Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[F:11][C:12]([F:33])([F:32])[C:13]1[CH:14]=[C:15]([C:19]2[N:20]=[C:21]([CH:24]3[CH2:29][CH2:28][CH:27]([CH2:30][NH2:31])[CH2:26][CH2:25]3)[NH:22][CH:23]=2)[CH:16]=[CH:17][CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[F:33][C:12]([F:11])([F:32])[C:13]1[CH:14]=[C:15]([C:19]2[N:20]=[C:21]([C@H:24]3[CH2:25][CH2:26][C@H:27]([CH2:30][NH:31][S:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)(=[O:9])=[O:8])[CH2:28][CH2:29]3)[NH:22][CH:23]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: NCC1CCC(c2nc(-c3cccc(C(F)(F)F)c3)c[nH]2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NC[C@H]1CC[C@H](c2nc(-c3cccc(C(F)(F)F)c3)c[nH]2)CC1)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyridine-3-sulfonyl chloride (0.34 mmol) was added to a solution of C-{4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-cyclohexyl}-methylamine (0.31 mmol) and triethylamine (0.62 mmol) in CH2Cl2 (5 mL). The mixture was stirred overnight at room temperature, diluted with CH2Cl2, washed with saturated NaHCO3, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash chromatography (90:10 CH2Cl2/MeOH) to give Pyridine-3-sulfonic acid trans-{4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-cyclohexylmethyl}-amide.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=4)=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.[C:23]([O-])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([C:7]2[NH:6][C:5]3[CH:21]=[CH:22][C:2]([NH:1][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:3][C:4]=3[N:8]=2)=[CH:10][CH:11]=1
Reactant: Nc1ccc2[nH]c(-c3ccc(-c4ccccn4)cc3)nc2c1
Reactant: O=C([O-])c1ccccc1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(-c4ccccn4)cc3)nc2c1)c1ccccc1

Procedure:
Compound 479 was prepared from 5-amino-2-(4-(pyridin-2-yl)phenyl)-1H-benzimidazole and benzoate by standard conditions. [M+H]+ calcd for C25H18N4O: 391.16; found: 390.91.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][O:40][C:41]1[CH:42]=[C:43]([CH:45]=[C:46](B2OC(C)(C)C(C)(C)O2)[CH:47]=1)[NH2:44].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:44][C:43]1[CH:45]=[C:46]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:47]=[C:41]([O:40][CH3:39])[CH:42]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: COc1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(N)cc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Yield: 56.1 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (0.25 g, 0.42 mmol) was treated with 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.26 g, 1.05 mmol), sodium carbonate (0.11 g, 1.05 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.10 g, 0.13 mmol) and 10.6 ml 1,2-dimethoxyethane and 2.4 ml water as a solvents according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100% n-hexane-ethyl acetate) to obtain 0.15 g (54% yield) of the title compound.
Reaction SMILES: C([Li])CCC.[C:6]1([NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=2[O:21][CH3:22])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C.Cl>O1CCCC1>[NH:12]([C:13]([C:14]1[CH:19]=[CH:18][C:17]([B:24]([OH:29])[OH:25])=[CH:16][C:15]=1[O:21][CH3:22])=[O:23])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1cc(Br)ccc1C(=O)Nc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(B(O)O)ccc1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
n-Butyl lithium (1.6 M in hexane solution, 5.1 ml, 8.16 mmol) was added slowly to a solution of N1-phenyl-4-bromo-2-methoxybenzamide (1.0 g, 3.26 mmol) in tetrahydrofuran (25 mL) at −78° C. After 30 minutes, triisopropyl borate (1.13 mL, 4.90 mmol) was added rapidly. The reaction mixture was allowed to warm up to room temperature after 15 minutes and stirred at room temperature for 16 hours. Hydrochloric acid (2.5N, 18 mL) was added and the mixture was stirred for 5 h hours. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was re-crystallized from ethyl acetate/heptane to give 4-(anilinocarbonyl)-3-methoxyphenylboronic acid (0.549 g, 62%). 