Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])O.[Na+].[C:16]([C:18]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25])([CH3:20])[CH3:19])#[N:17]>O1CCCC1>[Cl:9][C:5]1[C:6]([OH:8])=[CH:7][C:2]([NH:1][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[C:21]([C:18]([C:16]#[N:17])([CH3:19])[CH3:20])[CH:22]=2)=[C:3]([F:10])[CH:4]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Reactant: Nc1cc(O)c(Cl)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(O)c(Cl)cc2F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
To a two-layer solution of 5-amino-2-chloro-4-fluorophenol (3.50 g, 21.7 mmol) in tetrahydrofuran (35 mL)/1N aqueous sodium hydrogen carbonate solution (65 mL) was added a solution of 3-(1-cyano-1-methylethyl)benzoyl chloride synthesized above in tetrahydrofuran (30 mL), and the mixture was stirred at room temperature for 4 hr. The aqueous layer was separated, and extracted with ethyl acetate (200 mL). The combined organic layer was washed with water (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (5.18 g, 72%) as a gray powder.
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21](B5OC(C)(C)C(C)(C)O5)[CH:20]=4)=[O:17])=[CH:14][C:15]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:43]1[CH:47]=[CH:46][NH:45][N:44]=1>COCCOC.O.C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:43]5[CH:47]=[CH:46][NH:45][N:44]=5)[CH:20]=4)=[O:17])=[CH:14][C:15]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1
Reactant: CC1(C)OB(c2cccc(NC(=O)c3ccc4cc5n(c4c3)CCCNC5=O)c2)OC1(C)C
Reactant: Brc1cc[nH]n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Solvent: COCCOC
Product: O=C(Nc1cccc(-c2cc[nH]n2)c1)c1ccc2cc3n(c2c1)CCCNC3=O
Temperature: 150 °C

Procedure:
To a solution of 1-oxo-N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxamide in DME:H2O:ethanol (7:3:2 v/v/v, 2.0 mL) is added K3PO4 (34.3 mg, 0.162 mmol) and Pd(dppf)Cl2 CH2Cl2 adduct (11 mg, 0.0135 mmol). The solution is added to a microwave vial containing 3-bromo-1H-pyrazole (29.8 mg, 0.15 mmol). The resulting mixture is heated in a microwave reactor at 150° C. for 30 minutes. The mixture is filtered through Celite (100 mg) washed with ethyl acetate (3×1 mL) and concentrated in vacuo. The residue is purified by mass triggered HPLC to provide the title compound as a (31 mg, 39%).
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.Br[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH3:22])[CH:20]=2)[N:15]=[C:14]([CH3:23])[CH:13]=1.C([O-])([O-])=O.[Na+].[Na+].[C:30]([C:32]1[CH:37]=[CH:36][C:35](OB(O)O)=[CH:34][CH:33]=1)#[N:31]>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.O.CO.C1(C)C=CC=CC=1>[C:30]([C:32]1[CH:37]=[CH:36][C:35]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH3:22])[CH:20]=3)[N:15]=[C:14]([CH3:23])[CH:13]=2)=[CH:34][CH:33]=1)#[N:31]
Reactant: Cc1ccc2nc(C)cc(Br)c2c1
Reactant: N#Cc1ccc(OB(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccc2ncccc2c1
Solvent: O
Product: Cc1ccc2nc(C)cc(-c3ccc(C#N)cc3)c2c1
Yield: 88.2 %

Procedure:
