Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:19])([O:4][C:5]([NH:7][C:8](=[N:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])SC)=[O:6])[CH3:3].[NH:20]1[CH2:25][CH2:24][S:23][CH2:22][CH2:21]1.CCN(CC)CC.CS>CN(C=O)C.CCOC(C)=O.[Hg]Cl>[C:2]([O:4][C:5](=[O:6])[NH:7][C:8](=[N:11][C:12]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:18])[N:20]1[CH2:25][CH2:24][S:23][CH2:22][CH2:21]1)([CH3:1])([CH3:3])[CH3:19]
Reactant: C1CSCCN1
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: CS
Agent: Cl[Hg]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCSCC1
Reaction time: 18 h

Procedure:
A solution of [[[(1,1-dimethylethoxy)carbonyl]amino]-(methylthio)methylene]-carbamic acid, 1,1-dimethylethyl ester [CAS 107819-90-9] (21 g, 0.0723 mol) in DMF (450 mL) was treated sequentially with thiomorpholine (7 mL, 0.0723 mol), mercury chloride (19.6 g, 0.0723 mol), and Et3N (30 mL, 0.22 mol) and the reaction mixture was stirred for 18 h. The mixture was diluted with EtOAc and filtered through a pad of diatomaceous earth. The filtrate was concentrated, diluted with water and EtOAc and filtered again through a pad of diatomaceous earth. The filtrate aqueous layer was separated and extracted with EtOAc (2×). The combined organic layers were washed with water, then satd. aq. NaCl, dried, and concentrated. The solid was triturated with 20% Et2O/40-60° C. petrol. The solid was filtered off and was washed with 20% Et2O/40-60° C. petrol followed by 40-60° C. petrol. The solid was dried under vacuum to give 21.2 g (85%) as a white solid. Note: The reaction was performed with a trap for gaseous loss of methanethiol.
Reaction SMILES: [Br:1]Br.[BrH:3].[C:4]([C:7]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)(=[O:6])[CH3:5].CCOCC>C(Cl)Cl>[BrH:1].[Br:3][CH2:5][C:4]([C:7]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)=[O:6]
Reactant: BrBr
Reactant: CC(=O)C1(c2ccccc2)CCNCC1
Agent: Br
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(CBr)C1(c2ccccc2)CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
7.9 g of bromine are added rapidly at RT to a suspension of 14 g of 4-acetyl-4-phenylpiperidine hydrobromide in 200 ml of DCM and the reaction mixture is stirred overnight at RT. It is diluted by the addition of 200 ml of ether and the precipitate formed is wrung and washed with ether to give 16.7 g of the expected product after drying under vacuum.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:32])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([O:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])[CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1.Cl.O>C(OCC)C.[Cl-].[Zn+2].[Cl-]>[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([OH:32])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([O:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])[CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(Cc1ccc(C)c(OC(F)(F)C(F)F)c1)C(=O)c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(Cc1ccc(C)c(OC(F)(F)C(F)F)c1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
To a solution of zinc chloride (3.04 g, 22.3 mmol) in diethyl ether (70 ml) was added sodium borohydride (1.69 g, 44.6 mmol), and the mixture was stirred at room temperature for 30 min. Insoluble material was filtered off and a solution of ethyl 3-(4-fluorophenyl)-2-((4-methyl-3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)-3-oxopropionate (4.8 g, 11.2 mmol) in diethyl ether (50 ml) was added to the filtrate. The mixture was stirred at room temperature for 30 min. and 1N hydrochloric acid was added to the reaction solution under ice-cooling to quench the reaction. Then, water (100 ml) was added and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((4-methyl-3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)propionate (4.69 g, 97%) as a colorless oil.
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[CH2:18][N:19]([CH3:21])[CH3:20])C1C=CC=CC=1>C(O)C.[Pd]>[CH3:21][N:19]([CH2:18][CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][CH2:17][NH:8]1)[CH3:20]
Reactant: CN(C)CC1c2ccccc2CCN1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CN(C)CC1NCCc2ccccc21
Reaction time: 4 h
Yield: 98.2 %