1H NMR (DMSO-d6) δ 3.91 (s, 3H), 7.08 (m, 1H), 7.33 (m, 2H), 7.47 (d, J=7.57 Hz, 1H), 7.59 (m, 2H), 7.73 (d, J=7.36 Hz, 2H), 8.24 (s, 2H), 10.10 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][C@@H:19]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:20]([OH:26])[CH2:21][C:22]([O:24][CH3:25])=[O:23]>C(Cl)(Cl)Cl.CO>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][C@@H:19]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C@@H:20]([OH:26])[CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl (3S,4S)-4-amino-3-hydroxy-5-phenylpentanoate (Novabiochem), the title compound was prepared as a solid. The action was monitored by tlc (Rf=0.2 in 95:5 CHCl3/MeOH) and the product was purified by flash column chromatography using 95:5 CHCl3/MeOH as the eluent.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][O:9][C:10]2[CH:23]=[CH:22][C:13]3[C@H:14]([CH2:17][C:18]([O:20]C)=[O:19])[CH2:15][O:16][C:12]=3[CH:11]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:24]1[C:29]([CH3:30])=[CH:28][C:27]([O:31][C@H:32]2[CH2:36][CH2:35][O:34][CH2:33]2)=[CH:26][C:25]=1[CH3:37].[OH-].[Li+]>O1CCCC1.CO>[CH3:1][C:2]1[C:7]([CH2:8][O:9][C:10]2[CH:23]=[CH:22][C:13]3[C@H:14]([CH2:17][C:18]([OH:20])=[O:19])[CH2:15][O:16][C:12]=3[CH:11]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:24]1[C:25]([CH3:37])=[CH:26][C:27]([O:31][C@H:32]2[CH2:36][CH2:35][O:34][CH2:33]2)=[CH:28][C:29]=1[CH3:30]
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[C@H]5CCOC5)cc4C)c3C)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(O[C@H]2CCOC2)cc(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
Methyl 2-((S)-6-((2,2′,6′-trimethyl-4′-(((S)-tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 12f (100 mg, 0.20 mmol) was dissolved in 4 mL of a mixture of the solvents tetrahydrofuran and methanol (V/V=1:1), followed by addition of 2M aqueous lithium hydroxide solution (1 mL, 2 mmol). The reaction solution was stirred for 2 hours. The resulting solution was concentrated under reduced pressure. The residue was mixed with 10 mL of water, 1M hydrochloric acid was added dropwise to adjust the pH to 1˜2 and extracted with ethyl acetate (20 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purifed using a method of preparative separation to obtain the title compound 2-((S)-6-((2,2′,6′-trimethyl-4′-(((S)— tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid 12 (80 mg, yield 83.0%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:52]=[C:53]([F:55])[CH:54]=1)[CH2:5][C@H:6]([C:37](N1[C@@H](CC2C=CC=CC=2)COC1=O)=[O:38])[C@@H:7]([CH:9]1[CH2:18][C:17]2[C:12](=[C:13]([O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH:14]=[CH:15][CH:16]=2)[CH2:11][N:10]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[OH:8].[Li+].[OH-:57].OO>C1COCC1.O>[F:55][C:53]1[CH:52]=[C:4]([CH:3]=[C:2]([F:1])[CH:54]=1)[CH2:5][C@@H:6]([C@@H:7]([CH:9]1[CH2:18][C:17]2[C:12](=[C:13]([O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:25])[CH3:26])[CH:21]([CH3:23])[CH3:22])[CH:14]=[CH:15][CH:16]=2)[CH2:11][N:10]1[C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[OH:8])[C:37]([OH:57])=[O:38]
Reactant: CC(C)[Si](Oc1cccc2c1CN(C(=O)OC(C)(C)C)C([C@@H](O)[C@H](Cc1cc(F)cc(F)c1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C2)(C(C)C)C(C)C
Reactant: [OH-]
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](Oc1cccc2c1CN(C(=O)OC(C)(C)C)C([C@@H](O)[C@H](Cc1cc(F)cc(F)c1)C(=O)O)C2)(C(C)C)C(C)C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 3-((1S,2S)-2-(3,5-difluorobenzyl)-3-((S)-4-benzyl-2-oxooxazolidin-3-yl)-1-hydroxy-3-oxopropyl)-8-(triisopropylsilyloxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (Step F (9), 2.0 g, 2.57 mmol) in THF (50 mL) was added a solution of LiOH (123 mg, 5.13 mmol) in H2O (8 mL), then 30% H2O2 (3.0 g, 25.7 mmol) was added at −5° C. This reaction mixture was stirred from −5° C. to 0° C. over 1 h and stirred at rt for 3 h. Solvent was removed and ethyl acetate (500 mL) was added. The mixture was washed with 1N HCl, and H2O, dried (Na2SO4), and concentrated in vacuo to give the crude product which was ready for next step without purification. MS (ESI) (M−H)− 618.22.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]([C:20]1[N:25]=[CH:24][C:23]([CH:26]([CH:30]([CH3:32])[CH3:31])[C:27]([OH:29])=[O:28])=[CH:22][N:21]=1)([CH3:19])[CH3:18].[C:33]([CH:35](O)[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:37]=1)#[CH:34]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:19][C:17]([C:20]1[N:21]=[CH:22][C:23]([CH:26]([CH:30]([CH3:32])[CH3:31])[C:27]([O:29][CH:35]([C:33]#[CH:34])[C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([O:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH:37]=2)=[O:28])=[CH:24][N:25]=1)([CH3:16])[CH3:18]