In example 1-6, a compound represented by the chemical formula (38) was synthesized through the following processes as an example quinoline derivative. First, a solution in which 4-bromo-2,6-dimethylquinoline (1.05 g) identical to that in the example 1-4 and Pd(Ph3P)4 (0.31 g) were added to toluene (8.5 ml), a solution in which Na2CO3 (1.81 g) was added to water (8.5 ml), and a solution in which 4-cyanophenylboric acid (0.726 g) was added to methanol (2.8 ml) were mixed and allowed to react for 22 hours in a nitrogen atmosphere at a temperature of 80° C. The reaction solution was poured into water and extracted using chloroform. The chloroform layer was dried using Na2SO4 and the Na2SO4 was removed by filtering. The solvent was removed under reduced pressure and the residue was purified through column chromatography (silica gel, hexane/ethyl acetate=2/1) to obtain 4-(4-cyanophenyl)-2,6-dimethylquinoline (1.013 g) represented by the following chemical formula (48).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:15][C:16]1[S:20][C:19]2[C:21]3([O:42][CH2:43][C:44]([F:46])([F:45])[C:18]=2[CH:17]=1)[CH2:26][CH2:25][N:24]([CH2:27][C:28]1[C:29]([CH3:41])=[N:30][N:31]([C:33]2[C:38]([CH2:39]O)=[CH:37][CH:36]=[CH:35][N:34]=2)[CH:32]=1)[CH2:23][CH2:22]3.[C:47]1(=[O:57])[NH:51][C:50](=[O:52])[C:49]2=[CH:53][CH:54]=[CH:55][CH:56]=[C:48]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:15][C:16]1[S:20][C:19]2[C:21]3([O:42][CH2:43][C:44]([F:45])([F:46])[C:18]=2[CH:17]=1)[CH2:22][CH2:23][N:24]([CH2:27][C:28]1[C:29]([CH3:41])=[N:30][N:31]([C:33]2[C:38]([CH2:39][N:51]4[C:47](=[O:57])[C:48]5[C:49](=[CH:53][CH:54]=[CH:55][CH:56]=5)[C:50]4=[O:52])=[CH:37][CH:36]=[CH:35][N:34]=2)[CH:32]=1)[CH2:25][CH2:26]3
Reactant: Cc1nn(-c2ncccc2CO)cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1nn(-c2ncccc2CN2C(=O)c3ccccc3C2=O)cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
Diisopropyl azodicarboxylate (0.105 mL, 0.54 mmol) is added to a solution of [2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methanol (0.173 g, 0.36 mmol), phthalimide (0.079 mg, 0.54 mmol) and triphenylphosphine (0.142 g, 0.54 mmol) in toluene (3 mL) at 0° C. The mixture is stirred at room temperature overnight. The solvent is removed and the residue is purified first using a 2 g SCX cartridge and after evaporation of the 2 N ammonia in methanol fraction by normal phase Isco chromatography eluting with hexane/ethanol (3%-30%) to give 0.201 g of 2-[[2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methyl]isoindoline-1,3-dione. MS (m/z): 610 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:19]2[C:14](=[C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:16]=[C:17]([CH3:20])[N:18]=2)[C:13](C#N)=[CH:12]1.[OH-].[NH4+]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:19]2[C:14](=[C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:16]=[C:17]([CH3:20])[N:18]=2)[CH:13]=[CH:12]1
Reactant: Cc1cc(-c2ccccc2)c2c(C#N)cn(-c3ccc(C(C)C)cc3Br)c2n1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cc(-c2ccccc2)c2ccn(-c3ccc(C(C)C)cc3Br)c2n1
Yield: 91.5 %

Procedure:
A mixture 130 mg (0.302 mmole) of 1-(2-bromo-4-isopropylphenyl)-3-cyano-6-methyl-4-phenyl-7-azaindole (Example 66) and 10 mL of 65% sulfuric acid were refluxed for one hour. The mixture was poured onto ice, Conc. ammonium hydroxide was added until the mixture was basic to pH paper. The mixture was extracted with ethyl acetate. The extract was evaporated and chromatographed on silica gel with 70:30 hexane-ethyl acetate. There was obtained 112 mg (92% yield) of 1-(2-bromo-4-isopropylphenyl)-6-methyl-4-phenyl-7-azaindole. Mass spec: (m+H)+=405.10; calculated, 405.10.