Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[OH:23][CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:24]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([CH2:35][OH:36])=[CH:27][CH:26]=2)=[O:23])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(CO)c2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1ccc(CO)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (300 mg, 0.96 mmol) in acetonitrile (30 ml) were added 4-(hydroxymethyl)-1-naphthalenecarboxylic acid (194 mg, 0.96 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (275 mg, 1.44 mmol) and 1-hydroxy-1H-benzotriazole (147 mg, 0.96 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml), and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=2:1). Recrystallization from ethyl acetate-hexane gave the title compound (365 mg, 77%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3([C:19]#[N:20])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:2]1.[C:21]1(=O)[CH2:24][CH2:23][CH2:22]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C(=O)([O-])[O-].[Na+].[Na+]>[CH:21]1([N:1]2[CH2:4][CH:3]([CH2:5][O:6][C:7]3[CH:8]=[CH:9][C:10]([C:13]4([C:19]#[N:20])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[CH:11][CH:12]=3)[CH2:2]2)[CH2:24][CH2:23][CH2:22]1
Reactant: O=C1CCC1
Reactant: N#CC1(c2ccc(OCC3CNC3)cc2)CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#CC1(c2ccc(OCC3CN(C4CCC4)C3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
4-[4-(azetidin-3-ylmethoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile (0.29, 0.73 mmol) was dissolved in THF (2 mL). Cyclobutanone (0.06 mL, 0.80 mmol) and acetic acid (0.042 mL, 0.73 mmol) were added. The mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (0.311 g, 1.47 mmol) was added. The mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with 10% aqueous sodium carbonate (5 mL) then extracted with DCM (2×50 mL). The organics were combined, dried over sodium sulphate, filtered and concentrated in vacuo to provide a clear oil. This was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (96:4:0.4 to 95:5:0.5) to provide the title compound (0.194 g, 81%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 1.60-1.70 (m, 2H), 1.70-1.80 (m, 2H), 1.80-1.90 (m, 2H), 1.95-2.00 (m, 2H), 2.0-2.15 (m, 2H), 2.9 (m, 1H), 3.1 (t, 2H), 3.16 (m, 1H), 3.4 (t, 2H), 3.9 (m, 2H), 4.10 (m, 4H), 6.90 (d, 2H), 7.40 (d, 2H). HRMS ESI+ m/z 327.2059 [MH]+.
Reaction SMILES: [CH:1]([CH:3]=O)=O.[NH2:5][C:6]1[C:7](=[O:17])[NH:8][C:9]([CH2:13][O:14][CH2:15][CH3:16])=[N:10][C:11]=1[NH2:12].C>O>[CH2:15]([O:14][CH2:13][C:9]1[NH:8][C:7](=[O:17])[C:6]2[C:11](=[N:12][CH:1]=[CH:3][N:5]=2)[N:10]=1)[CH3:16]
Reactant: O=CC=O
Reactant: CCOCc1nc(N)c(N)c(=O)[nH]1
Agent: C
Solvent: O
Product: CCOCc1nc2nccnc2c(=O)[nH]1
Reaction time: 0.17 h

