Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:42])([F:41])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Br[CH2:44][C:45]([C:47]1[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=1)=[O:46]>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:41])([F:42])[CH2:37]2)[C:30]2[N:35]=[N:34][N:33]([CH2:44][C:45]([C:47]3[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=3)=[O:46])[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CC(=O)c3ccc(Cl)cc3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), 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 2-bromo-1-(4-chlorophenyl)ethanone and isolated as light-yellow solid. MS (m/e): 435.3 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([CH3:14])=[N:11]2)=[CH:6][C:5]=1[F:15])[CH3:2].[Se](=O)=[O:17].C(Cl)Cl.[O-]S([O-])(=O)=O.[Mg+2]>O1CCOCC1.O>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([CH:14]=[O:17])=[N:11]2)=[CH:6][C:5]=1[F:15])[CH3:2]
Reactant: O=[Se]=O
Reactant: CCOc1cc2nc(C)ccc2cc1F
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CCOc1cc2nc(C=O)ccc2cc1F

Procedure:
To 7-ethoxy-6-fluoro-2-methylquinoline (180 mg, 0.877 mmol) in dioxane/water (5 mL/0.05 mL) was added selenium dioxide (136 mg, 1.23 mmol) and the reaction was heated to reflux for 2 hours. After cooling, DCM was added followed by MgSO4. After concentration, the residue was used in the next step without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]2.[F:24][C:25]([F:37])([F:36])[O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.O>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:30]4[CH:29]=[CH:28][C:27]([O:26][C:25]([F:24])([F:36])[F:37])=[CH:32][CH:31]=4)=[CH:10][CH:9]=3)[CH:5]=[C:6]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:14]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2n1Cc1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2n1Cc1ccc(C)cc1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
A mixture of ethyl 5-bromo-1-(4-methylbenzyl)-1H-indole-2-Carboxylate (5.8 g, 15.54 mmol), 4-(trifluoromethoxy)phenylboronic acid (8.2 g, 38.85 mmol), potassium carbonate (5.4 g, 38.85 mmol), [1′1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with methylene (1:1) (4.41 g, 5.44 mmol) in dioxane-water (10:1, 154 mL) was stirred at 70° C. for two days. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with water and brine, and then concentrated to an oil. This residue was crystallized from ethyl ether to afford the title compound as an off-white solid, m.p. 77–78° C. Mass spectrum (ESI, [M+H]+) m/z 454. 1H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.78 (d, 2H, J=8.70 Hz), 7.67 (d, 1H, J=8.85 Hz), 7.61 (dd, 1H, J=8.70 and 1.68 Hz), 7.44 (s, 1H), 7.42–7.41 (m, 3H), 7.06 (d, 2H, J=7.94 Hz), 6.94 (d, 2H, J=8.09 Hz), 5.83 (s, 2H), 4.29 (q, 2H), 2.21 (s, 3H), and 1.30 ppm (t, 3H).
Reaction SMILES: [NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][C:12]([O:14]CC1C=CC=CC=1)=[O:13])=[O:9])=[O:5])[CH3:3]>C(O)C.[Pd]>[NH:1]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C@H:2]([C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][C:12]([OH:14])=[O:13])=[O:9])=[O:5])[CH3:3]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)NCC(=O)O
Reaction time: 24 h

Procedure:
0.5 g (1.3 mmol) of Boc-Ala-Gly-Gly-OBzl (13) is dissolved in 25 ml of absolute ethanol (Aldrich) in a 50 ml round bottom flask equipped with a stirring bar, followed by addition of 50 mg of 10% Pd-C (Aldrich). The reaction mixture is stirred under hydrogen gas atmosphere using a balloon. After 24 h, the Pd-C catalyst is filtered out from the reaction mixture, and the filtrate is concentrated to furnish Boc-Ala-Gly-Gly-OH (14). 1H-NMR (CDCl3): 1.39 (3H, d, J=7.2 Hz), 1.43 (9H, s), 3.99-4.15 (5H, m), 5.03 (1H, br), 6.91-7.03 (2H, br). FABMS: 325 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:12]#[N:13].F[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23]>>[F:11][C:8]1[CH:9]=[CH:10][C:4]2[C:3]([C:12]#[N:13])=[C:2]([NH:1][C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[N+:22]([O-:24])=[O:23])[S:6][C:5]=2[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: N#Cc1c(N)sc2cc(F)ccc12
Product: N#Cc1c(Nc2cc(F)ccc2[N+](=O)[O-])sc2cc(F)ccc12
Yield: 92.4 %

