)cc2C1=O
Solvent: c1ccncc1
Product: CN1CC(=O)Nc2ccc(C#N)cc2C1=O

Procedure:
15.0 g of 7-bromo-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione and 7.5 g of copper (I) cyanide (freshly prepared) are mixed well in a mortar and heated from 165° to 195° with 7.2 ml of dry pyridine (freshly distilled over potassium hydroxide) under argon over a period of 3 hours. After cooling to 150°, the solid mass is dissolved in about 250 ml of boiling dimethylformamide. The mixture is left to cool, poured into 800 ml of ice-water and extracted three times with 500 ml of chloroform each time. The organic extracts are washed with 250 ml of 2N hydrochloric acid and three times with 500 ml of water each time, dried in the presence of active carbon and evaporated. The residue is dissolved in about 1 l of methanol. The solution is concentrated to a volume of 250 ml, treated with active carbon and cooled to 5°. The precipitated material is filtered off under suction and dried, there being obtained 7-cyano-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione as white crystals of melting point 256°-258°.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[C:28](O)(=[O:33])[CH2:29]/[CH:30]=[CH:31]/[CH3:32]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:33])[CH2:29]/[CH:30]=[CH:31]/[CH3:32])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: C/C=C/CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: C/C=C/CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (95 mg, 92%), MS (ISP) m/z=413.5 [(M+H)+], mp 175.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and (E)-pent-3-enoic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][C:8]([NH:12][C:13]1[N:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=1)=[CH:7]2.[NH:21]1[CH:25]=[CH:24][C:23](B(O)O)=[N:22]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:21]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[CH:10]=[N:9][C:8]([NH:12][C:13]2[N:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=2)=[CH:7]3)=[N:22]1
Reactant: N#Cc1cnc(Nc2cc3cccc(Br)c3cn2)cn1
Reactant: OB(O)c1cc[nH]n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cnc(Nc2cc3cccc(-c4cc[nH]n4)c3cn2)cn1
Temperature: 140 °C
Yield: 30 %

Procedure:
A mixture of 5-(8-bromoisoquinolin-3-ylamino)pyrazine-2-carbonitrile (65 mg, 0.20 mmol), 1H-pyrazol-3-yl boronic acid (33 mg, 0.30 mmol) and aqueous sodium carbonate (0.5M, 0.60 mL, 0.30 mmol) in DMF (2 mL) was degassed for 15 minutes before the addition of tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.10 mmol). The mixture was further degassed for 5 minutes and then heated to 140° C. for 20 minutes in a microwave reactor. The cooled mixture was partitioned between ethyl acetate and water. The aqueous layer was further extracted with ethyl acetate and the combined organics were washed with water and brine, dried (Na2SO4), and passed sequentially through two PS-Thiol cartridges. The eluent was concentrated to a yellow solid which was dissolved in methanol and purified by SPE on a MP-TsOH cartridge, eluting with 2 M ammonia in methanol. Concentration of the eluent gave the required product as a light yellow solid (18 mg, 0.06 mmol, 29%). 1H NMR (DMSO, 400 MHz) δ 13.25 (br s, 1H), 11.10 (br s, 1H), 10.00 (s, 1H), 8.84 (s, 1H), 8.72 (s, 1H), 8.55 (s, 1H), 7.80-8.00 (m, 2H), 7.70-7.80 (m, 2H), 6.80 (s, 1H). LCMS (2) Rt=2.46 min, m/z (ESI+) 314 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][N:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:10](=[O:21])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:22]I>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][N:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:10](=[O:21])[C:9]=2[CH3:22])=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CC(c3ccc(F)cc3)=CC2=O)cc1
Reactant: CI
Product: COc1ccc(N2CC(c3ccc(F)cc3)=C(C)C2=O)cc1

Procedure:
In a manner similar to that described in Preparation 4, 4-(4-fluorophenyl)-1,5-dihydro-1-(4-methoxyphenyl)-2H-pyrrol-2-one is reacted with methyl iodide to give the title compound.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][O:10][CH2:11][CH2:12][C:13](O)=O.Cl.N>>[CH3:9][O:10][CH2:11][CH2:12][C:13]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=1
Reactant: Nc1ccccc1N
Reactant: COCCC(=O)O
Agent: Cl
Agent: N
Product: COCCc1nc2ccccc2[nH]1
Yield: 91.8 %

Procedure:
A mixture of 3.17 g (29.3 mmols) of o-phenylenediamine, 3.75 g (36.0 mmols) of 3-methoxypropionic acid [J. Am. Chem. Soc., 70, 1004 (1948)]and 32 ml of a 4 normal aqueous hydrochloric acid solution was heated under reflux for 14 hours. After cooling, the mixture was neutralized with a 28-30% aqueous ammonia solution. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol =20/1) to afford 4.74 g (yield: 92%) of 2-(2-methoxyethyl)benzimidazole.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:11](=O)([O-])[O-].[K+].[K+]>C(=O)(OC)OC.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: N#CCc1ccc(Br)cc1
Agent: [K+]
Solvent: COC(=O)OC
Solvent: CCOC(C)=O
Product: CC(C#N)c1ccc(Br)cc1
Yield: 1498.8 %

