Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[C:8]2([CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:17]([O:19]C)=O.[N+]([O-])(O)=O.[NH2:25][C:26]([NH2:28])=[NH:27].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(O)(=O)C>[NH2:28][C:26]1[N:25]=[C:17]([OH:19])[C:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C:8]3([CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH2:9]3)[C:2]=2[N:27]=1
Reactant: N=C(N)N
Reactant: COC(=O)C1CCCCC2(Cc3ccccc3C2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(O)c2c(n1)C1(CCCC2)Cc2ccccc2C1
Temperature: 25 °C

Procedure:
A mixture of Example 19B (490 mg, 1.799 mmol), guanidine nitrate (439 mg, 3.60 mmol), and potassium carbonate (497 mg, 3.60 mmol) in DMF (4 mL) was heated overnight at 120° C. After this time, the mixture was cooled to room temperature, then poured into 50 mL of water. The pH was adjusted to about 5 with acetic acid, then the precipitate was collected by filtration, washed with water, and air-dried. The sample was further dried azeotropically with toluene to yield the title compound. 1H NMR (300 MHz, DMSO-d6) δ 10.70 (br, 1H), 7.07-7.20 (m, 4H), 6.14 (br s, 2H), 3.58 (d, J=16.0 Hz, 2H), 2.95 (m, 1H), 2.90 (m, 1H), 2.57-2.66 (m, 2H), 1.59-1.74 (m, 4H), 1.49 (m, 2H). MS (DCI+) m/z 282 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[S:17]1[CH:21]=[C:20]([CH2:22]Cl)[N:19]=[CH:18]1>CN(C=O)C.[Cl-].[Na+].O>[S:17]1[CH:21]=[C:20]([CH2:22][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[N:19]=[CH:18]1
Reactant: O=Cc1ccc(O)cc1
Reactant: ClCc1cscn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2cscn2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.3 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (12.1 g, 100 mmol) and potassium carbonate (41.5 g, 0.30 mole) in DMF (100 mL) was added 4-thiazolylmethyl chloride hydrochloride (17.0 g, 100 mmol), and the resulting mixture was stirred at ambient temperature for 48 hours. The mixture was then poured into brine and filtered to collect the precipitated solid. The solid was washed with water (500 mL) and 10% ethyl ether in hexane and dried in vacuo to provide 17.6 g of 4-(4-thiazolylmethoxy)benzaldehyde.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:6][N:7]=1.[BH4-].[Na+].[C:19]([OH:26])(=[O:25])/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23]>CO.O.C(O)C>[C:19]([OH:26])(=[O:25])/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23].[CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]2[C:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:9][CH:10]=[C:3]12
Reactant: CC1=NCCn2c1ccc2-c1ccccc1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: O
Product: CC1NCCn2c(-c3ccccc3)ccc21
Yield: 37 %

Procedure:
3,4-Dihydro-1-methyl-6-phenylpyrrolo[1,2-a]pyrazine (1.1 g) was dissolved in a mixture of 50 ml of methanol and 5 ml of water under argon. The solution was treated portionwise with 0.9 g of sodium borohydride while stirring and stirred at room temperature overnight. Thereafter, the methanol was removed in a vacuum, the residue was taken up in 100 ml of methylene chloride and washed with 100 ml of 10% ammonia solution. The phases were separated and the aqueous phase was extracted twice with 50 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The crude product, 1.1 g of yellow oil, was dissolved in a 10-fold amount of ethanol and boiled briefly with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. The separated colourless crystals were recrystallized from a 30-fold amount of methanol. There was obtained 0.5 g (37%) of 1,2,3,4-tetrahydro-1-methyl-6-phenylpyrrolo[1,2-a]pyrazine fumarate (1:1); m.pt.: 153°-154° C. (dec.).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[SH:30][C:31]1[N:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([OH:35])=O.[CH:40]12[CH2:46][CH:43]([CH2:44][CH2:45]1)[CH2:42][CH:41]2[CH2:47][NH2:48]>CN(C=O)C.CC(=O)OCC.C(Cl)Cl.CO>[CH:40]12[CH2:46][CH:43]([CH2:44][CH2:45]1)[CH2:42][CH:41]2[CH2:47][NH:48][C:33](=[O:35])[C:32]1[CH:36]=[CH:37][CH:38]=[N:39][C:31]=1[SH:30]
Reactant: NCC1CC2CCC1C2
Reactant: O=C(O)c1cccnc1S
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(NCC1CC2CCC1C2)c1cccnc1S
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
4.82 g (15.0 mmol) of TBTU and 3.54 g (35 mmol) of N-methyl-morpholine were added to a solution of 1.55 g (10.0 mmol) of 2-mercapto-nicotinic acid in DMF (30 ml), and the mixture was stirred for 30 min at RT. 1.25 g (10.0 mmol) of bicyclo-[2.2.1]heptan-2-ylmethanamine were then added, and stirring was carried out for 16 h at RT. The mixture was then diluted with EA and washed with sat. aq. NH4Cl sol., a 1N aq. NaHCO3 sol. and brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. CC (DCM/MeOH 99:1) of the residue yielded 308 mg 1.39 g (5.3 mmol, 53%) of N-(bicyclo[2.2.1]heptan-2-ylmethyl)-2-mercapto-nicotinamide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C@H:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])=[CH:25][CH:24]=1)[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15]C(C)(C)C)=[O:14])=[CH:9][C:8]=1[Cl:20].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:37])[C@H:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])=[CH:25][CH:24]=1)[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9][C:8]=1[Cl:20]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2OC)cc1)NC(=O)c1ccc(C(=O)OC(C)(C)C)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2OC)cc1)NC(=O)c1ccc(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 115.7 %