Procedure:
3.5 g (0.024 mole) of a 40% aqueous solution of glyoxal are added to a suspension of 3.7 g (0.020 mole) of 5,6-diamino-2-(ethoxymethyl)-4(3H)-pyrimidinone in 30 ml of water. The mixture is brought gradually to reflux and kept refluxing for 1 hour. After the addition of Norit, refluxing is continued for a further 10 minutes and the reaction mixture is then filtered. The aqueous solution obtained is extracted with dichloromethane. These organic extracts are treated as in section c of Example 25. Yld: 2.5 g (61%), m.p. 168°-169° C. The product is identical to that obtained in Example 1.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:27]3[CH2:32][CH2:31][C@H:30]([C:33](O)=[O:34])[CH2:29][CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.Cl.CN.C[CH2:40][N:41](C(C)C)C(C)C.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH3:40][NH:41][C:33]([C@H:30]1[CH2:31][CH2:32][C@H:27]([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)=[N:18]4)=[CH:13][CH:12]=3)[N:9]=2)[CH2:28][CH2:29]1)=[O:34]
Reactant: Nc1nccn2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)nc2[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CNC(=O)[C@H]1CC[C@H](c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn32)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A DMF solution (3 mL) of trans-4-[8-amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid (260 mg, 0.56 mmol) and methylamine hydrochloride (379 mg, 5.6 mmol) in a sealed tube was charged with DIEA (0.98 mL, 5.6 mmol), 0.6M HOAt in DMF (0.93 mL, 0.56 mmol), and then EDC (161 mg, 0.84 mmol). The reaction mixture stirred at rt for 16 h. The reaction mixture was concentrated to solids, taken up in CH2Cl2, charged with silica, and concentrated to brown solids. The crude material was purified by silica gel column chromatography [Jones Flashmaster, 5 g/25 mL cartridge, eluting with 2%˜7N NH3 in MeOH/CH2Cl2]. The purified material was recrystallized from MeOH/CH2Cl2/diethyl ether to the desired product as a light yellow solid; 1H NMR (DMSO-d6, 400 MHz) δ 1.56-1.73 (m, 4H), 1.85-1.91 (m, 2H), 2.01-2.06 (m, 2H), 2.17-2.25 (m, 1H), 2.52 (d, 3H, J=4.4 Hz), 3.12-3.20 (m, 1H), 6.17 (s, 2H), 7.09 (d, 1H, J=4.8 Hz), 7.51-7.59 (m, 4H), 7.73 (d, 1H, J=4.8 Hz), 7.90 (dd, 1H, J=2.0 Hz, 8.4 Hz), 8.09 (d, 1H, J=8.4 Hz), 8.18 (d, 1H, J=8.8 Hz), 8.23 (s, 1H), 8.30 (d, 2H, J=7.6 Hz), 8.51 (d, 1H, J=8.4 Hz); MS (ES+): m/z 477.0 [MH+]; HPLC: tR=2.1 min (Micromass Platform II, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:21][N:20](S(CC5CCCC5)(=O)=O)[CH2:19]4)[C:14]([F:31])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:32][O:33][CH2:34][C:35](Cl)=[O:36]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:19][N:20]([C:35](=[O:36])[CH2:34][O:33][CH3:32])[CH2:21]4)[C:14]([F:31])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=S(=O)(CC1CCCC1)N1CC(Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Reactant: COCC(=O)Cl
Product: COCC(=O)N1CC(Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Yield: 51 %

Procedure:
According to the procedure for compound 469 using methoxyacetyl chloride afforded 11.7 mg (51% yield) of 468, as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][O:8][C:9]2[C:18]([CH3:19])=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][C:10]=2[CH3:20])[CH2:4][O:3]1.[CH2:22](C1C=C(C=C(C)C=1O)C#N)C.CC1(C)O[C@@H](CO)CO1>>[CH3:1][C:2]1([CH3:21])[O:6][C@@H:5]([CH2:7][O:8][C:9]2[C:10]([CH3:20])=[CH:11][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:17][C:18]=2[CH2:19][CH3:22])[CH2:4][O:3]1
Reactant: CCc1cc(C#N)cc(C)c1O
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC1COC(C)(C)O1
Agent: CC1(C)OC[C@H](CO)O1
Product: CCc1cc(C(=N)NO)cc(C)c1OC[C@H]1COC(C)(C)O1

Procedure:
The title compound is prepared in analogy to rac-4-(2,2-dimethyl-[1,3]dioxolan-4-yl methoxy)-N-hydroxy-3,5-dimethyl-benzamidine from 3-ethyl-4-hydroxy-5-methyl-benzonitrile and (S)-(2,2-dimethyl-[1,3]dioxolan-4-yl)methanol; LC-MS*: tR=0.97 min.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH2:12][N:13]([CH3:17])[CH2:14]2)=[CH:9][CH:8]=1)(=O)=O.[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O)#[N:29].C(=O)([O-])[O-].[Cs+].[Cs+]>O.CN(C)C=O>[Cl:25][C:20]1[CH:19]=[C:18]([CH:11]2[C:10]3[C:15](=[CH:16][C:7]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[C:28]#[N:29])=[CH:8][CH:9]=3)[CH2:14][N:13]([CH3:17])[CH2:12]2)[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: CN1Cc2cc(OS(=O)(=O)C(F)(F)F)ccc2C(c2ccc(Cl)c(Cl)c2)C1
Reactant: N#Cc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2cc(-c3ccccc3C#N)ccc2C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 90 °C
Yield: 63 %

