Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCCCCC.C([Li])CCC.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[C:1]1([C:7]#[C:8][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: BrCCCCCCOC1CCCCO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: C(#Cc1ccccc1)CCCCCCOC1CCCCO1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
To a solution of 11.2 g of phenylacetylene dissolved in 100 ml of tetrahydrofuran, 78.8 ml of 1.6M-hexane solution of n-butyl lithium was added dropwise at 5°-8° C. Then 150 ml of a hexamethylphosphoramide solution containing 29.4 g of 1-bromo-6-(2-tetrahydropyranyloxy)-hexane was added dropwise at 10°-20° C. After stirring at 20° C. for 30 minutes, the reaction mixture was poured into ice-water and extracted with hexane. The organic layer was washed with water, dried and then the organic solvent was distilled off. The residue was purified by silica gel column chromatography (solvent: hexane-ethyl acetate=10:1), to give 18.3 g of 1-phenyl-8-(2-tetrahydropyranyloxy)-1-octyne as an oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.CC(C)([O-])C.[Na+].C1OCCOCCOCCOCCOCCOC1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: C1COCCN1
Agent: [Pd]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Brc1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.7 %

Procedure:
A solution of 1-bromo-4-iodobenzene (5.0 g, 18 mmol), morpholine (1.85 mL, 21 mmol), sodium tert-butoxide (2.4 g, 25 mmol), 18-crown-6 (6.6 g, 25 mmol) in THF (150 mL) was purged with Ar for 20 min, then BINAP (0.11 g, 0.18 mmol) and Pd2(dba)3 (0.16 g, 0.18 mmol) was added. The mixture turned dark after stirring at room temperature overnight. The solvent was concentrated under reduced pressure and the residue was dissolved in diethyl ether and washed with water. The organic phase was mixed with silica gel, and the solvent was evaporated to dryness. The residue was purified by silica gel column chromatography (EtOAc in hexanes 5%) to of white precipitate (250 mg, 5% yield). 1H NMR (CDCl3): 7.3 (d, 2H), 6.85 (d, 4H), 3.1 (d, 4H).
Reaction SMILES: [Br:1][C:2]1[C:15]2[CH:14]=[CH:13][C:12]3[N:11]=[C:10](NC(=O)C(C)(C)C)[NH:9][C:8](=[O:23])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CCOCC>[CH2:24]([NH:31][C:10]1[NH:9][C:8](=[O:23])[C:7]2[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[C:15]=3[CH:14]=[CH:13][C:12]=2[N:11]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)C(=O)Nc1nc2ccc3c(Br)cccc3c2c(=O)[nH]1
Reactant: NCc1ccccc1
Solvent: CCOCC
Product: O=c1[nH]c(NCc2ccccc2)nc2ccc3c(Br)cccc3c12

Procedure:
A mixture of N-(7-bromo-1,2-dihydro-1-oxobenz[f]quinazolin-3-yl)pivalamide (0.3 g, 0.8 mmole) and benzylamine (10 ml) was stirred and heated at reflux under a nitrogen atmosphere for 18 hours. The cooled reaction mixture was then mixed with 4 volumes of ether to cause precipitation of the product. The precipitate was filtered and recrystallized from methanol to give 3-(benzylamino)-7-bromobenzo-[f]quinazolin-1(2H)-one as an off-white solid. (0.11 g, 37%) 1H NMR(DMSO-d6, 200 MHz) δ: 4.62(d, J=5.7 Hz, 2H, CH2); 7.02(m, 1H, benzyl-NH); 7.20-7.55(m, 7H, Ar); 7.79(dd, J=7.5, 1.1 Hz, 1H, Ar); 8.30(d, J=9.2 Hz, 1H, Ar); 9.74(d, J=8.6 Hz, 1H, Ar); 11.2(br s, 1H, pyr-NH).
