Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([O:6][C@@H]2CCC[C@H]2O)=[CH:4][C:3]=1F.[Br:16][C:17]1[N:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C12OC1CCCC2>>[Br:16][C:17]1[N:22]=[CH:21][C:20]([O:23][C@@H:4]2[CH2:3][CH2:2][CH2:14][CH2:13][C@H:5]2[OH:6])=[CH:19][CH:18]=1
Reactant: Oc1ccc(Br)nc1
Reactant: O[C@@H]1CCC[C@H]1Oc1ccc(Br)c(F)c1
Agent: C1CCC2OC2C1
Product: O[C@@H]1CCCC[C@H]1Oc1ccc(Br)nc1

Procedure:
The title compound of Step 1 was prepared according to the general procedure for the synthesis of trans-2-(4-bromo-3-fluorophenoxy)cyclopentanol in Preparation 3, except that 6-bromopyridin-3-ol was used instead of 4-bromo-3-fluorophenol, and 7-oxabicyclo[4.1.0]heptane in place of 6-oxabicyclo[3.1.0]hexane. The crude product (preparation run in four batches) was recrystallized from heptane to provide trans-2-[(6-bromopyridin-3-yl)oxy]cyclohexanol as an off-white solid. Yield: 11.09 g, 40.75 mmol, 46%. 1H NMR (500 MHz, CDCl3) δ 1.27-1.46 (m, 4H), 1.76-1.80 (m, 2H), 2.09-2.13 (m, 2H), 2.41 (d, J=2.6 Hz, 1H), 3.74 (m, 1H), 4.00 (m, 1H), 7.17 (dd, J=8.7, 3.1 Hz, 1H), 7.37 (d, J=8.5 Hz, 1H), 8.10 (d, J=3.0 Hz, 1H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]1([CH2:15][O:16][C:17]2[CH:25]=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>CN(C=O)C>[Br:1][C:25]1[C:17]([O:16][CH2:15][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:18][C:19]2[O:23][CH2:22][O:21][C:20]=2[CH:24]=1
Reactant: c1ccc(COc2ccc3c(c2)OCO3)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cc2c(cc1OCc1ccccc1)OCO2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-bromosuccinimide (10.7 g, 0.06 mol) in dry DMF (70 ml) was added dropwise and with stirring a solution of 5-phenylmethoxy-1,3-benzodioxole (13.68, 0.06 mol) in dry DMF (80 ml). The resulting solution was stirred for 24 h at room temperature, poured into 300 ml of H2O and extracted with chloroform (3×70 ml). The organic layer was washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was recrystallized from absolute EtOH affording 17.4 g (94.5%) of 6-bromo-5-phenylmethoxy)-1,3-benzodioxole as white crystals mp 61.5°-62° C.; NMR (CDCl3, 90 MHz) δ 5.04 (S, 2H, CH2Ph), 5.91 (S, 2H, OCH2O), 6.56 (S, 1H, ArH), 6.99 (S, 1H, ArH), 7.14-7.63 (m, 5H, CH2Ph). Anal. calcd. for C14H11BrO3 : C, 54.75; H, 3.61; Br, 26.01. Found: C, 54.81; H, 3.64; Br, 25.68.
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][NH:13][CH3:14].O>CCO>[CH3:12][N:13]([CH3:14])[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CNC
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCO
Solvent: O
Product: CN(C)c1ccc(N)cc1[N+](=O)[O-]
Yield: 98.3 %

