Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[C:12]1([NH:11][C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: Clc1ncnc2[nH]ccc12
Solvent: c1ccncc1
Product: c1ccc(Nc2ncnc3[nH]ccc23)cc1
Yield: 16 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 16% yield from 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (1.0 eq) and aniline (5.0 eq) in pyridine. (M.P. 234-236° C.; GC-MS: 211(MH+); anal. RP18-HPLC RT: 3.11 min.)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.O>COCCOC>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:16])[CH:10]([CH2:25][C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:29])[F:30])=[CH:28][CH:27]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)c1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
To a solution of ethyl 3-(3,4-difluorophenyl)-3-oxopropionate (9 g, 39.4 mmol) in 1,2-dimethoxyethane (50 ml) was added sodium hydride (60% in oil, 1.58 g, 39.4 mmol) under ice-cooling and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 4-trifluoromethylbenzyl bromide (9.43 g, 39.4 mmol) in 1,2-dimethoxyethane (50 ml) and the reaction solution was stirred at room temperature for 3 hrs. The reaction solution was poured into water (200 ml) and extracted with ethyl acetate (200ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:hexane=1:1) and recrystallized from diisopropyl ether-hexane to give ethyl 3-(3,4-difluorophenyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate (10.9 g, 71%).
Reaction SMILES: [Li+].[BH4-].[Br:3][C:4]1[C:13]([Cl:14])=[CH:12][C:11]([N:15]([C:20]2[C:39]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][C:23]3[C:24]([C:34](=[O:37])[NH:35][CH3:36])=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[O:26][C:22]=3[CH:21]=2)[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:10][C:5]=1[C:6](OC)=[O:7].CCN(C(C)C)C(C)C.[CH2:52](Cl)[O:53][CH3:54].C([O-])(O)=O.[Na+]>O1CCCC1.CO>[Br:3][C:4]1[C:5]([CH2:6][O:7][CH2:52][O:53][CH3:54])=[CH:10][C:11]([N:15]([C:20]2[C:39]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][C:23]3[C:24]([C:34]([NH:35][CH3:36])=[O:37])=[C:25]([C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)[O:26][C:22]=3[CH:21]=2)[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:13]=1[Cl:14]
Reactant: COCCl
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(Cl)c(Br)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(Cl)c(Br)c(COCOC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
LiBH4 (2.85 ml, 5.71 mmol) solution (2M in THF) was added dropwise to a 0° C. solution of methyl 2-bromo-3-chloro-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate (1.24 g, 1.90 mmol) in Tetrahydrofuran (THF) (13.5 ml) and Methanol (1.3 ml). The reaction mixture was stirred at 0° C. for 1 h and quenched with 1M NaOH. The reaction mixture was diluted with EtOAc and water. The organic layer was washed with brine, dried (Na2SO4), filtered and evaporated. The crude alcohol was taken up in THF (14 mL). DIEA (1.0 ml, 5.71 mmol) and MOM-Cl (0.36 ml, 4.76 mmol) were added and the reaction mixture was stirred at 50° C. overnight. Sat′d NaHCO3 was added and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered, evaporated and purified by silica gel chromatography (0-50% EtOAc/hexanes) to obtain the title compound (1.08 g, 85%) as a white foam. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.86-7.93 (m, 2H), 7.61 (s, 1H), 7.50 (d, 1H), 7.49 (s, 1H), 7.42 (d, J=2.83 Hz, 1H), 7.18-7.25 (m, 2H), 5.80 (br. s., 1H), 4.73 (s, 2H), 4.62 (s, 2H), 3.38 (s, 3H), 3.27 (s, 3H), 3.01 (d, J=4.98 Hz, 3H), 2.05-2.14 (m, 1H), 0.75-1.11 (m, 3H), 0.58 (br. s., 1H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19][CH2:20][C:21](=O)[NH2:22])[C:15]([OH:17])=O)[N:13]=1)=[O:7].[NH2:24][CH:25]1[C:43](=[O:44])[N:27]2[C:28]([C:40]([OH:42])=[O:41])=[C:29]([CH2:32][S:33][C:34]3[N:38]([CH3:39])[N:37]=[N:36][N:35]=3)[CH2:30][S:31][C@H:26]12.Cl>O1CCCC1.CC(C)=O.C(OCC)(=O)C.C(N(CC)CC)C.CN(C)C=O>[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19][CH2:20][C:21]#[N:22])[C:15]([NH:24][CH:25]2[C:43](=[O:44])[N:27]3[C:28]([C:40]([OH:42])=[O:41])=[C:29]([CH2:32][S:33][C:34]4[N:38]([CH3:39])[N:37]=[N:36][N:35]=4)[CH2:30][S:31][C@H:26]23)=[O:17])[N:13]=1)=[O:7]
Reactant: NC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: Cl
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC#N)c3csc(NC=O)n3)[C@H]2SC1
Yield: 51.1 %

