Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:23])[CH:3]=1.[C:24]([C:28]1[CH:33]=[C:32]([CH2:34][OH:35])[C:31]([CH3:36])=[CH:30][C:29]=1[S:37]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:24]([C:28]1[CH:33]=[C:32]([CH2:34][OH:35])[C:31]([CH3:36])=[CH:30][C:29]=1[S:37][C:3]1[C:4](=[O:23])[O:5][C:6]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:7][C:2]=1[OH:1])([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Reactant: O=C1C=C(O)CC(CCc2cccc(O)c2)(c2ccccc2)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3cccc(O)c3)(c3ccccc3)OC2=O)c(C(C)(C)C)cc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared as described in General Method 9 using 4-hydroxy-6-[2-(3-hydroxy-phenyl)-ethyl]-6-phenyl-5,6-dihydro-pyran-2-one (0.155 g, 0.5 mmol) from Example UU, toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl) ester (prepared in Example FFF; 0.2 g, 0.55 mmol), K2CO3 (0.27 g, 1.95 mmol), and DMF (3 mL). The solution was stirred overnight at room temperature, concentrated and the residue partitioned between 1N HCI and EtOAc. The organic phase was dried (MgSO4), and concentrated. Purification by silica gel chromatography, eluting with MeOH:CHCl3 :hexane (5:90:10 to 10:90:10) gave the title compound, m.p. 132-135° C. 1H NMR (DMSO-d6) δ 1.45 (s, 9 H), 1.76 (s, 3 H), 2.08-2.24 (m, 3 H), 2.48 (m, 1 H), 3.41 (dd, 2 H), 4.32 (s, 2 H), 4.91 (br s, 1 H), 6.17 (s, 1 H), 6.46-6.55 (m, 3 H), 7.02 (t, 1 H), 7.22 (s, 1 H), 7.35-7.46 (m, 5 H), 9.23 (s, 1 H), 12.15 (bs, 1 H).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([O-:10])=[O:9])[CH2:3][CH2:4][C:5](O)=[O:6].[Na+].Cl>>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:8]([OH:10])=[O:9]
Reactant: N[C@@H](CCC(=O)O)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: O=C1CC[C@@H](C(=O)O)N1

Procedure:
20 g of monosodium glutamate (Aldrich) was mixed with 11 mL of HCl 32% and the pH was adjusted to about 2.5 (using HCl). The mixture was heated to above 100° C. in an autoclave for 10 hours. Then, the solution was evaporated to dryness to obtain the L-pyroglutamic acid.
Reaction SMILES: Cl.[NH2:2][OH:3].O.O.O.C([O-])(=O)C.[Na+].[OH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:14]=1[C:20](=O)[CH3:21]>CCO.O.O>[OH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:14]=1[C:20](=[N:2][OH:3])[CH3:21]
Reactant: NO
Reactant: CC(=O)c1c(O)cccc1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=NO)c1c(O)cccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of hydroxylamine hydrochloride (756 mg, 10.9 mmol) and sodium acetate trihydrate (1.71 g, 12.6 mmol) dissolved in 23 ml of a mixture of EtOH/H2O (7/3) was added to a solution of 2′,6′-dihydroxyacetophenone (1.5 g, 9.9 mmol) in 12 ml of a 7/3 EtOH/H2O mixture. After refluxing and stirring under N2 for 2 hours, additional hydroxylamine hydrochloride (340 mg, 4.9 mmol) and sodium acetate trihydrate (570 mg, 4.19 mmol) dissolved in 7 ml of water were added and the reflux was continued for additional 30 minutes. After cooling down to room temperature, the volatiles were removed. Then water was added and the solid obtained was filtered, washed with water and dried. This afforded 1.3 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:15](=[S:16])[N:14]([C:17]3[CH:18]=[C:19]([C:25]([F:28])([F:27])[F:26])[C:20]([C:23]#[N:24])=[N:21][CH:22]=3)[C:13](=[O:29])[C:9]32[CH2:12][CH2:11][CH2:10]3)=[CH:4][C:3]=1[OH:30].[CH2:31](OC(OCC)OCC)C>CN(C=O)C.O>[O:30]1[C:3]2[CH:4]=[C:5]([N:8]3[C:15](=[S:16])[N:14]([C:17]4[CH:18]=[C:19]([C:25]([F:28])([F:27])[F:26])[C:20]([C:23]#[N:24])=[N:21][CH:22]=4)[C:13](=[O:29])[C:9]43[CH2:12][CH2:11][CH2:10]4)[CH:6]=[CH:7][C:2]=2[N:1]=[CH:31]1
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(N)c(O)c3)C2=S)cc1C(F)(F)F
Reactant: CCOC(OCC)OCC
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc4ncoc4c3)C2=S)cc1C(F)(F)F
Temperature: 100 °C
Yield: 37.1 %