Procedure:
In an alternative preparation: 4-Fluoro-3-nitro-aniline (20 g, 128 mmol) was dissolved in EtOH (300 mL) and dimethylamine (5.6 M solution in EtOH, 360 mL, 2.02 mol) was added in a steady stream. After refluxing for 18 h, the reaction mixture was cooled and 100 mL water was added. EtOH was removed by evaporation and the residue was extracted with Et2O (3×100 mL). The combined organics were washed with brine, filtered, and the solvent was evaporated to afford 22.8 g of 4-(dimethylamino)-3-nitroaniline as a black oil. This was dissolved in EtOH (80 mL) and HNO3 (69% aq, 18.5 mL, 22.1 mmol) added dropwise followed by cyanamide (50% wt in water, 37 mL, 476 mmol). The mixture was heated at reflux for 18 h. Once cooled, the mixture was poured into Et2I (1 L). The ethereal supernatant was decanted and the residue was treated with propan-2-ol, followed by Et2O to give 19.0 g of the corresponding guanidine nitrate as a tan solid. This was stirred with K2CO3 (15.04 g, 108.8 mmol) in 2-methoxyethanol (250 mL) for 10 min before adding 3-dimethylamino-1-(2,4-dimethylthiazol-5-yl)-propenone (9.53 g, 45.33 mmol). The mixture was heated at 125° C. for 18 h. The reaction mixture was concentrated and diluted with EtOAc, filtered through a pad of silica and evaporated to give a dark oil, which was purified by chromatography, using EtOAc to elute the title product as a reddish solid. Recrystallisation from toluene yielded 7.3 g pure title compounds.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8](Br)=[CH:7][C:5]=2[N:6]=1.CN(C)CCN(C)C.C([Li])(C)(C)C.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C.S(=O)(=O)(O)O>C1COCC1.CCCCC>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([B:25]([OH:30])[OH:26])=[CH:7][C:5]=2[N:6]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Nc1nc2cc(Br)ccc2s1
Agent: CN(C)CCN(C)C
Agent: O=S(=O)(O)O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: Nc1nc2cc(B(O)O)ccc2s1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of Intermediate 63 (459.1 mg) in anhydrous THF (30 ml) was added with N,N,N′,N′-tetramethylethylenediamine (1.51 ml, WAKO), cooled to −78° C. under argon atmosphere, then added dropwise with 1.62 M solution of t-butyllithium in pentane (7.06 ml) and stirred for 30 minutes. The reaction mixture was added dropwise with (iPrO)3B (2.77 ml), stirred for 30 minutes, then warmed to room temperature and further stirred for 1.5 hours. The reaction mixture was added with 0.5 M aqueous sulfuric acid (7.5 mL) and extracted with diethyl ether (50 ml×3). The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure to obtain crude 2-amino-5-benzothiazoleboronic acid. According to the procedure described in the synthesis method of Compound of Example 001 (Preparation Method 4, Step d-1) with the modifications that the reaction was carried out for 12 hours, and the purification was performed by flash column chromatography (hexane:ethyl acetate=2:1), the above compound was reacted with Intermediate 3 (344 mg), 2 M aqueous sodium carbonate (4.5 ml) and (Ph3P)4Pd (179 mg) and treated to obtain the title compound (Compound No. 284, 76 mg).
Reaction SMILES: [C:1]1([O:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[C:21]2[CH2:27][CH2:28][NH2:29]>C(Cl)Cl>[C:1]1([O:7][C:8](=[O:9])[NH:29][CH2:28][CH2:27][C:21]2[C:20]3[C:24](=[CH:25][CH:26]=[C:18]([F:17])[CH:19]=3)[NH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1c[nH]c2ccc(F)cc12
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NCCc1c[nH]c2ccc(F)cc12)Oc1ccccc1
Reaction time: 24 h

Procedure:
Chloroformic acid phenyl ester (310 μl, 2.45 mmole) and pyridine (415 μl, 5.13 mmole) were added to a solution of 2-(5-fluoro-1H-indol-3-yl)-ethylamine (0.5 g, 2.33 mmole) in abs. DCM (10 ml). Stirring was then performed for 24 h at RT. Working up was performed by extracting the batch with water (2×20 ml), with 1M HCl (2×20 ml) and with 1M NaOH (2×20 ml). The organic phase was dried with Na2SO4 and evaporated. [2-(5-Fluoro-1H-indol-3-yl)-ethyl]-carbamic acid phenyl ester was obtained as a colorless solid in a yield of 0.69 g (100%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>C(O)CCC>[OH:28][C@H:25]1[CH2:26][CH2:27][C@H:22]([NH:21][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:23][CH2:24]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=C(Nc1nc2cccc(Cl)n2n1)c1cccnc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: O=C(Nc1nc2cccc(N[C@H]3CC[C@H](O)CC3)n2n1)c1cccnc1
Reaction time: 0.67 h

