Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.CNC(=O)[O-].[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]2[CH:20]([CH3:28])[CH:21]3[CH2:25][NH:24][CH2:23][CH:22]3[C:26]=2[CH:27]=1>CC#N.O.CCOC(C)=O>[CH3:14][O:15][C:16]1[C:17]([Br:8])=[CH:18][C:19]2[CH:20]([CH3:28])[CH:21]3[CH2:25][NH:24][CH2:23][CH:22]3[C:26]=2[CH:27]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(c1)C1CNCC1C2C
Agent: CNC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: COc1cc2c(cc1Br)C(C)C1CNCC21
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.1 %

Procedure:
NBS (70 mg, 0.4 mmol) was added to a solution of N-methylcarbamate-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 2, step A) (0.1 g, 0.36 mmol) in CH3CN (3.6 mL), and stirred overnight at room temperature. The reaction was diluted with H2O and EtOAc and filtered through an Extrelut column. The column was washed with EtOAc and the filtrate was concentrated to afford 120 mg (94%) of the subtitle compound. MS calculated for C16H20BrNO3+H: 342, observed: 342.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][C:5](=[O:15])[C:6]([CH3:14])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.CC(C)=O.CC(C)([O-])C.[K+].[C:26]1([S:32](Cl)(=O)=O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1.O>[C:8]1([C:6]2([CH3:14])[C:5](=[O:15])[N:4]([S:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:3]([S:2][CH3:1])=[N:7]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CSC1=NC(C)(c2ccccc2)C(=O)N1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CSC1=NC(C)(c2ccccc2)C(=O)N1Sc1ccccc1
Reaction time: 1 h

Procedure:
0.6 g (2.7 mmol) of 2-methylthio-4-methyl-4-phenyl-2-imidazolin-5-one in solution in 50 ml of anhydrous tetrahydrofuran (THF) is charged to a 10 0 ml, three-necked, round-bottomed flask under an inert atmosphere. The solution is stirred with a magnetic stirrer and is cooled to 0° C. (ice bath+acetone). 0.30 g (1 molar equivalent) of potassium tert-butoxide is added and the mixture is stirred for 10 minutes at 0° C. A solution containing 0.40 g of phenylsulfonyl chloride (phenylthio chloride) and 10 ml of anhydrous THF is then run in. The mixture is then left to return to more temperature for one hour. The reaction mixture is run into 100 ml of water. Extraction is carried out with 100 ml of ethyl acetate. The organic phase is washed 4 times with water and dried over sodium sulfate.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[CH2:6][CH2:7][CH:8]3[C:13]([C:4]=2[CH:3]=1)=[N:12][N:11]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:10](=[O:21])[CH2:9]3.[CH3:24][CH:25](Cl)[CH2:26][N:27]([CH3:29])[CH3:28].C([O-])(=O)/C=C/C([O-])=O>>[F:1][C:2]1[CH:23]=[CH:22][C:5]2[CH2:6][CH2:7][CH:8]3[C:13]([C:4]=2[CH:3]=1)=[N:12][N:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH:25]([CH3:24])[CH2:26][N:27]([CH3:29])[CH3:28])=[CH:16][CH:15]=1)[C:10](=[O:21])[CH2:9]3
Reactant: CC(Cl)CN(C)C
Reactant: O=C1CC2CCc3ccc(F)cc3C2=NN1c1ccc(O)cc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Product: CC(CN(C)C)Oc1ccc(N2N=C3c4cc(F)ccc4CCC3CC2=O)cc1

Procedure:
By conducting reactions and treatments in the same manner as in Example 1 using 9-fluoro-2-(4-hydroxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one and 1-methyl-2-dimethylaminoethyl chloride, there are obtained crude crystals, which are subjected to silica gel column chromatography. The crystals obtained from fractions at earlier stage are converted into fumarate, followed by recrystallization from ethanol to give 9-fluoro-2-[4-(1-methyl-2-dimethylaminoethoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.fumarate.1/2 hydrate [referred to as compound of Example 11a], m.p. 176°-179° C. (decomposition). The crystals obtained from fractions at later stage are converted into fumarate, which is recrystallized from water to give 9-fluoro-2-[4-(2-dimethylaminopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.fumarate [referred to as compound of Example 11b], m.p. 194°-195° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([CH3:15])[C:3]=1[C:16]([F:19])([F:18])[F:17].[CH3:20][N:21]1C(=O)CCC1>O>[C:20]([C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([CH3:15])[C:3]=1[C:16]([F:19])([F:18])[F:17])#[N:21]
Reactant: CN1CCCC1=O
Reactant: Cc1c(NC(=O)C(C)(C)C)ccc(Cl)c1C(F)(F)F
Solvent: O
Product: Cc1c(NC(=O)C(C)(C)C)ccc(C#N)c1C(F)(F)F
Temperature: 220 °C
Yield: 51.7 %