Procedure:
A mixture of 5-(5-(4-amino-3-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile (60 mg, 0.14 mmol) and triethylorthoformate (0.050 mL, 0.28 mmol) in anhydrous DMF (1 mL) was heated at 100° C., 1 h. The mixture was diluted with water, extracted with EtOAc (3×), the organics combined and washed with water (2×), brine, dried (MgSO4) and concentrated. Purification by column chromatography, eluting with 30% EtOAc/hexanes provided 23 mg of 5-(5-(benzo[d]oxazol-6-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 9.24 (d, 1H), 8.95 (s, 1H), 8.78 (d, 1H), 8.05 (d, 1H), 7.94 (d, 1H), 7.45 (dd, 1H), 2.74-2.61 (m, 2H), 2.59-2.47 (m, 2H), 2.03-1.90 (m, 1H), 1.61-1.48 (m, 1H). LCMS [M+1]+ 444.0.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([O:11][CH3:12])=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[C:13]([O:15]C)=O.[CH:17]([NH2:19])=O>>[CH3:12][O:11][C:7]1[C:6]2[C:2]3[N:1]=[CH:17][NH:19][C:13](=[O:15])[C:3]=3[S:4][C:5]=2[CH:10]=[CH:9][CH:8]=1
Reactant: NC=O
Reactant: COC(=O)c1sc2cccc(OC)c2c1N
Product: COc1cccc2sc3c(=O)[nH]cnc3c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.5 %

Procedure:
A mixture of methyl 3-amino-4-methoxybenzothiophene-2-carboxylate (202mg, 0.85mmol) and formamide (2mL) is heated at 135 C. for 1 hr and the temperature is raised to 190 C. After 8 hr the reaction is cooled to r.t. Upon cooling, black solid forms and is collected by filtration. The precipitate is air dried to give 9-methoxy-4-oxo-3H-benzothieno[3,2-d]pyrimidine (45 mg, 22.5%). 1H NMR (DMSO) δ12.0 (1H, brs), 8.31 (1H, s)7.70-7.55 (2H, m), 7.10 (1H, d, J=7.7 Hz), 3.97 (3H, s).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]([C:17]1[CH:22]=[CH:21][C:20]([N:23]([CH3:33])[S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[CH:19][CH:18]=1)(O)[C:12]([F:15])([F:14])[F:13])[CH3:2].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]([C:17]1[CH:22]=[CH:21][C:20]([N:23]([CH3:33])[S:24]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)(=[O:25])=[O:26])=[CH:19][CH:18]=1)[C:12]([F:13])([F:14])[F:15])[CH3:2]
Reactant: CCOCCn1cccc1C(O)(c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOCCn1cccc1C(c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
To a solution of 32 mg (0.07 mmol) of N-(4-{1-[1-(2-ethoxyethyl)-1H-pyrrol-2-yl]-2,2,2-trifluoro-1-hydroxyethyl}-phenyl)-N-methyl-benzenesulfonamide (Example 78) in 2 mL of CH2Cl2 at 0° C. were added 1.05 mL (6.57 mmol) of triethylsilane followed by 167 μL (1.32 mmol) of boron trifluoride diethyl etherate dropwise. The mixture was warmed to room temperature and stirred for 1.75 h. After this time, the reaction mixture was cooled to 0° C., quenched by the addition of a saturated aqueous solution of sodium bicarbonate, allowed to warm to room temperature, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel (hexanes:EtOAc, 4:1) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[C:11]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[F:21])[CH:16]=O)#[N:12]>>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]2[N:1]=[C:2]3[CH:3]([C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7]3)[CH:16]([C:15]3[CH:18]=[CH:19][C:20]([F:21])=[C:13]([CH:14]=3)[C:11]#[N:12])[C:3]=2[C:4](=[O:10])[CH2:5]1
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: CC1(C)CC(=O)C=C(N)C1
Product: CC1(C)CC(=O)C2C(=NC3=C(C(=O)CC(C)(C)C3)C2c2ccc(F)c(C#N)c2)C1