Procedure:
A solution of N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B4), 100 mg; 0.37 mmol; 1.0 eq.), trans-4-aminocyclohexanol hydrochloride (ABCR), 277 mg; 1.83 mmol; 5.0 eq.), DIEA (472 mg; 3.65 mmol; 10.0 eq.) in n-butanol (1.0 mL) was heated at 220° C. for 20 min under microwave irradiation. The reaction mixture was directly purified by reverse phase chromatography (Starting with water then up to 60% ACN in water in 40 min.). The title compound was isolated after lyophilisation as a white powder (31 mg, 24%). HPLC, Rt: 1.77 min. (purity 80.2%). LC/MS, M+(ESI): 353.1, M−(ESI): 351.1.
Reaction SMILES: [C:1]([C:3]1[N:7]([C@@H:8]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]2[OH:10])[CH:6]=[N:5][C:4]=1[C:17]#[N:18])#[CH:2].[OH:19]O>N.CO>[C:1]([C:3]1[N:7]([C@@H:8]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]2[OH:10])[CH:6]=[N:5][C:4]=1[C:17]([NH2:18])=[O:19])#[CH:2]
Reactant: C#Cc1c(C#N)ncn1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: OO
Agent: N
Solvent: CO
Product: C#Cc1c(C(N)=O)ncn1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 127 mg (0.51 mmol) of 5-ethynyl-1-β-D-ribofuranosylimidazole-4-carbonitrile dissolved in 6 ml of a solvent mixture of aqueous ammonia and methanol (1:1) was added 0.5 ml of hydrogen peroxide, and the reaction was carried out with stirring at room temperature for 45 minutes. After the reaction, the solvent was evaporated, and the residue was adsorbed onto chloroform solvent mixture, and crystallized from ethanol to obtain white crystals of 5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[C:5]([CH2:9][CH2:10][CH2:11][CH3:12])=[C:4]([CH3:13])[N:3]=1.P(Cl)(Cl)([Cl:16])=O>>[CH2:9]([C:5]1[C:6]([Cl:16])=[N:7][C:2]([NH2:1])=[N:3][C:4]=1[CH3:13])[CH2:10][CH2:11][CH3:12]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCc1c(C)nc(N)nc1O
Product: CCCCc1c(C)nc(N)nc1Cl
Yield: 29 %

Procedure:
2-Amino-5-butyl-6-methylpyrimidine-4-ol (1.0 g, 5.52 mmol) and phosphorus oxychloride (12 ml) were refluxed for 3 hours. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography(n-hexane: ethyl acetate=2:1) to give the object compound (325 mg, 29%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[C:7]([CH3:21])=[N:8][C:9]2[N:10]([N:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:15]=2)[C:11]=1O)[CH3:2].CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:34]>>[Cl:34][C:11]1[N:10]2[N:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:15]=[C:9]2[N:8]=[C:7]([CH3:21])[C:6]=1[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:22]
Reactant: CCOC(=O)Cc1c(C)nc2cc(C(=O)OCC)nn2c1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)Cc1c(C)nc2cc(C(=O)OCC)nn2c1Cl
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 83 %

