Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:19]3[C:24]([CH:25]=2)=[C:23]([CH:26]=O)[CH:22]=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:4])=[O:3].[CH3:36][O:37][CH2:38][CH2:39][NH2:40].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[C:19]3[C:24]([CH:25]=2)=[C:23]([CH2:26][NH:40][CH2:39][CH2:38][O:37][CH3:36])[CH:22]=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:3])=[O:4]
Reactant: COc1cc(-c2cc3c(C=O)cccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Reactant: COCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COCCNCc1cccc2c1cc(-c1cc(OC)c(OS(C)(=O)=O)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C
Yield: 34.4 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-4-formylindol-2-yl]isoindolinone (0.252 g, 0.503 mmol) was dissolved in acetonitrile (15.0 mL), and the solution was treated with 2-methoxyethylamine (0.875 mL, 10.1 mmol), acetic acid (0.576 mL, 10.1 mmol) and sodium triacetoxyborohydride (0.533 g, 2.52 mmol), followed by purification of the residue by flash column chromatography (chloroform/methanol=3/1) to obtain 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-4-(2-methoxyethylaminomethyl)indol-2-yl]isoindolinone (0.0968 g, yield 34%).
Reaction SMILES: [NH2:1][OH:2].[CH3:3][C:4]1[CH:13]=[C:12]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH:25]=[CH:26][CH:27]=[C:28]3[CH2:33][CH2:32][S:31][CH2:30][CH2:29]3)(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1>O1CCCC1>[CH3:3][C:4]1[CH:13]=[C:12]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([S:22]([CH2:25][CH:26]([NH:1][OH:2])[CH:27]=[C:28]3[CH2:33][CH2:32][S:31][CH2:30][CH2:29]3)(=[O:23])=[O:24])=[CH:20][CH:21]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1cc(COc2ccc(S(=O)(=O)C=CC=C3CCSCC3)cc2)c2ccccc2n1
Reactant: NO
Solvent: C1CCOC1
Product: Cc1cc(COc2ccc(S(=O)(=O)CC(C=C3CCSCC3)NO)cc2)c2ccccc2n1
Reaction time: 54 h
Yield: 63 %

Procedure:
A 50% aqueous solution of hydroxylamine (2 mL) was added to a solution of 0.18 g (0.40 mmol) of 2-methyl-4-{4-[3-(tetrahydrothiopyran-4-ylidene)-1-propene-1-sulfonyl]phenoxymethyl}quinoline obtained in the same manner as Example 9 (9-1) and (9-2) in tetrahydrofuran (5 mL) at room temperature and stirred for 54 hours. After the reaction was completed, the solvent was removed under a reduced pressure, the residue was extracted with chloroform, and the organic layer was dried over magnesium sulfate. After drying, the solution was filtered and the filtrate was concentrated under a reduced pressure, and the obtained residue was subjected to column chromatography on silica gel (silica gel 4 g, developing solvent; chloroform:methanol=20:1) to obtain 0.12 g (yield 63%) of N-{2-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl]-1-(tetrahydrothiopyran-4-ylidenemethyl)ethyl}hydroxylamine (III-17) as a white crystal. Its physical properties are shown below.
Reaction SMILES: [CH3:1][C:2]([CH3:11])=[CH:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[CH2:12]([C:14]1[CH:19]=[C:18]([O:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:17]=[C:16]([CH3:29])[C:15]=1O)[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:12]([C:14]1[CH:19]=[C:18]([O:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:17]=[C:16]([CH3:29])[C:15]=1[O:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][CH:3]=[C:2]([CH3:11])[CH3:1])[CH3:13]
Reactant: CCc1cc(OC(=O)c2ccccc2)cc(C)c1O
Reactant: CC(C)=CCOCCCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1cc(OC(=O)c2ccccc2)cc(C)c1OCCCCOCC=C(C)C
Yield: 78.9 %