Procedure:
Reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 3-cyano-4-fluorobenzaldehyde in an analogous manner to that described in Example 1 gave 5-(2,3,4,5,6,7,8,9-octahydro-3,3,6,6-tetramethyl-1,8-dioxo-1H-acridin-9-yl)-2-fluorobenzonitrile. Crystallization from ethanol gave a pale yellow-green crystalline solid of melting point 274-275° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22]([N:24]([CH2:40][CH3:41])[CH2:25][CH2:26][NH:27][C:28]([C:30]1[N:35]=[C:34]2[CH2:36][O:37][C:38](=O)[C:33]2=[CH:32][CH:31]=1)=[O:29])[CH3:23].Cl>C1COCC1.O1CCOCC1>[CH2:40]([N:24]([CH2:22][CH3:23])[CH2:25][CH2:26][NH:27][C:28]([C:30]1[N:35]=[C:34]2[CH2:36][O:37][C:38](=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[C:33]2=[CH:32][CH:31]=1)=[O:29])[CH3:41]
Reactant: CCN(CC)CCNC(=O)c1ccc2c(n1)COC2=O
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCN(CC)CCNC(=O)c1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.7 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (76 mg, 0.46 mmol) in THF (3 mL) is treated with a solution of lithium bis(trimethylsilyl)amide (1.2 mL of a 1M solution in THF, 1.2 mmol) dropwise. The resulting solution is stirred at room temperature for 10 min. A solution of 5-oxo-5,7-dihydro-furo[3,4-b]pyridine-2-carboxylic acid (2-diethylamino-ethyl)-amide (70 mg, 0.25 mmol) in THF (2 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 4 h and is poured into a cold 4M HCl solution in dioxane (3 mL) at 0° C. The resulting mixture is stirred at room temperature overnight. The reaction mixture is concentrated to partially remove the dioxane and is then partitioned between EtOAc and saturated aqueous NaHCO3 solution. The organic phase is collected and the aqueous phase is extracted with additional EtOAc. The combined organic extracts are dried (Na2SO4), filtered and concentrated. The residue is purified by chromatography (silica gel, MeOH-Chloroform). The product containing fraction are concentrated and the residue is treated with EtOAc-hexane (1:1). The solid is collected by filtration to give the title compound as an orange solid (51 mg, 49%).
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:12])=[N:8][NH:9]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:12])=[N:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C)n[nH]c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1n[nH]c2cc(O)ccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 93 %

Procedure:
A solution of 6-methoxy-3-methyl-1H-indazole(2.0 g, Reference Example 49) in dichloromethane (75 ml) was cooled to 0° C. then treated with a solution of boron tribromide in dichloromethane (54 ml, 1M). The mixture was allowed to warm to room temperature and then stirred for 12 hours. The solution was poured into an ice-saturated sodium bicarbonate mixture and the aqueous layer was extracted three times with ethyl acetate (50 ml). The combined extracts were dried over sodium sulphate then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and hexane (2:1, v/v) to yield the title compound (1.7 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:8][C@@H:9]3[CH2:21][C@@H:10]3[C:11]=2[N:12]([C:14]2[CH:19]=[C:18](Br)[CH:17]=[CH:16][N:15]=2)[N:13]=1)=[O:5])[CH3:2].[ClH:22]>C(#N)C.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:8][C@@H:9]3[CH2:21][C@@H:10]3[C:11]=2[N:12]([C:14]2[CH:19]=[C:18]([Cl:22])[CH:17]=[CH:16][N:15]=2)[N:13]=1)=[O:5])[CH3:2]
Reactant: Cl
Reactant: CCOC(=O)c1nn(-c2cc(Br)ccn2)c2c1C[C@@H]1C[C@H]21
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@@H]1C[C@H]21
Temperature: 80 °C
Reaction time: 6 h
Yield: 93.3 %

