Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.I[CH2:12]I.C[Li]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:12])[CH2:9][O:10]2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: ICI
Agent: [Li]C
Solvent: C1CCOC1
Product: CC1(c2ccc(Br)cc2)CO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-(4-Bromo-phenyl)-2-methyl-oxirane was synthesized according to the scheme shown in FIG. 5. 4′-Bromoacetophenone (0.60 g, 3 mmol) and diiodomethane (1.6 g, 6 mmol) were dissolved in 12 mL dry THF. Methyllithium (5.6 mL, 1.6M in ether) was added via syringe in 10 min at 0° C. The resulting clear yellow solution was stirred at 0° C. for 30 min and was then warmed up to room temperature. After stirring at room temperature for 1 hour, the reaction mixture was quenched with ice. The resulting mixture was extracted with EtOAc, washed with brine and dried over Na2SO4. After removing the solvent, fairly pure product (0.62 g) was obtained as yellow solid, which was directly used for next step without further purification. ESI MS m/z 213, 215 (M+H).
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:28]=[CH:27][C:10]3[N:11]([CH2:14][C:15]4[CH:26]=[CH:25][C:18]5[N:19]=[C:20](S(C)=O)[S:21][C:17]=5[CH:16]=4)[CH:12]=[N:13][C:9]=3[CH:8]=2)=[N:3]1.Cl.[NH2:30][C@@H:31]1[CH2:36][CH2:35][CH2:34][C@@H:33]([OH:37])[C@H:32]1[OH:38].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:28]=[CH:27][C:10]3[N:11]([CH2:14][C:15]4[CH:26]=[CH:25][C:18]5[N:19]=[C:20]([NH:30][C@@H:31]6[CH2:36][CH2:35][CH2:34][C@@H:33]([OH:37])[C@H:32]6[OH:38])[S:21][C:17]=5[CH:16]=4)[CH:12]=[N:13][C:9]=3[CH:8]=2)=[N:3]1
Reactant: Cn1nnc(-c2ccc3c(c2)ncn3Cc2ccc3nc(S(C)=O)sc3c2)n1
Reactant: N[C@@H]1CCC[C@@H](O)[C@H]1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cn1nnc(-c2ccc3c(c2)ncn3Cc2ccc3nc(N[C@@H]4CCC[C@@H](O)[C@H]4O)sc3c2)n1
Temperature: 120 °C
Yield: 9.7 %

