Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:44]=[CH:43][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]4[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=4)=[CH:31][CH:30]=3)([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)[CH3:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[N:45]([C:47]1[CH:52]=[CH:51][C:50]([NH:53][C:54](=[O:56])[CH3:55])=[CH:49][CH:48]=1)=O.[C:57]([OH:60])(=O)[CH3:58]>C(O)C>[C:54]([NH:53][C:50]1[CH:51]=[CH:52][C:47]([N:45]=[N:42][C:39]2[CH:40]=[CH:41][C:36]([O:35][C:32]3[CH:33]=[CH:34][C:29]([C:13]([C:15]4[CH:16]=[CH:17][C:18]([O:21][C:22]5[CH:27]=[CH:26][C:25]([N:28]=[N:45][C:47]6[CH:52]=[CH:51][C:50]([NH:53][C:57](=[O:60])[CH3:58])=[CH:49][CH:48]=6)=[CH:24][CH:23]=5)=[CH:19][CH:20]=4)([C:10]4[CH:9]=[CH:8][C:7]([O:6][C:5]5[CH:4]=[CH:3][C:2]([N:1]=[N:45][C:47]6[CH:48]=[CH:49][C:50]([NH:53][C:54](=[O:56])[CH3:55])=[CH:51][CH:52]=6)=[CH:44][CH:43]=5)=[CH:12][CH:11]=4)[CH3:14])=[CH:30][CH:31]=3)=[CH:37][CH:38]=2)=[CH:48][CH:49]=1)(=[O:56])[CH3:55]
Reactant: CC(c1ccc(Oc2ccc(N)cc2)cc1)(c1ccc(Oc2ccc(N)cc2)cc1)c1ccc(Oc2ccc(N)cc2)cc1
Reactant: CC(=O)O
Reactant: CC(=O)Nc1ccc(N=O)cc1
Solvent: CCO
Product: CC(=O)Nc1ccc(N=Nc2ccc(Oc3ccc(C(C)(c4ccc(Oc5ccc(N=Nc6ccc(NC(C)=O)cc6)cc5)cc4)c4ccc(Oc5ccc(N=Nc6ccc(NC(C)=O)cc6)cc5)cc4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 61 %

Procedure:
1,1,1-Tris(4-(4-aminophenoxy)phenyl)ethane (Example 2; 0.580 g, 1.00 mmol), N-(4-nitrosophenyl)acetamide (Example 3; 0.985 g, 6 mmol) and acetic acid (20 mL) were charged into a 150 mL round-bottomed flask equipped with a magnetic stir bar. The mixture was stirred at room temperature for 48 hours. The mixture was at first turned into a greenish solution, and then yellow particles started to precipitate out of the solution. The mixture was diluted by deionized water (100 mL). Solids were collected and washed with water (500 mL), followed by ethanol (200 mL) to remove most of the unreacted nitroso reagent. The solid was then extracted by hot acetone (100 mL) four times. The acetone extract was concentrated on a rotary evaporator to give yellow solids as raw product. The raw product was slurried in hot ethanol (50 mL) and filtered twice after cooling to room temperature in between to give 0.62 g (61%) of yellow solids, mp 220° C. (dec.). 1H-NMR (d6-DMSO, δ in ppm): 2.09 (s, 9H, COCH3), 2.15 (s, 3H, CCH3) 7.03-7.15 (m, 18H), 7.79-7.87 (m, 18H) 10.28 (s, 3H, NHCO). 13C-NMR (d6-DMSO, δ in ppm): 24.16, 30.28, 51.00, 118.50, 118.86, 119.18, 123.42, 124.35, 129.99, 142.09, 144.50, 147.38, 147.77, 153.78, 159.07, 168.06.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[N:31](S(C2C=CC(C)=CC=2)(=O)=O)[C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH2:23][NH:24][CH2:25][C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[C:17]2[CH:16]=1.[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[NH:31][C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH2:23][NH:24][CH2:25][C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[C:17]2[CH:16]=1
Reactant: COc1cc2c(-c3cc4c(CNCc5cccs5)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(-c3cc4c(CNCc5cccs5)ccnc4[nH]3)cn(C)c2cc1OC
Yield: 69.1 %