Procedure:
To a solution of (1aS,5aS)-2-(4-bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (2.1 g, 6.0 mmol) in acetonitrile (30 mL) was added concentrated HCl (1.4 mL, 18.0 mmol). The reaction was stirred for 6 h at 80° C., and then diluted with H2O. The solid was filtered, washed with H2O, and dried to give (1aS,5aS)-2-(4-chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (1.7 g) which contained ˜20% of the hydrolyzed acid. The aforementioned ester was dissolved in dioxane (10 mL). After addition of 1 N LiOH (9.0 mL), the reaction was stirred for 4 h at 40° C. The reaction was cooled down to room temperature, diluted with H2O, and acidified with 4 N HCl to form a precipitate. The solid was filtered, washed with H2O, and dried to give the title compound. LCMS m/z=276.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17](S(C)=O)[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[NH2:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[OH:31].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17]([NH:24][C@@H:25]5[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]5[OH:31])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Temperature: 125 °C
Yield: 39.7 %

Procedure:
A stirred mixture of 6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (90 mg, 0.260 mmol) from Step 4 of this Example, (1R,2R)-(−)-2-aminocyclohexanol (120 mg, 1.03 mmol), and DIEA (133 mg, 1.03 mmol) in anhydrous DMA (3 mL) was heated at 125° C. for 15 h. After the reaction mixture had cooled to rt, the mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford (1R,2R)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (41 mg) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.42 (s, 1H), 8.08 (dd, J=2.4, 9.4 Hz, 1H), 7.98 (d, J=7.5 Hz, 1H), 7.66 (s, 1H), 7.17-7.33 (m, 2H), 5.48 (s, 2H), 4.76 (br s, 1H), 3.45-3.55 (m, 2H), 2.03 (m, 1H), 1.87 (m, 1H), 1.55-1.67 (m, 2H), 1.10-1.33 (m, 4H). LCMS (ESI) m/z 398 (M+H)+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:43])[CH2:30][CH2:31][C:32]([N:34]([CH3:42])[C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)=[O:33]>>[CH3:43][N:29]([CH3:28])[CH2:30][CH2:31][C:32]([N:34]([C:35]1[CH:36]=[CH:37][C:38]([NH:41]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:39][CH:40]=1)[CH3:42])=[O:33]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CN(C)CCC(=O)N(C)c1ccc(N)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(C)C(=O)CCN(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-((2-dimethylamino-ethyl)-carbonyl)-N-methyl-p-phenylenediamine Rf value: 0.5 (aluminium oxide, methylene chloride/methanol=20:1) C29H30N4O4
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[S:7]C(=O)[O:9][C:5]=2[CH:4]=1.[OH-].[K+].Cl>CO.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([SH:7])=[C:5]([OH:9])[CH:4]=1
Reactant: COc1ccc2sc(=O)oc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(S)c(O)c1
Reaction time: 0.17 h
Yield: 91.6 %

Procedure:
4.50 g (24.8 mmol) 6-methoxy-1,3-benzoxathiol-2-one was suspended in 56 mL methanol and mixed with 4.40 g (66.4 mmol) 85% potassium hydroxide, which had previously been dissolved in 11 mL methanol and 17 mL water. The suspension dissolved, forming a yellow color and was stirred for approximately 10 minutes (TLC control). After the end of the reaction the reaction mixture was cautiously acidified to a pH of 1 using 1N aqueous hydrochloric acid, the methanol was removed under a reduced pressure and the residue was extracted twice with ethyl acetate. The organic phases were combined and each was washed twice with water, saturated sodium chloride solution and again with water. After drying with sodium sulfate and removing the solvent under a reduced pressure, 3.55 g (92%) 5-methoxy-2-mercaptophenol was obtained as a light-yellowish fluid. The raw product (GCMS 100%, M=156) was used further without further purification.
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]2[NH:13][C:12](=[O:14])[C:11](=[C:15]([CH3:17])[CH3:16])[CH2:10][C@@H:9]2[OH:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(OCC)(=O)C.[Pd]>[CH:1]1([CH2:7][CH:8]2[NH:13][C:12](=[O:14])[CH:11]([CH:15]([CH3:16])[CH3:17])[CH2:10][CH:9]2[OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: CC(C)=C1C[C@H](O)[C@H](CC2CCCCC2)NC1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)C1CC(O)C(CC2CCCCC2)NC1=O