Procedure:
To a mixture of 0.52 g of 4-(3-methyl-2-butenyloxy)butanol, 0.77 g of 2-ethyl-6-methyl-4-benzoyloxyphenol, 0.87 g of triphenylphosphine and 20 ml of tetrahydrofuran was slowly added dropwise 0.73 g of diisopropyl azodicarboxylate with stirring under ice cooling. After stirring at room temperature for 6 hours, the reaction mixture was concentrated. The residue was subjected to silica gel chromatography, which afforded 0.94 g of 3-ethyl-5-methyl-1-benzoyloxy-4-(4-(3-methyl-2-butenyloxy)butyloxy)benzene (yield, 79%), nD20.0 1.5361.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:6]=1)=[O:4].[OH-].[Na+]>CO>[O:11]([C:7]1[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=[CH:9][N:8]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccnc(Oc2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccnc(Oc2ccccc2)n1
Reaction time: 1.5 h
Yield: 60 %

Procedure:
To a solution of 2-phenoxy-pyrimidine-4-carboxylic acid methyl ester, 16, (1.72 g, 74.8 mmol) in methanol (50 mL) is added a 50% NaOH solution (10 mL) at room temperature. After stirring for 1.5 hours the solvent is removed in vacuo and the remaining aqueous phase is extracted with ethyl acetate. The aqueous phase can then be carefully acidified with concentrated HCl and the white solid which forms extracted twice with ethyl acetate. The organic layers are combined, dried and concentrated in vacuo to afford 0.95 g (60% yield) of the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]2.[OH2:19]>C(Cl)Cl.CC#N>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[C:8](=[O:19])[N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]2
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Cl)ncc2C1
Reactant: O
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCc2cc(Cl)ncc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a solution of NaIO4 (9.56 g, 44.7 mmol) and RuCl3 (927 mg, 4.47 mmol) in water (50 mL), DCM (50 mL) and MeCN (2 mL) was added a solution of tert-butyl 6-chloro-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (4.0 g, 14.9 mmol) in DCM (25 mL). This reaction was stirred at room temperature for 2 h. At completion, the reaction was and was quenched with isopropanol (10 mL), filtered over celite and the filter cake was washed with DCM (20 mL). The filtrate was partitioned in a separatory funnel and the layers were separated. The organic layer was extracted with DCM (2×20 mL) and the combined organics were dried over Na2SO4, then filtered and concentrated. The residue was purified by flash chromatography over silica gel (20-50% EtOAc/hexane eluent) to give tert-butyl 6-chloro-1-oxo-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (3.0 g, 71% yield) as a yellow crystalline solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.92 (s, 1H), 7.47 (s, 1H), 4.03 (t, J=6.3 Hz, 2H), 3.09 (t, J=6.1 Hz, 2H), 1.54-1.62 (m, 9H); MS (EI) m/z=283.7 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10](C(OCC)=O)[C:11]([O:13][C:14](C)(C)[CH3:15])=[O:12])=[N:8][CH:9]=1)([O-:3])=[O:2].C(O)(C(F)(F)F)=O.C(Cl)Cl>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of tert-butyl ethyl (5-nitropyridin-2-yl)propanedioate (4.10 g, 13.2 mmol) in a mixed solution of TFA/DCM (4 mL/20 mL) was stirred for 5 hours at room temperature. The mixture was concentrated under reduce pressure. The residue was dissolved with DCM, washed with sat. NaHCO3, dried over anhydrous Na2SO4 and concentrated to give ethyl (5-nitropyridin-2-yl)acetate. 1H-NMR (400 MHz, CDCl3) δ 9.41 (s, 1H), 8.58 (d, J=8.4 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 4.16 (q, J=7.2 Hz, 2H), 4.02 (s, 2H), 1.22 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:10]=[CH:11][N:12](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:13]=2)=[CH:4][CH:3]=1.[O:33]=[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]1[C:40]1[CH:47]=[CH:46][C:43]([CH2:44]Br)=[CH:42][CH:41]=1>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[N:10]([CH2:44][C:43]3[CH:46]=[CH:47][C:40]([N:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]4=[O:33])=[CH:41][CH:42]=3)[CH:11]=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(Oc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reactant: O=c1ccccn1-c1ccc(CBr)cc1
Solvent: CC#N
Product: O=c1ccccn1-c1ccc(Cn2cncc2Oc2ccc(Br)cc2)cc1
Temperature: 60 °C