Procedure:
10.5 g of 2-benzyl-1-dimethylaminomethyl-1,2,3,4-tetrahydroisoquinoline were dissolved in 250 ml of 95% ethanol, 1.8 g of 5% Pd on charcoal were added, and the mixture was hydrogenated at room pressure and temperature for 4 hours. After filtration, and evaporation i.v., 7 g of product were obtained, sufficiently pure for the subsequent step.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]([C:15]([F:18])([F:17])[F:16])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(O)C.[NH4+].[Cl-]>[Fe]>[NH2:12][C:11]1[C:2]([CH3:1])=[C:3]([CH:8]=[C:9]([C:15]([F:16])([F:17])[F:18])[CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)c1cc(C(F)(F)F)cc(N)c1C
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 2-methyl-3-nitro-5-(trifluoromethyl)benzoate (1 equiv.) in ethanol (2 mL per 1 mmol), was added NH4Cl solution (5.1 equiv., dissolved in water. Volume of water equivalent to volume of ethanol) followed by Fe powder (8 equiv.). the resulting reaction mixture was stirred at 90° C. for 1 h. On completion, the reaction mixture was filtered and the filtrate concentrated till dryness. The resulting solid was dissolved in saturated sodium bicarbonate solution and the aqueous layer extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford solid methyl 3-amino-2-methyl-5-(trifluoromethyl)benzoate in quantitative yield.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][CH2:8][OH:9])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[CH2:11]([C:27](O)=[O:28])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.ClCCCl>[OH:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][C:16]2[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][C:27]([O:9][CH2:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([OH:10])=[CH:2][CH:1]=3)=[O:28])=[CH:14][CH:15]=2)=[CH:25][CH:24]=1
Reactant: O=C(O)CCc1ccc(Oc2ccc(O)cc2)cc1
Reactant: OCCc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCCl
Product: O=C(CCc1ccc(Oc2ccc(O)cc2)cc1)OCCc1ccc(O)cc1
Temperature: 25 °C

Procedure:
Into a 500 mL round bottomed flask fitted with an overhead stirrer, and a modified Dean-stark trap for solvents heavier than water are added 10 g (72 mmol) of tyrosol, 30 g (78 mmol) of desaminothyronine, 0.65 g (3.4 mmol) of 4-toluenesulfonic acid monohydrate and 200 mL of 1,2-dichloroethane (DCE). A water-cooled reflux condenser is placed on top of the modified Dean-stark trap and the contents of the flask are heated to reflux while being stirred. The reaction is continued until approximately 1.4 mL of water collected in the modified Dean-stark trap above the DCE and the water collection essentially stops (about 4 hours of reflux). The reaction mixture is cooled to room temperature and the crude product is dissolved in 100 mL of ethyl acetate and washed twice with 100 mL portions of 5% sodium bicarbonate solution. After drying over magnesium sulfate the organic layer is concentrated and precipitated with hexane. The resulting white crystalline solid is collected by filtration and dried in a vacuum oven at 25° C. The product is characterized by elemental analysis, hplc, and 1H NMR.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[OH-].[K+].Cl[O-].[Na+]>C(O)C.CCOCC>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[O:11][C:8]1[CH:9]=[CH:10][C:4]2=[N+:1]([O-:3])[O:2][N:6]=[C:5]2[CH:7]=1
Reactant: Nc1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCO
Solvent: CCOCC
Product: [O-][n+]1onc2cc(Oc3ccc(Cl)cc3Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Nitro-5-(2,4-dichlorophenoxy)aniline (1.6 g, 5.4 mmol) is dissolved in a solution of potassium hydroxide (0.33 g, 5.9 mmol) in ~150 ml of ethanol. The mixture is cooled to -5°, and sodium hypochlorite (17 ml of 5.3% solution, 0.9 g, 11.8 mmol) is added dropwise over 20 minutes. The reaction is stirred at RT overnight, then cooled to 10° and ~2 ml of sodium hypochlorite is added. One hour later, the reaction is stripped. The residue is taken up in ether, washed with water, dried, stripped and purified by prep. TLC (10% ethyl acetate/hexane) to yield 5-(2,4-dichlorophenoxy)benzo-2,1,3-oxadiazole N-oxide, m.p. 92°-93°.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[CH:16]=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:4]1.[N:17]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[C:23]#[N:24])=[C:18]=[O:19]>O1CCOCC1>[N:11]1[C:10]2[NH:14][CH:15]=[CH:16][C:9]=2[C:8]([N:5]2[CH2:6][CH2:7][C@@H:3]([N:2]([CH3:1])[C:18]([NH:17][C:20]3[CH:27]=[CH:26][CH:25]=[C:22]([C:23]#[N:24])[CH:21]=3)=[O:19])[CH2:4]2)=[N:13][CH:12]=1
Reactant: CN[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Reactant: N#Cc1cccc(N=C=O)c1
Solvent: C1COCCO1
Product: CN(C(=O)Nc1cccc(C#N)c1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1