Procedure:
A solution of the product of Example 5 (24.7 g, 98.4 retool) in 500 mL of ethyl acetate was treated with 2.5 g of dry palladium on carbon and hydrogenated at 4 atmospheres of hydrogen for 4 hours at ambient temperature. The reaction mixture was filtered and concentrated to a white foamy solid which was taken on without further purification. m.p. 97°-99° C. [α]D =-95.1° (c=1.075, CHCl3). IR (KBr) 3605, 3400, 2925, 1642 cm-1. 1H NMR (300 MHz, CDCl3) δ6.3 (bs, 1H), 4.11 (m, J=4.5, 1H), 3.47 (m, 1H), 2.72 (bs, 1H), 2.5 (m, 1H), 2.3 (m, 1H), 1.9 (m, 1H), 1.8-1.5 (m, 8H), 1.43-1.12 (m, 6H), 0.97 (d, 3H), 0.87 (m, 3H). 13C NMR (75.5 Hz, CDCl3) ppm 174.2, 67.1, 52.6, 44.3, 37.7, 34.5, 33.8, 32.4, 27.6, 26.4, 26.3, 26.2, 26.0, 20.2, 17.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][NH:14][C:13](=O)[C:12]=1[N+:18]([O-:20])=[O:19].FC(F)(F)S(O)(=O)=O.[CH3:29][O:30][CH2:31][CH:32]([NH2:35])[CH2:33][CH3:34]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:35][CH:32]([CH2:31][O:30][CH3:29])[CH2:33][CH3:34])[C:12]=1[N+:18]([O-:20])=[O:19]
Reactant: COc1cc(Cl)c(-c2cc[nH]c(=O)c2[N+](=O)[O-])cc1F
Reactant: CCC(N)COC
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC(COC)Nc1nccc(-c2cc(F)c(OC)cc2Cl)c1[N+](=O)[O-]
Yield: 13 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-Chloro-5-fluoro-4-methoxy-phenyl)-3-nitro-1H-pyridin-2-one (0.3 g, 0.70 mmol), prepared substantially as described in Part C of Example 19a, and 1-methoxymethyl-propylamine (0.28 g, 2.79 mmol) were treated substantially as described in Part C of Example 19a to produce 35 mg (13%) of crude [4-(2-chloro-5-fluoro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine.
Reaction SMILES: [C:1]1(=O)[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.C(O)(=O)C.[CH3:13][O:14][CH2:15][C:16]([NH2:22])=[CH:17][C:18]([O:20][CH3:21])=[O:19].S(S([O-])=O)([O-])=O.[Na+].[Na+].[OH-].[Na+]>C(OCC)(=O)C>[OH:7][C:4]1[CH:3]=[C:2]2[C:1](=[CH:6][CH:5]=1)[NH:22][C:16]([CH2:15][O:14][CH3:13])=[C:17]2[C:18]([O:20][CH3:21])=[O:19]
Reactant: O=C1C=CC(=O)C=C1
Reactant: COCC(N)=CC(=O)OC
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COCc1[nH]c2ccc(O)cc2c1C(=O)OC
Yield: 44.6 %