Procedure:
In the same manner as in Starting Material Synthesis Example 51 and using 2-amino-6-fluorobenzo[b]thiophene-3-carbonitrile (4.9 g) and 2,4-difluoro-nitrobenzene (4.1 g), 6-fluoro-2-(5-fluoro-2-nitroanilino)benzo[b]thiophene-3-carbonitrile (7.8 g) was obtained.
Reaction SMILES: [C:1]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[NH:19][C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:21])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[N+:27]([O-])([OH:29])=[O:28]>C(O)(=O)C.C(OC(=O)C)(=O)C>[C:1]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[N+:27]([O-:29])=[O:28])[CH:12]=[CH:11][C:10]=1[NH:19][C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:21])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C(=O)Nc1ccc2ccccc2c1NC(=O)C(=O)OCC
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(=O)Nc1ccc2cccc([N+](=O)[O-])c2c1NC(=O)C(=O)OCC
Temperature: 0 °C

Procedure:
A partial suspension of 1,2-diethoxalylaminonaphthalene (1,79 g, 5 mmol) in 7 ml of acetic acid and 7 ml of acetic anhydride was treated dropwise with a solution of nitric acid (1.8 ml, 43 mmol, d 1.52) in 7 ml of acetic acid, with stirring at 0° C. The resulting solution was stirred at 0° C. for 11/2 h and then poured on 150 ml of ice/water. The yellow precipitate was isolated, dried and recrystallized from ethanol with decolourising carbon giving 0.67 g (33%) of the required compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([N:43]2[CH:47]=[N:46][CH:45]=[N:44]2)=[CH:38][C:37]=1[CH3:48].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:48][C:37]1[CH:38]=[C:39]([N:43]2[CH:47]=[N:46][CH:45]=[N:44]2)[CH:40]=[C:41]([CH3:42])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: Cc1cc(-n2cncn2)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-n6cncn6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydro-benzofuran-3-yl)acetate and 1-(4-bromo-3,5-dimethylphenyl)-1H-1,2,4-triazole following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 7): tR=1.16 min; Mass spectrum (ESI+): m/z=514 [M+H]+.
Reaction SMILES: ClC1C(CCCl)=C(C2C=CC=C(OC)C=2)N=C(N2CCOCC2)N=1.CC1C=CC=CC=1N.C[O:34][C:35]1[CH:36]=[C:37]([C:41]2[C:42]3[CH2:55][CH2:54][N:53]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=4[CH3:62])[C:43]=3[N:44]=[C:45]([N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)[N:46]=2)[CH:38]=[CH:39][CH:40]=1>>[N:47]1([C:45]2[N:46]=[C:41]([C:37]3[CH:36]=[C:35]([OH:34])[CH:40]=[CH:39][CH:38]=3)[C:42]3[CH2:55][CH2:54][N:53]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=4[CH3:62])[C:43]=3[N:44]=2)[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccccc2C)c1
Agent: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Solvent: Cc1ccccc1N
Product: Cc1ccccc1N1CCc2c(-c3cccc(O)c3)nc(N3CCOCC3)nc21

Procedure:
In the same manner as Example 1-A-01, from 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]-morpholine and 2-methylaniline, 4-(3-methoxy-phenyl)-2-morpholin-4-yl-7-o-tolyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine was obtained, and subsequently, further in the same manner as Example 1-A-09, the desired compound was obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:26]([NH:28][CH3:29])=[O:27])=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18]C(=O)OC(C)(C)C)=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>>[C:1]([NH:4][C:5]1[S:6][C:7]([C:26]([NH:28][CH3:29])=[O:27])=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CNC(=O)c1sc(NC(C)=O)nc1CCc1ccc(NC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1sc(NC(C)=O)nc1CCc1ccc(N)cc1
Temperature: 25 °C
Yield: 67.8 %