Procedure:
To a suspension of 6-((5-(2-methyl-2H-tetrazol-5-yl)-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (330 mg, 0.8 mmol) and (1R,2S,3R)-3-aminocyclohexane-1,2-diol hydrochloride (391 mg, 2.4 mmol), prepared as described in Gauthier Errasti, et al, Org. Lett. 2009, 13, 2912-2915, in anhydrous NMP (3.0 mL) was added DIEA (703 μL, 4.0 mmol). The mixture was heated in a sealed tube at 120° C. for 15 h. Additional (1R,2S,3R)-3-aminocyclohexane-1,2-diol hydrochloride (258 mg, 1.6 mmol) and DIEA (703 μL, 4.0 mmol) were added, and the mixture was heated at 140° C. for a further 15 h. The mixture was cooled to rt and was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford (1R,2S,3R)-3-((6-((5-(2-methyl-2H-tetrazol-5-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol (37 mg, 10%) as a white powder. 1H NMR (500 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.29 (s, 1H), 7.90-7.98 (m, 2H), 7.74 (d, J=8.4 Hz, 1H), 7.69 (s, 1H), 7.31 (m, 1H), 7.23 (dd, J=1.5, 8.4 Hz, 1H), 5.52 (s, 2H), 4.41 (s, 3H), 3.93 (m, 1H), 3.79 (m, 1H), 3.25 (m, 1H), 1.91 (m, 1H), 1.52-1.69 (m, 3H), 1.32-1.44 (m, 2H), 1.15-1.25 (m, 2H); LCMS (ESI) m/z 477 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[O:24]CC1C=CC=CC=1)C1C=CC=CC=1>CCO.[Pd]>[CH:9]1([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[OH:24])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][NH:8]1
Reactant: Fc1ccc(OCc2ccccc2)c(C2c3ccccc3CN2Cc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(F)cc1C1NCc2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution under N2 of (±)-2-benzyl-1-(2-benzyloxy-5-fluoro-phenyl)-2,3-dihydro-1H-isoindole (181 mg, 0.44 mmol, 1.0 eq.) in EtOH (20 mL), palladium on activated carbon (10 wt. %, 60 mg) was added. The flask was evacuated and backfilled with H2 (3×). The black suspension was stirred at r.t. under an H2-atmosphere for 18 hours. The suspension was filtered through Celite, the Celite rinsed with EtOH. The filtrate was concentrated in vacuo. The residue was filtered and then purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give (±)-2-(2,3-dihydro-1H-isoindol-1-yl)-4-fluoro-phenol.
Reaction SMILES: [OH:1][C:2]1([C:9]2[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[OH:1][C:2]1([C:9]2[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=2)[CH2:7][CH2:6][CH:5]([N:15]2[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)=[O:21])[CH2:16]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: Cn1ccnc1C1(O)CCC(=O)CC1
Product: Cn1ccnc1C1(O)CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-(1-methyl-1H-imidazol-2-yl)-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [NH2:1][CH:2]([CH2:17][CH2:18][CH2:19][CH:20]1[O:24][CH2:23][CH2:22][O:21]1)[C:3](N(C(C)C(O)C1C=CC=CC=1)C)=[O:4].[OH2:25]>>[NH2:1][C@@H:2]([CH2:17][CH2:18][CH2:19][CH:20]1[O:24][CH2:23][CH2:22][O:21]1)[C:3]([OH:4])=[O:25]
Reactant: O
Reactant: CC(C(O)c1ccccc1)N(C)C(=O)C(N)CCCC1OCCO1
Product: N[C@@H](CCCC1OCCO1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 250 ml flask equipped with an argon inlet, magnetic stir bar and reflux condenser was charged with 5.9 g of the product from Example 1 and water (80 ml). The reaction was refluxed for seven hours and then allowed to stir overnight at room temperature. The reaction mixture was diluted with water (120 ml) and washed with methylene chloride (2×50 ml). The combined methylene chloride layers were extracted once with water (50 ml), and the combined aqueous layers were concentrated in vacuo. The residue was concentrated in vacuo from 100% ethanol (2×100 ml) to a solid. The solid was dissolved in water (15 ml) and the solution was stirred with a magnetic stir bar as 100% ethanol (150 ml) was added in a slow stream. Stirring was stopped, and the mixture was allowed to stand for one hour and then filtered. The solids were washed with 100% ethanol (2×25 ml), air-dried for 15 minutes, and then volatiles were removed under high vacuum overnight to give 2.0 g of the desired product as a white powder; m.p. 224-226°(decomp.).
Reaction SMILES: [ClH:1].NC1NC2C=C(N3C(=O)C=CC3=O)C=CC=2N=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[N:27]=[C:26]([N:28](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[N:25](C(OC(C)(C)C)=O)[C:24]=2[CH:50]=1.[CH3:51][C:52]1([CH3:60])[CH2:57][C:56](=[O:58])[O:55][C:54](=O)[CH2:53]1>>[ClH:1].[NH2:28][C:26]1[NH:25][C:24]2[CH:50]=[C:20]([N:19]3[C:54](=[O:55])[CH2:53][C:52]([CH3:60])([CH3:51])[CH2:57][C:56]3=[O:58])[CH:21]=[CH:22][C:23]=2[N:27]=1
Reactant: CC1(C)CC(=O)OC(=O)C1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc2ccc(N)cc2n1C(=O)OC(C)(C)C
Agent: Cl
Agent: Nc1nc2ccc(N3C(=O)C=CC3=O)cc2[nH]1
Product: CC1(C)CC(=O)N(c2ccc3nc(N)[nH]c3c2)C(=O)C1
Yield: 98 %