Procedure:
A solution of phosphoryl chloride (3.68 g.), N,N-dimethylformamide (1.75 g.) and tetrahydrofuran (4 ml.) was stirred at -5° to -10° C. for 30 minutes and added to a suspension of 2-(2-formamidothiazol-4-yl)-2-carbamoylmethoxyiminoacetic acid (syn isomer, 2 g.) in tetrahydrofuran (16 ml.). The mixture was stirred at the same temperature to give an activated acid solution. On the other hand, a suspension of 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (3.62 g.) in 50% aqueous acetone (36 ml.) was adjusted to pH 7.5 with triethylamine. The activated acid solution was added dropwise to the above solution at 0° to -5° C. while keeping at pH 7.5 to 8.0 with triethylamine and stirred at the same temperature for 30 minutes. Ethyl acetate (100 ml.) was added to the resultant solution and adjusted to pH 2.5 with 10% hydrochloric acid. After filtration, the filtrate was extracted with ethyl acetate (100 ml.) twice. The extracts were washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether and the precipitates were collected by filtration to give 7-[2-(2-formamidothiazol-4-yl)-2-cyanomethoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 2.12 g.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([S:29]([CH3:31])=[O:30])[CH:4]=1)#[N:2].C(C1C=CC([C@@H]2C(C#N)=C(C)N(C3C=CC=C(C(F)(F)F)C=3)C(=O)N2)=C([S@](C)=O)C=1)#N.[H-].[Na+].[CH3:65][S:66](Cl)(=[O:68])=[O:67].[Cl-].[NH4+]>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[S:66]([CH3:65])(=[O:68])=[O:67])=[C:5]([S@:29]([CH3:31])=[O:30])[CH:4]=1)#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Agent: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2[S@](C)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2[S@](C)=O)N(S(C)(=O)=O)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47 %