Procedure:
A mixture of 4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl trifluoromethanesulfonate (100 mg, 0.23 mmol) which was prepared in Step G of Example 11, 2-cyanophenylboronic acid (51 mg, 0.35 mmol) and cesium carbonate (225 mg, 0.69 mmol) in water (1 mL) and N,N-dimethylformamide (2 mL) was degassed with argon and then [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (8 mg, 0.01 mmol) was added. The mixture was degassed again and then heated to 90° C. for 3 hours. The mixture was partitioned between water and ethyl acetate (3×) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was partially purified by preparative thin-layer chromatography (1:4 hexanes/ethyl acetate) to give 2-(4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)benzonitrile (57 mg, 63%) as a brown solid: ESI MS m/z 393, 395 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=2)[CH:4]=[N:3][CH:2]=1.[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>>[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:7]([C:8]2[CH:9]=[CH:10][C:11]([C:14](=[O:16])[CH3:15])=[CH:12][CH:13]=2)[C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)=[CH:20][CH:19]=1
Reactant: CC(=O)c1ccc(Nc2cncnc2)cc1
Reactant: BrCc1ccc(Br)cc1
Product: CC(=O)c1ccc(N(Cc2ccc(Br)cc2)c2cncnc2)cc1

Procedure:
Starting compounds: 4'-[N-(pyrimidin-5-yl)amino]acetophenone and 4-bromobenzyl bromide
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([NH2:11])[CH:3]=1.[CH3:12][C:13]1[C:18]([C:19](O)=[O:20])=[CH:17][N:16]=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:14]=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>[CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([NH:11][C:19]([C:18]2[C:13]([CH3:12])=[N:14][C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:16][CH:17]=2)=[O:20])[CH:3]=1
Reactant: Cc1cn(N)c2cccnc12
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1cc(C)c2ncccc21
Temperature: 150 °C
Reaction time: 1 h

Procedure:
A mixture of 3-methyl-pyrrolo[3,2-b]pyridin-1-yl amine (839 mg, <5.71 mmol), 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (1.32 g, 6.13 mmol), HATU (2.6 g, 6.85 mmol), DIPEA (2.21 g 17.1 mmol) in DMF (17 mL) is stirred at 150° C. for 1 h. The reaction is quenched with water and ether. The water layer is concentrated in vacuo. The residue is chromatographed through silica gel eluting with a mixture of DCM, MeOH and triethylamine (9.5:0.5:0.05) to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide (134 mg). MS: 345 345 (M+H); 1H NMR (300 MHz, CD3OD): δ 9.22 (s, 1H), 8.79 (d, 1H), 8.64 (d, 1H), 8.40(d, 1H), 8.05 (t, 1H), 7.87 (d, 1H), 7.60 (t, 1H), 7.49 (s, 1H) 7.30 (dd, 1H), 2.87 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[OH:10].[F:11][C:12]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:13]=1[C:14](Cl)=[O:15]>>[OH:10][C:3]1[C:4]([Cl:9])=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[NH:1][C:14](=[O:15])[C:13]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:12]=1[F:11]
Reactant: Nc1cc(Cl)cc(Cl)c1O
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1F
Product: O=C(Nc1cc(Cl)cc(Cl)c1O)c1cc([N+](=O)[O-])ccc1F

Procedure:
Prepared by the method of Example 15a), from 2-amino-4,6-dichlorophenol (409 mg, 2.3 mmol) and 2-fluoro-5-nitrobenzoyl chloride (468 mg, 2.3 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([OH:16])[CH:5]([N:11]1[CH2:14][CH2:13][C:12]1=[O:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[N-:17]=[N+:18]=[N-:19].[Na+]>CS(C)=O.ClCCl>[N:17]([CH2:2][CH2:3][CH:4]([OH:16])[CH:5]([N:11]1[CH2:14][CH2:13][C:12]1=[O:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N+:18]=[N-:19]
Reactant: CCOC(=O)C(C(O)CCCl)N1CCC1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)C(C(O)CCN=[N+]=[N-])N1CCC1=O
Yield: 73 %

