Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][C:17](O)=[O:18])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.O/[N:21]=[C:22](/[C:24]1[CH:29]=[CH:28][NH:27][C:26](=[O:30])[CH:25]=1)\[NH2:23].C(N=C=NC(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(#N)C.CCOC(C)=O>[F:8][C:6]1[CH:5]=[C:4]([C:9]2([CH2:15][CH2:16][C:17]3[O:18][N:23]=[C:22]([C:24]4[CH:29]=[CH:28][NH:27][C:26](=[O:30])[CH:25]=4)[N:21]=3)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: N/C(=N\O)c1cc[nH]c(=O)c1
Reactant: O=C(O)CCC1(c2cc(F)cc(F)c2)CCCCC1
Agent: CC(C)N=C=NC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=c1cc(-c2noc(CCC3(c4cc(F)cc(F)c4)CCCCC3)n2)cc[nH]1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 16.6 %

Procedure:
To a solution of 3-(1-(3,5-difluorophenyl)cyclohexyl)propanoic acid (20 mg, 0.075 mmol) and (Z)—N′-hydroxy-2-oxo-1,2-dihydropyridine-4-carboximidamide (11.42 mg, 0.075 mmol) in acetonitrile (1 mL) was added N,N′-diisopropylcarbodiimide (0.013 mL, 0.082 mmol), and the mixture was stirred for 2.5 hrs at room temp. TBAF (0.112 mL, 0.112 mmol) was added and the mixture was stirred for 40 hrs at room temp. After addition of EtOAc the mixture was washed with water and brine, dried over Na2SO4 and evaporated to give an oily residue which was purified by Combiflash (12 g silica gel). Elution with 7:93 MeOH—CH2Cl2 gave a white solid residue which was repurified by prep HPLC to give 4-(5-(2-(1-(3,5-difluorophenyl)cyclohexyl)ethyl)-1,2,4-oxadiazol-3-yl)pyridin-2(1H)-one (4.8 mg, 16.64% yield) as a white solid. HPLC: tR=3.95 min, Waters Sunfire C18 4.6×50 mm, 4 min gradient, Detection Wave length 220 nm, Starting solvent: 10% aq. MeOH-0.1% TFA; Final solvent: 90% aq. MeOH-0.1% TFA. LC/MS: m/e 386.13 (M+H)+. 1H NMR (400 MHz, CDCl3): δ ppm 7.45 (1 H, d), 7.24 (1H, s), 6.84-6.88 (3 H, m), 6.65 (1H, m), 2.56-2.6 (2 H, m), 2.05-2.07 (4 H, m), 1.23-1.63 (8 H, m).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][OH:14])[O:9]2)=[CH:4][CH:3]=1.[C:15](N1C=CN=C1)(N1C=CN=C1)=[O:16]>C1COCC1>[OH:14][CH2:13][CH:8]1[O:9][C:10]2[C:5](=[CH:4][CH:3]=[C:2]3[NH:1][C:15](=[O:16])[NH:12][C:11]3=2)[CH2:6][CH2:7]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc2c(c1N)OC(CO)CC2
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc3c(c2[nH]1)OC(CO)CC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
To a solution of (7,8-diamino-chroman-2-yl)-methanol (194 mg, 1 mmol) in THF (50 mL) was added 1,1′-carbonyldiimidazole (CDI) (81 mg, 1.5 mmol). The resulting solution was stirred for 8 hours at room temperature and the solvent was evaporated in vacuo to a residue. The residue was purified by chromatography (50% CH2Cl2-hexanes) to give 139 mg (63% yield) of the title compound: mp 240° C.; 1H NMR (400 MHz, CDCl3) δ1.65 (m, 1H), 2.01 (m, 1H), 2.70 (m, 2H), 3.55 (m, 1H), 3.63 (m, 1H), 4.05 (m, 1H), 4.68 (bs, 1H, OH), 6.41 (d, J=7.9, 1H), 6.60 (d, J=7.9, 1H), 10.36 (s, 1H), 10.37 (s, 1H); IR: 3250, 3080, 2980, 1700, 1500, 1210 cm−1; MS 220 [M]+.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([NH:23][CH2:24][C@@H:25]4[CH2:29][CH2:28][CH2:27][O:26]4)[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.[C:30](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[CH3:30][N:21]1[CH2:20][CH2:19][C:17]2[N:18]=[C:13]([NH:12][C:9]3[CH:8]=[CH:7][C:6]([C:5]4[O:1][CH:2]=[N:3][CH:4]=4)=[CH:11][CH:10]=3)[N:14]=[C:15]([NH:23][CH2:24][C@@H:25]3[CH2:29][CH2:28][CH2:27][O:26]3)[C:16]=2[CH2:22]1
Reactant: c1ncc(-c2ccc(Nc3nc4c(c(NC[C@@H]5CCCO5)n3)CNCC4)cc2)o1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(NC[C@@H]3CCCO3)c2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.2 %