Procedure:
[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]thiophen-2-ylmethylamine is prepared as described in Example 179a starting with 0.11 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]thiophen-2-ylmethylamine instead of the [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl] (4-trifluoromethylsulfanylbenzyl)amine used in Example 179a and 0.85 cm3 of 5N potassium hydroxide. 0.056 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]thiophen-2-ylmethylamine is obtained, the characteristics of which are as follows:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].[CH2:11]([O:13]C(OCC)OCC)[CH3:12].[CH2:21](O)[CH3:22]>>[CH2:21]([O:4][C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([O:13][CH2:11][CH3:12])[CH2:2][CH3:3])[CH3:22]
Reactant: CCO
Reactant: CCC(=O)c1ccccc1
Reactant: CCOC(OCC)OCC
Product: CCOC(CC)(OCC)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71 %

Procedure:
To a solution of propiophenone (20 mL, 0.15 mol) in ethanol (EtOH) (20 mL) was added triethylorthoformate (32.4 mL, 0.20 mol). A stream of HCl gas was bubbled through this solution for approximately 15 seconds, then the golden solution was stirred for 20 hours at ambient temperature. The solution was then treated with NaOMe/EtOH until basic, followed by filtration. The filtrate was concentrated by removal of the EtOH in vacuo. The product was isolated via vacuum distillation to give the title compound (22.2 g, 71%). 1H NMR (300 MHz, CDCl3)δ7.51-7.47 (m, 2H), δ7.36-7.23 (m, 3H), δ3.47-3.17 (m, 4H), δ1.92 (quartet, J=7.5 Hz, 2H), δ1.20 (t, J=7.1 Hz, 6H), δ0.57 J=7.5 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][C:8]=1F)#[N:2].[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C>[N:20]([C:8]1[CH:7]=[CH:6][C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:3]=1[C:1]#[N:2])=[N+:21]=[N-:22]
Reactant: COC(=O)c1ccnc(-c2ccc(F)c(C#N)c2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccnc(-c2ccc(N=[N+]=[N-])c(C#N)c2)c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Methyl 2-(3-cyano-4-fluorophenyl)isonicotinate and sodium azide were dissolved in a DMF solution, followed by stirring at 50° C. for 4 hours to obtain methyl 2-(4-azido-3-cyanophenyl)isonicotinate. NMRC: 7.38 (1H, d), 7.84 (1H, dd), 8.46 (1H, d)
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][CH2:30][CH2:31][C:32](O)=[O:33].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C1CCN2C(=NCCC2)CC1.Cl>CN(C)C=O.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:23])[CH:10]([NH:22][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][C:25]2[S:24][CH:28]=[CH:27][CH:26]=2)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(F)cc1
Reactant: O=C(O)CCCc1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: O=C(CCCc1cccs1)NC(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(F)cc1
Reaction time: 8 h
Yield: 55.5 %

Procedure:
To a solution of 1-(4-fluorophenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (600 mg,1.73 mmol) and 4-(2-thienyl)butyric acid (323 mg, 1.90 mmol) in N,N-dimethylformamide (10 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (496 mg, 2.59 mmol), 1-hydroxy-1H-benzotriazole (396 mg, 2.59 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.28 ml, 1.90 mmol) and the mixture was stirred overnight. To the reaction solution were added 1N aqueous hydrochloric acid solution (10 ml) and water (100 ml), and the mixture was extracted with ethyl acetate (50 ml×2). The extract was washed with 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give N-(2-(4-fluorophenyl)-2-oxo-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-(2-thienyl)butyramide (445 mg, 56%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][CH2:54][NH2:55])=[CH:49][CH:48]=1>CN(C=O)C.O>[Cl:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][CH2:54][NH:55][C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)=[O:12])=[CH:49][CH:48]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCCc1ccc(Cl)cc1)c1ccc2[nH]ncc2c1
Reaction time: 8 h
Yield: 41.7 %