Reaction SMILES: C([O:5][C:6]([CH:8]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[N:9]1[C:13]2[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=2[N:11](C(OC(C)(C)C)=O)[C:10]1=[O:27])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:18]([C:15]1[CH:16]=[CH:17][C:12]2[NH:11][C:10](=[O:27])[N:9]([CH:8]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:6]([OH:7])=[O:5])[C:13]=2[CH:14]=1)#[N:19]
Reactant: CC(C)(C)OC(=O)C(c1ccccc1)n1c(=O)n(C(=O)OC(C)(C)C)c2ccc(C#N)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc2[nH]c(=O)n(C(C(=O)O)c3ccccc3)c2c1
Temperature: 25 °C

Procedure:
tert-Butyl 3-(tert-butoxycarbonylphenylmethyl)-5-cyano-2-oxo-2,3-dihydrobenzimidazole-1-carboxylate 695 mg (1.55 mmol) of tert-butyl 3-(tert-butoxycarbonylphenylmethyl)-5-cyano-2-oxo-2,3-dihydrobenzimidazole-1-carboxylate (VIIc) were dissolved in dichloromethane (30 ml) and, while stirring at room temperature, trifluoroacetic acid (20 ml) was added. The reaction solution was stirred for 2 h and then the solvent and excess trifluoroacetic acid were removed in vacuo. The residue was taken up again in toluene, concentrated in vacuo and then dried in vacuo. Yield: 449 mg (99%) of white solid
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:20]=[C:11]3[C:12]4[C:17]([CH2:18][CH2:19][N:10]3[N:9]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:5]=[CH:6][CH:7]=1.[O-][CH2:22][CH3:23].[Na+].C(I)C>C(O)C>[CH2:22]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:20]=[C:11]3[C:12]4[C:17]([CH2:18][CH2:19][N:10]3[N:9]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:5]=[CH:6][CH:7]=1)[CH3:23]
Reactant: Oc1cccc(-c2nc3n(n2)CCc2ccccc2-3)c1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCI
Product: CCOc1cccc(-c2nc3n(n2)CCc2ccccc2-3)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(3-Hydroxyphenyl)-5,6-dihydro-s-triazolo-[5,1-a]isoquinoline (3.95 g.) is added to 60 ml. of ethanol containing one equivalent proportion of sodium ethoxide. To this mixture is added 1.57 ml. of ethyl iodide in 15 ml. of ethanol. After stirring for one hour at room temperature, a further 1.57 ml. of ethyl iodide is added and the mixture is refluxed for 18 hours. The solvent is distilled off and the residue is washed with water and extracted with dichloromethane. Evaporation of the solvent and crystallization of the residue from ethanol gives 3.87 g. of the title product; m.p. 102°-3° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29][CH2:30]Br)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.C(N(CC)CC)C>CN(C=O)C.[I-].[Na+]>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29][CH2:30][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnn2c(CCCCBr)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: C1CCNC1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncnn2c(CCCCN3CCCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 55 °C
Yield: 83.1 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(4-bromobutyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (440 mg, 0.93 mmol) in DMF (5.0 mL) was added pyrrolidine (155 μL, 1.86 mmol), triethylamine (387 μl, 2.78 mmol), and sodium iodide (1.4 mg, 0.009 mmol). The reaction was heated (55° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (25 mL) and water (25 mL). The layers were separated and the organic was washed with water (2×20 mL), brine, dried (Na2SO4) and evaporated to afford 360 mg (84%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 1 H), 7.87 (s, 1 H), 7.78 (d, 1 H), 7.56 (s, 1 H), 7.36-7.26 (m, 5 H), 7.13 (dd, 1 H), 6.57 (s, 1 H), 5.64 (s, 2 H), 2.88 (t, 2 H), 2.42-2.33 (m, 6 H), 1.78-1.66 (m, 2 H), 1.67-1.60 (m, 4 H), 1.57-1.46 (m, 2H); ES-MS m/z 466.3 [M+H]+, HPLC RT (min) 2.20.