Procedure:
tert-Butyl 4-(2-{2-(acetylamino)-5-[(methylamino)carbonyl]-1,3-thiazol-4-yl}ethyl)phenylcarbamate (95 mg) and trifluoroacetic acid (2 ml) were combined at 0° C. The reaction mixture was stirred at room temperature for an hour, and concentrated in vacuo. The residue was dissolved in chloroform. The organic solution was washed with 1N sodium hydroxide solution, water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative silica gel column chromatography with chloroform/methanol (10:1) as an eluent to give 2-(acetylamino)-4-[2-(4-aminophenyl)ethyl]-N-methyl-1,3-thiazole-5-carboxamide (49 mg) as an off-white amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([OH:6])=[O:5].[C:13](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:13][O:5][C:4](=[O:6])[C:3]1[C:7]([CH3:12])=[CH:8][C:9]([Cl:11])=[N:10][C:2]=1[Cl:1]
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1c(C)cc(Cl)nc1Cl
Yield: 98.4 %

Procedure:
To a solution of 8.05 g (39.1 mmol) of 2,6-dichloro-4-methyl-nicotinic acid [Lamm, G. Ger. Offen. (1977), DE 2538950] in 100 ml of DMF was added 8.10 g (58.6 mmol) of potassium carbonate. While stirring, 12.16 ml=27.7 g (195.4 mmol) of iodomethane was added drop by drop and the reaction mixture was stirred for 6 hours at RT. It was then poured into crashed ice and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated to give 8.47 g (99%) of the title compound as light yellow solid. MS: 219.0 (M+, 2Cl).
Reaction SMILES: [CH:1]1([O:5][C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:46])[C@@H:15]([NH:28]C(OCC3C4C=CC=CC=4C4C3=CC=CC=4)=O)[CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:10][CH2:9]2)=[O:7])[CH2:4][CH2:3][CH2:2]1.N1CCOCC1>CN(C=O)C>[CH:1]1([O:5][C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:46])[C@@H:15]([NH2:28])[CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:10][CH2:9]2)=[O:7])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(N[C@@H](CCCCOCc1ccccc1)C(=O)N1CCN(C(=O)OC2CCC2)CC1)OCC1c2ccccc2-c2ccccc21
Solvent: C1COCCN1
Solvent: CN(C)C=O
Product: N[C@@H](CCCCOCc1ccccc1)C(=O)N1CCN(C(=O)OC2CCC2)CC1
Reaction time: 2 h

Procedure:
To a solution of 726 mg (S)-4-[6-Benzyloxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)-hexanoyl]-piperazine-1-carboxylic acid cyclobutyl ester in 4.0 ml DMF were added at room temperature 1.0 ml morpholine. After stirring for 2 h the reaction mixture was evaporated and the crude product thus obtained used in the next step without further purification.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].Br[CH:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:12]>>[CH2:1]([N:3]([CH:11]([CH3:12])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCNc1ccccc1
Reactant: CCCCCC(C)Br
Product: CCCCCC(C)N(CC)c1ccccc1

Procedure:
N-Ethyl-N-(1-methylhexyl)aniline was prepared from N-ethylaniline and 2-bromoheptane using the same method as in Example 3i).
Reaction SMILES: I[C:2]1[C:7]([C:8]([NH:10][NH:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:18][CH3:19])[N:5]=[CH:4][CH:3]=1.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CS(C)=O.[Cu]I>[CH3:19][O:18][C:6]1[C:7]2[C:8](=[O:9])[NH:10][N:11]([CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:2]=2[CH:3]=[CH:4][N:5]=1
Reactant: COc1nccc(I)c1C(=O)NNC1CCOCC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: COc1nccc2c1c(=O)[nH]n2C1CCOCC1
Yield: 67.5 %