Procedure:
A solution of 50.0 g (225.0 mmol) of 4-bromophenyl-acetonitrile and 1.8 g (12.8 mmol) of potassium carbonate in 387 mL of dimethyl carbonate was heated to 180° C. in a sealed vessel for 16 hours. The solution was then cooled, diluted with 200 ml of ethyl acetate and washed once with 100 ml water, once with 100 ml of 10% aqueous sodium bisulfate and once with 100 ml brine. The organic portion was dried (MgSO4), filtered and concentrated in vacuo. The residue was distilled under vacuum through a short path distillation apparatus to afford 40.3 g (85%) of the title compound.
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([Br:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][NH2:41])[CH2:34][CH2:33]1>>[Br:24][C:20]1[CH:21]=[C:22]([F:23])[C:17]([CH2:16][O:15][C:12]2[C:11]([C:27]([NH2:28])=[O:29])=[C:10]([NH:9][C:8]([NH:41][CH2:40][CH2:39][CH2:38][N:35]3[CH2:34][CH2:33][N:32]([CH3:31])[CH2:37][CH2:36]3)=[O:7])[S:14][N:13]=2)=[C:18]([F:26])[C:19]=1[F:25]
Reactant: NC(=O)c1c(OCc2c(F)cc(Br)c(F)c2F)nsc1NC(=O)Oc1ccccc1
Reactant: CN1CCN(CCCN)CC1
Product: CN1CCN(CCCNC(=O)Nc2snc(OCc3c(F)cc(Br)c(F)c3F)c2C(N)=O)CC1

Procedure:
The title compound was prepared from [3-(4-bromo-2,3,6-trifluoro-benzyloxy)-4-carbamoyl-isothiazol-5-yl]-carbamic acid phenyl ester and 3-(4-methyl-piperazin-1-yl)-propylamine by the procedure analogous to Example 1. MS (APCl, m/z): 565 and 567 [M+H]+.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10]Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br-:12].[Na+]>CC(C)=O>[N:1]1([C:7]([O:9][CH2:10][Br:12])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(OCCl)N1CCOCC1
Reactant: [Br-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(OCBr)N1CCOCC1
Temperature: 60 °C
Yield: 80.2 %

Procedure:
Chloromethyl morpholine-4-carboxylate [285] (0.3 g, 1.67 mmol, 1.0 eq) and sodium bromide (0.86 g, 8.3 mmol, 5.0 eq) was taken in acetone (10 ml). The reaction was refluxed at 60° C. for 24 h. Reaction progress was monitored by TLC/1H NMR. The reaction was filtered off and filtrate was evaporated to dryness under reduced pressure to yield light brown gel, bromomethyl morpholine-4-carboxylate [286] (0.30 g, 80%)
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[Cl:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31](O)=[O:32])[CH:27]=[CH:28][CH:29]=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>CN(C=O)C.O>[Cl:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([N:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[C:20]5[C:15](=[N:16][CH:17]=[N:18][C:19]=5[NH2:21])[N:14]([CH3:22])[N:13]=4)=[CH:9][CH:10]=3)[CH2:5][CH2:4]2)=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2ccc3c(c2)CCN3C(=O)Cc2cccc(Cl)c2)c2c(N)ncnc21
Temperature: 25 °C

Procedure:
In a 20 mL vial with cap, to the solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 2HCl (70 mg, 0.206 mmol), (3-chlorophenyl)acetic acid (35.2 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added Hunig's base (0.144 mL, 0.825 mmol). The mixture was stirred at rt for over night. LCMS showed reaction was completed. The reaction was poured into water, off-white solid formed. The solid was filtered to give the title compound as an off-white solid. The final product has about 0.5 equivalent of DMF. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.28 (s, 2H), 3.94 (s, 5H), 4.26 (t, J=8.59 Hz, 2H), 7.28 (d, J=7.33 Hz, 1H), 7.35-7.41 (m, 3H), 7.44 (d, J=9.85 Hz, 1H), 7.52 (s, 1H), 8.18 (d, J=8.34 Hz, 1H), 8.25 (s, 1H).
Reaction SMILES: [C:1]([CH:5]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6](Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([C:20]1C=CC=C[C:21]=1[O-:22])(C)(C)C.[Na+].ClCC(OCC)=O>>[C:1]([CH:5]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([O:22][CH2:21][CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C(Oc1ccccc1)C(=O)Cl
Reactant: CC(C)(C)c1ccccc1[O-]
Agent: [Na+]
Solvent: CCOC(=O)CCl
Product: CCOC(=O)C(Oc1ccccc1)C(C)(C)C

Procedure:
The synthesis of this product required the preparation of t-butylphenoxyacetyl chloride from sodium t-butylphenoxide and ethyl chloroacetate. The ethyl t-butylphenoxyacetate obtained is cleaved with potassium hydroxide in order to liberate the t-butylphenoxyacetic acid. The acid chloride is obtained by heating this acid in thionyl chloride. After removing the excess thionyl chloride, the t-butylphenoxyacetyl chloride is reacted with deoxyguanosine according to the procedure described by SCHULHOF et al. for 2-N-phenoxyacetyldeoxyguanosine [Nucleic Acids Res., 15(2), p. 397-415, (1987)].