Procedure:
N-[2-Chloro-4-(tert-butoxycarbonyl)benzoyl]-4-(2-methoxyphenyl)-L-phenylalanine methyl ester (305 mg) was dissolved in anhydrous CH2Cl2 (2 mL) under N2 and TFA (2 mL) was added. The mixture was stirred at room temperature for 2 h to give N-[2-chloro-4-carboxybenzoyl]-4-(2-methoxyphenyl)-L-phenylalanine methyl ester (315 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:5]=O.[CH3:15][C:16]([C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=1)=[O:17].[OH-].[Na+]>CO>[OH:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:15]/[C:16]([C:18]2[CH:19]=[C:20]([O:28][CH3:29])[C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=2)=[O:17])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCOc1ccc(C=O)cc1O
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCOc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1O
Yield: 11.1 %

Procedure:
A mixture of 3-hydroxy-4-butoxybenzaldehyde (1.0 g, 5.2 mmol), 3,4,5-trimethoxyacetophenone (1.08 g, 5.2 mmol) and 50% w/v of aqueous sodium hydroxide (8.25 ml, 0.103 mol) in methanol (10 ml) at room temperature for 18 h. An orange solid was isolated by filtration and was sequentially washed with cold methanol and ether and finally dried in a vacuum dessicator. Purification was achieved using column chromatography (SiO2, petroleum:ether (40:60 v/v) with an increasing gradient of ethyl acetate) which gave 0.224 g (11.3%) of a yellow solid: 1H-NMR (CDCl3) δ 7.7 (d, 1H), 7.3 (m, 4H), 7.1 (dd, 1H), 6.9 (d, 1H), 5.7 (t, 1H), 5.7 (s, 1H), 4.1 (t, 2H), 4.0 (s×2, 9H), 1.8 (m, 2H), 1.5 (m, 2H), 1.0 (t, 3H). 13C-NMR (CDCl3) δ 189.1, 157.6, 153.2, 146.1, 144.7, 133.8, 122.9, 119.9, 112.7, 111.4, 106.1, 68.9, 60.9, 56.4, 31.2, 19.2, 15.01, 13.8. Mass Spectrum m/e (M+1) 387. Anal. Calcd. for C22H26O6: C, 68.38; H, 6.78. Found C, 68.57; H, 7.01.
Reaction SMILES: [OH-].[Na+].[CH:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([NH2:14])[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.Cl[C:16]1([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[NH:18][C:17]1=[O:26]>O1CCOCC1>[Cl:25][C:21]1[CH:20]=[C:19]2[C:24]([C:16]([NH:14][CH:10]([CH2:9][C:6]3[CH:5]=[CH:4][CH:3]=[CH:8][CH:7]=3)[C:11]([OH:13])=[O:12])([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=3)[C:17](=[O:26])[NH:18]2)=[CH:23][CH:22]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cl)Cc1cccc(Cl)c1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)C(Cc1ccccc1)NC1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To an aqueous solution of NaOH (1N, 10 mL) at 0° C. was added L-2-amino-3-phenyl-propionic acid (1.47 g, 8.92 mmol), followed by the addition of solution of 3,6-dichloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (3 g, 8.1 mmol) in 1,4-dioxane (3 mL). After the reaction mixture was stirred at 0° C. for 4 h, the solution was concentrated and extracted with diethyl ether. The organic layer was dried over Na2SO4, filtered and concentrated.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19])C(OCC)=O)[CH3:2].[Li+].[Cl-].O>CS(C)=O>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 74.3 %