Procedure:
(5)-N2-(4-(Oxazol-5-yl)phenyl)-N4-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (120 mg, 0.31 mmol) was dissolved in methanol (3 mL). Acetic acid (0.018 mL, 0.31 mmol) was added followed by formaldehyde (0.023 mL, 0.31 mmol). The reaction mixture was stirred at room temperature for 15 minutes and sodium cyanoborohydride (19.22 mg, 0.31 mmol) MP—CNBH3 was added. The reaction was stirred at room temperature overnight, MP—CNBH3 was filtered off and the solvent was evaporated under reduced pressure. Purification by HPLC gave (S)-6-methyl-N2-(4-(oxazol-5-yl)phenyl)-N4-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (67.0 mg, 48%). MS (ES+) m/z 407.2 (M+H)+
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[C@H:10]([CH:18]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[C@H:10]([CH2:18][N:30]2[CH2:31][CH2:32][CH:27]([C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=3)[CH2:28][CH2:29]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccsc1
Reactant: Fc1ccc(C2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Fc1ccc(C2CCN(C[C@@H]3CN(Cc4ccccc4)C[C@H]3c3ccsc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1.0 g (16.4 mmol) of 1-benzyl-3-(S)-formyl-4-(R)-(3-thienyl)pyrrolidine and 2.94 g (23.4 mmol) of 4-(4-fluorophenyl)piperidine in 50 mL of 1,2-dichlorethane was added 4.96 g (23.4 mmol) of sodium triacetoxyborohydride and the solution was stirred at rt for 16 h. The reaction was poured into 50 mL of saturated NaHCO3 solution and the mixture was extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica, acetone:hexanes, 1:3) to afford the title compound. 1H NMR (CDCl3) δ6.97-7.10 (m, 4H), 3.72 (d, 1H, J=13.1 hz), 3.64 (d, 1H, J=13.0 Hz), 3.11-3.14 (m, 1H); Mass Spectrum (ESI) m/e 435 (M+1); [α]D=−13.3 (c.=0.06, CHCl3)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:17][CH3:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:10]([CH3:15])=[CH:11][CH:12]=[C:13]2[CH3:14])[CH:5]=[CH:6][C:7]=1[O:8][CH2:17][CH3:18]
Reactant: Cc1ccc(C)n1-c1ccc(O)c(Cl)c1
Reactant: CCBr
Product: CCOc1ccc(-n2c(C)ccc2C)cc1Cl

Procedure:
Using the general procedure outlined in EXAMPLE 1, 1-(3-chloro-4-hydroxyphenyl)-2,5-dimethylpyrrole (1.11 g, 5 mmol) and an excess of bromoethane (1.0 mL) reacted to give 1-(3-chloro-4-ethoxyphenyl)-2,5-dimethylpyrrole as a tan solid: 1H NMR (CDCl3, 500 MHz) δ 7.27 (d, 1H), 7.08 (dd, 1H), 6.99 (dd, 1H), 5.89 (s, 2H), 4.18 (q, 2H), 2.04 (s, 6H), 1.53 (t, 3H); MS (ESI) 250 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][S:10]([CH2:13][C:14](O)=O)(=[O:12])=[O:11])=[CH:5][C:4]=1[N+:17]([O-:19])=[O:18].N1CCCCC1.[CH3:26][O:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[C:29]=1C=O>N1C=CC=CC=1>[CH3:26][O:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[C:29]=1/[CH:14]=[CH:13]/[S:10]([CH2:9][C:6]1[CH:5]=[C:4]([N+:17]([O-:19])=[O:18])[C:3]([O:2][CH3:1])=[N:8][CH:7]=1)(=[O:12])=[O:11]
Reactant: COc1cccc(OC)c1C=O
Reactant: COc1ncc(CS(=O)(=O)CC(=O)O)cc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1cccc(OC)c1/C=C/S(=O)(=O)Cc1cnc(OC)c([N+](=O)[O-])c1