Procedure:
A solution of ethyl 5-chloro-3-hydroxy-2-(2-oxoazetidin-1-yl)valerate (3.45 g, 13.8 mmol) and sodium azide (1.10 g, 17 mmol) in dry dimethylsulphoxide (20 ml) was stirred between 55° and 65° C. for 5 hours. The reaction mixture was diluted with dichloromethane and the organic layer was washed three times with water before being dried (MgSO4) and evaporated. The residue was chromatographed on silica gel (Merck Art. 9385), eluting with ethyl acetate/hexane (2:1), to give ethyl 5-azido-3-hydroxy-2-(2-oxoazetidin-1-yl)valerate as a pale yellow oil in 73% yield (2.59 g). Bulb to bulb distillation at 0.2 mmHg between 185°-195° C. further purified the product to a colourless oil. νmax (KBr) 3405, 2102 and 1733 cm-1 ; δH (CHCl3, 250 MHz) 1.31 (3H,t,J 7 Hz), 1.81 (1H,m), 1.87 (1H,m), 3.03 (2H,t,J 3 Hz), 3.40 (2H,m), 3.53 (2H,m), 4.00 (1H,d,J 3.5 Hz), 4.25 (3H,m) and 4.53 (1H,d,J 4.5 Hz, exchangeable). (Found: C, 46.93; H, 6.46; N, 21.83%. C10H16N3O4 requires C,46.87; H, 6.29; N, 21.86%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]=[CH:12][C:13]1[CH:18]=[C:17](Br)[CH:16]=[CH:15][C:14]=1[OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.[CH2:24]([O:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:24]([O:31][C:32]1[CH:37]=[C:36]([C:17]2[CH:16]=[CH:15][C:14]([OH:20])=[C:13]([CH:12]=[CH:11][CH2:10][CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:18]=2)[CH:35]=[CH:34][CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Reactant: Oc1ccc(Br)cc1C=CCCOCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc(-c2cccc(OCc3ccccc3)c2)cc1C=CCCOCc1ccccc1

Procedure:
10.3 g (31 mmol) of 2-(4-benzyloxybut-1-enyl)-4-bromophenol, 5.5 g (20 mmol) of sodium metaborate octahydrate and 0.6 g (0.84 mmol) of bis(triphenylphosphine)palladium(II) chloride are initially introduced in 20 ml of THF and 60 ml of water, and, after addition of 0.03 ml of hydrazine hydrate, a solution of 6.0 g (26 mmol) of 3-benzyloxybenzeneboronic acid in 40 ml of THF is added dropwise. The batch is heated under reflux overnight and subsequently extracted four times with dichloromethane. The combined org. phases are washed with water and dried over sodium sulfate. The solvent is removed in vacuo, and the crude product is recrystallised once each from toluene and ethanol, giving 3′-benzyloxy-3-(4-benzyloxybut-1-enyl)biphenyl-4-ol as a colourless solid.
Reaction SMILES: [CH2:1]([CH:3]1[NH:12][C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:14])[CH3:2].O1CCOCC1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C([O-])(O)=O.[Na+].O>[CH2:1]([C:3]1[C:4](=[O:14])[NH:5][C:6]2[C:11]([N:12]=1)=[CH:10][CH:9]=[C:8]([F:13])[CH:7]=2)[CH3:2]
Reactant: CCC1Nc2ccc(F)cc2NC1=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1nc2ccc(F)cc2[nH]c1=O
Yield: 94.8 %

Procedure:
To a homogeneous solution of 3-ethyl-7-fluoro-3,4-dihydroquinoxalin-2(1H)-one (60.61 g, 312.1 mmol) and 1,4-dioxane (1350 ml) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (75.91 g, 327.7 mmol) and the mixture was stirred using an overhead stirrer at rt for 2.5 h. At this time, the mixture was concentrated under reduced pressure to give a brown residue. The brown residue was suspended in saturated aqueous NaHCO3 (2 L), stirred for 30 min, filtered, washed with saturated aqueous NaHCO3 (1 L) to give a light green solid. The light green solid was re-suspended in saturated aqueous NaHCO3 (500 mL), well mixed, filtered, and washed with saturated aqueous NaHCO3 (500 mL) to give an off-white solid. The off-white solid was suspended in water (500 mL), well mixed, filtered, washed with water (1 L), air-dried overnight, and dried under high vacuum at 22° C. for 2 h to give 3-ethyl-7-fluoroquinoxalin-2(1H)-one (56.87 g, 94.8% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.36 (br. S, 1H), 7.76 (dd, J=9.0, 5.9 Hz, 1H), 7.11 (td, J=8.8, 2.7 Hz, 1H), 7.00 (dd, J=9.6, 2.7 Hz, 1H), 2.78 (q, J=7.4 Hz, 2H), 1.20 (t, J=7.4 Hz, 3H) Mass Spectrum (ESI) m/e=193.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[Br:12].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1>[Br:12][C:3]1[CH:4]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:6]=[CH:7][C:2]=1[NH:1][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: Nc1ccc(C(F)(F)F)cc1Br
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(C(F)(F)F)cc2Br)cc1
Temperature: 0 °C
Reaction time: 52 h