Procedure:
2-(5-Chloro-2-nitro-phenyl)-malonic acid diethyl ester (10.3 g, 32.6 mmol) in DMSO (200 mL) containing LiCl (2.9 g, 68.4 mmol) and water (0.6 mL, 33.3 mmol) was set stirring and heated to 100° C. After 5 h the mixture was cooled to room temperature and added to water (750 mL). The product was extracted with two portions of EtOAc. The organics were combined, washed with water, dried (MgSO4) and evaporated to give 5.9 g (75%) of a clear yellow oil. TLC (silica, 25% EtOAc/hexanes): Rf=0.50. 1H NMR (400 MHz, CDCl3): 8.21 (d, J=8.8 Hz, 1H), 7.56 (dd, J=8.8, 2.3 Hz, 2H), 7.47 (d, J=2.3 Hz, 1H), 4.30 (q, J=7.2 Hz, 2H), 4.12 (s, 2H), 1.38 (t, J=7.1 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([O:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:5]=2[N:4]([CH3:25])[CH:3]=1.[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28].C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[CH3:25][N:4]1[C:5]2[C:10]([O:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[N:9][CH:8]=[N:7][C:6]=2[C:2]([C:33]2[CH:34]=[CH:35][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:31][CH:32]=2)=[CH:3]1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cn1cc(Br)c2ncnc(OC3CCN(C(=O)OC(C)(C)C)CC3)c21
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: C1COCCO1
Product: Cn1cc(-c2ccc(S(C)(=O)=O)cc2)c2ncnc(OC3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 100 °C
Reaction time: 12 h
Yield: 84.5 %

Procedure:
tert-butyl 4-(7-bromo-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)piperidine-1-carboxylate (15 mg), 4-methanesulfonyl-phenylboronic acid (33 mg), Pd(PPh3)4 (7.5 mg) and 2N Na2CO3 (0.33 mL) were mixed with 1,4-dioxane (2 mL), and stirred at 100° C. for 12 hours in a hermetically sealed reactor. The reaction mixture was cooled to room temperature, extracted with ethyl acetate and distilled water, and the organic layer thus obtained was washed with water and a saline solution. Subsequently, the washed organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (15 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[C:20]([C:23]5[C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[CH:26]=[N:25][CH:24]=5)[CH:21]=4)[NH:16][N:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl>CO>[CH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23]([C:20]2[CH:21]=[C:22]3[C:14]([C:11]4[NH:10][C:9]5[CH:8]=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=5[N:12]=4)=[N:15][NH:16][C:17]3=[N:18][CH:19]=2)=[CH:24][N:25]=1
Reactant: COC(=O)c1cccc2[nH]c(-c3n[nH]c4ncc(-c5cncc6ccccc56)cc34)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc2[nH]c(-c3n[nH]c4ncc(-c5cncc6ccccc56)cc34)nc12
Temperature: 80 °C
Yield: 82.7 %

Procedure:
Compound 108 (1.5 g, 3.57 mmol) was suspended in a 10% aqueous sodium hydroxide solution (20 mL) and MeOH (10 mL). The suspension was heated to 80° C. for five hours. The reaction mixture was cooled to room temperature then acidified with 1M hydrochloric acid. The resulting precipitate was collected and the filtrate was concentrated to remove the residual MeOH. Additional precipitate was collected and combined with the previous portion and dried to afford Compound 17 (1.2 g, 83%) as a grey solid. 1H NMR (400 MHz, CD3OD) δ 9.81 (s, 1H), 9.14 (s, 1H), 8.89 (m, 2H), 8.61 (d, 1H, J=8.4 Hz), 8.23 (m, 2H), 8.06 (m, 2H), 8.03 (d, 1H, J=8.0 Hz), 7.44 (t, 1H, J=8.0 Hz); MS (ESI) m/z: 407 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.S(=O)(=O)(O)O.[Br:17]N1C(=O)CCC1=O>FC(F)(F)C(O)=O>[Br:17][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]=1[CH3:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Br)cc(F)cc1[N+](=O)[O-]
Reaction time: 16 h
Yield: 114.8 %