Procedure:
The reaction was carried out under argon. The diastereomer mixture of (RS,4S)-4-[4-cyano-2-(methylsulfinyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile and (SS,4S)-4-[4-cyano-2-(methylsulfinyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (444.4 mg, 1000 μmol) was initially charged in THF (10 ml), and sodium hydride (60% in mineral oil; 56 mg, 1400 μmol) was added at 0° C. The mixture was warmed to RT and stirred for 20 min. A solution of methanesulfonyl chloride (160.4 mg, 1400 μmol; 1.4 eq.) in THF (5 ml) was then slowly added dropwise. After a reaction time of 16 h, more methanesulfonyl chloride (54 mg, 467 μmol; 0.47 eq.) was added and the mixture was stirred at RT for another 60 min. Saturated ammonium chloride solution (50 ml) was added, and the reaction mixture then extracted with ethyl acetate (3×30 ml). The combined organic phases were dried over solid sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→80:20). This gave the title compound as a colorless solid (245 mg, 47% of theory).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[K+].[CH3:13]I>CC(C)=O.C(OCC)(=O)C>[CH3:13][N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH2:1]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Cn1c(N)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-aminobenzimidazole (3.0 g, 0.0225 mol) in acetone (30 ml) was added KOH (6.32 g, 0.112 mol) followed by methyl iodide (3.51 g, 0.025 mol) and stirred at room temperature for 10 min. The reaction mixture was diluted with ethyl acetate and the organic layer washed with water, brine and dried over anhydrous Na2SO4 to afford crude residue which was column purified to yield the desired product: 1H NMR (300 MHz, DMSO-d6) δ 3.47 (s, 3H), 6.34 (br s, 2H), 6.82-6.92 (m, 2H), 7.06-7.09 (m, 2H); ESI-MS (m/z) 148.49 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[F:21][C:22]([F:39])([F:38])[CH:23]([C:28]1[CH:29]=[CH:30][C:31]([O:36][CH3:37])=[C:32]([CH:35]=1)[CH:33]=O)[C:24]([F:27])([F:26])[F:25].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:2]([NH:1][CH2:33][C:32]2[CH:35]=[C:28]([CH:23]([C:22]([F:39])([F:21])[F:38])[C:24]([F:25])([F:26])[F:27])[CH:29]=[CH:30][C:31]=2[O:36][CH3:37])[C@@H:3]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Reactant: COc1ccc(C(C(F)(F)F)C(F)(F)F)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C(C(F)(F)F)C(F)(F)F)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Yield: 103.7 %

Procedure:
To a stirred and ice-cooled solution of Compound 12 (100 mg, 0.3 mmol) and Compound 9 (100 mg, 0.3 mmol) in dry CH2Cl2 (10 ml) was added NaBH(OAc)3 (210 mg, 1 mmol) in one portion. After the mixture was stirred at room temperature for 20 hours. The mixture was poured into NaHCO3 aq., and extracted with CH2Cl2. The combined extracts were dried (Na2SO4), and concentrated in vacuo to give Compound 13 as a yellow oil (170 mg).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[O:29]1[C:33]2([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:32][CH2:31][CH2:30]1>>[CH3:28][N:4]1[C:3]([CH2:2][N:36]2[CH2:37][CH2:38][C:33]3([O:29][CH2:30][CH2:31][CH2:32]3)[CH2:34][CH2:35]2)=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1COC2(C1)CCNCC2
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC4(CCCO4)CC3)n(C)c2n1

Procedure:
Alternatively, following General Procedure E for Displacement of alkyl bromide with amines, 4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine and 1-oxa-8-azaspiro[4.5]decane were reacted to give 370.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N+:3]=1[O-].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:17]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH2:12][OH:17])[N:3]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1cc(C)[n+]([O-])c(Cl)c1
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)nc(CO)c1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 66 %

Procedure:
To a stirring solution of 7.61 g (37.8 mmol) of 2-chloro-4-(methoxycarbonyl)-6-methylpyridine 1-oxide in 60 mL of CH2Cl2 was added 24 mL of trifluoroacetic anhydride slowly. The solution was stirred at r.t. for 15.5 h. The temperature was increased to 50° C., and the solution was stirred at 50° C. for 5.5 h and then concentrated. The crude residue was dissolved in 50 mL of THF, and 7% NaHCO3 solution (aqueous) was added to a pH=8. The solution was stirred at r.t. for about 40 h, and EtOAc was added. The aqueous layer was extracted with EtOAc (3×), and the combined extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (50% EtOAc/hexanes) provided 4.99 g of methyl 2-chloro-6-(hydroxymethyl)isonicotinate as a pale yellow solid in 66% yield.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]4[N:18]=[CH:17][N:16]([C:19]5[CH:20]=[C:21]([NH2:33])[CH:22]=[C:23]([C:25]6[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=6[F:32])[CH:24]=5)[C:13]4=[N:14][CH:15]=3)[N:7]=[N:6]2)[CH2:3][CH2:2]1.[CH:34]1([C:37](O)=[O:38])[CH2:36][CH2:35]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>[CH:1]1([CH2:4][N:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]4[N:18]=[CH:17][N:16]([C:19]5[CH:20]=[C:21]([NH:33][C:37]([CH:34]6[CH2:36][CH2:35]6)=[O:38])[CH:22]=[C:23]([C:25]6[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=6[F:32])[CH:24]=5)[C:13]4=[N:14][CH:15]=3)[N:7]=[N:6]2)[CH2:2][CH2:3]1
Reactant: O=C(O)C1CC1
Reactant: Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn(CC5CC5)nn4)cnc32)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn(CC5CC5)nn4)cnc32)c1)C1CC1
Reaction time: 16 h
Yield: 51 %