Procedure:
To a stirred solution of the 1H-indazole-5carboxylic acid (215 mg, 1.32 mmol) and HBTU (553 mg, 1.45 mmol) in DMF (5 mL) was added DIEA (277 μL, 1.59 mmol) followed by 2-(4chlorophenyl)ethylamine (222 μL, 1.59 mmol). The reaction was stirred overnight, then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. The crude product was purified over silica gel on a Biotage Horizon high-performance flash chromatography system (25+M silica gel cartridge) eluting with a gradient of 0.5% MeOH/DCM to 10% MeOH/DCM to give N-(4-chlorophenethyl)-1H-indazole-5-carboxamide (0.165 g, 42%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([O:18][C:19]3[C:20]([F:29])=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23]([CH3:28])=[CH:22]4)=[N:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:30][CH3:31].[C:32]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:34])[CH3:33]>CN(C)C=O.C(OCC)(=O)C>[C:32]([N:35]1[CH2:40][CH2:39][N:38]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12]([O:18][C:19]4[C:20]([F:29])=[C:21]5[C:25](=[CH:26][CH:27]=4)[NH:24][C:23]([CH3:28])=[CH:22]5)=[N:13][CH:14]=[N:15]3)=[CH:10][C:9]=2[O:30][CH3:31])[CH2:37][CH2:36]1)(=[O:34])[CH3:33]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCOCCBr
Reactant: CC(=O)N1CCNCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCOCCN1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
A mixture of 7-[2-(2-bromoethoxy)ethoxy]-6-methoxy-4-(4-fluoro-2-methylindol-5-yloxy)quinazoline (165 mg, 0.38 mmol) and 1-acetylpiperazine (129 mg, 1.01 mmol) in N,N-dimethylformamide (4 ml) was stirred overnight at ambient temperature. The mixture was diluted with ethyl acetate, washed with brine (×2), dried (MgSO4) and concentrated under reduced pressure. Column chromatography of the residue, eluting with 5% 7N ammonia in methanol/methylene chloride gave 7-{2-[2-(4-acetylpiperazin-1-yl)ethoxy]ethoxy}-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (130 mg, 72%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[P:11]([Cl:16])(Cl)(Cl)(Cl)[Cl:12].Cl.C(O)=[O:19]>C(Cl)(Cl)(Cl)Cl>[Cl:12][P:11]([Cl:16])([NH:6][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1])=[O:19]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=CO
Reactant: Cc1ccccc1C(N)=O
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccccc1C(=O)NP(=O)(Cl)Cl

Procedure:
A mixture containing 48 g (0.36 mole) of 2-methylbenzamide, 74 g (0.36 mole) of phosphorus pentachloride and 500 ml of AR carbon tetrachloride was heated at 60°-70° for 30 min. at which time the HCl gas evolution had ceased. The solution was cooled to 30° and 16.9 g (0.36 mole) of 97% formic acid added dropwise. Stirring was continued following the addition for 40-50 min. The product was colleted, washed with AR carbon tetrachloride and air-dried to give 56 g, m.p. 91°-93°.
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][OH:11].Br[CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:16][C:15]([CH3:17])=[CH:14][CH2:13][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][OH:11]
Reactant: CC(C)=CCBr
Reactant: OCc1nc2ccccc2[nH]1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)=CCn1c(CO)nc2ccccc21
Yield: 36.1 %