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([F:33])=[C:16]([NH:18][C:19](=[O:32])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4([C:29]#[N:30])[CH2:28][CH2:27]4)[C:21]=3[Cl:31])[CH:17]=1)[N:5]=2.N1C=CC=CC=1.[CH:40]1([C:43](Cl)=[O:44])[CH2:42][CH2:41]1.C(=O)([O-])O.[Na+]>O1CCCC1.C1(C(Cl)=O)CC1.O>[Cl:31][C:21]1[C:22]([C:26]2([C:29]#[N:30])[CH2:28][CH2:27]2)=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([NH:18][C:16]1[CH:17]=[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:43]([CH:40]4[CH2:42][CH2:41]4)=[O:44])=[N:10][C:9]3=[CH:8][CH:7]=2)[CH:13]=[CH:14][C:15]=1[F:33])=[O:32]
Reactant: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc5nc(N)sc5n4)ccc3F)c2Cl)CC1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc5nc(NC(=O)C6CC6)sc5n4)ccc3F)c2Cl)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2-fluorophenyl}-2-chloro-3-(1-cyanocyclopropyl)benzamide (9.0 g, 18.8 mmol) and pyridine (2.3 mL, 28.1 mmol) in tetrahydrofuran (90 mL) was added dropwise cyclopropanecarbonyl chloride (1.89 mL, 20.8 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. Cyclopropanecarbonyl chloride (63 μL, 0.69 mmol) was further added and the mixture was stirred at room temperature for 12 hr. Water (100 mL) and saturated aqueous sodium hydrogen carbonate solution (100 mL) were added to the reaction mixture to give a suspension, and the mixture was stirred at room temperature for 30 min. The precipitate was collected by filtration, repeatedly washed with water, and dried under reduced pressure to give the title compound (9.85 g, 96%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:62]=[CH:61][C:53]2[N:54]([CH3:60])[C:55]([CH:57]([NH2:59])[CH3:58])=[N:56][C:52]=2[CH:51]=1.ClCl>CN(C)C=O.ClCCl.C(O)C>[Cl:49][C:50]1[CH:62]=[CH:61][C:53]2[N:54]([CH3:60])[C:55]([CH:57]([NH:59][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH3:58])=[N:56][C:52]=2[CH:51]=1
Reactant: CC(N)c1nc2cc(Cl)ccc2n1C
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)NC(C)c2nc3cc(Cl)ccc3n2C)ccc1C(=O)N1CCCC1
Yield: 71 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and rac.-1-(5-chloro-1-methyl-1H-benzimidazol-2-yl)ethylamine in dimethylformamide. Yield: 71%; Rf value: 0.47 (silica gel; dichloromethane/ethanol=9:1); C23H25ClN4O2 (424.93); mass spectrum: (M+H)+=425/427 (chlorine isotope) and (M−H)−=423/425 (chlorine isotope).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].[CH2:13](O)[CH2:14][CH:15]=[CH2:16]>>[C:1]([O:12][CH2:16][CH2:15][CH:14]=[CH2:13])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: C=CCCO
Reactant: C=CCCCCCCCC(=O)O
Product: C=CCCCCCCCC(=O)OCCC=C

Procedure:
Following the aforementioned procedure, diene was prepared from dec-9-enoic acid and but-3-en-1-ol. The resulting yellow oil was purified by silica gel chromatography (30:1 hexanes:diethyl ether) to afford the desired product as a colorless oil. IR (neat): 3077 (m), 2927 (s), 2855 (s), 1737 (s), 1641 (m), 1458 (m), 1418 (m), 1353 (m), 1243 (s), 1170 (s), 1115 (m), 992 (s), 912 (s), 725 (m), 635 (m); 1H NMR (400 MHz, CDCl3): δ 5.86-5.74 (2H, m), 5.14-4.91 (4H, m), 4.12 (211, t, J=6.8 Hz), 2.38 (2H, ddt, J=13.6, 6.8, 1.4 Hz), 2.29 (2H, t, J=7.6 Hz), 2.06-2.01 (2H, m), 1.63-1.59 (2H, m), 1.39-1.26 (8H, m); 13C NMR (100 MHz, CDCl3): δ 174.0, 139.3, 134.2, 117.3, 114.3, 63.4, 34.5, 33.9, 33.3, 29.2, 29.2, 29.1, 29.0, 25.1; HRMS (ESI+) [M+H]+ calcd for C14H25O2: 225.1855. found: 225.1855.