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[C:9]([CH2:13][O:14][C:15]1[CH:45]=[CH:44][C:18]([CH2:19][CH2:20][NH:21][CH2:22][CH:23]([OH:43])[CH2:24][O:25][C:26]2[CH:35]=[C:34]3[C:29]([C:30](=[O:42])[CH:31]=[C:32]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[O:33]3)=[CH:28][CH:27]=2)=[CH:17][CH:16]=1)([O:11]C)=[O:10].Cl.C(O)(=O)/C=C\C(O)=O.C(Cl)(Cl)Cl.CO.C(O)(=O)C>CO.O.[OH-].[Na+]>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[C:9]([CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][CH2:20][NH:21][CH2:22][CH:23]([OH:43])[CH2:24][O:25][C:26]2[CH:35]=[C:34]3[C:29]([C:30](=[O:42])[CH:31]=[C:32]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[O:33]3)=[CH:28][CH:27]=2)=[CH:44][CH:45]=1)([OH:11])=[O:10]
Reactant: COC(=O)COc1ccc(CCNCC(O)COc2ccc3c(=O)cc(-c4ccccc4)oc3c2)cc1
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: O=C(O)COc1ccc(CCNCC(O)COc2ccc3c(=O)cc(-c4ccccc4)oc3c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of Example 15 (1.9 g, 3.77 mmol) in methanol-water (2:1) was made strongly basic with 5% aqueous NaOH and stirred at room temperature for 1.5 hours followed by gentle warming to complete the hydrolysis. The solution was then acidified to pH 4-5 with conc. HCl, the precipitated gum was washed with water and taken up in hot methanol. The suspension was made strongly acidic with conc. HCl resulting in a solution which was left to crystallize. The precipitated solid showed the presence of a substantial amount of the starting ester, presumed to be formed during the purification step. This material was redissolved in aqueous NaOH over 1 hour and acidified to pH 5, the precipitated gum was washed with 3 portions of water, taken up in hot methanol and treated with 3 equivalents of maleic acid. The presence of the reformed ester was again shown by TLC chloroform-methanol-acetic acid 15:5:1). The solid was washed successively with hot isopropanol then hot ethanol. The white solid thus isolated proved to be the free base of the desired compound. Suspension of the material in 75 ml 95% ethanol and treatment with enough maleic acid to give a clear solution followed by crystallization afforded the title compound in 1.44 g (63%) recovery, mp 170° C. (d) with softening at 135° C.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][C:7](=[O:9])[O:6][C:4]1=[O:5].[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[NH2:14]>C1(C)C(C)=CC=CC=1>[Cl:10][C:11]1[CH:12]=[C:13]([N:14]=[C:4]([OH:5])[CH:3]([O:2][CH3:1])[CH2:8][C:7]([OH:6])=[O:9])[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: COC1CC(=O)OC1=O
Reactant: Nc1cc(Cl)cc(Cl)c1
Solvent: Cc1ccccc1C
Product: COC(CC(=O)O)C(O)=Nc1cc(Cl)cc(Cl)c1
Yield: 75 %

Procedure:
130 g (1 mole) of 2-methoxysuccinic acid anhydride and 162 g (1 mole) of 3,5-dichloroaniline are heated under reflux for three hours, in 1500 ml of xylene. The resulting water is azeotropically separated off by means of a water separator. The xylene is then distilled off and the crude product is recrystallized from methanol/water. Melting point: 125° to 126° C.; yield: 75% of the theoretical yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH:11]=[CH2:12])=[CH:4][CH:3]=1>CCCCCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[CH:11]=[CH2:12])=[CH:4][CH:3]=1
Reactant: C=C[C@H]1C[C@@H]1c1ccc(Br)cc1