Procedure:
To a solution of 5-(6-(1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)-3H-imidazo-[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-amine (50 mg, 0.11 mmol) in DMF was added cyclopropanecarboxylic acid (11 mg, 0.13, mmol, 1.2 eq.) followed by HATU (91 mg, 0.24 mmol, 2.0 eq.) and DIPEA (43 mg, 0.33 mmol, 3.0 eq). The mixture was stirred for 16 h and quenched extracted as in Example 1(d). The solvent was distilled off to afford the crude residue which was purified by column chromatography to give the product in 51% yield (25 mg). 1H NMR (300 MHz, DMSO): δ 10.6 (s, 1H) 8.99 (d, 2H), 8.88 (d, 1H), 8.62 (d, 1H), 8.31 (d, 1H), 7.92 (d, 1H), 7.76-7.71 (m, 2H), 7.47-7.40 (m, 1H), 7.29-7.24 (m, 1H), 4.33-4.30 (d, 2H), 3.64-3.62 (m, 2H), 3.12-3.09 (m, 2H), 1.87-1.83 (m, 1H), 0.63-0.61 (t, 2H), 0.49-0.48 (t, 2H); LC-MS (ESI): Calculated mass: 511.5; Observed mass: 511.8 [M+H]+ (rt: 1.63 min).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:3]=1.C([N-]C(C)C)(C)C.[Li+].[I:27]Cl.ClCCl>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([I:27])[N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:3]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1ncn2C
Reactant: ClI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(I)n2C
Temperature: -78 °C
Yield: 40.5 %

Procedure:
To (S)-4-(2-chloro-9-methyl-9H-purin-6-yl)-3-methylmorpholine (750.0 mg, 2.80 mmol) in anhydrous THF (16 mL) at −78° C. under N2 was added freshly prepared lithium diisopropylamide in THF (2.0 eq). The resultant wine colored reaction was stirred at −78° C. After 1 h iodine monochloride in dichloromethane (4.2 mL, 4.2 mmol, 1.0 M, 1.5 eq.) was added and stirred at RT for 16 h. The reaction mixture was quenched with saturated aqueous sodium thiosulfate. Volatile solvent was then evaporated in vacuo, and the crude was diluted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water and brine, then dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was purified by column chromotagraphy (Si-PPC, gradient 0 to 100% ethyl acetate in hexane) to give the desired compound as a solid (446.4 mg, 40.5%). 1H NMR (CDCl3, 400 MHz) δ ppm 5.28 (broad s, 2H), 3.99 (m, 1H), 3.75 (m, 2H), 3.67 (s, 3H), 3.59 (m, 1H), 3.49 (broad s, 1H), 1.38 (d, 3H); LC-MS m/z (method A)=394/396 [M+H]+, RT=1.92 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[C:7]([C:16](O)=[O:17])[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.B>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[C:7]([CH2:16][OH:17])[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: O=C(O)c1cc2ccc(Br)cc2c2ccccc12
Agent: B
Solvent: C1CCOC1
Product: OCc1cc2ccc(Br)cc2c2ccccc12
Temperature: 25 °C
Reaction time: 19 h
Yield: 99.8 %