Procedure:
To a solution of N-(4-chloro-2-methyl-3-(trifluoromethyl)phenyl) pivalamide (3c) (0.4 g, 1.36 mmol) in NMP (5 mL) CuCN (0.3 g, 34.0 mmol) was added at room temperature under nitrogen atmosphere and heated to 220° C. for 36 h. The reaction mixture was slowly brought to room temperature, diluted with water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give the crude compound which was purified by column chromatography to furnish the nitrile 3d (0.2 g, 52%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH:20]=O)[C:13](=[O:22])[C@@H:12]1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:25]1[C:27]2([CH2:32][CH2:31][NH:30][CH2:29][C@H:28]2[OH:33])[CH2:26]1.C(N(CC)CC)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].N>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][N:30]2[CH2:31][CH2:32][C:27]3([CH2:25][CH2:26]3)[C@H:28]([OH:33])[CH2:29]2)[C:13](=[O:22])[C@@H:12]1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@@H]1CNCCC12CC2
Reactant: C[C@H]1C(=O)N(CCCC=O)CCN1C(=O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: C[C@H]1C(=O)N(CCCCN2CCC3(CC3)[C@H](O)C2)CCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a solution of (S)-4-(4-hydroxy-butyl)-2-methyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (1.67 g, 5.21 mmol) in dichloromethane (18 mL) were added at room temperature trichloroisocyanuric acid (1.28 g, 5.21 mmol) and 2,2,6,6-tetramethylpiperidin-1-oxyl (8 mg, 0.05 mmol), upon which an exothermic reaction (Tmax=36° C.) under gas evolution started. The reaction mixture was stirred for 5 min, then insoluble material was removed by filtration. The filtrate was washed with 1 M aq. sodium thiosulfate solution and brine, dried (MgSO4), filtered, and evaporated to afford (S)-4-(4-oxo-butyl)-2-methyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (1.56 g). This aldehyde (MS (ISP)=319.1 (M+H)+) was taken up in dichloromethane (9 mL) and added at room temperature to a suspension of (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2; 853 mg, 5.21 mmol), triethylamine (527 mg, 5.21 mmol), acetic acid (626 mg, 10.4 mmol), and sodium triacetoxyborohydride (1.21 g, 5.73 mmol) in dichloromethane (9 mL). The reaction mixture was stirred for 30 min, then cooled to 0° C. and treated with 25% aq. ammonia solution (1.07 mL), then allowed to reach room temperature and concentrated in vacuo. Chromatography (SiO2; dichloromethane→dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) afforded the title compound (1.26 g, 56%). Colorless gum, MS (ISP)=430.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8](Br)[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2].[N+:13]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]>C1(C)C=CC=CC=1.C1(P([Pd-4](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:13]([O-:15])=[O:14])[CH:21]=2)[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CCOC(=O)c1cncc(Br)c1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cncc(-c2cccc([N+](=O)[O-])c2)c1

Procedure:
n.m.r. δ values include 1.5 (t, 3 H), 4.5 (q, 2 H), 7.75 (t, 1 H), 8.0 (d, 1 H), 8.3 (d, 1 H), 8.6-8.5 (m, 2 H), 9.0 (s, 1 H), 9.3 (s, 1 H); from 3-bromo-5-pyridine carboxylic acid ethyl ester (985 mg) in toluene (15 mL), tetrakis(triphenylphosphino)palladium(0) (161 mg) and 3-nitrophenylboronic acid (860 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21]O)[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.CS(Cl)(=O)=O.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)ccc21
Reactant: C1COCCN1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 42 %

Procedure:
A solution of N-(4-chlorobenzyl)-6-(hydroxymethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide from the product of Example 2 (140 mg), collidine (0.061 mL), and DMAP (8.1 mg) in 6.7 mL anhydrous DMF is cooled to 0° C. Methanesulfonyl chloride (0.12 mL) is added dropwise. The reaction is stirred at room temperature for approx. 2-3 hrs. Morpholine (0.34 mL) is added. The product is precipitated by addition of H2O. The crude product is adsorbed onto silica and chromatographed eluting with 2% MeOH in CH2Cl2. Fractions homogenous by TLC are combined and condensed to afford 70.1 mg (42%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:12])[CH2:10][CH3:11].BrBr.[H-].[Na+].[C:19]([CH2:21][C:22]([O:24][CH3:25])=[O:23])#[N:20].BrC(C)C(C1C=CC=CC=1C(F)(F)F)=O>C(Cl)(Cl)(Cl)Cl.C1COCC1>[CH3:25][O:24][C:22](=[O:23])[CH:21]([C:19]#[N:20])[CH:10]([CH3:11])[C:9](=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:1])([F:13])[F:14]
Reactant: COC(=O)CC#N
Reactant: CCC(=O)c1ccccc1C(F)(F)F
Agent: BrBr
Agent: CC(Br)C(=O)c1ccccc1C(F)(F)F
Agent: [H-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)C(C#N)C(C)C(=O)c1ccccc1C(F)(F)F
Temperature: 20 °C
Reaction time: 3 h
Yield: 92.6 %