Solvent: CCCCCC
Product: C=C[C@@H]1C[C@H]1c1ccc(Br)cc1

Procedure:
The aldehyde intermediate from Example 29E (2.35 g, 10.44 mmol) was converted to the alkene by the methods outlined in Example 26E, followed by chromatography (100% hexane) provided the title compound. 1H NMR (300 MHz, CDCl3): δ 1.07-1.19 (m, 2H), 1.60-1.71 (m, 1H), 1.83-1.91 (m, 1H), 4.91-4.97 (m, 1H), 5.05-5.14 (m, 1H), 5.45-5.59 (m, 1H), 6.93 (d, J=9 Hz, 2H), 7.36 (d, J=9 Hz, 2H). MS (DCl—NH3) m/z 241 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.Cl[Sn](Cl)(Cl)Cl.C(O[C@H:31]1[C@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@@H:33]([CH2:44][C@@H:45]([N:67]=[N+:68]=[N-:69])[CH2:46][CH2:47][C@H:48]([NH:56][S:57]([C:60]2[CH:65]=[CH:64][C:63]([CH3:66])=[CH:62][CH:61]=2)(=[O:59])=[O:58])[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[O:32]1)(=O)C>ClC(Cl)C>[C:37]([O:36][C@@H:35]1[C@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@@H:33]([CH2:44][C@@H:45]([N:67]=[N+:68]=[N-:69])[CH2:46][CH2:47][C@H:48]([NH:56][S:57]([C:60]2[CH:65]=[CH:64][C:63]([CH3:66])=[CH:62][CH:61]=2)(=[O:58])=[O:59])[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[O:32][C@H:31]1[N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][C:9]([NH:11][CH2:12][CH2:13][NH:14][C:15]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:21])=[N:10][C:2]=2[NH2:1])(=[O:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)NCCNc1nc(N)c2nc[nH]c2n1
Reactant: CC(=O)O[C@@H]1O[C@H](C[C@H](CC[C@H](NS(=O)(=O)c2ccc(C)cc2)C(=O)OC(C)(C)C)N=[N+]=[N-])[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C[C@H](CC[C@H](NS(=O)(=O)c2ccc(C)cc2)C(=O)OC(C)(C)C)N=[N+]=[N-])O[C@H]1n1cnc2c(N)nc(NCCNC(=O)OC(C)(C)C)nc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture consisting of Compound 27A (10 molar equivalents) in an appropriate solvent is added SnCl4 (equimolar) in dichloroethane. A mixture consisting of (2S,3R,4R,5R)-5-((2S,5S)-2-azido-6-(tert-butoxy)-5-(4-methylphenylsulfonamido)-6-oxohexyl)tetrahydrofuran-2,3,4-triyl triacetate (limiting reagent, prepared in the manner of Rapoport et. al. as 25β) is added and the mixture stirred at room temperature for 16 hours. The mixture is partitioned between ethyl acetate and 0.5N Na2HPO4 and the organics washed with brine, dried and evaporated. The residue is chromatographed on silica gel to obtain the title intermediate.
Reaction SMILES: [C:1]1([CH:7]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:8]2[CH2:13][CH2:12][C:11](=[N:14]O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[C:1]1([CH:7]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:8]2[CH2:9][CH2:10][CH:11]([NH2:14])[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ON=C1CCC(C(c2ccccc2)N2CCCCC2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NC1CCC(C(c2ccccc2)N2CCCCC2)CC1
Reaction time: 4 h

Procedure:
A solution of 4-(phenylpiperidin-1-yl-methyl)cyclohexanone oxime (1.60 g, 5.6 mmol) in absolute tetrahydrofuran (20 ml) was added dropwise at 60° C., under argon, to a suspension of lithium aluminium hydride (425 mg, 11.2 mmol) in absolute tetrahydrofuran (50 ml), and stirring was carried out for 4 h at that temperature. After cooling, water (2 ml) and 4 N sodium hydroxide solution (0.5 ml) were added dropwise. The suspension was filtered, and the filtrate was dried over sodium sulfate and concentrated in vacuo.