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:18]3[C:13](=[C:14]([F:20])[C:15]([F:19])=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:4][N:3]=1.Cl.[NH:22]1[C:27]2[N:28]=[CH:29][CH:30]=[CH:31][C:26]=2[C:25]2([CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[O:24][C:23]1=[O:37].C(=O)([O-])[O-].[K+].[K+].O.C(#N)C>CN1C(=O)CCC1>[F:20][C:14]1[C:15]([F:19])=[CH:16][CH:17]=[C:18]2[C:13]=1[CH2:12][CH2:11][N:10]2[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:34]2[CH2:33][CH2:32][C:25]3([O:24][C:23](=[O:37])[NH:22][C:27]4[N:28]=[CH:29][CH:30]=[CH:31][C:26]3=4)[CH2:36][CH2:35]2)[CH:7]=1)=[O:9]
Reactant: O=C(c1ccnc(Cl)c1)N1CCc2c1ccc(F)c2F
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1Nc2ncccc2C2(CCN(c3cc(C(=O)N4CCc5c4ccc(F)c5F)ccn3)CC2)O1
Temperature: 130 °C
Reaction time: 10 h

Procedure:
0.23 g (0.78 mmol) (2-chloro-pyridin-4-yl)-(4,5-difluoro-2,3-dihydro-indol-1-yl)-methanone were added to 0.20 g (0.78 mmol) spiro[piperidine-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one-hydrochloride and 0.11 g (0.78 mmol) potassium carbonate in 3.0 mL NMP. The reaction mixture was first of all stirred for 10 h at 130° C., then cooled to RT and then stirred overnight at RT. The crude product was combined with water/acetonitrile and purified by preparative HPLC-MS. The product fractions were combined and evaporated down. The residue was triturated with diisopropylether, suction filtered and dried in the air.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([CH2:13][N:14]2[CH:18]=[CH:17][N:16]=[C:15]2[C:19]([C:21]2[C:22]3[CH2:23][CH2:24][CH2:25][CH2:26][C:27]=3[CH:28]=[CH:29][CH:30]=2)=[O:20])[CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH3:38][S:39]([O:12][CH2:11][CH2:10][C@@H:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[C:15]1[C:19]([C:21]1[C:22]2[CH2:23][CH2:24][CH2:25][CH2:26][C:27]=2[CH:28]=[CH:29][CH:30]=1)=[O:20])(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1cccc2c1CCCC2)c1nccn1C[C@@H](CCO)c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC[C@H](Cn1ccnc1C(=O)c1cccc2c1CCCC2)c1ccc(Cl)c(Cl)c1
Reaction time: 4 h
Yield: 102.5 %

Procedure:
3(S)-(3,4-Dichlorophenyl)-4-[2-(1,2,3,4-tetrahydro-5-naphthoyl)imidazol-1-yl]butan-1-ol (0.68 g) (see Preparation 103) and triethylamine (0.22 g) were dissolved in dichloromethane (15 ml), the solution cooled in an ice-bath and methanesulphonyl chloride (0.22 g) added. The mixture was stirred for 4 hours before removal of the solvent under reduced pressure to give a residue which was partitioned between ethyl acetate and water. The organic phase was separated and washed with saturated aqueous sodium hydrogen carbonate solution before being dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure to give 1-methanesulphonyloxy-3(S)-(3,4-dichlorophenyl)-4-[2-(1,2,3,4-tetrahydro-5-naphthoyl)imidazol-1-yl]butane (0.82 g) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)([O-:3])=[O:2].ClN1C(=[O:19])CCC1=O.OP(O)(O)=O.[OH-].[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CC(O)=O>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:19])[NH:8]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=C1Cc2c(cccc2[N+](=O)[O-])N1
Temperature: 70 °C

Procedure:
A mixture of 4-nitroindole (12.2 g, 75.2 mmol) and N-chlorosuccinimide (6.07 g, 30.1 mmol) in CHCl3 (500 mL) was heated at reflux for 30 h, then concentrated under reduced pressure to give an orange solid. The solid was dissolved in AcOH (200 mL) and the resulting solution was warmed to 70° C., then 85% H3PO4 (80 mL) was added over 2 min. The mixture was heated to reflux for 90 min then cooled on ice. The cooled mixture was adjusted to pH 6 by addition of 10 N NaOH (450 mL), followed by aqueous NaHCO3, keeping the temperature below 30° C. The mixture was extracted with EtOAc (3×1 L) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was partially purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, and then triturated with MeOH to give the title compound. MS: m/z=179 (M+1).
Reaction SMILES: [C:1]1([CH:7]([N:9]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([Li])CCC.CI.O>O1CCCC1.CCCCCC>[CH3:23][C:18]1[C:17]2[O:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH3:8])[C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: [Li]CCCC
Reactant: CC(c1ccccc1)N1c2ccccc2Oc2ccccc21
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cccc2c1Oc1ccccc1N2C(C)c1ccccc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
2.87 g (10 mmoles) of N-(α-phenylethyl)phenoxazine were dissolved, under nitrogen atmosphere, in 100 ml of dry tetrahydrofuran. The solution was cooled to -20° C. and 7.2 ml of a 1.67N solution of n-butyllithium (12 mmoles) in hexane was added thereto. The resulting mixture was stirred for 1 hour at -20° C. and then treated with 1.7 g (12 mmoles, 0.74 ml) of methyl iodide. Stirring was continued for an additional hour at the same temperature. The reaction solution was then poured into water (200 ml) and extracted with ethyl acetate (2×50 ml). The combined extracts were dried over sodium sulfate and the solvent removed under reduced pressure. The oily residue (2.96 g) was purified by thin layer chromatography (TLC) using hexane as solvent, to yield 4-methyl-N-(α-phenylethyl)phenoxazine, as an oil: ir: 2925; 2875; 1603 cm-1 ; nmr: (CDCl3) 1.80 ppm (d, 3H), 2.23 ppm (s, 3H), 7.17 ppm (c, 1H), 6.20-6.80 ppm (m, 7H), 7.60 ppm (m, 5H).
Reaction SMILES: N1C=CC=CC=1C.Cl[S:9]([OH:12])(=O)=[O:10].[CH2:13]([O:20][C:21]([NH:23][C@H:24]([C:28]([NH2:30])=[O:29])[C@@H:25]([CH3:27])[OH:26])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.P([O-])([O-])([O-])=O>C(Cl)Cl>[S:9](=[N:30][C:28](=[O:29])[C@H:24]([C@@H:25]([CH3:27])[OH:26])[NH:23][C:21]([O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:22])(=[O:12])=[O:10]
Reactant: O=S(=O)(O)Cl
Reactant: C[C@@H](O)[C@H](NC(=O)OCc1ccccc1)C(N)=O
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccn1
Product: C[C@@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)N=S(=O)=O

Procedure:
A solution of 2-picoline (17.8 ml) in 90 ml of methylene chloride was cooled to -5° C. (ice-brine) and chlorosulfonic acid (5.97 ml) was added at such a rate as to maintain the internal reaction temperature below 5° C. The resulting solution was added via canula, to a suspension of 7.56 g of benzyloxycarbonylthreonine amide, O-mesylate in 120 ml of methylene chloride. The resulting heterogeneous mixture was refluxed for about 16 hours yielding a clear solution. The solution was poured into 500 ml of pH 4.5 phosphate buffer (0.5M) and further diluted with 120 ml of methylene chloride. The separated organic layer was washed once with 100 ml of buffer solution and the combined aqueous phases were treated with 10.2 g of tetra-n-butyl-ammonium hydrogensulfate and extracted with methylene chloride (one 300 ml portion and two 150 ml portions). After drying the combined organic extracts over sodium sulfate, the solution was concentrated to yield 12.7 g of N-sulfonyl benzyloxycarbonylthreonine amide, O-mesylate, tetrabutylammonium salt.