Procedure:
A mixture of 4-(4-bromophenyloxy)-1-trityl-1H-imidazole (0.345 g, 0.72 mmol) and the bromide from Example 1, Step 3 (0.19 g, 0.72 mmol) in anhydrous acetonitrile (10 mL) was heated under reflux at 60° C. for 24 h. The resultant solution was concentrated, and the residue dissolved in methanol. The methanolic solution was heated under reflux for 3 h, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 1:1 v/v 5% methanol in chloroform and chloroform saturated with ammonia gas. Collection and concentration of appropriate fractions provide the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][CH:41]=[CH:40][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH:18]2[O:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:33][CH2:34][CH2:35][C:36]([O:38]C)=[O:37])=[CH:13][CH:12]=1>O1CCOCC1.[OH-].[Na+].O>[CH3:1][O:2][C:3]1[CH:43]=[CH:42][CH:41]=[CH:40][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH:18]2[O:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:15][CH:16]=1
Reactant: COC(=O)CCCc1ccccc1OCCOC1CNCCC1c1ccc(OCCCOCc2ccccc2OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccccc1COCCCOc1ccc(C2CCNCC2OCCOc2ccccc2CCCC(=O)O)cc1
Temperature: 25 °C

Procedure:
A solution of 0.30 g of methyl 4-{2-[2-(4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidin-3-yloxy)ethoxy]phenyl}butyrate (Example 137) in 5 ml of dioxane and 2 ml of 2N NaOH is stirred at 80° C. over 7 hours. The reaction mixture is cooled to room temperature, diluted with water and washed with tert-butyl methyl ether. The combined organic phases are acidified to pH 6 with 1N HCl and subsequently extracted with ethyl acetate (2×). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.08 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=4.37.
Reaction SMILES: [C:1]([C:5]1[C:14]2[CH:13]=[C:12]([NH:15][CH2:16][CH3:17])[CH:11]=[CH:10][C:9]=2[C:8]([CH3:19])([CH3:18])[CH2:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].F[C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][N:22]=1.CCOCC>C1(C)C=CC=CC=1>[C:1]([C:5]1[C:14]2[CH:13]=[C:12]([N:15]([CH2:16][CH3:17])[C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][N:22]=3)[CH:11]=[CH:10][C:9]=2[C:8]([CH3:18])([CH3:19])[CH2:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc(F)nc1
Reactant: CCNc1ccc2c(c1)C(C(C)(C)C)=CCC2(C)C
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCN(c1ccc2c(c1)C(C(C)(C)C)=CCC2(C)C)c1ccc(C(=O)O)cn1
Temperature: 125 °C
Yield: 8.6 %

Procedure:
To a mixture of 85 mg (0.37 mmol) of (8-t-butyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-ethyl-amine (Compound 169) and 0.11 g (0.78 mmol) of 6-fluoro-nicotinic acid was added a small amount of ether and toluene to help stirring. The resulting mixture was heated at 100-150° C. for 1 h. The mixture was cooled. The product was purified by flash chromatography (silica, 50% ethyl acetate in hexanes to give the title compound as a white solid (12 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([CH3:18])[OH:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:24]>>[NH2:24][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([CH3:18])[OH:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: N
Reactant: CCOCc1nc2c(Cl)nc3ccccc3c2n1CC(C)(C)O
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)O