Procedure:
A solution of 2-((6-methoxy-5-nitropyridin-3-yl)methylsulfonyl)acetic acid (0.29 g, 1 mmol) in dry pyridine (20 mL) was treated with piperidine (2 mL), followed by 2,6-dimethoxybenzaldehyde (0.17 g, 1 mmol). The mixture was refluxed for 6 h, and evaporated to dryness. The residue was purified by column chromatography using a mixture of EtOAc/PE (1:2, v/v) to yield the titled compound. HR-MS (ESI+) m/z 394.8362; C17H18N2O7S requires 394.0835.
Reaction SMILES: C(O[C:5]1([C:11]#[CH:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)(=O)C.[CH2:13]([CH2:15][NH2:16])[OH:14]>>[C:11]([C:5]1([NH:16][CH2:15][CH2:13][OH:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1)#[CH:12]
Reactant: NCCO
Reactant: C#CC1(OC(C)=O)CCCCC1
Product: C#CC1(NCCO)CCCCC1

Procedure:
This was synthesized in the same manner as in Production Example 18 except that 1-acetoxy-1-ethynylcyclohexane (Production Example 17) and ethanolamine were used.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)=O>CCO>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:7][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: NC(=S)c1ccc(F)cc1
Reactant: Cc1ccc(C(=O)CBr)cc1
Solvent: CCO
Product: Cc1ccc(-c2csc(-c3ccc(F)cc3)n2)cc1
Temperature: 25 °C
Yield: 44.3 %

Procedure:
To a solution of the crude product of 4-fluorothiobenzamide (2.0 g, 12.9 mmol) in EtOH (30 ml) is added 2-bromo-4′ methylacetophenone (2.75 g, 12.9 mmol). The mixture is heated to reflux for 24 hours. The course of the reaction is followed by thin layer chromatography. Upon completion of the reaction the solution is cooled to room temperature and the white precipitate filtered and dried under vacuum to yield 2-(4′-fluorophenyl)-4-(p-tolyl) thiazole (1.54 g, 54%).
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][CH3:6])[CH2:3][OH:4].[C:7]([C:11]1[CH:18]=[CH:17][CH:16]=[C:13]([CH:14]=O)[C:12]=1[OH:19])([CH3:10])([CH3:9])[CH3:8]>CO>[C:7]([C:11]1[CH:18]=[CH:17][CH:16]=[C:13]([CH:14]=[N:1][C@H:2]([CH2:5][CH3:6])[CH2:3][OH:4])[C:12]=1[OH:19])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1cccc(C=O)c1O
Reactant: CC[C@@H](N)CO
Solvent: CO
Product: CC[C@H](CO)N=Cc1cccc(C(C)(C)C)c1O
Yield: 81.9 %

Procedure:
0.98 g of (R)-2-amino-1-butanol and 1.78 g of 3-tertbutylsalicylaldehyde were disolved in 15 ml of methanol to prepare a methanol solution. The methanol solution was heated under reflux over 6 hours to obtain a reaction mixture. The solvent of the mixture was removed by distillation in vacuo to obtain a concentrated solution. The concentrated solution was placed on a silica gel column and eluted with a mixture of hexane and ethyl acetate (hexane:ethyl acetate=3:1) to give 2.04 g of (R)-2-[N-(3-tert-butylsalicylidene)amino]-1-butanol as yellow syrup (yield: 82%).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:12]1[N:17]=[CH:16][C:15]([CH2:18][N:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[CH:14][C:13]=1[C:32]1[N:40]=[C:39]([CH3:41])[N:38]=[C:37]2[C:33]=1[N:34]=[CH:35][N:36]2[CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][O:43]1.[NH2:48][C:49]1[CH:50]=[N:51][C:52]([O:55][CH3:56])=[CH:53][CH:54]=1.O1CCCC1>>[CH3:56][O:55][C:52]1[N:51]=[CH:50][C:49]([NH:48][C:12]2[N:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:14][C:13]=2[C:32]2[N:40]=[C:39]([CH3:41])[N:38]=[C:37]3[C:33]=2[N:34]=[CH:35][N:36]3[CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)=[CH:54][CH:53]=1
Reactant: Cc1nc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)cnc2F)c2ncn(C3CCCCO3)c2n1
Reactant: COc1ccc(N)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Nc2ncc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Reaction time: 1 h
Yield: 75 %