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.COCCOC.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.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>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: OB(O)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
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: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.9 %

Procedure:
A mixture of Pd(PPh3)4 (354 mg, 1.58 mmol), 2-chloro-5-nitropyridine (5.00 g, 31.5 mmol), and phenylboronic acid (4.61 g, 37.8 mmol) was degassed and filled with nitrogen gas three times. The mixture was treated with 40 mL of DME and aqueous 2 M potassium carbonate (80.0 mmol) solution and heated to reflux. After 4 hours, the reaction mixture was cooled to room temperature and diluted with 100 mL of ethyl acetate and 50 mL of water. The phases were separated and the aqueous layer was extracted with three 100 mL portions of ethyl acetate. The combined organic layers were washed with 100 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography on SiO2 (0% to 50% ethyl acetate in hexanes, gradient) give 4.60 g of 5-nitro-2-phenylpyridine (73% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.C(N(CC)CC)C.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1.CCOC(C)=O.O>[CH2:21]([NH:28][C:8]([C:7]1[C:6]([Cl:11])=[N:5][C:4]([S:12][CH3:13])=[N:3][C:2]=1[Cl:1])=[O:9])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CSc1nc(Cl)c(C(=O)Cl)c(Cl)n1
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1nc(Cl)c(C(=O)NCc2ccccc2)c(Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4,6-dichloro-2-methylsulfanylpyrimidine-5-carbonyl chloride in THF (15 mL), triethylamine (2.3 mmol) and benzylamine (2.5 mmol) are added at 0° C. After stirred at room temperature for 2 h, the reaction mixture is diluted with AcOEt and H2O. The mixture is extracted twice with AcOEt. The organic layer is dried over Na2SO4, filtered, and concentrated. The residue is purified by silica gel column chromatography to give 4,6-dichloro-2-methylsulfanylpyrimidine-5-carboxylic acid benzylamide as a white solid. 1H-NMR (CDCl3), δ 2.57 (3H, s), 4.66 (2H, d), 6.08 (1H, br s), 7.31-7.35 (2H, m), 7.36-7.38 (3H, m).
Reaction SMILES: CS(O[CH2:6][CH:7]1[O:12][C:11]2[CH:13]=[C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[CH:16][C:10]=2[O:9][CH2:8]1)(=O)=O.[I-:24].[Na+]>C(C(C)=O)C.C(OCC)(=O)C>[I:24][CH2:6][CH:7]1[O:12][C:11]2[CH:13]=[C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[CH:16][C:10]=2[O:9][CH2:8]1
Reactant: CS(=O)(=O)OCC1COc2ccc(Oc3ccccc3)cc2O1
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: ICC1COc2ccc(Oc3ccccc3)cc2O1

Procedure:
2-Methanesulfonyloxymethyl-7-phenoxy-1,4-benzodioxane (1.85 g, 5.5 mmol) and sodium iodide (1.54 g, 11.0 mmol) are taken up in methyl ethyl ketone (60 mL) and heated at reflux for 3 hours. The mixture is cooled, diluted with ethyl acetate, washed with aqueous sodium bicarbonate, dried over magnesium sulfate and evaporated to give 2-iodomethyl-7-phenoxy-1,4-benzodioxane as a tan solid. This is used without further purification.