Reaction SMILES: [Br:1]C1N(C2N=C(I)N=C(N)C=2N=1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O.[C:22]([O:25][C@@H:26]1[C@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@@H:29]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[O:28][C@@:27]1(Br)[N:40]1[C:49]2[N:48]=[C:47]([I:50])[N:46]=[C:44]([NH2:45])[C:43]=2[N:42]=[CH:41]1)(=[O:24])[CH3:23]>>[C:22]([O:25][C@@H:26]1[C@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@@H:29]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[O:28][C@H:27]1[N:40]1[C:49]2[N:48]=[C:47]([I:50])[N:46]=[C:44]([NH2:45])[C:43]=2[N:42]=[C:41]1[Br:1])(=[O:24])[CH3:23]
Reactant: CC(=O)OC[C@H]1O[C@@](Br)(n2cnc3c(N)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Nc1nc(I)nc2c1nc(Br)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: CC(=O)OC[C@H]1O[C@@H](n2c(Br)nc3c(N)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Amination of compound 5 or 6 to obtain the 8-alkylamino-2-iodoadenosines 7–10 was generally as follows: to 8-bromo-2-iodoadenosine (5) or 2′,3′,5′-tri-O-acetyl-2-iodo-bromoadenosine (6) (0.17 mmol) the appropriate alkylamine was added (excess) and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and the product was crystallised from water.
Reaction SMILES: [C:1]([C:9]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:10]=1[C:11]([N:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH3:14])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].Cl>CO.O1CCOCC1>[CH3:25][O:24][C:21]1[CH:20]=[C:10]2[C:9]([C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:15]([C:16]([O:18][CH3:19])=[O:17])[N:13]([CH3:14])[C:11]2=[O:12])=[CH:23][CH:22]=1
Reactant: COC(=O)CN(C)C(=O)c1cc(OC)ccc1C(=O)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2)c2ccc(OC)cc2c(=O)n1C
Temperature: 25 °C

Procedure:
The amide 4 from the previous step was dissolved in methanol (10 ml) and treated with 25% NaOMe in methanol (1 ml). The resulting yellow mixture was then heated at 65 C for 1 h. After cooling to room temperature the reaction mixture was acidified with 1M HCl in dioxane. The resulting mixture was filtered to remove NaCl. The filtrate was concentrated and the residue purified by automated flash chromatography.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([C:6]#[CH:7])[CH2:3][CH2:4][OH:5].[Cl:9][C:10]1[CH:15]=[CH:14][C:13](O)=[CH:12][CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([O:5][CH2:4][CH2:3][C:2]([CH3:8])([CH3:1])[C:6]#[CH:7])=[CH:12][CH:11]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: C#CC(C)(C)CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C#CC(C)(C)CCOc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
To a solution of 5.0 g (44.6 mmol) of 3,3-dimethyl-4-pentyn-1-ol and 5.7 g (44.6 mmol) of 4-chlorophenol in 125 ml of tetrahydrofuran cooled to 0° C. is added 11.7 g (44.6 mmol) of triphenyl phosphine followed by 7.8 g (7.0 ml, 44.6 mmol) of diethyl azodicarboxylate. The reaction mixture is allowed to warm to room temperature and stirred overnight. The solvent is evaporated and the residue triturated with hexane. The solid is filtered, washed with hexane and the resulting filtrate evaporated. The residue is subjected to flash chromatography (silica gel) using hexane as eluting solvent to afford 5.0 g of colorless crystalline solid: m.p. 42°-45° C.; NMR (CDCl3) δ1.3 (6H, s), 1.9 (2H, t, J=6.5 Hz), 2.12 (1H, s), 4.15 (2H, t, J=6.6 Hz), 6.8 (2H, d, J=9.0 Hz), 7.2 (2H, d, J=9.0 Hz).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:21][CH3:22]>CC(C)=O>[CH2:21]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1)[CH3:22]
Reactant: CCI
Reactant: Ic1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN1CCN(c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 21 h