Procedure:
A solution of (R)—N-methyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine (50 mg, 0.230 mmol) and 3-isocyanatobenzonitrile (37 mg, 0.257 mmol) in 1,4-dioxane (1 mL) was refluxed overnight. The volatiles were removed under vacuum and the residue was purified by flash chromatography to give the title compound. MS (m/z): 362 (M+H)+.
Reaction SMILES: [CH:1](=O)[CH3:2].ClC(Cl)C.[C:8]1([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][C:18]([C:24]4[N:25]=[C:26]([CH2:34][CH:35]5[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]5)[N:27]5[CH:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]=45)=[CH:19][CH:20]=3)[N:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:1]([N:38]1[CH2:39][CH2:40][CH:35]([CH2:34][C:26]2[N:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]3=[C:24]([C:18]3[CH:17]=[C:16]4[C:21]([CH:22]=[CH:23][C:14]([C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=5)=[N:15]4)=[CH:20][CH:19]=3)[N:25]=2)[CH2:36][CH2:37]1)[CH3:2]
Reactant: Nc1nccn2c(CC3CCNCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCN1CCC(Cc2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetaldehyde (6.76 mg, 0.15 mmol) in dichloroethane (5 mL, 2 equiv) was added to 1-(2-Phenyl-quinolin-7-yl)-3-piperidin-4-ylmethyl-imidazo[1,5-a]pyrazin-8-ylamine (100.00 mg, 0.23 mmol) and sodium triacetoxyborohydride (65.0 mg, 306.8 mmol). The reaction mixture was stirred at rt overnight. The crude product was purified by a 5 g Jones silica gel (dry loaded with silica, wetted with 100% CH2Cl2, eluted with 100% CH2Cl2→3% (7N NH3) in MeOH/CH2Cl2→6% (7N NH3) in MeOH/CH2Cl2) and afforded the desired product. 1H NMR (400 MHz, METHANOL-d) δ 8.38 (1 H, d, J=8.66), 8.25 (1 H, s), 8.08 (2 H, dd, J=1.64 Hz, J=1.08), 8.00 (2 H, m), 7.79 (1 H, dd, J=2.06, J=1.70), 7.51 (1 H, d, J=5.15), 7.44 (3 H, m), 7.00 (1 H, d, J=5.12), 3.06 (2 H, d, J=10.88), 2.97 (2 H, d, J=7.08), 2.54 (2 H, d, J=5.80), 2.18 (2 H, m), 1.98 (1H, m), 1.75 (2 H, d, J=13.12), 1.43 (2 H, m), 1.07 (3 H, t); MS (ES+): m/z 435.12/436.10 (15/5) [MH+]; HPLC: tR=1.71 min (OpenLynx, polar—5 min).
Reaction SMILES: CI.[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12][C:13]#[N:14].[C:15](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.CO>[CH3:15][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12][C:13]#[N:14]
Reactant: O=C([O-])[O-]
Reactant: N#CCc1nc2ccccc2[nH]1
Agent: [K+]
Solvent: CO
Solvent: CI
Solvent: O
Product: Cn1c(CC#N)nc2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 14.7 %