Procedure:
A solution of 4-iodo-2-methoxy-N′-(tetrahydro-2H-pyran-4-yl)nicotinohydrazide (500 mg), L-proline (30.5 mg), potassium carbonate (366 mg) and copper(I) iodide (25.2 mg) in DMSO (25 mL) was stirred overnight at room temperature under nitrogen atmosphere. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (223 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)#[N:25].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([C:24]#[N:25])[CH:31]=2)=[CH:17][CH:16]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
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: [I-]
Solvent: O
Solvent: COCCOC
Product: N#Cc1cccc(Cc2ccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)cc2)c1
Yield: 58.2 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(3-cyanobenzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.075 g; 0.216 mmol), 3-cyanophenylboronic acid (0.034 g; 0.229 mmol), tetrakis(triphenylphosphine)palladium(0) (0.013 g; 0.011 mmol), sodium carbonate (0.045 g; 0.431 mmol), sodium iodide (0.064 g; 0.431 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.052 g (56%) of the title compound as a white solid.
Reaction SMILES: [Br:1]Br.[C:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH:14]=[CH2:15])(=[O:5])[CH3:4]>C(=S)=S>[Br-:1].[Br-:1].[C:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH:14]=[CH2:15])(=[O:5])[CH3:4]
Reactant: BrBr
Agent: C=CCc1ccccc1OC(C)=O
Solvent: S=C=S
Product: [Br-]

Procedure:
A solution of bromine (90 g) in carbon disulphide (100 ml) was added dropwise to a well stirred solution of O-acetyl-2-allylphenol (100 g) in carbon disulphide (300 ml) at -10° C. over 1 hour. The solution was evaporated to dryness in vacuo, to afford O-acetyl-2-allylphenol dibromide which was immediately dissolved in dry ethanol (300 ml) containing 10 ml of a saturated ethanolic-hydrogen chloride solution. The solution was heated under gentle reflux for 2 hours, and then evaporated to dryness in vacuo. The residue was triturated with n-pentane, and the solid 2-allylphenol dibromide (135 g) was collected and washed twice with portions of n-pentane. The product is pure enough for further reaction. 2-Allylphenol dibromide (135 g) in dry ethanol (300 ml) was treated with a solution of sodium ethoxide (38 g) in ethanol (100 ml) with cooling and stirring, keeping the temperature of the reaction between 30° and 35° C. After addition, the reaction was stirred at room temperature for 1 hour, and then evaporated to dryness in vacuo. The residue was partioned between n-pentane and water. The n-pentane fraction was washed with 2% sodium hydroxide solution, water, and dried (Na2SO4). Evaporation to dryness in vacuo afforded crude (2,3-dihydro-2-benzofuranyl)-methyl bromide (90 g), which distilled at 110°-118° C./0.5 mm to afford product (78 g) of slightly higher purity.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1B(O)O>>[Cl:8][C:6]1[CH:7]=[C:2]([C:10]2[S:9][CH:13]=[CH:12][CH:11]=2)[CH:3]=[N:4][CH:5]=1
Reactant: OB(O)c1cccs1
Reactant: Clc1cncc(Cl)c1
Product: Clc1cncc(-c2cccs2)c1
Yield: 16 %

Procedure:
The title compound (0.21 g, 1.08 mmol) was prepared from 3,5-dichloropyridine (1.0 g, 6.76 mmol) and 2-thiophene boronic acid (0.95 g, 7.43 mmol) as described in EXAMPLE 48, Part B.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].[F:11][C:12]([F:23])([F:22])[O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl>O.CN(C=O)C>[F:11][C:12]([F:22])([F:23])[O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[NH:3][C:2]2=[O:10])=[CH:16][CH:15]=1
Reactant: O=c1[nH]c2ccccc2[nH]1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2n1Cc1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Yield: 0 %