Procedure:
To a solution of 2′-trifluoromethyl-propiophenone (10 g, 48 mmol) in carbon tetrachloride (50 ml) was added a solution of bromine (2.72 mL, 52.8 mmol) in carbon tetrachloride (20 mL) dropwise. After the addition was complete, stirring was continued for another 2 h. The solution was washed with satd NaHCO3 and water, dried (anhyd Na2SO4) and concentrated under reduced pressure to give 2-bromo-1-(2-trifluoromethyl-phenyl)-propan-1-one as an oil (12.8 g, 95%), which was used in the next step without purification. 1H-NMR (CDCl3): δ 7.73 (m, 2H), 7.58-7.67 (m, 2H), 4.96 (q, 1H), 1.90 (d, 3H). To a solution of 2′-trifluoromethyl-propiophenone (10 g, 48 mmol) in carbon tetrachloride (50 ml) was added a solution of bromine (2.72 mL, 52.8 mmol) in carbon tetrachloride (20 m To a suspension of NaH (60%, 2.88 g, 72 mmol) in anhyd THF (200 mL) was added methyl cyanoacetate (4.5 mL, 50 mmol). After this mixture was stirred for 3 h at 20° C., a solution of 2-bromo-1-(2-trifluoromethyl-phenyl)-propan-1-one (13.5 g, 48 mmol) was added and the mixture was stirred overnight at 20° C. The mixture was quenched with water and the organic layer was separated. The aqueous layer was extracted with EtOAc. The combined extracts were washed with brine, dried (anhyd Na2SO4) and concentrated under reduced pressure to afford the title compound as an oil (13.3 g, 93%), which was used in the next step without purification. MS (ES): 300 (MH+).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([C:17](=[N:19][OH:20])[CH3:18])[CH2:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1.[CH3:21][C:22]([CH3:24])=[O:23].O>CCCCCC.O1CCCC1>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2([C:17](=[N:19][OH:20])[CH2:18][C:22]([OH:23])([CH3:24])[CH3:21])[CH2:14][CH2:15][CH2:16]2)=[CH:11][CH:12]=1
Reactant: CC(C)=O
Reactant: CC(=NO)C1(c2ccc(Cl)cc2)CCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)CC(=NO)C1(c2ccc(Cl)cc2)CCC1
Temperature: -5 °C
Reaction time: 16 h