Procedure:
4-Chloro-α,α-dimethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1-ethanol (1.0 g, 3 mmol, Example 100) and 7% methanolic ammonia (30 mL) were placed in a steel pressure vessel at about 150-160° C. for 6 hours. The vessel was cooled to below room temperature and the reaction solution removed and treated with methanolic potassium hydroxide. The solution was then evaporated to a low volume and diluted with water. The resulting precipitate was collected, washed with water and dried to provide 0.7 g of the crude product as a solid. The crude product was recrystallized from a mixture of ethyl acetate and methanol to provide a colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.C([Sn](CCCC)(CCCC)[C:24]1[CH:29]=[CH:28][N:27]=[N:26][CH:25]=1)CCC>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].C(Cl)Cl.O1CCOCC1>[CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([C:24]3[CH:29]=[CH:28][N:27]=[N:26][CH:25]=3)[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]=2[C:6]([CH3:14])=[CH:7]1)([CH3:13])[CH3:12]
Reactant: COC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1cc(-c2ccnnc2)cc2c1c(C)cn2C(C)C
Temperature: 105 °C

Procedure:
To a 50 ml round bottom flask was added; methyl 6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxylate (150 mg, 0.484 mmol), PdCl2(dppf)-CH2Cl2 adduct (39.5 mg, 0.048 mmol) and 1,4-Dioxane (4836 μl) followed with 4-(tributylstannyl)pyridazine (179 mg, 0.484 mmol) and a magnetic stir bar. The flask was equipped with a reflux condenser and an exhaust bubbler and heated to 105° C. The reaction solution changed to a dark brown at 30 minutes. LCMS (105 C—3 h) showed the reaction to be complete. The reaction solvent was removed in-vacuo and the remaining residue taken up with DMSO. (1.5 ml). The DMSO solution was purified by reverse phase HPLC using a Phenomenex Gemini 100×30 mm column, neutral acetonitrile and 0.1% formic acid in water, 40-70%, 10 min gradient. The desired fractions were dried in a Genovac EZ-2 evaporator and the solid residues combined. The product, methyl 1-isopropyl-3-methyl-6-(pyridazin-4-yl)-1H-indole-4-carboxylate, was obtained as a white solid. 1H NMR (400 MHz, METHANOL-δ4) 9.68 (δ, J=1.26 Hz, 1H), 9.19 (d, J=5.56 Hz, 1H), 8.20 (d, J=1.52 Hz, 1H), 8.13 (dd, J=2.53, 5.56 Hz, 1H), 7.98 (d, J=1.52 Hz, 1H), 7.48 (s, 1H), 4.96 (dt, J=6.60, 13.33 Hz, 1H), 4.00 (s, 3H), 2.39 (s, 3H), 1.56 (d, 6H). MS(ES) [M+H]+ 310.2.
Reaction SMILES: [F:1][C:2]([F:32])([CH2:7][CH2:8][C@H:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:18]([CH2:19][C@@H:20]([OH:31])[CH2:21][C@@H:22]2[OH:30])=[CH:17][CH2:16]3)[CH2:13][CH2:12]1)[CH3:10])[C:3]([OH:6])([CH3:5])[CH3:4].C(O[C:37](=[O:39])[CH3:38])(=O)C>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:3]([O:30][C@@H:22]1[C@@:23]2([CH3:24])[C:18](=[CH:17][CH2:16][C@@H:15]3[C@@H:25]2[CH2:26][CH2:27][C@@:28]2([CH3:29])[C@H:14]3[CH2:13][CH2:12][C@@H:11]2[C@H:9]([CH3:10])[CH2:8][CH2:7][C:2]([F:32])([F:1])[C:3]([O:6][C:22](=[O:30])[CH3:21])([CH3:4])[CH3:5])[CH2:19][C@@H:20]([O:31][C:37](=[O:39])[CH3:38])[CH2:21]1)(=[O:6])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](CCC(F)(F)C(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(F)(F)C(C)(C)OC(C)=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1