Procedure:
Following the same procedure to synthesize 1-(2-amino-1H-benzo[d]imidazol-6-yl)-1H-pyrrole-2,5-dione hydrochloride, tert-butyl 6-amino-2-(bis(tert-butoxycarbonyl)amino)-1H-benzo[d]imidazole-1-carboxylate (0.300 g, 0.669 mmol) was reacted with 4,4-dimethyldihydro-2H-pyran-2,6(3H)-dione (0.095 g, 0.669 mmol) to give the title product (0.202 g, 98% yield) as a yellow solid. 1H NMR (300 MHz, CD3OD) δ 7.86 (s, 1H), δ 7.28 (s, 2H), δ 2.49 (s, 2H), δ 2.39 (s, 2H), δ 1.15 (s, 6H) ppm; 13C NMR (75 MHz, CD3OD) 174.8, 171.7, 151.2, 134.9, 129.8, 126.1, 116.4, 111.3, 103.8, 45.4, 33.1, 27.2 ppm; HRMS (ESI) Calcd for C14H16N4O2 (M+) 272.1273. Found 272.1282.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:18](Cl)(=[O:20])[CH3:19]>C(=S)=S>[C:18]([C:2]1[CH:3]=[CH:4][C:5]2[S:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]=2[CH:1]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)sc1ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc2sc3ccccc3c2c1

Procedure:
Dibenzothiophene (18.4g.) and anhydrous aluminium chloride (13.3g.) were mechanically stirred in carbon disulphide (100 ml.) while acetyl chloride (7.85g.) in carbon disulphide (20 ml.) was added dropwise over 0.5 hr. The temperature of the mixture rose to 30° C. After a total of 4 hr. stirring the mixture was poured on to ice and extracted with chloroform. The extract was washed with sodium bicarbonate solution, dried with magnesium sulphate, and evaporated. The residue was distilled under vacuum and a fraction, b.pt. 160°-180° C. at 0.6 mm. Hg, was extracted by boiling with ether, and the residue recrystallised twice from methanol to give colourless crystals of 2-acetyldibenzothiophene m.pt. 97°-100° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[CH3:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[S:21](Cl)(=[O:23])=[O:22]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:21]([C:13]1[N:12]([CH3:11])[C:20]2[C:15]([CH:14]=1)=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:22])=[O:23]
Reactant: Cc1noc(N)c1Br
Reactant: Cn1c(S(=O)(=O)Cl)cc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2cc3ccccc3n2C)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-1-methylindole-2-sulfonamide was prepared by the method of Example 41 with 4-bromo-3-methyl-5-aminoisoxazole (1.0 mmols, 0.18 g), NaH (2.5 mmols, 60 mg), 1-methylindole-2-sulfonyl chloride (1.2 mmols, 0.26 g) and THF (7 ml). Recrystallization from chloroform and hexane provided 0.28 g (77%) of a brown solid, m.p. 132-134° C.
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)[O:4]1.C[Si](C)(C)[O:12][C:13]([O:22][CH3:23])=[CH:14][C:15]([O:17][Si](C)(C)C)=[CH2:16].C([O-])(O)=O.[Na+]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:13]([CH:14]1[C:15](=[O:17])[CH2:16][CH:5]2[O:4][CH:3]1[CH2:7][CH2:6]2)([O:22][CH3:23])=[O:12]
Reactant: COC1CCC(OC)O1
Reactant: C=C(C=C(OC)O[Si](C)(C)C)O[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1C(=O)CC2CCC1O2
Reaction time: 0.5 h
Yield: 37 %