Procedure:
Methyl iodide (1.24 ml, 19.19 mmol) is added to a solution of (1H-benzoimidazol-2-yl)-acetonitrile (3.13 g, 19.91 mmol) and potassium carbonate (2.75 g, 19.91 mmol) in 20 ml of dimethylformamide. It is stirred for 24 hours at room temperature, and additional potassium carbonate (2.8 g, 20.27 mmol) and additional methyl iodide (1.3 ml, 20.12 mmol) are added. It is stirred for another 24 hours at room temperature, water and methanol are added, and the solvent is distilled off in a vacuum. The residue is mixed with 200 ml of water and extracted three times in succession with 200 ml each of dichloromethane. The combined organic phases are dried on sodium sulfate, concentrated by evaporation, and after purification by chromatography on silica gel, 502 mg of the title compound is obtained.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:15]([CH3:16])=[C:14]([Cl:17])[CH:13]=[CH:12][C:11]=1[S:18]([Cl:21])(=[O:20])=[O:19]>ClC(Cl)C(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][CH2:16][C:15]1[C:10]([Cl:9])=[C:11]([S:18]([Cl:21])(=[O:20])=[O:19])[CH:12]=[CH:13][C:14]=1[Cl:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Cl)ccc(S(=O)(=O)Cl)c1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)C(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(Cl)c(CBr)c1Cl
Temperature: 120 °C
Yield: 47.1 %

Procedure:
85.44 g (0.48 mol) of N-bromosuccinimide and then 200 mg of benzoyl peroxide are added to a solution, at room temperature, of 41.52 g (0.16 mol) of 2,4-dichloro-3-methylbenzenesulfonyl chloride in 150 ml of 1,1,2,2-tetrachloroethane. The reaction mixture is heated at 120° C. for 2 hours. It is cooled and filtered and the filtrate is washed successively with water, with saturated sodium bicarbonate solution and finally with water until the washings are neutral. The organic phase collected from the filtrate is then dried over magnesium sulfate and concentrated. Recrystallization from hexane gives 25.53 g of the expected product in the form of white crystals (yield =47%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:21]([CH2:22][CH:23]=O)=[CH:20][CH:19]=[C:18]([Cl:25])[N:17]=1.[NH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:15][C:16]1[C:21]([CH2:22][CH2:23][NH:26][CH:27]2[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:32]2)=[CH:20][CH:19]=[C:18]([Cl:25])[N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=CCc1ccc(Cl)nc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(NCCc2ccc(Cl)nc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
Sodium triacetoxy borohydride (9.47 g) was added to a THF (60 mL) solution of (2,6-dichloropyridin-3-yl)acetaldehyde (5.66 g) and tert-butyl 4-aminopiperidine-1-carboxylate (7.16 g), and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to obtain the title compound (10.5 g).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+:10].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]=[C:19]=[S:20].[CH3:21][CH2:22][OH:23]>C1COCC1.C(#N)C>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[C:22](=[O:23])[CH:21]=[CH:17][C:12]([C:13]#[N:18])=[C:19]1[S-:20].[Na+:10]
Reactant: S=C=Nc1ccccc1Cl
Reactant: CCO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: N#Cc1ccc(=O)n(-c2ccccc2Cl)c1[S-]
Temperature: 25 °C
Yield: 88 %