Procedure:
To a solution of 4-amino-3-bromobenzotrifluoride (20.0 g, 83.3 mmol) in pyridine at room temperature is added p-toluenesulfonyl chloride (19.8 g, 104.1 mmol) in portions over 3 minutes, and the resulting mixture stirred for 52 hours. The suspension is poured into an ice-water mix (300 ml), filtered; and the filtered solid is washed with water (250 ml). The solid is dissolved in dichloromethane (200 ml) and the resulting solution is washed with 1N HCl (2×150 ml), water (2×200 ml), dried (Na2SO4), and concentrated to a solid. The solid is suspended in ethanol (700 ml) and heated at reflux for 10 minutes, filtered while hot to remove insolubles, and the filtered solids washed with ethanol (250 ml). After concentration of the filtrate, the resulting solid is suspended in methanol (500 ml), treated with K2CO3 (2.0 g, 14.4 mmol), and the mixture is stirred at room temperature for 46 hours. After filtration of the suspension, the filtered solid is washed with methanol (150 ml), and the filtrate is concentrated to give the title compound as a foam. Mass spectrum (ES+): 394 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[NH:12])[S:10][CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[CH2:15]([O:22][C:23](ON1C(=O)CCC1=O)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[CH2:15]([O:22][C:23]([NH:12][C:9](=[N:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[S:10][CH3:11])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CSC(=N)NC(=O)OC(C)(C)C
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CSC(=NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Yield: 92.4 %

Procedure:
N-(tert-butyloxycarbonyl)-S-methylisothiourea (2 g) was dissolved in dichloromethane (20 ml). To the solution, a 4N sodium hydroxide solution (2 ml) was added with stirring. The reaction mixture was placed in an ice bath; N-(benzyloxy-carbonyloxy)-succinimid (2.62 g) in dichloromethane (20 ml) was added dropwise together with a 2N sodium hydroxide solution to keep the pH around 11. After addition was complete, the reaction mixture was stirred overnight at room temperature. The dichloromethane layer was separated, and the aqueous layer was washed twice with dichloromethane. The combined organic layers were washed with water and dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by chromatography on silica (eluent: heptane/ethyl acetate=3/2 v/v %) to yield N-(benzyloxy-carbonyl)-N'-(tert-butyloxycarbonyl)-S-methylisothiourea (3.15 g).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.CI.[H-].[Na+].[C:23](OCC)(=O)C>CN(C)C=O>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:23])=[CH:16][CH:17]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(C)=O
Reactant: Oc1ccc(OCCCCCn2ccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(OCCCCCn2ccnc2)cc1
Reaction time: 0.08 h

Procedure:
To a solution of 1.87 g p-[5-(1-imidazolyl)pentyloxy]phenol and 0.46 ml methyl iodide in 18 ml anhydrous N,N-dimethylformamide, was added under ice cooling and with stirring 290 mg of 60% sodium hydride in oil, and stirring was continued at room temperature for five minutes. Ethyl acetate was added to the reaction mixture, the precipitate which separated out was filtered off, and the filtrate was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography [chloroform/methanol/28% ammonia water (50:1:0.1)], affording 2.0 g of 1-[5-(1-imidazolyl)pentyloxy]-4-methoxybenzene as oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1.[CH3:34][Si:35]([C:38]#[CH:39])([CH3:37])[CH3:36].CCN(CC)CC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:22][C:18]1[CH:17]=[C:16]2[NH:15][C:14](=[O:23])[C:13]3([CH:12]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)[CH2:11][C:10](=[O:31])[NH:9][CH:8]3[C:6]3[CH:7]=[C:2]([C:39]#[C:38][Si:35]([CH3:37])([CH3:36])[CH3:34])[CH:3]=[CH:4][C:5]=3[O:32][CH3:33])[C:21]2=[CH:20][CH:19]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(Br)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C#C[Si](C)(C)C)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in example 214e, racemic (2′R,3′R,4′S)-2′-[5-bromo-2-methoxy-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′-dione reacted with PdCl2(PPh3)2, CuI, trimethylsilyl acetylene and Et3N (Aldrich, 0.62 mL) in DMF to give the title compound. MS (H+),