Procedure:
LiHMDS (1.0 M in THF, 3.75 mL, 3.75 mmol) was slowly added to a stirred mixture of tert-butyl 4-((6-fluoro-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)methyl)piperazine-1-carboxylate (0.6397 g, 1.250 mmol) and 3-amino-6-methoxypyridine (Aldrich, St. Louis, Mo.; 186 mg, 1.50 mmol) in tetrahydrofuran (10 mL, 1.250 mmol) at 0° C. and the mixture was stirred at the same temperature for 1 h before being quenched with NH4Cl(aq) (10 mL) and water (10 mL). The separated aqueous layer was extracted with EtOAc(3×15 mL) and the combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by flash column chromatograph (hexanes to 50% ethyl acetate/hexanes) to give tert-butyl 4-((6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)methyl)piperazine-1-carboxylate (0.577 g, 0.937 mmol, 74.9% yield) as a yellow foam. LCMS (API-ES) m/z 616 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[S:22](=[O:25])(=[O:24])[NH2:23])=[CH:12][CH:11]=2)[C:7]2[CH:26]=[C:27]([C:31]3[N:35]([CH3:36])[C:34]4[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=4[N:32]=3)[CH:28]=[C:29]([CH3:30])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[CH:41]1([N:47]=[C:48]=[O:49])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>N1C=CC=CC=1>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[S:22]([NH:23][C:48]([NH:47][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)=[O:49])(=[O:24])=[O:25])=[CH:14][CH:15]=2)[C:7]2[CH:26]=[C:27]([C:31]3[N:35]([CH3:36])[C:34]4[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=4[N:32]=3)[CH:28]=[C:29]([CH3:30])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: O=C=NC1CCCCC1
Reactant: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Solvent: c1ccncc1
Product: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)NC2CCCCC2)cc1

Procedure:
0.275 g of 4'-[(2-n-Propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-sulphamoyl-biphenyl is refluxed for 20 hours in 2 ml of pyridine with 0.5 ml of cyclohexylisocyanate. The mixture is then evaporated down, the residue is suspended in acetone and the insoluble solid is filtered off. After the filtrate has been evaporated down the crude produce thus obtained is purified by column chromatography over silica gel (eluant: dichloromethane/ethanol=50:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.C(OCC)C>CN(C)C=O>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:12]3([S:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)(=[O:10])=[O:11])[S:16][C:15](=[O:17])[NH:14][C:13]3=[O:18])=[CH:22][CH:23]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc(S(=O)(=O)C2SC(=O)NC2=O)cc1
Reactant: Clc1ccc(-c2ccc(CBr)cc2)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)C2(Cc3ccc(-c4ccc(Cl)cc4)cc3)SC(=O)NC2=O)cc1

Procedure:
Prepared analogously to Example 9 from from 5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione and 4′-bromomethyl-4-chlorobiphenyl in N,N-dimethylformamide. Trituration with diethyl ether provided an off-white solid. 1H NMR: δ 7.99 (s, 1H), 7.93 (dm, J=9.0 Hz, 2H), 7.45-7.49 (m, 4H), 7.38-7.41 (m, 2H), 7.23-7.26 (m, 2H), 7.06 (dm, J=9.0 Hz, 2H), 3.97, (A of AB, J=13.7 Hz, 1H), 3.92 (s, 3H), 3.39 (B of AB, J=13.7 Hz, 1H). MS (m/e): 486.0 & 488.0 (M−H)−Cl isotopes. Anal: Calc for C23H18ClNO5S2.C3H7NO: 55.66% C, 4.49% H, 4.99% N; Found: 55.57% C, 4.41% H, 4.85% N. MP: 197-200° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[CH2:10]Br.C(O)(=[O:14])C.C([O-])(=O)C.[K+]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[CH2:10][OH:14]
Reactant: CC(=O)O
Reactant: Fc1cc(Br)c(CBr)cc1Cl
Agent: CC(=O)[O-]
Agent: [K+]
Product: OCc1cc(Cl)c(F)cc1Br
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
A solution of 227 mmol of 1-bromo-2-bromomethyl-4-chloro-5-fluoro-benzene (example 10d) in 300 ml of glacial acetic acid containing 495 mmol of potassium acetate is heated to reflux for 3 hours. The mixture is concentrated and then partitioned between water and diethyl ether. After repeated extractions with diethyl ether, the combined organic layers are washed successively with saturated sodium bicarbonate-solution solution and water, dried over magnesium sulfate and concentrated. The crude acetate is dissolved in 200 ml of methanol and treated slowly with a methanolic KOH solution (33.4 g in 100 ml). The reaction mixture is stirred for 35 minutes at room temperature, then neutralized with acetic acid and concentrated under reduced pressure. The residue is partitioned between water and diethyl ether. Concentration of the organic phase affords the crude title compound which is purified by flash chromatography (SiO2 60 F) to afford the title compound which is identified based on the Rf value.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>O1CCCC1>[C:18]1([S:24]([N:4]2[C:5]3[N:6]=[CH:7][N:8]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[C:10]=3[C:2]([I:1])=[CH:3]2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COCCOc1ncnc2[nH]cc(I)c12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCOc1ncnc2c1c(I)cn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.2 %