Procedure:
To a solution of 4-fluoro-2-nitrotoluene (3.44 g) in trifluoroacetic acid (13 mL) was added concentrated sulfuric acid (4 mL) followed by N-bromosuccinimide (5.92 g). The reaction mixture was stirred for 16 h and was then quenched with brine, extracted into ethyl acetate, and dried (MgSO4). The solvent was removed in vacuo to furnish crude 1-bromo-5-fluoro-2-methyl-3-nitro-benzene (5.96 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([OH:33])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([Br:34])[CH:3]=1.[N:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42](=O)[O:43]C2C=CC=CC=2)=[CH:37][CH:36]=1>O1CCOCC1>[Br:34][C:4]1[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]([OH:33])([C:25]([F:26])([F:27])[F:28])[C:29]([F:31])([F:32])[F:30])=[CH:22][CH:23]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:6][C:7]([F:8])=[C:2]([NH:1][C:42]([NH:41][C:38]2[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=2)=[O:43])[CH:3]=1
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Reactant: Nc1cc(Br)c(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Solvent: C1COCCO1
Product: O=C(Nc1ccncc1)Nc1cc(Br)c(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Temperature: 80 °C
Yield: 5.4 %

Procedure:
(4-Amino-2-bromo-5-fluorophenyl)(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-1-yl)methanone (0.358 mmol, 200 mg) and phenyl pyridin-4-ylcarbamate (0.537 mmol, 115 mg) were combined in dioxane (2 mL) and heated to 80° C. overnight in a reactivial. The reaction mixture was concentrated under vacuum and the residue was purified by column chromatography (dichloromethane—4% methanol/dichloromethane) to afford title compound (13 mg). MS (ESI) m/z 679.3 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=1)([CH3:14])[C:6](=[O:13])[NH:7]2.B(Br)(Br)Br.Cl>ClCCl>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)([CH3:14])[C:6](=[O:13])[NH:7]2
Reactant: COc1ccc(C2(C)C(=O)Nc3cc(Cl)cc(Cl)c3C2=O)cc1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: CC1(c2ccc(O)cc2)C(=O)Nc2cc(Cl)cc(Cl)c2C1=O
Reaction time: 20 h
Yield: 73.4 %

Procedure:
To a pre-cooled (−78° C.) solution of 5,7-dichloro-3-(4-methoxy-phenyl)-3-methyl-1H-quinoline-2,4-dione (0.23 g, 0.77 mmol) in dichloromethane (5.0 mL) was added BBr3 (1.40 mL, 1.0 M dichloromethane solution) by syringe. The reaction was conducted for 20 hours at room temperature and qeunched by carefully addition of 1N HCl aqueous solution. Resultant was extracted with ethyl acetate (50 mL×2), washed with brine (50 mL) and water (50 mL×2), and dried over magnesium sulfate. After concentration of the organic phase, the residue was subjected to purify by a flash column chromatography (n-hexane:EtOAc=5:1) to give a pure objective compound (0.19 g, 83%) as yellow solid: 1H NMR (300 MHz, CD3OD) δ 1.58 (s, 3H, CH3), 6.65-6.71 (m, 2H, ArH), 6.91 (d, J=1.9 Hz, 1H, ArH), 6.94-6.99 (m, 2H, ArH), 7.03-7.06 (m, 1H, ArH); m.p. 222-223° C.; MS(EI) m/e 335 [M+], 188, 140, 120; HRMS m/e cacld. for C16H11NO3Cl2 335.0116, found 335.0112.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]3[C:29]([NH2:34])=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[C:35](N1C=CN=C1)(N1C=CN=C1)=[S:36]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]3[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[NH:34][C:35]3=[S:36])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: Nc1ccccc1NCCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Fc1ccc(Cn2c(CC3CCN(CCn4c(=S)[nH]c5ccccc54)CC3)nc3ccccc32)cc1
Yield: 41.5 %

Procedure:
A mixture of 6 parts of N1 -[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]-1,2-benzenediamine, 2.7 parts of 1,1'-thiocarbonylbis[1H-imidazole] and 90 parts of tetrahydrofuran was stirred and refluxed for 1 hour. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The oily residue was stirred in acetonitrile. The product was filtered off and crystallized from ethanol. The product was filtered off and dried, yielding 2.8 parts (41.5%) of 1-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]-1,3-dihydro-2H-benzimidazole-2-thione; mp. 157.1° C. (493).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH3:9].C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOCC1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH2:9][Br:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Br)ccc1Br
Agent: c1ccc(COOCc2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cc(Br)ccc1Br
Reaction time: 24 h
Yield: 55.2 %