Procedure:
A mixture of ethyl 6-(2-ethoxy-2-oxoethyl)-7-hydroxy-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (25 g, 81 mmol), and N,N-dimethylaniline (20.6 mL, 163 mmol) in POCl3 (100 mL) was heated at 120° C. for 3 h. Then the reaction was cooled to rt and concentrated in vacuo to half the volume. It was poured into a large quantity of ice water and stirred for 20 min. Precipitates formed and were collected by filtration. This solid was dissolved in ethyl acetate (1 L) and washed with water. The aqueous phase was back-extracted with ethyl acetate and the combined organic layers were washed with brine (200 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude was then triturated with EtOAc/hexane to afford ethyl 7-chloro-6-(2-ethoxy-2-oxoethyl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (22 g, 67.5 mmol, 83% yield) as light yellow solid. 1H NMR (500 MHz, CDCl3) δ 7.21 (s, 1H), 4.52 (q, J=7.2 Hz, 2H), 4.24 (q, J=7.2 Hz, 2H), 3.94 (s, 2H), 2.66 (s, 3H), 1.48 (t, J=7.0 Hz, 3H), 1.30 (t, J=7.2 Hz, 3H). LCMS (M+1)=326.2.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]1[CH:25]=[CH:24][N:23]([C:26]2([CH2:30][C:31]#[N:32])[CH2:29][NH:28][CH2:27]2)[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]1[CH:25]=[CH:24][N:23]([C:26]2([CH2:30][C:31]#[N:32])[CH2:29][N:28]([CH3:35])[CH2:27]2)[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nnc2ccc3c(cc(-c4ccn(C5(CC#N)CNC5)n4)n3Cc3ccccc3)n12
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nnc2ccc3c(cc(-c4ccn(C5(CC#N)CN(C)C5)n4)n3Cc3ccccc3)n12
Reaction time: 0.3 h

Procedure:
To a mixture of {3-[3-(6-benzyl-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (11 mg, 0.026 mmol, from Example 90) in DCM (0.50 mL) was added formaldehyde (10 mg, 0.13 mmol, 37 wt % in water, Aldrich), followed by sodium triacetoxyborohydride (16 mg, 0.078 mmol). The reaction was complete in 18 minutes. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH) afforded product. Yield: (8.2 mg, 72%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].ClCCl.[CH2:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=[O:35])[CH:29]=[CH:28]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(N(CC)CC)C>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:19]([CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=[O:35])[CH:29]=[CH:28]2)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:7])=[O:6]
Reactant: O=c1ccc2cc(OCCCCNCc3ccccc3)ccc2[nH]1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1ccc2cc(OCCCCN(Cc3ccccc3)S(=O)(=O)CCCCl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
6.6 ml of 3-chloropropanesulfonyl chloride was dropwise added, at 0° C., to a dichloromethane solution containing 8 g of 6-(4-benzylaminobutoxy)carbostyril and 7.6 ml of triethylamine. The mixture was stirred at room temperature for 1 day. The reaction mixture was washed with 10% hydrochloric acid and water in this order and dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was dissolved in 30 ml of dioxane. To the solution was added 10.ml of a 10% potassium hydroxide solution, followed by stirring at room temperature for 30 minutes. The reaction mixture was neutralized with 10% hydrochloric acid, followed by extraction with chloroform. The extract was dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was crystallized from diethyl ether to obtain 7.3 g of 6-{4-[N-(3-chloro-propylsulfonyl)-N-benzylamino]butoxy}carbostyril.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22](=[O:31])[C:23]3[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:30])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22](=[O:31])[C:23]3[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:30])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:32]([F:33])([F:34])[F:35]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1c(F)cccc1Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1c(F)cccc1Cl
Temperature: 25 °C
Yield: 69.1 %