Procedure:
To 5-iodo-4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidine (25, 3.67 g, 11.5 mmol) in 60.0 mL of tetrahydrofuran under an atmosphere of nitrogen, sodium hydride (506.0 mg, 12.65 mmol) is added. The reaction is stirred at room temperature for 20 minutes, then benzenesulfonyl chloride (26, 1.614 mL, 12.65 mmol) is added. The reaction is stirred at room temperature for 30 minutes, then poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 15-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (27, 4.50 g). MS (ESI) [M+H+]+=460.0.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>>[F:12][C:13]1[CH:14]=[C:15]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: Brc1ccc2ccccc2c1
Reactant: COc1ccc(B(O)O)cc1F
Product: COc1ccc(-c2ccc3ccccc3c2)cc1F

Procedure:
The title compound was prepared by reacting 2-bromonaphthalene (0.31 g, 1.50 mmol) with 3-fluoro-4-methoxyphenylboronic acid (0.31 g, 1.80 mmol) according to method A to yield 0.30 g (79%) of a white solid: mp 108–110° C.; 1H NMR (CDCl3): δ (3.96, 3H, s), 7.04–7.10 (1H, m), 7.43–7.52 (4H, m), 7.68 (1H, dd, J=1.81 Hz, J=8.57 Hz), 7.84–7.92 (3H, m), 7.97 (1H, d, J=1.05 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20](OC)=[O:21].[H-].[Na+].O>CN(C=O)C>[OH:21][CH:20]=[C:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)Cc1ccccc1OCc1ccccc1
Reactant: COC=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(=CO)c1ccccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methyl 2-benzyloxyphenylacetate (26.99 g) and methyl formate (126.62 g) in dry DMF (300 ml) were added dropwise to a stirred suspension of sodium hydride (50% disp. in oil, 10.13 g) in DMF (300 ml) at 0° C. After stirring at 0° C. for two hours the mixture was poured into water (1000 ml) and washed with ether (2×150 ml). The aqueous layer was acidified to pH4 with 6M hydrochloric acid then extracted with ether (2×350 ml). The extracts were dried and concentrated under reduced pressure to afford crude methyl 3-hydroxy-2-[2'-benzyloxyphenyl]propenoate as a yellow oil, infrared maxima (film): 1720, 1660 cm-1.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]([O:10][C:11]2[N:16]=[CH:15][C:14]([NH2:17])=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3].[CH3:18][C:19]([O:22][C:23]([NH:25][C@@H:26]([C:28](O)=[O:29])[CH3:27])=[O:24])([CH3:21])[CH3:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(#N)C>[CH3:27][C@@H:26]([NH:25][C:23](=[O:24])[O:22][C:19]([CH3:21])([CH3:20])[CH3:18])[C:28]([NH:17][C:14]1[CH:13]=[N:12][C:11]([O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([CH:2]([CH3:1])[CH3:3])[CH:5]=2)=[N:16][CH:15]=1)=[O:29]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)c1cccc(Oc2ncc(N)cn2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)c1cccc(Oc2ncc(NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)cn2)c1
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of 2-{[3-(1-methylethyl)phenyl]oxy}-5-pyrimidinamine (Intermediate 85, 229 mg) in acetonitrile (20 mL) were added N-{[(1,1-dimethylethyl)oxy]carbonyl}-D-alanine (378 mg, 2 mmol), HBTU (474 mg, 1.25 mmol) and DIPEA (387 mg, 3 mmol) and the mixture was heated at reflux and stirred overnight. The resulting mixture was concentrated under vacuum and water (100 mL) was added. It was extracted with ethyl acetate (3 times 100 mL) and the combined organic layers were dried over sodium sulphate and evaporated to afford a brown oil, which was purified by silica gel chromatography (mobile phase: ethyl acetate: petroleum ether=1/5−1/2) to afford the title compound (300 mg).
Reaction SMILES: [OH:1][C@:2]12[C:19]([CH3:21])([CH3:20])[C:18](=O)[CH2:17][CH2:16][C@:15]1([CH3:23])[C@@H:14]1[C@H:5]([C@H:6]3[C@@:10]([CH2:12][CH2:13]1)([CH3:11])[C@@H:9]([OH:24])[CH2:8][CH2:7]3)[CH2:4][C@@H:3]2[OH:25].[ClH:26].Cl.[NH:28]1[CH2:32][CH2:31][C@@H:30]([O:33][NH2:34])[CH2:29]1>>[ClH:26].[NH:28]1[CH2:32][CH2:31][C@@H:30]([O:33]/[N:34]=[C:18]2/[C:19]([CH3:21])([CH3:20])[C@@:2]3([OH:1])[C@:15]([CH3:23])([CH2:16][CH2:17]/2)[C@@H:14]2[C@H:5]([C@H:6]4[C@@:10]([CH2:12][CH2:13]2)([CH3:11])[C@@H:9]([OH:24])[CH2:8][CH2:7]4)[CH2:4][C@@H:3]3[OH:25])[CH2:29]1
Reactant: NO[C@@H]1CCNC1
Reactant: CC1(C)C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](O)CC[C@H]4[C@@H]3C[C@H](O)[C@@]12O
Agent: Cl
Product: CC1(C)/C(=N/O[C@@H]2CCNC2)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](O)CC[C@H]4[C@@H]3C[C@H](O)[C@@]12O
Yield: 90 %