Procedure:
When a mixture of [1α,3β]-24,24-difluorocholest-5-en-1,3,25-triol in pyridine is reacted with acetic anhydride and a catalytic amount of 4-dimethylaminopyridine, [1α,3β]-24,24-difluorocholest-5-en-1,3,25-triol 1,3,25-triacetate can be obtained.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9])([CH3:3])[CH3:2].[BH4-].[Na+].C(Cl)Cl>CO>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][OH:9])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)Oc1cccc(CO)c1

Procedure:
To a 1 molar solution of 3-isopropoxy benzaldehyde (102 g, 0.621 moles) in methanol (620 mL) cooled to 0° was added (slowly) sodium borohydride powder (25.8 g, 0.683 moles)-dissolved in a minimum of methylene chloride and passed through a plug of silica gel washing with more methylene chloride until the silica gel was free of the product. The eluent was stripped to an oil and pumped on high vacuum overnight.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([CH3:16])[C:9]=1[Br:17])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:17][C:9]1[C:10]([CH3:16])=[CH:11][C:12]([O:14][CH3:15])=[CH:13][C:8]=1[NH2:7]
Reactant: COc1cc(C)c(Br)c(NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C)c(Br)c(N)c1
Temperature: 25 °C
Reaction time: 1.3 h
Yield: 99.5 %

Procedure:
A solution of (2-bromo-5-methoxy-3-methyl-phenyl)-carbamic acid tert-butyl ester ((Example 198: step b) 3.00 g, 9.49 mmol) in CH2Cl2 (50 mL) was treated with trifluoroacetic acid (7.00 mL) dropwise. The solution was stirred at room temperature 1.3 h. The solvents were evaporated in vacuo to yield the product 2-bromo-5-methoxy-3-methyl-phenylamine (2.04 g, 65%) as a yellow solid trifluoroacetate salt. The crude mixture was used directly in the next reaction.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][N:8]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[N:9]1.[CH2:16]([Cl:18])[Cl:17]>CN(C=O)C>[Cl:17][CH:16]([Cl:18])[C:11]1[CH:10]=[N:9][N:8]([CH3:7])[C:12]=1[N+:13]([O-:15])=[O:14]
Reactant: ClCCl
Reactant: Cn1nccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ncc(C(Cl)Cl)c1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 18 %

Procedure:
To a solution of potassium tert-butoxide (157 ml, 11.0M in THF) and anhydrous DMF (40 ml) at −78° C. was added a mixture of 1-methyl-5-nitro-1H-pyrazole (5.0 g, 39 mmol) in anhydrous methylene chloride (3.5 mL) and anhydrous DMF (25 mL) via dropwise addition. The reaction was stirred at −78° C. for 30 minutes and quenched by the careful addition of acetic acid (20 mL) in methanol (40 mL). The resulting mixture was allowed to warm to room temperature and poured into ice-water and extracted with ethyl acetate. The organic phase was washed with water and brine and dried over by sodium sulfate. Chromatography on silica gel with hexanes and ethyl acetate (3:1→2:1) gave 1.47 g of 4-dichloromethyl-1-methyl-5-nitro-1H-pyrazole (18%): 1H NMR (300 MHz, CDCl3) δ 7.88 (s, 1H), 6.85 (s, 1H), 4.23 (s, 3H); MS (m/e): 210.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].[F:21][CH2:22][CH2:23][NH:24][CH2:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[Cl:1][C:2]1[C:3]([N:28]2[CH2:29][CH2:30][CH:26]([CH2:25][NH:24][CH2:23][CH2:22][F:21])[CH2:27]2)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18]
Reactant: FCCNCC1CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2c(Cl)c(N3CCC(CNCCF)C3)c(F)cc2c1=O
Reaction time: 8 h
Yield: 14.1 %