Procedure:
A mixture of 4-chloro-N-[5-chloro-2-(2-chloro-6-fluoro-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (100 mg, 0.17 mmol) in 4 M HCl in dioxane (5 mL) and water (1 mL) was heated at reflux for 3 h. The reaction mixture was cooled to room temperature, evaporated to dryness, and neutralized with saturated aqueous NaHCO3 solution to pH 7-8. The mixture was extracted with EtOAc (2×25 mL), dried (Na2SO4), filtered and concentrated. The residual solid was purified by flash column chromatography (70% EtOAc-hexanes) on silica gel to afford 4-chloro-N-[5-chloro-2-(2-chloro-6-fluoro-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (62 mg) as an off white solid in 67% yield. MS m/z: 527 (M+H), 549 (M+Na).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.B>C(COC)OC.O1CCCC1>[CH2:9]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([I:1])=[CH:3][CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccc(I)cc1
Reactant: O=Cc1ccccc1
Agent: B
Solvent: C1CCOC1
Solvent: COCCOC
Product: Ic1ccc(NCc2ccccc2)cc1

Procedure:
2.19 Grams of p-iodoaniline and 1.06 g of benzaldehyde were dissolved in 50 ml of glyme and the resulting solution heated to 60° for two hours. The temperature was maintained for an additional hour after the addition of 30 ml of a 1 M solution of borane in tetrahydrofuran. The excess boron hydride was then destroyed by the addition of about 10 ml of methanol. To this mixture was added 100 ml of a 0.3 M solution of sodium hydroxide and the resulting solution extracted with 100 ml of ether to yield N-benzyl-p-iodoaniline, Rf =0.70.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]=[CH:6][CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH3:2].C(O[CH2:23][N:24]([CH2:32][Si](C)(C)C)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)CCCC.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]([C@H:5]1[C@@H:6]([CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:32][N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:23]1)=[O:16])[CH3:2]
Reactant: CCCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)C=CCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1CNC(=O)OC(C)(C)C
Reaction time: 0.17 h

Procedure:
To a solution of 2 g of 4-tert-butoxycarbonylamino-but-2-enoic acid ethyl ester (8.72 mmol) and 5.12 g N-[(pentyloxy)methyl]-N-[(trimethylsilyl)methyl]-benzene-methanamine (17.4 mmol) in ml dichloromethane was added 10 micro-1. trifluoroacetic acid. The reaction was monitored by TLC. The reaction was complete after 10 min. The mixture was diluted with dichloromethane, washed with sat. sodium bicarbonate solution and brine, dried over Mg sulfate, filtered and the filtrate evaporated. The residue was purified by filtration over a short silica column, using a 7/3 hexane/ethyl acetate mixture as eluent.
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].[Br:5][C:6]1[CH:11]=[C:10]([N+]([O-])=O)[CH:9]=[C:8]([Br:15])[N:7]=1>>[Br:5][C:6]1[CH:11]=[C:10]([O:2][CH3:1])[CH:9]=[C:8]([Br:15])[N:7]=1
Reactant: O=[N+]([O-])c1cc(Br)nc(Br)c1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Product: COc1cc(Br)nc(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.1 %

Procedure:
Methanol (1.48 g, 46.1 mmol) is slowly added to a cooled suspension (0° C.) of NaH (2.12 g, 53.2 mmol, 60% dispersion in mineral oil, washed with hexane prior to use) in THF (20 mL). Upon completion of the addition the mixture is stirred at 0° C. for 150 min before 2,6-dibromo-4-nitropyridine (10.0 g, 35.4 mmol) is added. The temperature rises to 14° C. The mixture is stirred at rt for 3 h before the reaction is quenched with sat. aq. NH4Cl solution. The mixture is diluted with water and extracted twice with EA (250 mL). The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with DCM to give 2,6-dibromo-4-methoxy-pyridine (6.43 g) as an off-white solid; LC-MS: tR=0.90 min, [M+1]+=267.75.
Reaction SMILES: C(OC(=O)[N:7]([CH2:23][CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([NH:34][C:35]3[O:36][C:37]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:38][N:39]=3)[CH:32]=2)[NH:27][C:26]=1[C:46]1[CH:51]=[C:50]([CH3:52])[CH:49]=[C:48]([CH3:53])[CH:47]=1)[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][CH:13]=1)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH3:52][C:50]1[CH:51]=[C:46]([C:26]2[NH:27][C:28]3[C:33]([C:25]=2[CH2:24][CH2:23][NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][S:19]([CH3:22])(=[O:20])=[O:21])=[CH:16][CH:17]=2)=[CH:32][C:31]([NH:34][C:35]2[O:36][C:37]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:38][N:39]=2)=[CH:30][CH:29]=3)[CH:47]=[C:48]([CH3:53])[CH:49]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(Nc4ncc(-c5ccccc5)o4)cc3c2CCN(CCCCc2ccc(NS(C)(=O)=O)cc2)C(=O)OC(C)(C)C)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)cc(-c2[nH]c3ccc(Nc4ncc(-c5ccccc5)o4)cc3c2CCNCCCCc2ccc(NS(C)(=O)=O)cc2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 92.4 %