Reactant: C#CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CC(C)C(C(=O)O)c1cnc(C(C)(C)C)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C#CC(OC(=O)C(c1cnc(C(C)(C)C)nc1)C(C)C)c1cccc(Oc2ccccc2)c1
Yield: 90.5 %

Procedure:
A solution of N,N'-dicyclohexylcarbodiimide (0.2 g) in dichloromethane (5 cm3) was added to a stirred mixture of (RS)-2-[2-(2-methylprop-2-yl)pyrimidin-5-yl]-3-methylbutyric acid (0.26 g), (RS)-α-ethynyl-3-phenoxybenzyl alcohol (0.224 g), 4-dimethylaminopyridine (0.02 g) and dry dichloromethane (5 cm3) and the resultant mixture stirred for 2 hours. The precipitate which formed was removed by filtration and the filtrate concentrated by evaporation of the solvent under reduced pressure. The residual oil was purified by column chromatography using a silica column eluted with a mixture of ethyl acetate (1 part by volume) and petroleum ether (boiling range 60° to 80° C., 1 part by volume) to yield (RS)-1-ethynyl-1-(3-phenoxyphenyl)methyl (RS)-2-[2-(2-methylprop-2-yl)-pyrimidin-5-yl]-3-methylbutyrate (0.4g), as a mixture of diastereoisomers.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[Cl:11][C:12]1[N:17]=[CH:16][C:15]([CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH:21]3[O:25][C:26](=[O:28])[CH:27]=[C:20]23)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH:3]([C:27]1[C:26](=[O:28])[O:25][CH:21]2[CH2:22][CH2:23][CH2:24][N:19]([CH2:18][C:15]3[CH:16]=[N:17][C:12]([Cl:11])=[CH:13][CH:14]=3)[C:20]=12)=[O:4]
Reactant: CN(C)C=O
Reactant: O=C1C=C2C(CCCN2Cc2ccc(Cl)nc2)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: O=CC1=C2C(CCCN2Cc2ccc(Cl)nc2)OC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
With ice-cooling, 1.89 ml (24.56 mmol) of N,N-dimethylformamide and 0.28 ml (3.02 mmol) of phosphoryl chloride are initially charged, and after one hour 500 mg (1.89 mmol) of 4-[(6-chloropyridin-3-yl)methyl]-5,6,7,7a-tetrahydrofuro[3,2-b]pyridin-2(4H)-one (1-2) are added. The mixture is then stirred at room temperature for two hours. The reaction mixture is then made alkaline using sodium carbonate, and the precipitated solid is filtered off and washed with water. This gives 0.33 g (56% of theory) of 3-formyl-4-[(6-chloropyridin-3-yl)methyl]-5,6,7,7a-tetrahydrofuro[3,2-b]pyridin-2(4H)-one.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])C.[C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])[CH3:17].CC(C)([O-])C.[K+].C(O)(=O)C>C1COCC1>[C:19]1([C:16](=[O:18])[CH2:17][C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:5])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)c1ccccc1
Reactant: CCOC(=O)c1cnc2ccccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(CC(=O)c1cnc2ccccc2c1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of ethyl-3-quinolinate (0.50 gm, 0.0025 mole) and acetophenone (0.30 gm, 0.0025 mole) was added to an ice-cold suspension of potassium tertiary butoxide in THF (5.0 ml). The reaction mixture was stirred at room temp. for 2 hours, acidified with a dilute acetic acid (10%). The resulting solid was filtered, air dried and recrystallised from boiling ethyl acetate to yield the desired product as a pale yellow colour solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].Br[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([O:10][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:2]([F:1])[CH:3]=1)#[N:6]
Reactant: N#Cc1ccc(O)c(F)c1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1ccc(C#N)cc1F
Temperature: 80 °C
Yield: 97.1 %

Procedure:
3-fluoro-4-hydroxybenzonitrile (ABCR F03756F.AB, 2 g; 14.59 mmol; 1 eq.) was dissolved in DMF (40 mL). Then ethyl 4-bromobutyrate (4.27 g; 21.88 mmol; 1.50 eq.) and potassium carbonate (3.02 g; 21.88 mmol; 1.50 eq.) were added to the reaction mixture and it was heated to 80° C. for 2 hours. The reaction mixture was cooled to RT and diluted with EtOAc. The organic layer was washed with water (3×), brine, dried over MgSO4 and concentrated affording the title compound as a yellow solid (3.56 g, 97%). 1H NMR (DMSO-d6, 300 MHz) δ 7.86-7.83 (d, J=11.43 Hz, 1H), 7.68-7.66 (d, J=8.73 Hz, 1H), 7.37-7.32 (m, 1H), 4.20-4.03 (m, 4H), 2.46-2.44 (m, 2H), 2.03-1.99 (m, 2H), 1.19-1.15 (t, J=6.62 Hz, 3H). HPLC (Method A) Rt 4.47 min (Purity: 98.8%).