Procedure:
A solution of 3-bromo-phenanthrene-9-carboxylic acid (6.27 g, 20.8 mmol) in 100 ml of THF was cooled to 0° C. and a solution of borane in THF (1.0M, 25 ml, 25 mmol) was added dropwise. The cooling bath was removed, and the solution was stirred at room temperature for 19 hours and was then quenched by the cautious addition of methanol (25 ml). The solution was evaporated to dryness in vacuo and the residue was dissolved in methanol --CH2Cl2 (1:1) and again evaporated. After one repetition of this dissolution-evaporation process, 5.96 g (100%) of the title compound was obtained as a brown solid which was used in the next reaction without purification.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH2:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:13][C:14](=[O:23])[C@H:15]([CH2:17][C:18]1[N:22]=[CH:21][NH:20][CH:19]=1)[NH2:16].CO.[OH-].[Na+].Cl>C1COCC1.C(OCC)(=O)C.O>[CH2:1]([NH:8][C:9]([NH2:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C@H:15]([C:14]([OH:23])=[O:13])[CH2:17][C:18]1[N:22]=[CH:21][NH:20][CH:19]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: Cl
Agent: NC(=O)NCc1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: N[C@@H](Cc1c[nH]cn1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
To a solution of the ester from Step 1 (1.9 g, 3.5 mmol) in THF:methanol (10 mL each) and water (2 mL) was added sodium hydroxide (0.4 g, 10 mmol), and the solution was stirred overnight at room temperature. The solution was added to 1N HCl:ethyl acetate (30 mL each). The organic layer was separated and washed with 1N HC1, brine, dried over MgSO4, and concentrated. The product was obtained as a white foam (0.53 g, 53%); ES-MS 289 (m+1).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH2:3]1.N>[Ni].O>[CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH2:10][NH2:11])[CH2:3]1
Reactant: C[C@@H]1CN(c2ccccc2C#N)CCN1
Agent: [Ni]
Agent: N
Solvent: O
Product: C[C@@H]1CN(c2ccccc2CN)CCN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
A mixture of 2-((R)-3-methyl-piperazin-1-yl)-benzonitrile (542 mg, 2.69 mmol), Raney Nickel (3 mL of a slurry in water), ammonia (15 mL, 2M solution in EtOH) was evacuated and flushed with H2, then stirred at room temperature for 3 h. The reaction mixture was filtered through celite, rinsed with MeOH, concentrated and dried in vacuum to afford 2-((R)-3-methyl-piperazin-1-yl)-benzylamine (526 mg) as an orange viscous oil. m/z (M+1) 206.29.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[N:10]=2)[CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[F:24])[NH2:20]>C(O)CCC>[NH2:15][C:11]1[N:10]=[C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:20][C:19]3[CH:21]=[CH:22][C:23]([F:24])=[C:17]([Cl:16])[CH:18]=3)[N:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cccc(Nc2cc(Cl)ncn2)n1
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: CCCCO
Product: Nc1cccc(Nc2cc(Nc3ccc(F)c(Cl)c3)ncn2)n1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 232.9 %