Procedure:
NaHMDS (13.2 mL, 1.0M in THF, 13.2 mmol) was added slowly to a solution of 2-chlorophenyl isothiocyanate (1.02 g, 6.0 mmol) in THF (50 mL) and acetonitrile (5 mL) at −78° C. The mixture was warmed to r.t. over 1 h. N,N-Dimethyluracil (841 mg, 6.0 mmol) and EtOH (75 mL) were added and the mixture heated at reflux for 4 h. Volatiles were removed in vacuo and the residue was dissolved in hot EtOH (10 mL). Et2O (˜100 mL) was added slowly to precipitate out the product. The solid was filtered off, washed with Et2O (2×30 mL) and dried to give the title compound (1.5 g, 88%) (v. hygroscopic). δH (DMSO-d6) 7.35-7.32 (1H, m), 7.25-7.20 (2H, m), 7.15 (1H, d, J 9.1 Hz), 7.05-7.01 (1H, m), 5.85 (1H, br s), 5.58 (1H, d, J 9.1 Hz). LCMS (ES+) RT 3.06 minutes, 285 (M+H)+.
Reaction SMILES: O1CCN([C:7]23[C:34]4[CH:33]=[CH:32][C:31]([CH2:35][OH:36])=[CH:30][C:29]=4[O:28][CH2:27][CH:8]2[C:9]([C:12]2[O:16][N:15]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:13]=2[C:23]([F:26])([F:25])[F:24])=[N:10][O:11]3)CC1.C(O)(C(F)(F)F)=O>ClC(Cl)C.ClCCl>[C:17]1([C:14]2[C:13]([C:23]([F:26])([F:25])[F:24])=[C:12]([C:9]3[C:8]4[CH2:27][O:28][C:29]5[CH:30]=[C:31]([CH2:35][OH:36])[CH:32]=[CH:33][C:34]=5[C:7]=4[O:11][N:10]=3)[O:16][N:15]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCc1ccc2c(c1)OCC1C(c3onc(-c4ccccc4)c3C(F)(F)F)=NOC21N1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: OCc1ccc2c(c1)OCc1c(-c3onc(-c4ccccc4)c3C(F)(F)F)noc1-2
Temperature: 80 °C
Yield: 46.4 %

Procedure:
To a solution of (9b-morpholino-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,9b-dihydro-3aH-chromeno[3,4-d]isoxazol-7-yl)methanol (Preparation 60G 0.070 g, 0.140 mmol) in dichloroethane (1.0 mL) at room temperature was added TFA (0.016 mL, 0.209 mmol). The reaction mixture was heated at 80° C. for 60 min. The reaction mixture was diluted with dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded a pale yellow solid which was triturated with methanol with sonication and dried to give (3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4H-chromeno[3,4-d]isoxazol-7-yl)methanol (0.027 g, 0.065 mmol, 47% yield) as a white solid. The product had an HPLC ret. time=3.18 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=414.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[CH2:25]([N:27](CC)CC)C.N#CBr>C(#N)C>[C:25]([N:21]1[CH2:20][CH2:19][N:18]([C@H:16]([CH3:17])[C@:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])([OH:24])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH2:23][CH2:22]1)#[N:27]
Reactant: CCN(CC)CC
Reactant: C[C@@H](N1CCNCC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: N#CBr
Solvent: CC#N
Product: C[C@@H](N1CCN(C#N)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.9 %