Yield: 84.9 %

Procedure:
To a stirred mixture of 1-(4-iodophenyl)piperazine (5.76 g, 20 mmol) and K2CO3 (5.44 g, 40 mmol) in acetone (200 mL) was added iodoethane (2.58 mL, 32 mmol) dropwise over 1 min. After addition, the resulting mixture was stirred at rt for 21 h. The resulting precipitate was filtered off and rinsed with EtOAc (2×60 mL). The filtrate was concentrated to dryness to give a whiteish yellow solid. Trituration with MeOH (10 mL) and H2O (250 mL), followed by suction filtration (rinsed with H2O) gave the title compound as a yellow solid (5.37 g, 85%) after drying. 1H NMR (400 MHz, DMSO-d6) δ 7.46 (d, J=7.6 Hz, 2H), 6.76 (d, J=8.0 Hz, 2H), 3.13-3.07 (m, 4H), 2.48-2.43 (m, 4H), 2.34 (q, J=7.2 Hz, 2H), 1.01 (t, J=7.2 Hz, 3H); MS ESI 317.0 [M+H]+, calcd. for [C12H171N2+H]+ 317.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Br-].[F:28][C:29]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:30]=1[CH2:31][Zn+]>C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:31][C:30]5[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:29]=5[F:28])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Fc1ccc(C[Zn+])c(F)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: [Br-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Cc5ccc(F)cc5F)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2,4-difluoro-benzylzinc bromide following a procedure analogous to that described in Step 6 of Intermediate 1; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II) dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 9): tR=0.91 min; Mass spectrum (ESI+): m/z=491 [M+Na]+.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=1.[CH:21](OC)=[O:22]>C1COCC1.Cl>[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[C:19]=1[CH:21]=[O:22]
Reactant: COC=O
Reactant: Clc1cncc(Cl)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1c(Cl)cncc1Cl
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (1.6M in hexanes, 9.3 ml, 14.9 mmol) was added dropwise at 0° C. to a solution of diisopropylamine (1.95 ml, 14.9 mmol) in THF (30 ml). After 15 min. at 0° C., the solution was cooled to −78° C. and 3,5-dichloropyridine (2.0 g, 13.5 mmol) was added. After 1 h, methyl formate (0.92 ml) was added and the mixture warmed to room temperature over 2 h, diluted with 1N hydrochloric acid and extracted twice with ethyl acetate. The extracts were washed with brine, dried over sodium sulphate and evaporated to give a yellow oil which solidified, m.p. 110-111° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:19]([Mg]Br)[CH2:20][CH3:21]>C1COCC1.CCOCC>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[CH:4][N:3]=[C:2]3[CH2:19][CH2:20][CH3:21])=[CH:13][CH:14]=1
Reactant: Fc1ccc(-c2ccc3ncnc(Cl)c3c2)cc1
Reactant: CCC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCc1ncnc2ccc(-c3ccc(F)cc3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of 4-chloro-6-(4-fluorophenyl)-quinazoline (258 mg, 1 mmol) and Fe(acac)3 (17 mg, 0.05 mmol) in THF (5 ml) was added n-propyl magnesium bromide (600 ul of 2M THF solution). The reaction was stirred at RT for 1 hour at RT then diluted with ether (5 ml) and quenched with 3 drops 2N HCl. The mixture was further diluted with ether and extracted with H2O. The aqueous layer was neutralized with a saturated aqueous NaHCO3 solution and extracted 3× with ether. The combined organics were washed once with NaHCO3 and once with a saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by column chromatography on SiO2 using EtOAc/hex (10-30% EtOAc) to give the title compound (115 mg, 43% yield) which was characterized by mass spectrum as follows: (m/z): 267 ([M+H]) 100).