Procedure:
To a solution of benzimidazolinone (4.02 g, 30 mmol) in abs. DMF (20 mL) there were added 4-trifluoromethoxybenzyl bromide (5 g, 19.6 mmol), potassium carbonate (7.0 g, 50.7 mmol), and a catalytic amount of potassium iodide under a blanket of argon. The reaction mixture was heated to 100° C. over a period of 2 h. Following cooling, the reaction mixture was poured into a mixture of ice (200 g) and 2N hydrochloric acid solution in H2O (100 mL). The resulting precipitate was separated with the aid of a frit and then dried. The residue was taken up in EtOAc (150 mL) and the insoluble components separated. The solvent was removed in vacuo, and the residue was recrystallized from a little EtOAc (20 mL), and the dibenzylated product (S) was precipitated. The mother liquor was again concentrated in vacuo, the residue recrystallized from ethanol, and the precipitated solid matter (S) separated by filtration. The filtrate was purified by means of column chromatography (SiO2, cyclohexane/EtOAc 1:4), and there was obtained 1-(4-trifluoromethoxybenzyl)-1,3-dihydrobenzimidazol-2-one (R) (1.60 mg, 26% of theory, mp: 145-148° C.).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[N:6][CH:7]=[N:8][CH:9]=1)([O-:3])=[O:2].Cl[C:19]1[O:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1>CN1CCCC1=O.O>[O:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[NH:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=[CH:7][N:6]=2)=[CH:12][CH:13]=1
Reactant: Clc1nc2ccccc2o1
Reactant: Nc1ccc(Nc2ncncc2[N+](=O)[O-])cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1cncnc1Nc1ccc(Nc2nc3ccccc3o2)cc1
Temperature: 120 °C
Reaction time: 0.75 h
Yield: 42.9 %

Procedure:
A mixture of N-(5-nitropyrimidin-4-yl)benzene-1,4-diamine (256 mg), 2-chloro-1,3-benzoxazole (110 mg) in N-methylpyrrolidone (3 mL) was stirred at 120° C. for 45 min. After this time, the reaction mixture was cooled to ambient temperature, diluted with water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL) then brine (50 mL), dried over sodium sulfate, and filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 1:3 ethyl acetate/methylene chloride) to afford N-1,3-benzoxazol-2-yl-N′-(5-nitropyrimidin-4-yl)benzene-1,4-diamine (107 mg) as a red solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH2:20])=[CH:15][CH:14]=1.OO.C(=O)(O)[O-:34].[Na+]>CO.O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]=[N:20][OH:34])=[CH:17][CH:18]=1)[CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1
Reactant: O=C([O-])O
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CO
Product: ON=Cc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reaction time: 3 h
Yield: 63 %

Procedure:
To a stirred solution of N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (200 mg, 0.50 mmol) in MeOH (5 mL) was added solid sodium tungstate dihydrate (332 mg, 1.0 mmol) followed by a 35 wt % aqueous solution of hydrogen peroxide (2.9 mL, 30 mmol). The resulting suspension was stirred 3 h, then saturated aqueous sodium bicarbonate (5 mL) was added. The phases were separated and the aqueous layer was extracted with CH2Cl2 (3×10 mL), then the combined organic extracts were washed once with brine (10 mL), dried (MgSO4), and concentrated in vacuo. Purification of the crude material by flash chromatography (silica gel, 75:1:1 CH2Cl2MeOH/NH4OH) afforded the title compound (130 mg, 63%) as a white solid. 1H NMR (CDCl3) δ 1.63–1.66 (m, 1H), 1.97–2.07 (m, 2H), 2.25–2.27 (m, 1H), 2.66–2.72 (m, 1H), 2.80–2.85 (m, 1H), 3.65 (d, 1H, J=14 Hz), 3.71 (d, 1H, J=14 Hz), 5.03 (d, 1H, J=16 Hz), 4.14 (dd, 1H, J=9, 7 Hz), 4.21 (d, 1H, J=16 Hz), 7.11–7.19 (m, 3H), 7.41–7.48 (m, 6H), 7.65 (br d, 1H, J=5 Hz), 8.18 (s, 1H), 8.67 (dd, 1H, J=5, 1 Hz); 13C NMR (CDCl3) δ 22.2, 23.9, 30.2, 49.5, 55.0, 61.2, 112.1, 119.4, 122.7, 123.3, 127.8, 130.1, 133.0, 136.2, 138.7, 141.4, 147.8, 150.0, 156.2, 157.7. ES-MS m/z 412 (M+H). Anal. Calcd. for C25H25N5O.0.4H2O.0.3CH2Cl2: C, 68.41; H, 5.99; N, 15.77. Found: C, 68.57; H, 5.86; N, 15.48.