Procedure:
To a cooled (0° C.) mixture of (2R,3R)-2-(2,4-difluorophenyl)-3-(piperazin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol 2 (250 mg, 0.74 mmol) and triethylamine (0.42 ml, 3 mmol) in acetonitrile (15 ml) was added cyanogen bromide (160 mg, 1.5 mmol) in acetonitrile (0.5 ml). The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure. To the resulting residue water was added and extracted with ethyl acetate (3×20 ml). The combined organic extract was washed with water, brine and dried over magnesium sulphate. The solvent was removed and the product was purified on a column of silica gel (hexane/EtOAc, 1:1) to give the title compound as a colorless solid (150 mg, 56%).
Reaction SMILES: O[CH2:2][C@H:3]([NH:7][C:8]([C:10]1[NH:11][C:12]([C:15]2[CH:20]=[C:19]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH:18]=[C:17]([O:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])[CH:16]=2)=[CH:13][CH:14]=1)=[O:9])[C@@H:4]([OH:6])[CH3:5].CS(O)(=O)=O.C(N(CC)CC)C.[Cl-].[NH4+]>O1CCCC1>[CH3:36][O:35][CH2:34][C@@H:33]([O:32][C:17]1[CH:16]=[C:15]([C:12]2[NH:11][C:10]([C:8]3[O:9][CH2:2][C@@H:3]([C@@H:4]([OH:6])[CH3:5])[N:7]=3)=[CH:14][CH:13]=2)[CH:20]=[C:19]([O:21][Si:22]([CH:29]([CH3:30])[CH3:31])([CH:26]([CH3:27])[CH3:28])[CH:23]([CH3:24])[CH3:25])[CH:18]=1)[CH3:37]
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)N[C@@H](CO)[C@H](C)O)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C3=N[C@H]([C@H](C)O)CO3)[nH]2)c1
Reaction time: 4 h
Yield: 51.8 %

Procedure:
N-[(2S,3S)-1,3-Dihydroxybutan-2-yl]-5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(tripropan-2-ylsilyl)oxy]phenyl)-1H-pyrrole-2-carboxamide (1.76 g, 3.29 mmol) synthesized in Example (112a) was dissolved in tetrahydrofuran (20 mL), and anhydrous methanesulfonic acid (0.54 g, 3.10 mmol) and triethylamine (1.00 mL, 7.17 mmol) were added at −40° C., followed by stirring at the same temperature for 4 hours under nitrogen atmosphere, and then at 50° C. overnight. To the reaction solution, a saturated aqueous ammonium chloride solution (50 mL) was added, and extraction was carried out with methylene chloride (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=2%-5%) to afford the desired compound (880 mg, yield 52%) as a white foam.
Reaction SMILES: C[O-].[Na+].[SH:4][C:5]1[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:8][N:9]=1.F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>C(O)C>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([S:4][C:5]2[N:6]([CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:7]=[CH:8][N:9]=2)=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Sc1nccn1Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Sc2nccn2Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 0.85 g (15.8 mmoles) of sodium methoxide and 15 ml of ethanol was refluxed for 5 minutes and then cooled to room temperature. To this solution was added 1.5 g (7.9 mmoles) of 2-mercapto-1-phenylmethylimidazole. After stirring for 10 minutes, 1.1 g (7.9 mmoles) of 1-fluoro-4-nitrobenzene was added and the mixture refluxed for 4 hours. An additional 0.85 g of sodium methoxide was added and the mixture refluxed for 9 hours. The mixture was filtered and the filtrate cooled and the resulting precipitate collected by filtration. The solid was recrystallized from dichloromethane/methanol to give the product as beige prisms, mp 122°-123° C.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[NH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[NH2:14]>CCO>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:13][NH:14][C:2](=[O:4])[C:1]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:6]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NNc1ccccn1
Solvent: CCO
Product: Nc1ccccc1C(=O)NNc1ccccn1
Temperature: 25 °C
Yield: 546.1 %

Procedure:
A mixture of isatoic anhydride (3.51 g, 2.15 mmol) and 2-hydrazinopyridine (2.40 g, 2.20 mmol) in 35 ml of EtOH was refluxed for 17 hours. After refluxing for 15 minutes, the suspension turned into a brown solution and gas evolution was observed. At the end of the 17 hour period, the reaction mixture was cooled to room temperature and the brown solution was concentrated on a rotary evaporator. The residue was chromatographed on silica gel with 65% EtOAc in hexanes. The fractions containing the product were collected and concentrated. The solid was triturated with ether (100 ml) for 15 minutes and collected by filtration. It was air-dried to give 2.68 g of 2-amino-benzoic acid N′-pyridin-2-yl-hydrazide (Intermediate 9) as a white solid. MS (APCI): 229 (M+1, 100%).