Procedure:
A mixture of N-(6-chloro-pyrimidin-4-yl)-pyridine-2,6-diamine (1.000 g, 4.512 mmol) and 3-chloro-4-fluoroaniline (1.380 mmol) in 10 mL of n-butanol in a sealed vial was heated at 120° C. for 24 h. The sample was cooled, was concentrated to remove most of the n-butanol, and was then diluted with EtOAc and sat. NaHCO3 solution. The sample was stirred at room temperature for 30 min and was filtered. The solid was washed with fresh EtOAc and water and vacuum dried to give 1.063 g of N-(6-amino-pyridin-2-yl)-N′-(3-chloro-4-fluorophenyl)-pyrimidine-4,6-diamine (Int-E) as tan solid. MS (ES) (m/z) 331/333 (M+1, 100/65%). TLC (SiO2, 10% MeOH in CHCl3): Rf 0.25.
Reaction SMILES: C(Cl)Cl.[C:4]1([OH:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1(C)C=CC=CC=1>[OH:10][C:4]1[CH:9]=[CH:8][C:7]([C:4]2([C:7]3[CH:8]=[CH:9][C:4]([OH:10])=[CH:5][CH:6]=3)[CH2:9][CH2:8][CH:7]([C:7]3[CH:8]=[CH:9][C:4]([OH:10])=[CH:5][CH:6]=3)[CH2:6][CH2:5]2)=[CH:6][CH:5]=1
Reactant: Oc1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Oc1ccc(C2CCC(c3ccc(O)cc3)(c3ccc(O)cc3)CC2)cc1

Procedure:
After heating, the thick paste was diluted with 450 mL toluene, cooled in an ice/water bath and isolated by filtration. It was treated with portions of toluene and methylene chloride until the amount of residual phenol was less than 1 area percent by HPLC analysis. The solid was isolated by filtration and was 90% pure by HPLC analysis, product weight, 57.7 g (76%).
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]([CH3:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13].CN(CCN(C)C)C.[Br:29]C(Cl)(Cl)C(Cl)(Cl)Br>C1COCC1>[OH:11][CH:4]1[C:5]2[C:10](=[C:9]([Br:29])[CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[C:12]([CH3:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13]
Reactant: CC(C)(c1ccccc1)N1C(=O)c2ccccc2C1O
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: CC(C)(c1ccccc1)N1C(=O)c2c(Br)cccc2C1O
Yield: 85 %

Procedure:
In a similar manner to Step 3 of Example 16, 3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (2.00 g, 7.48 mmol) was dissolved in THF (80 mL), and the solution was treated with TMEDA (2.50 mL, 16.5 mmol), sec-butyl lithium-hexane solution (0.99 mol/L, 16.6 mL, 16.5 mmol) and 1,2-dibromotetrachloroethane (2.92 g, 8.98 mmol), followed by purification by flash column chromatography (chloroform/methanol=95/5 to 90/10) to obtain 3-hydroxy-7-bromo-2-(1-methyl-1-phenylethyl)isoindolinone (2.20 g, yield 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl.N[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[OH:19].C[Si](C)(C)N[Si](C)(C)C.[Na].BrCC1CCCCO1>CC(O)C.[Ni](I)I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:15][CH:16]2[CH2:17][CH2:18][CH2:13][CH2:14][O:19]2)=[CH:4][CH:3]=1
Reactant: NC1CCCCC1O
Reactant: OB(O)c1ccc(Cl)cc1
Agent: I[Ni]I
Agent: BrCC1CCCCO1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CC(C)O
Product: Clc1ccc(CC2CCCCO2)cc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a stirred mixture of (4-chlorophenyl)dihydroxyborane (524.0 mg, 3.351 mmol), 2-aminocyclohexanol hydrochloride (42 mg, 0.28 mmol) and nickel iodide (87.3 mg, 0.279 mmol) in i-PrOH (10.00 mL) was added sodium hexamethyldisilazane (1.075 g, 5.864 mmol) at 0° C. Then the mixture was stirred at rt for 5 min before, 2-(bromomethyl)tetrahydro-2-H-pyran (500.00 mg, 2.79 mmol) was added by syringe. The resulting mixture was then stirred at 60° C. for 5 h. The solvent was then removed under reduced pressure and the resulting residue was purified by a flash chromatography(5% AcOEt in hexane). 1H NMR (400 MHz, MeOD) δ 1.20-1.34 (m, 1H), 1.43-1.62 (m, 4H), 1.75-1.85 (m, 1H), 2.61-2.80 (m, 2H), 3.36-3.54 (m, 2H), 3.85-3.95 (m, 1H), 7.12-7.32 (m, 4H).