Procedure:
32.4 g (300 mmol) of 1,4-benzoquinone was dissolved in 200 ml of ethyl acetate, 200 ml (350 mmol) of acetic acid was added thereto, followed by dropwise addition of 14.5 g (100 mmol) of methyl 4-methoxy-3-amino-2-butenoate. With stirring, the reaction mixture was heated for 15 hours while keeping the inner temperature at 50° C. To this was then added dropwise 200 ml of an aqueous solution containing 52.2 g (300 mmol) of sodium hydrosulfite. The mixture was further stirred at room temperature for 2 hours while controlling the reaction mixture within a pH range of from 4.5 to 7.5 with 5 N sodium hydroxide. Thereafter, crystals thus precipitated were collected by filtration and washed with ethyl acetate to obtain 7.33 g of crude crystals. The filtrate and the washings were combined and then allowed to separate into organic and water layers. The water layer was extracted with 50 ml of ethyl acetate, and the resulting ethyl acetate layer was combined with the organic layer. The thus combined organic layer was washed with saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was filtered off and the solvent was distilled off under reduced pressure, the resulting residue was purified by an alumina column chromatography (eluent: ethyl acetate). Main fractions thus obtained were concentrated, and the concentrated residue was slurried with 150 ml of ethyl acetate. The thus obtained crude product was combined with the crude crystals previously collected by filtration, and the combined product was recrystallized from 260 ml of ethyl acetate to obtain 10.5 g of the title compound with a yield of 44.2%.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[NH:8][C:6]=2[N:7]=1.C(O)(=O)C.C(O)(=O)C.C(O)(=O)C.C(O)(=O)C.C(O[C@@H:32]1[O:44][C@H:43]([CH2:45][O:46][C:47](=[O:49])[CH3:48])[C@@H:38]([O:39][C:40](=[O:42])[CH3:41])[C@H:33]1[O:34][C:35](=[O:37])[CH3:36])(=O)C>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:32]3[O:44][C@H:43]([CH2:45][O:46][C:47](=[O:49])[CH3:48])[C@@H:38]([O:39][C:40](=[O:42])[CH3:41])[C@H:33]3[O:34][C:35](=[O:37])[CH3:36])[C:6]=2[N:7]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Nc1ncc2sc(=O)[nH]c2n1
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3cnc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 150 °C
Yield: 39.9 %

Procedure:
Compound 86 (62 mg, 0.4 mmol), 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose tetraacetate (128 mg, 0.4 mmol), and catalytic bis(p-nitrophenyl)hydrogen phosphate (13 mg, 0.04 mmol) were mixed and placed in a 500 ml flask. The reaction vessel was carefully placed under vacuum (˜5.0 mmHg) and lowered into an oil bath heated at 150° C. for 10 minutes. After cooling to room temperature, the solids were washed with ethyl acetate. The crude product was purified by flash column. (silica, 5 to 35% ethyl acetate gradient in chloroform) to yield 68 mg of compound 79 (40%) as a white solid as a white powder identical in all respects to material isolated in Example 38, step 2.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:27]=[CH:26][C:9]([C:10]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][N:15]3[CH:23]=[CH:24][CH:25]=[C:14]3[CH2:13]2)=[O:11])=[CH:8][CH:7]=1)CCC.[F:36][C:37]1[CH:38]=[C:39](Br)[CH:40]=[C:41]([F:43])[CH:42]=1>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[F:36][C:37]1[CH:38]=[C:39]([C:6]2[CH:7]=[CH:8][C:9]([C:10]([N:12]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[CH2:16][N:15]4[CH:23]=[CH:24][CH:25]=[C:14]4[CH2:13]3)=[O:11])=[CH:26][CH:27]=2)[CH:40]=[C:41]([F:43])[CH:42]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(c1ccc(-c2cc(F)cc(F)c2)cc1)N1Cc2cccn2Cc2ccccc21

Procedure:
A mixture of 1.5 g of 10,11-dihydro-10-[4-(tributylstannyl)benzoyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 1 ml of 3,5-difluoro-1-bromobenzene and 200 mg of tetrakis(triphenylphosphine)palladium(O) in 200 ml of toluene is refluxed for 16 hours. The reaction mixture is filtered and the filtrate evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 30% ethyl acetate-hexane to give 700 mg of the desired product as a solid. Mass spectrum: M+H:401.