Procedure:
To 2,5-dimethoxytetrahydrofuran (39.6 g, 0.3 mol) in CH2Cl2 (anhydrous, 200 mL) at -78° C. under nitrogen was added TiCl4 (66 mL, 0.6 mol). After stirring for 30 min, 1,3-bis(trimethylsiloxy)-1-methoxybuta-1,3-diene, 2, (78 g, 0.3 mol) in CH2Cl2 (anhydrous, 400 mL) was added at a rate such that the internal temperature was maintained below -55° C. The mixture was stirred for 3 h. Saturated NaHCO3 was added until the mixture was neutral to pH paper. The aqueous layer was extracted with ether (3×1 L). The dried (MgSO4) combined organic layers were concentrated to dryness. The residue was purified by flash chromatography (20% EtOAc/hexanes) to afford 20.5 g (37%) of 3 as a light brown oil.
Reaction SMILES: I[C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.C1(C)C=CC=CC=1[Mg]Cl.C([Mg]Cl)(C)C.[F:25][C:26]1[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=[O:29].Cl>O1CCCC1>[F:25][C:26]1[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]([C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1)[OH:29]
Reactant: Ic1c[nH]c2ncncc12
Reactant: O=Cc1cccc([N+](=O)[O-])c1F
Agent: CC(C)[Mg]Cl
Agent: Cc1ccccc1[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(C(O)c2c[nH]c3ncncc23)c1F
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
To 5-iodo-7H-pyrrolo[2,3-d]pyrimidine (35, 1.911 g, 7.799 mmol) 9.75 mL of tetrahydrofuran was added, the suspension was cooled to −5° C., and o-tolylmagnesium chloride (8.19 mL, 1.00 M in tetrahydrofuran, 8.19 mmol) was added. The reaction solution was stirred and kept between −5° C. and 0° C. for 30 minutes, then isopropylmagnesium chloride (4.29 mL, 2.0 M in tetrahydrofuran, 8.58 mmol) was slowly added dropwise. The reaction mixture was stirred and kept at 0° C. for 30 minutes, then 2-fluoro-3-nitro-benzaldehyde (36, 1.58 g, 9.36 mmol) in 4 mL of tetrahydrofuran was added dropwise using a syringe. The reaction mixture was stirred at −5° C. for 30 minutes and quenched with 1 N hydrochloric acid (1 equivalent) and extracted with ethyl acetate and saturated sodium bicarbonate in water. The organic layer was dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with a gradient of 60-80% ethyl acetate in hexanes (with 4% acetic acid). Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (37, 699 mg). MS(ESI) [M+H+]+=289.4.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([S:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[F:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[C:40]([OH:42])[CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([S:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:38]1[CH:39]=[C:40]([OH:42])[CH:41]=[C:36]([F:35])[CH:37]=1
Reactant: C[C@H](Nc1ncnc(N)c1Br)c1nn2ccc(Sc3ccccc3)c2c(=O)n1-c1ccccc1
Reactant: OB(O)c1cc(O)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C[C@H](Nc1ncnc(N)c1-c1cc(O)cc(F)c1)c1nn2ccc(Sc3ccccc3)c2c(=O)n1-c1ccccc1
Yield: 2.4 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-3-phenyl-5-(phenylthio)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (230 mg, 0.29 mmol) was treated with (3-fluoro-5-hydroxyphenyl)boronic acid (68 mg, 0.44 mmol), sodium carbonate (2M, 660 μl, 1.32 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (36 mg, 0.04 mmol) according to the method described in Example 3 to give 4 mg (3% yield) of the title compound as a solid. Purity 91%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1COCC1>[CH3:17][S:18]([O:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9])(=[O:20])=[O:19]
Reactant: O=C1OCCN1CCO
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCN1CCOC1=O

Procedure:
The 3-(2-hydroxyethyl)-2-oxazolidinone (Frinton Laboratories, 0.16 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound which was used directly in the next reaction.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:12]2[CH:17]=[C:16](F)[CH:15]=[CH:14][C:13]=2[N+:19]([O-:21])=[O:20])[C:10]=1[CH3:11])=[O:5])[CH3:2].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:12]2[CH:17]=[C:16]([N:22]3[CH:26]=[CH:25][N:24]=[CH:23]3)[CH:15]=[CH:14][C:13]=2[N+:19]([O-:21])=[O:20])[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)c1ncn(-c2cc(F)ccc2[N+](=O)[O-])c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1ncn(-c2cc(-n3ccnc3)ccc2[N+](=O)[O-])c1C
Temperature: 80 °C
Reaction time: 16 h
Yield: 60.8 %