Reaction SMILES: C[O-:2].[Na+].Cl[C:5]1[N:6]=[N:7][C:8]([S:11][C:12]2[O:13][C:14]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:15]=3[C:16]=2[CH3:17])=[CH:9][CH:10]=1>CO>[Cl:22][C:19]1[CH:20]=[CH:21][C:14]2[O:13][C:12]([S:11][C:8]3[CH:9]=[CH:10][C:5](=[O:2])[NH:6][N:7]=3)=[C:16]([CH3:17])[C:15]=2[CH:18]=1
Reactant: Cc1c(Sc2ccc(Cl)nn2)oc2ccc(Cl)cc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(Sc2ccc(=O)[nH]n2)oc2ccc(Cl)cc12

Procedure:
Sodium methoxide (299 mL, 1.31 mol, 5 equiv) was added to a slurry of 3-chloro-6-(5-chloro-3-methyl-benzofuran-2-ylsulfanyl)-pyridazine (the title compound of Example One) in methanol (500 mL, 6.1 vol). The resultant mixture was heated at 50° C. for five hours to provide, 3-(5-chloro-3-methyl-benzofuran-2-ylsulfanyl)-6-methoxy-pyridazine, which was not isolated. The reaction mixture was cooled to room temperature and concentrated hydrochloric acid (12N, 329 mL, 3.95 mol, 15 equiv) was added. The reaction mixture was heated at reflux for 15 hours and then cooled to room temperature. Water (400 mL) was added to the slurry and the mixture was cooled to 0° C. for 30 minutes. The solids were collected by filtration, dried under vacuum, and repulped in dichloromethane (600 mL, 8 vol) and isopropyl ether (150 mL, 2 vol) to afford the title compound of Example Two (71 g, 92%) as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]([CH:15]=[CH2:16])[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[Cu][C:18]#[N:19]>CN(C=O)C.O>[C:18]([C:2]1[CH:14]=[C:13]([CH:15]=[CH2:16])[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:19]
Reactant: N#C[Cu]
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)c(Br)c1
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1ccc(C(=O)OC(C)(C)C)c(C#N)c1
Temperature: 140 °C
Yield: 73.9 %

Procedure:
To a stirred solution of tert-butyl 2-bromo-4-vinylbenzoate (0.5 g, 1.77 mmol) in DMF (20 mL) was added copper(I) cyanide (CuCN; 0.23 g, 2.65 mmol), and the reaction mixture was heated at 140° C. for 3 h. The reaction mixture was cooled to 25° C., diluted with H2O, and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; eluting with 15% EtOAc in n-hexane) to afford the title compound as a white solid (0.3 g, 72%): mp 51-53° C.; 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.77 (s, 1H), 7.64 (d, J=8.4 Hz, 1H), 6.75 (dd, J=17.6, 10.8 Hz, 1H), 5.93 (d, J=17.6 Hz, 1H), 5.51 (d, J=10.8 Hz, 1H), 1.65 (s, 9H); ESIMS m/z 229.84 ([M+H]+); IR (thin film) 2370, 1709, 1142 cm−1.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:17][CH2:16][C:15]4[N:18]=[C:19]([C:21]5[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=5)[S:20][C:14]=4[C:13]3=[O:28])=[CH:8][C:7]=2[O:29][CH3:30])[CH2:2]1.[C:31](O)(=O)C.C=O.C([BH3-])#N.[Na+]>O.CO>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[S:20][C:14]3[C:13](=[O:28])[N:12]([C:9]4[CH:10]=[CH:11][C:6]([O:5][CH:3]5[CH2:4][N:1]([CH3:31])[CH2:2]5)=[C:7]([O:29][CH3:30])[CH:8]=4)[CH2:17][CH2:16][C:15]=3[N:18]=2)=[CH:26][CH:25]=1
Reactant: CC(=O)O
Reactant: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1OC1CNC1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1OC1CN(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