Procedure:
To a solution of (1H-benzoimidazol-2-yl)-methanol (457 mg, 3.09 mmol) and 4-bromo-2-methyl-2-butene (0.36 mL, 3.09 mmol) in DMF (10 mL) was added DIPEA (0.69 mL, 3.70 mmol) at 60° C. overnight and in the morning, the mixture was cooled and concentrated. The residue was dissolved in saturated NaHCO3 (20 mL) and extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated to afford a brown oil. Purification by flash column chromatography on silica gel using 2% MeOH/CH2Cl2 afforded [1-(3-methyl-but-2-enyl)-1H-benzoimidazol-2-yl]-methanol as a pale yellow solid (241 mg, 36%). 1H NMR (CDCl3) δ 1.72 (s, 3H), 1.87 (s, 3H), 4.80 (d, 2H, J=6.6 Hz), 4.86 (s, 2H), 5.21 (td, 1H, J=6.0, 1.2 Hz), 7.19-7.23 (m, 3H), 7.65-7.68 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10]2[CH2:16][C:13]3([CH2:15][CH2:14]3)[CH2:12][CH:11]2[C:17]([O:19]CC)=[O:18])=[CH:4][CH:3]=1.COCCOC.[OH-].[Li+].O>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH2:9][CH:10]2[CH2:16][C:13]3([CH2:14][CH2:15]3)[CH2:12][CH:11]2[C:17]([OH:19])=[O:18])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CC2(CC2)CC1CSc1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: COCCOC
Product: O=C(O)C1CC2(CC2)CC1CSc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of ethyl(5R/S,6R/S)-6-{[(4 fluorophenyl)sulfanyl]methyl}spiro[2.4]-heptane-5-carboxylate (66 mg, 0.22 mmol) in 0.3 mL methanol was added ethylene glycol dimethyl ether (1.0 mL) and 2 M aqueous solution of lithium hydroxide (1.0 mL). The reaction mixture was stirred at ambient temperature for 22 h and then poured into 30 mL water. The reaction mixture was washed with 30 mL ether and the aqueous layer was acidified with a 2 M aqueous solution of hydrochloric acid. The product was extracted into ethyl acetate and the combined ethyl acetate extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give (5R/S,6R/S)-6-{[(4-fluorophenyl)sulfanyl]-methyl}spiro[2.4]heptane-5-carboxylic acid as a colorless syrup.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3]([NH:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=2)[CH:7]=1)=[O:4].CCN(C(C)C)C(C)C.Br[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>CN(C=O)C>[Cl:18][C:14]1[CH:13]=[C:12]([C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:10]([CH3:11])[N:9]=2)[CH:17]=[CH:16][N:15]=1
Reactant: Cn1nc(-c2ccnc(Cl)c2)cc1NC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2ccnc(Cl)c2)cc1NC(=O)[C@H](Cc1ccccc1)NCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a 500 ml flask was added 2000 mg of (2S)-2-amino-N-(3-(2-chloropyridin-4-yl)-1-methyl-1H-pyrazol-5-yl)-3-phenylpropanamide 17.7.E, 50 ml of DMF, 1.4 ml of DIEA and the reaction was cooled to 0° C. To the reaction was then added 953 μl of tert-butyl bromoacetate and the reaction was stirred at 22° C. for 16 hours at which time the crude was partitioned between 800 ml EtAc, 2×200 ml of saturated brine, and 2×200 ml of water. (Note: no product observed in aqueous layer). The organic solvent was removed by rotary evaporation and the crude purified with a silica gel column (eluting with 50% EtAc in Hexane) to give 1.8 g of 17.8.A as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.Cl.[NH2:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32][CH2:31]1.CN(C=O)C>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17](=[O:19])(=[O:18])[NH:29][CH:30]2[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]2)=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)NC3CCC(O)CC3)sc2Br)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (300 mg; 0.72 mmol; 1 eq), is dissolved in anhydrous DCM (20 ml). The reaction is put under nitrogen. Triethylamine (0.7 ml; 5.05 mmol; 7 eq) and trans-4-aminocyclohexanol hydrochloride (547.1 mg; 3.61 mmol; 5 eq) are added successively. DMF (0.2 ml) is added to dissolve the amine and the reaction mixture is stirred overnight at room temperature. The reaction mixture is then washed with water, NH4Cl sat., brine and dried over MgSO4, affording the title compound (120 mg; 21%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH2:18])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[CH3:21][C:22]1[N:27]=[CH:26][C:25]([CH2:28][C:29]2[C:30](=[O:37])[N:31]=[C:32](SC)[NH:33][CH:34]=2)=[CH:24][N:23]=1>C(O)C>[CH3:21][C:22]1[N:23]=[CH:24][C:25]([CH2:28][C:29]2[C:30](=[O:37])[N:31]=[C:32]([NH:18][CH2:17][CH2:16][C:13]3[CH:14]=[CH:15][C:10]([O:9][C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:8][N:7]=4)=[CH:11][CH:12]=3)[NH:33][CH:34]=2)=[CH:26][N:27]=1
Reactant: NCCc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CSc1nc(=O)c(Cc2cnc(C)nc2)c[nH]1
Solvent: CCO
Product: Cc1ncc(Cc2c[nH]c(NCCc3ccc(Oc4ccc(C(F)(F)F)cn4)cc3)nc2=O)cn1
Temperature: 125 °C
Reaction time: 50 h
Yield: 19.9 %

Procedure:
2-[4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl]-ethylamine (0.354 mmol, 1 eq) and 5-(2-methyl-pyrimidin-5-ylmethyl)-2-methylsulfanyl-1H-pyrimidin-4-one (0.322 mmol, 0.9 eq) were dissolved in dry ethanol (300 μL) and stirred at 125° C. for 50 hours. Solvent was evaporated and crude product was purified on Biotage SP1 Snap Si 10; 15 ml/min in the gradient of MeOH in DCM: 0-10% in 25CV. The appropriate fractions were combined and evaporated in vacuo to give the required product 5-(2-methyl-pyrimidin-5-ylmethyl)-2-{2-[4-(5-trifluoromethyl-pyridin-2-yloxy)phenyl]ethylamino}-1H-pyrimidin-4-one (0.064 mmol, yield: 18%, HPLC-MS/UV:[M+H]+=483.37; rt: 0.89 mins; purity: 93%). 1H NMR (300 MHz; CDCl3) δ/ppm 2.66 (s, 3H), 2.93 (t, J=7.39, 2H), 3.54 (s, 2H), 3.60-3.70 (m, 2H), 5.39 (br.s., 1H), 7.01 (d, J=8.69, 1H), 7.08 (d, J=8.50 2H), 7.27-7.31 (m, 2H), 7.66 (s, 1H), 7.89 (dd, J=9.58, J=2.73, 1H), 8.36-8.42 (m, 1H), 8.51 (s, 2H), 11.21 (br.s., 1H)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1.[CH3:18][N:19](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.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>[C:18]([C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1)#[N:19]
Reactant: CC(C)(C)OC(=O)NCCc1cccc(Br)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCc1cccc(C#N)c1
Temperature: 150 °C
Yield: 64.3 %