Procedure:
A suspension of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (200 mg), 3-(2-fluoroethylaminomethyl)pyrrolidine (165 mg) and 1,8-diazabicyclo[5,4,0]-7-undecene (DBU, 100 mg) in absolute acetonitrile (2 ml) was refluxed for an hour. After cooling, the reaction mixture was concentrated and to the residue was added acetonitrile-ether (1:1, 5 ml). The solution was allowed to stand overnight at 5° C., then the resulting precipitate was collected by filtration and recrystallized from chloroform-methanol-ether to give the title compound (40 mg), mp 138°-142° C.
Reaction SMILES: Cl[CH2:2][C@H:3]([OH:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](/[CH:11]=[CH:12]/[C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])[CH:6]=1.[Na+].[I-].[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C=O)C>[N:24]([CH2:2][C@H:3]([OH:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](/[CH:11]=[CH:12]/[C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])[CH:6]=1)=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: O[C@@H](CCl)Cc1cccc(/C=C/c2c(Cl)cccc2Cl)c1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H](O)Cc1cccc(/C=C/c2c(Cl)cccc2Cl)c1
Temperature: 75 °C

Procedure:
To a solution of (R,E)-1-chloro-3-(3-(2,6-dichlorostyryl)phenyl)propan-2-ol (0.67 g, 1.96 mmol) in DMF (20 mL) was added NaI (˜25 mg, 0.16 mmol) and NaN3 (0.64 g, 9.8 mmol) and the reaction mixture was heated at 75° C. overnight. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The combined organics were washed with water, 5% aqueous LiCl and brine, filtered through Na2SO4 and concentrated under reduced pressure to give (R,E)-1-azido-3-(3-(2,6-dichlorostyryl)phenyl)propan-2-ol. This material was used in the next synthetic step without purification.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[N:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)(=O)=O)=CC=1.[CH3:30][C:31]1[C:32]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[N:33][CH:34]=[C:35]([N+:37]([O-:39])=[O:38])[CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:29][C:26]1[CH:27]=[N:28][C:23]([N:20]2[CH2:19][CH2:18][CH:17]([C@H:15]3[CH2:16][C@H:14]3[CH2:13][CH2:12][N:40]([C:32]3[C:31]([CH3:30])=[CH:36][C:35]([N+:37]([O-:39])=[O:38])=[CH:34][N:33]=3)[C:41](=[O:47])[O:42][C:43]([CH3:44])([CH3:45])[CH3:46])[CH2:22][CH2:21]2)=[N:24][CH:25]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1NC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])cnc1N(CC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1)C(=O)OC(C)(C)C
Temperature: 50 °C

Procedure:
2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethyl 4-methylbenzenesulfonate (95 mg, 0.22 mmol) from Step 1 of Example 2 and tert-butyl (3-methyl-5-nitropyridin-2-yl)carbamate (55 mg, 0.22 mmol) were added in DMF (2.2 mL), then cesium carbonate (212 mg, 0.65=101) was added and the reaction was heated to 50° C. overnight. The reaction was cooled to room temperature, water (20 mL) was added and extracted with ethyl acetate (50 mL), second wash with brine (20 mL). The organic phase was dried by magnesium sulfate, filtered, concentrated and purified by column chromatography through a 25 gram Biotage SNAP KP-Sil™ silica gel cartridge eluting with 6.3% ethyl acetate/hexanes to give the title compound as a pale yellow sticky solid.
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClN1C(=O)CCC1=O.[CH2:18]([P:21](=[O:28])([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])[CH:19]=[CH2:20].C(N(CC)CC)C>>[C:2]1([C:1]2[CH2:20][CH:19]([CH2:18][P:21](=[O:28])([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])[O:9][N:8]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCP(=O)(OCC)OCC
Reactant: ON=Cc1ccccc1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Product: CCOP(=O)(CC1CC(c2ccccc2)=NO1)OCC

Procedure:
In analogy to Example 1, 76.7 g of an oily crude product are obtained starting from 30.3 g (0.25 mol) of benzaldoxime, 36.7 g (0.275 mol) of N-chlorosuccinimide, 49 g (0.275 mol) of diethyl allylphosphonate and 38.2 ml (0.275 mol) of triethylamine and can be purified as described in Example 1.