Procedure:
A mixture of 4-ethoxycarbonyl-5-methyl-1-(2-nitro-5-fluorophenyl)-1H-imidazole (20.0 g, 68 mmol), imidazole (4.7 g, 69 mmol), potassium carbonate (9.5 g, 69 mmol) and acetonitrile (150 ml) was stirred at 80° C. for 16 h. The solvent was removed under reduced pressure and the residue dissolved in ethyl acetate and washed twice with water. The organic phase was dried (MgSO4), filtered and evaporated in vacuo to give 14.1 g (61%) of 4-ethoxycarbonyl-5-methyl-1-(2-nitro-5-(1-imidazolyl) phenyl)-1H-imidazole.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH:19]([CH3:21])[CH3:20])[N:16]=[CH:17][N:18]=1)[N:7]=3.[CH3:24][C:25]([OH:42])([CH3:41])[CH2:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>O1CCOCC1.O.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]>[CH:19]([N:15]1[C:14]([C:8]2[N:7]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([C:30]5[CH:29]=[N:28][N:27]([CH2:26][C:25]([CH3:41])([OH:42])[CH3:24])[CH:31]=5)=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][N:10]3[CH:9]=2)=[N:18][CH:17]=[N:16]1)([CH3:21])[CH3:20]
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3cnn(CC(C)(C)O)c3)cc1OCC2
Temperature: 25 °C
Yield: 72.7 %

Procedure:
Following the procedure as for 182, a solution of 8-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene 194 (7.84 g, 20.95 mmol), 2-methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol (11.15 g, 41.90 mmol) and cesium carbonate (20.47 g, 62.8 mmol) in dioxan (380 mL) and water (38 mL) was degassed by evacuation/bubbling argon (×3). 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride, dichloromethane (1.71 g, 2.09 mmol) was added and the reaction mixture heated at reflux for 2 h. The reaction mixture was diluted with water (250 mL) and extracted with ethyl acetate (3×100 mL). The combined organic fractions were washed with brine (100 mL), dried (MgSO4), and concentrated in vacuo to give a dark brown slurry. The slurry was triturated with hot IPA (˜50 mL), allowed to cool to RT and filtered. The solid was washed with cold IPA (˜30 mL) and dried in vacuo to give 180 as an off-white solid (6.6 g, 73%). LS/MS (ESI+): m/z 434 (M+H). 1H NMR (400 MHz, DMSO) δ 8.37 (d, J=8.4, 1H), 8.16 (s, 1H), 7.95 (s, 1H), 7.91 (s, 2H), 7.39 (dd, J=8.4, 1.7, 1H), 7.28 (d, J=1.7, 1H), 5.90 (dt, J=13.0, 6.5, 1H), 4.72 (s, 1H), 4.52 (q, J=6.2, 4H), 4.04 (s, 2H), 1.49 (d, J=6.6, 6H), 1.10 (s, 6H)
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[O:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.[CH:17](O)=O.C=O>>[ClH:1].[ClH:1].[CH3:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[O:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17]
Reactant: O=CO
Reactant: Cc1ccncc1OC[C@@H]1CCCN1
Agent: C=O
Agent: Cl
Product: Cc1ccncc1OC[C@@H]1CCCN1C

Procedure:
To a 330 mg sample of 4methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine (from Example 27 above) was added a solution of formic acid/ formaldehyde (1:2,2 mL). The mixture was heated at reflux for 5 hours, and the volatiles were removed by evaporation. The residue was dissolved in 1 mL of 20% NaOH. The solution was extracted with CH2Cl2 (3X), then the organic layer was dried (Na2SO4) and concentrated. The crude product was purified by chromatography over silica gel to afford 295 mg of the title compound. MS (DCI/NH3) m/e: 207 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.17 (s, 1H), 8.12 (d, J=5.5 Hz, 1H), 7.06 (d, J=5.5 Hz, 1H), 4.07 (dd, J=3.3, 10.6 Hz, 1H), 3.98 (dd, J=7.4, 10.6 Hz, 1H), 3.15-3.08 (m, 1H), 2.76-2.68 (m, 1H), 2.53 (s, 3H), 2.38-2.25 (m, 1H), 2.26 (s, 3H), 2.12-1.67 (m, 4H).
Reaction SMILES: CS[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=1.[ClH:12]>>[Cl:12][C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=1
Reactant: Cl
Reactant: CSc1nc2cccnc2[nH]1
Product: Clc1nc2cccnc2[nH]1
Temperature: 0 °C