Procedure:
tert-Butyl [2-(3-bromophenyl)ethyl]carbamate (0.60 g, 1.99 mmol) was dissolved in dry DMF (18 mL) in a under nitrogen atmosphere. Zinc cyanide (0.47 g, 3.99 mmol) and tetrakis(triphenylphosphine)palladium (0.18 g, 0.16 mmol) was added. The reaction mixture was heated in a microwave reactor at 150° C. for 20 mins. The procedure was repeated two more times with equal amount of starting material and the resulting three mixtures were combined and diluted with EtOAc. The mixture was washed with saturated aqueous NaHCO3 and water, dried with Na2SO4, filtered and evaporated. The crude product was purified using Biotage Horizon HPFC system using Heptane and EtOAc as eluant affording the title compound (0.95 g, 64.3%). 1H NMR (500 MHz, CDCl3): δ 1.39 (s, 9H), 2.82 (t, 2H), 3.34 (q, 2H), 4.75 (bs, 1H), 7.37-7.50 (m, 4H); 13C NMR (125 MHz, CDCl3): δ 28.57, 36.09, 41.63, 79.61, 112.69, 119.05, 129.56, 130.38, 132.57, 133.68, 140.86, 156.06.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].Cl.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1)([O-:15])=[O:14].CCN(CC)CC.C(Cl)Cl>C1COCC1>[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH2:27][CH2:26][N:25]([C:2]([O:4][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:3])[CH2:24][CH2:23]2)=[CH:20][CH:21]=1)([O-:15])=[O:14]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Benzyl chloroformate (0.515 mL, 3.61 mmol) was added to a mixture of 1-(4-nitrophenyl)piperazine hydrochloride (0.800 g, 3.28 mmol) and Et3N (1.14 mL, 8.21 mmol) in THF (20 mL) at 0° C. The resulting mixture was stirred at 0° C. for 1 hour then at room temperature for 2 hours. DCM (40 mL) was added and the organics were washed with saturated NaHCO3 (40 mL), water (40 mL) then dried over MgSO4. The volatiles removed in vacuo to give the title compound I3 as a yellow solid (1.11 g, 99%); 1H NMR (400 MHz, CDCl3) δ 8.04-8.01 (m, 2H), 7.32-7.18 (m, obscured), 7.15 (s, 1H), 6.72-6.69 (m, 2H), 5.06 (s, 2H), 3.62-3.54 (m, 4H), 3.37-3.26 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13])[C:5]([O:7]C)=[O:6].O.[OH-].[Li+].O1CCCC1.Cl>O.CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(C(C)Oc2ccccc2)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(C(=O)O)ccc1C(C)Oc1ccccc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 84.2 %

Procedure:
A mixture of methyl 3-methyl-4-(1-phenoxyethyl)benzoate (0.12 g, 0.44 mmol), lithium hydroxide monohydrate (285 mg, 6.8 mmol), tetrahydrofuran (15 mL), methanol (5 mL) and water (5 mL) was stirred at 20° C. for 4 hours. The mixture was neutralized to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (15 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to give 3-methyl-4-(1-phenoxyethyl)benzoic acid (95 mg, 84%).
Reaction SMILES: Br[C:2]1[C:3]([C:20]2[S:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1.[OH:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>>[Cl:25][C:22]1[S:21][C:20]([C:3]2[C:2]([C:31]3[CH:30]=[CH:29][CH:28]=[C:27]([OH:26])[CH:32]=3)=[CH:7][N:6]=[C:5]([NH:8][CH2:9][CH2:10][N:11]3[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]3=[O:19])[N:4]=2)=[CH:24][CH:23]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2ccc(Cl)s2)n1
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(-c2cccc(O)c2)c(-c2ccc(Cl)s2)n1

Procedure:
The title compound was prepared from 1-{2-[5-bromo-4-(5-chlorothiophen-2-yl)pyrimidin-2-ylamino]ethyl}-5,5-dimethylimidazolidine-2,4-dione and 3-hydroxyphenylboronic acid in a manner analogous to Example 269. MS (M+H)+ 458.