Procedure:
To a solution of 75 g (0.3 mol) of 2,5-dibromotoluene in 1 L of carbon tetrachloride was added 58.73 g (0.33 mol) of NBS and 50 mg of benzyl peroxide, and the resulting mixture was refluxed with stirring for 24 h. The mixture was cooled, and concentrated in vacuo. The residue was crystallized from hot methanol and washed with hexane to afford 54.5 g (55.7%) of 2.5-dibromobenzyl bromide as a solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([CH3:27])[C:25]2[C:11](=[CH:12][C:13]3[NH:17][C:16]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[N:15][C:14]=3[CH:24]=2)[NH:10][C:9]1=O.[Cl-].[Na+]>O1CCCC1>[CH3:7][C:8]1([CH3:27])[C:25]2[C:11](=[CH:12][C:13]3[NH:17][C:16]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[N:15][C:14]=3[CH:24]=2)[NH:10][CH2:9]1
Reactant: CC1(C)C(=O)Nc2cc3[nH]c(-c4ccncc4)nc3cc21
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CC1(C)CNc2cc3[nH]c(-c4ccncc4)nc3cc21

Procedure:
To a suspension of 3.5 g. lithium aluminium hydride in 100 ml. tetrahydrofuran is added dropwise at ambient temperature a solution of 5.3 g. (19 mmole) 7,7-dimethyl-6,7-dihydro-2-(pyridin-4-yl)-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one. The reaction mixture is heated to reflux for 6 hours, decomposed with an aqueous solution of sodium chloride, extracted with dichloromethane and methanol, dried, evaporated and chromatographed on silica gel, 1.9 g. (38% of theory) of the title compound being eluted; m.p. 147°-149° C.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(N2C=CN=C2)=CN=C(CCN)N=1.Cl[C:24]1[S:25][C:26]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:27]=2[N:28]=1.[Cl:34][C:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=1[C:42]1[C:47]([C:48]2[NH:49][CH:50]=[CH:51][N:52]=2)=[CH:46][N:45]=[C:44]([NH:53][CH2:54][CH2:55][NH:56]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:43]=1>>[Cl:34][C:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=1[C:42]1[C:47]([C:48]2[NH:52][CH:51]=[CH:50][N:49]=2)=[CH:46][N:45]=[C:44]([NH:53][CH2:54][CH2:55][NH:56][C:24]2[S:25][C:26]3[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:27]=3[N:28]=2)[N:43]=1
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Agent: NCCc1ncc(-n2ccnc2)c(-c2ccc(Cl)cc2Cl)n1
Product: Clc1ccc(-c2nc(NCCNc3nc4ccc(Cl)cc4s3)ncc2-c2ncc[nH]2)c(Cl)c1

Procedure:
[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]{2-[(6-chlorobenzothiazo 1-2-yl)amino]ethyl}amine was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-1-ylpyrimidin-2-ylethylamine and 2,6-dichlorobenzothiazole in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH2:14][CH2:13][C:12]=2[CH:16]=1>C(Cl)(Cl)(Cl)Cl>[Br:2][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH2:14][CH2:13][C:12]=2[CH:16]=1
Reactant: BrP(Br)Br
Reactant: OCCc1ccc2c(c1)CCO2
Solvent: ClC(Cl)(Cl)Cl
Product: BrCCc1ccc2c(c1)CCO2
Temperature: 25 °C

Procedure:
Phosphorous tribromide (0.37 g) was added to a solution of 5-(2-hydroxyethyl)-2,3-dihydrobenzofuran (0.612 g--see Preparation 30) in carbon tetrachloride (3 ml) and the mixture was heated under reflux for 3 hours. On cooling to room temperature, the mixture was partitioned between 10% aqueous sodium carbonate (20 ml) and dichloromethane (20 ml). The layers were separated and the aqueous layer was extracted with dichloromethane (2×10 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give the title compound as an oil which crystallised on standing, (0.584 g), m.p. 60°-62° C.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([O-])([O-])=O.[Na+].[Na+].C(B(CC)[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)C>COCCOC.O>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([C:2]2[C:11]([CH:12]=[O:13])=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:24]=1
Reactant: O=Cc1cc2ccccc2nc1Cl
Reactant: CCB(CC)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=Cc1cc2ccccc2nc1-c1cccnc1
Temperature: 90 °C
Yield: 70.3 %

Procedure:
A mixture of 2-chloroquinoline-3-carbaldehyde (5.0 g, 26.1 mmol), Na2CO3 (4.15 g, 39.1 mmol) and diethyl(3-pyridyl)borane (4.22 g, 28.7 mmol) in DME (100 mL) and water (30 mL) was degassed by bubbling nitrogen gas through it for 5 minutes. Tetrakis-(triphenylphosphine)palladium(0) (0.30 g, 0.261 mmol) was added and the mixture was heated at 90° C. for 5 h. The mixture was allowed to cool to room temperature. The resultant precipitate was filtered off and washed with water (5×50 mL) and diethyl ether (5×50 mL) to give the title compound (4.3 g, 70%) as a pale green solid. LCMS (ES+) 235 (M+H)+, RT 1.53 minutes.