Procedure:
2-(Methylthio)-3H-imidazo[4,5-b]pyridine (3.5 g) was dissolved in conc. HCl (10 mL), and then the mixture was cooled to 0° C. Chlorine gas was bubbled through the mixture for 2 h in iced bath. The mixture was poured onto ice, and neutralized to pH 7 with aqueous ammonium solution. The precipitate was collected by filtration to give the title compound as white crystals (1.0 g).
Reaction SMILES: [CH3:1][S:2][S:3][C:4]([CH3:8])([CH3:7])[CH:5]=O.[NH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[C:17]([CH2:19][OH:20])[N:16]=[C:15]([CH2:21][OH:22])[CH:14]=1.C(OC(NCCOC1C=C(CO)N=C(CO)C=1)=O)(C)(C)C.C([BH3-])#N.[Na+].[OH-].[Na+]>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)C>[CH3:7][C:4]([S:3][S:2][CH3:1])([CH3:8])[CH2:5][NH:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH2:21][OH:22])[N:16]=[C:17]([CH2:19][OH:20])[CH:18]=1
Reactant: NCCOc1cc(CO)nc(CO)c1
Reactant: CSSC(C)(C)C=O
Agent: [Ti+4]
Agent: CC(C)(C)OC(=O)NCCOc1cc(CO)nc(CO)c1
Agent: CC(C)[O-]
Solvent: C1CCOC1
Solvent: CCO
Product: CSSC(C)(C)CNCCOc1cc(CO)nc(CO)c1
Reaction time: 0.33 h

Procedure:
270 μl of 2-(methyldithio)isobutyraldehyde and 730 μl of titanium isopropoxide are added to a suspension of 390 mg of 4-[2-aminoethoxy]-2,6-bis(hydroxymethyl)pyridine (prepared after deprotection of the Boc group from 4-(2-(tert-butoxycarbonylamino)ethoxy)-2,6-bis(hydroxymethyl)pyridine described on page 101 of WO 07085930) in 2 ml of THF. After 20 min, an additional 270 μl of 2-(methyldithio)isobutyraldehyde and an additional 730 μl of titanium isopropoxide are added and the mixture is stirred at AT for 2 h. 6 ml of ethanol are then added to the mixture, the mixture is stirred at AT for 20 min and then 124 mg of sodium cyanoborohydride are added to the mixture. After stirring for 45 min, an additional 124 mg of sodium cyanoborohydride are added and, after stirring for 1 h, the mixture is concentrated under RP and the residue is diluted in AcOEt and water. The resulting precipitate is filtered off and dissolved in a 1M aqueous HCl solution. The aqueous phase obtained is brought to basic pH with a 5M aqueous sodium hydroxide solution and extracted three times with DCM, and the combined organic phases are concentrated under RP. 322 mg of 4-[2-(2-methyl-2-(methyldisulphanyl)propylamino)ethoxy]-2,6-bis(hydroxymethyl)pyridine are thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=2)[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[O:4]>O1CCCC1.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[O:4]
Reactant: COC(=O)c1ccc(-c2cccc([N+](=O)[O-])c2)cc1C(=O)OC
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2cccc(N)c2)cc1C(=O)OC

Procedure:
n.m.r. (DMSO-d6) δ values include 3.77 (s, 2 H), 3.91 (s, 3 H), 3.92 (s, 3 H), 6.70 (m, 1 H), 6.89 (s, 1 H), 6.97 (d, 1 H), 7.21 (d, 1 H), 7.69 (m, 1 H), 7.79 (d, 1 H), 7.85 (m, 1 H); from 3′-nitro-[1,1′-biphenyl]-3,4-dicarboxylic acid dimethyl ester (0.8 g) and 10% Pd/C (560 mg) in tetrahydrofuran (30 mL).