Procedure:
The title compound was prepared in 90% yield (121 mg) as described in Example 2 starting from 5α,6α,17β-trihydroxy-4,4-dimethylandrostan-3-one, (Preparation 5, 100 mg) and 3-(R)-pyrrolidinyloxyamine dihydrochloride (Preparation 12, 200 mg).
Reaction SMILES: [O:1]=[C:2]([NH:13][CH2:14][C:15]1[NH:16][C:17](=[O:25])[C:18]2[CH2:24][O:23][CH2:22][CH2:21][C:19]=2[N:20]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=O)[CH2:6][CH2:5]1.[CH2:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28][NH:27]1>>[O:25]=[C:17]1[NH:16][C:15]([CH2:14][NH:13][C:2](=[O:1])[CH2:3][N:4]2[CH2:9][CH2:8][CH:7]([C:10]([N:27]3[CH2:28][CH2:29][C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:26]3)=[O:12])[CH2:6][CH2:5]2)=[N:20][C:19]2[CH2:21][CH2:22][O:23][CH2:24][C:18]1=2
Reactant: O=C(CN1CCC(C(=O)O)CC1)NCc1nc2c(c(=O)[nH]1)COCC2
Reactant: c1ccc2c(c1)CCNC2
Product: O=C(CN1CCC(C(=O)N2CCc3ccccc3C2)CC1)NCc1nc2c(c(=O)[nH]1)COCC2
Yield: 9.9 %

Procedure:
The title compound (23 mg) was prepared following the general procedure of Example 1 from 1-(2-oxo-2-((4-oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methylamino)ethyl)piperidine-4-carboxylic acid (250 mg, 0.50 mmol) and 1,2,3,4-tetrahydroisoquinoline (66 mg, 0.50 mmol). 1H NMR (400 MHz, CDC3) δ 8.19 (br. s., 1H), 6.94-7.16 (m, 3H), 4.66 (s, 1H), 4.59 (s, 1H), 4.46 (s, 2H), 4.32 (d, J=5.1 Hz, 2H), 3.85 (t, J=5.3 Hz, 2H), 3.76 (t, J=6.1 Hz, 1H), 3.65 (t, J=5.8 Hz, 1H), 3.40 (br. s., 1H), 3.06 (br. s., 1H), 3.01 (s, 2H), 2.68-2.95 (m, 4H), 2.60 (br. s., 2H), 2.33-2.57 (m, 1H), 2.17 (t, J=11.4 Hz, 2H), 1.87 (dq, J=11.1, 10.9 Hz, 2H). HRMS calculated for C25H31N5O4 466.2454. found (ESI, [M+H]+), 466.2466. Retention time=1.25 min.