Mix 5-[4-(azetidin-3-yloxy)-3-methoxy-phenyl]-2-(4-chloro-phenyl)-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (3.1 g, 7.01 mmol) with anhydrous MeOH (100 mL) and treat with acetic acid (4.0 mL, 69.8 mmol) and formaldehyde (1.6 mL, 21.30 mmol, as a solution in water). Stir the mixture at room temperature for 30 min and then treat with sodium cyanoborohydride (1.3 g, 19.6 mmol). Stir the mixture at room temperature overnight and concentrate in vacuo. Partition the resulting residue between CH2Cl2 (100 mL) and saturated NaHCO3 (100 mL). Remove the organic solution and extract the aqueous phase with additional CH2Cl2 (2×100 mL). Combine the organic solutions and wash with water (50 mL), then dry, filter, and concentrate in vacuo. Purify the crude material by flash chromatography, using 8% MeOH (2M NH3)/CH2Cl2 as eluent, to give 1.6 g (50%) of the title compound as a yellow solid. ES/MS m/z (35Cl) 456 [M+1]+.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]=[CH:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:11][NH:12]2)=[CH:8][CH:7]=1.[OH-].[Li+].Cl>CO.O>[C:18]1([S:15]([C:10]2[C:9]3[C:13](=[CH:14][C:6]([CH:5]=[CH:4][C:3]([OH:24])=[O:2])=[CH:7][CH:8]=3)[NH:12][CH:11]=2)(=[O:17])=[O:16])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)C=Cc1ccc2c(S(=O)(=O)c3ccccc3)c[nH]c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C=Cc1ccc2c(S(=O)(=O)c3ccccc3)c[nH]c2c1
Yield: 58.2 %

Procedure:
To a solution of 23 (0.36 g, 1.05 mmol) in MeOH (10 mL) and water (2 ml), lithium hydroxide (0.05 g, 2.11 mmol) was added. The reaction mixture was refluxed for 6 h and was then concentrated under reduced pressure to provide a residue. The residue was dissolved in water. 3N HCl was added up to acidic pH and the mixture was extracted with EtOAc (20 mL×3). The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure to give a brown residue, which was recrystallized by EtOH to afford 24 (0.2 g). 1H NMR (500 MHz, CD3OD): δ 6.46 (d, J=15.8 Hz, 1H), 7.62-7.69 (m, 4H), 7.81 (s, 1H), 7.81 (d, J=16.0 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 8.12 (d, J=7.3 Hz, 2H), 8.21 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][N:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:40]1([CH3:63])[CH:45]=[CH:44][C:43]([S:46]([O:49][CH2:50][CH2:51]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:48])=[O:47])=[CH:42][CH:41]=1.O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:51][CH2:50][O:49][S:46]([C:43]2[CH:44]=[CH:45][C:40]([CH3:63])=[CH:41][CH:42]=2)(=[O:48])=[O:47])=[CH:22][N:21]=1)[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(O)cn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.4 %

Procedure:
To a solution of 150 mg di-tert-butyl (4R)—N-(tert-butoxycarbonyl)-4-[(5-hydroxypyridin-2-yl)methyl]-L-glutamate (0.32 mmol) in N,N-dimethylformamide (8 mL) was added 126 mg of cesium carbonate (0.39 mmol), followed by 143 mg of 1,2-ethanediol di-p-toluenesulfonate (0.39 mmol). The mixture was stirred for 5 h at room temperature. Water was added, the mixture was extracted with dichloromethane, and the organic layer was washed with brine, dried over magnesium sulfate, and evaporated. The crude product was purified by preparative HPLC (method A) to give 86 mg (40% yield) of the title compound.
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.[NH:29]1[CH2:33][CH2:32][CH:31]([CH2:34][OH:35])[CH2:30]1>>[CH3:28][N:4]1[C:3]([CH2:2][N:29]2[CH2:33][CH2:32][CH:31]([CH2:34][OH:35])[CH2:30]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: OCC1CCNC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(CO)C3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 1-pyrrolidin-3-ylmethanol via General Procedure E to give 19.1 mg of 299 following reverse phase purification. MS (Q1) 463.2 (M)+