Procedure:
To a solution of {2-[2-(3,5-dimethylphenyl)-5-(5-phenyloxazol-2-ylamino)-1H-indol-3-yl]-ethyl}-[4-(4-methanesulfonylaminophenyl)butyl]-carbamic acid tert-butyl ester (10 mg in 0.80 mL methylene chloride) at 0° C. was added 0.050 mL anisole followed by 0.20 mL trifluoroacetic acid and the mixture stirred at 0° C. After 3 hours, the mixture was concentrated in vacuo and the residual acid removed by azeotrope with toluene. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 90:7:1) gave the title compound (8 mg). m/e 648 (M+H)
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[Si:13]([O:20][CH2:21][CH2:22]Br)([C:16](C)(C)C)([CH3:15])C>CN(C=O)C>[CH2:5]([CH:21]([O:20][SiH:13]([CH3:15])[CH3:16])[CH2:22][N:9]1[C:10]2[C:6](=[CH:5][C:4]([Br:3])=[CH:12][CH:11]=2)[CH:7]=[CH:8]1)[CH2:4][CH2:12][CH3:11]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(Cn1ccc2cc(Br)ccc21)O[SiH](C)C
Reaction time: 1 h
Yield: 151.8 %

Procedure:
To a slurry of sodium hydride (12 g, 0.3 mol, 60% dispersion in oil) in DMF (200 mL) was added dropwise a solution of 5-bromoindole (50 g, 0.255 mol) in DMF (300 mL). After stirring for 15 minutes 2-t-butyldimethylsilyloxyethyl bromide (60 g, 0.255 mol, neat) was added dropwise and the reaction mixture stirred for 1 hour. The reaction mixture was partitioned between ice water and ethyl ether. The organic fraction was washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by column chromatography (silica, 3:1 hexane/acetone) to give 68.6 g of the title compound as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]([CH3:17])[C:11]2[CH2:15][O:14][C:13](=[O:16])[CH:12]=2)[CH:5]=[N:6][C:7]=1[Cl:8].C(N(CC)CC)C.[Cl:25]N1C(=O)CCC1=O>C(#N)C>[Cl:25][C:12]1[C:13](=[O:16])[O:14][CH2:15][C:11]=1[N:10]([CH2:9][C:4]1[CH:5]=[N:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH3:17]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN(Cc1cnc(Cl)c(Cl)c1)C1=CC(=O)OC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(Cc1cnc(Cl)c(Cl)c1)C1=C(Cl)C(=O)OC1
Reaction time: 1 h
Yield: 84.3 %

Procedure:
162 mg (0.59 mmol) of 4-[[(5,6-dichloropyridin-3-yl)methyl](methyl)amino]furan-2(5H)-one (10) are dissolved in 20 ml of acetonitrile, and 90 μl (0.65 mmol) of triethylamine and 158 mg (1.19 mmol) of N-chlorosuccinimide are added at room temperature. After 1 hour of stirring, the mixture is concentrated under reduced pressure. Purification of the residue by column chromato-graphy on silica gel (silica gel 60-Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (2:1) gives 153 mg (67% of theory) of 3-chloro-4-[[(5,6-dichloropyridin-3-yl)methyl](methyl)amino]furan-2(5H)-one.