Procedure:
A 1.6M solution of butyllithium in hexane (55 ml) was added to a stirred solution of the 1-[1-(4-chlorophenyl)cyclobutyl]ethanone oxime (8.94 g) in dry tetrahydrofuran (120 ml) the temperature being maintained below 0° C. for 40 minutes. The mixture was cooled to -5° C. and acetone (2.67 ml) was added dropwise. The temperature of the reaction mixture was allowed to rise to ambient temperature over a period of 16 hours. The mixture was cooled to 10° C. and water (100 ml) was added and the resulting aqueous mixture was washed with ether. The aqueous layer was acidified with 5N sulphuric acid and an oil separated. The oil was dissolved in ether and the ether solution was washed with water, dried and evaporated to yield 1-[1-(4-chlorophenyl)cyclobutyl]-3-hydroxy-3-methylbutan-1-one oxime.
Reaction SMILES: C(OC([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]=2)[CH2:8][CH2:7]1)=O)C.[BrH:22]>C(O)C>[BrH:22].[NH:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[N:9]1[CH2:10][CH2:11][CH2:12][NH:6][CH2:7][CH2:8]1
Reactant: CCOC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Agent: Br
Solvent: CCO
Product: c1ccc2[nH]c(N3CCCNCC3)nc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Combine 1-ethoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane (5.22 g, 18.1 mmol) and aqueous 48% hydrobromic acid solution (25 mL). Heat to reflux. After 4 hours, cool to ambient temperature and concentrate in vacuo to give a residue. Combine the residue and ethanol (150 mL). Evaporate in vacuo to a volume of about 75 mL and cool to give a solid. Collect solid by filtration, rinse with ethanol and then diethyl ether, and dry in vacuo to give 4-(1H-benzimidazol-2-yl)[1,4]diazepane hydrobromic acid salt. Elemental Analysis calculated for C12H16N4.2HBr: C, 38.12; H, 4.80; N, 14.82. Found: C, 38.17; H, 4.84; N, 14.60.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]3[O:10][C:9]2=[O:17])[CH:5]=[CH:6][CH:7]=1.CC(C[AlH]CC(C)C)C.S(=O)(=O)(O)O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]3[O:10][CH:9]2[OH:17])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC2CCCCC2C1c1cccc(Cl)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: OC1OC2CCCCC2C1c1cccc(Cl)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of 3-(3-chlorophenyl)hexahydro-1-benzofuran-2(3H)-one (540 mg, 2.19 mmol) in dry tetrahydrofuran (7 mL) was cooled to −78° C. under nitrogen and was treated dropwise with a solution of DiBAL (1.0 M in toluene, 3.07 mL, 3.07 mmol). The resulting solution was stirred at −78° C. for 2 h, after which time the reaction was treated a 1 M aqueous solution of sulfuric acid to dissolve precipitated salts. The reaction mixture was allowed to warm to room temperature and was partitioned between diethyl ether and water. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water, and brine and was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified via Biotage Horizon (FLASH 25 M, silica, gradient from 0% EtOAc/hexane to 35% EtOAc/hexane) to yield 0.38 g (69%) the lactol, 3-(3-chlorophenyl)octahydro-1-benzofuran-2-ol as a white foam. HRMS: calcd for C14H17ClO2−H, 251.0817. found (ESI, [M−H]−), 251.0835.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:5]([CH3:28])=[C:6]2[C:11](=[C:12]([CH3:15])[C:13]=1[CH3:14])[O:10][C:9]([CH3:27])([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[CH2:8][CH2:7]2.CN(C)C=O.[CH2:34](I)[CH3:35]>O.C1C=CC=CC=1>[CH2:34]([O:3][C:4]1[C:5]([CH3:28])=[C:6]2[C:11](=[C:12]([CH3:15])[C:13]=1[CH3:14])[O:10][C:9]([CH3:27])([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[CH2:8][CH2:7]2)[CH3:35]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc([N+](=O)[O-])cc1)O2
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccccc1
Product: CCOc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc([N+](=O)[O-])cc1)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.6 g of a 55% w/w suspension of sodium hydride in mineral oil was added to a mixture of 11 g of 6-hydroxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman and 100 ml of dimethylformamide, and the reaction mixture was stirred for 1 hour at room temperature. Then a mixture of 5.7 g of ethyl iodide and 5 ml of benzene was added dropwise, whilst ice-cooling, and the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was then poured into water and extracted with benzene. This extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled from the extract under reduced pressure, and the residue was purified by silica gel column chromatography eluted with a 3:7 by volume mixture of cyclohexane and benzene, to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13]Br)=[CH:6][C:5]=1[NH:15][C:16](=[O:31])[C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=1.[C:33]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:38]=[CH:37][C:36]([CH:39]=[N:40][OH:41])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:41]/[N:40]=[CH:39]/[C:36]2[CH:37]=[CH:38][C:33]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[CH:34][CH:35]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:31])[C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=1
Reactant: COC(=O)c1ccc(OCCCBr)cc1NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: ON=Cc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCO/N=C/c2ccc(-c3ccccc3)cc2)cc1NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 68.2 %

Procedure:
This compound was produced using similar methods as those used in Step 5, example 27, starting with 2-(3,5-bis-trifluoromethyl-benzoylamino)-4-(3-bromo-propoxy)-benzoic acid methyl ester (0.35 g, 0.66 mmol), biphenyl-4-carbaldehyde oxime (0.14 g, 0.70 mmol) and cesium carbonate (0.86 g, 2.65 mmol) in acetone (25 mL). The crude material was purified by flash chromatography through silica gel using diethyl ether/hexanes (0/100 gradient to 10/90) to give 4-[3-({[(1E)-1,1′-biphenyl-4-ylmethylidene]amino}oxy)propoxy]-2-{[3,5-bis(trifluoromethyl)benzoyl]amino}benzoic acid methyl ester (0.29 g, 68%) as a white solid. 1H NMR (500 MHz, DMSO-d6); δ 11.79 (s, 1H), 8.52 (s, 2H), 8.43 (s, 1H), 8.31 (s, 1H), 8.11 (d, 1H), 7.98 (d, 1H), 7.97-7.64 (AA′BB′, 4H), 7.45 (t, 2H), 7.37 (t, 1H), 6.89 (dd, 1H), 4.31 (t, 2H), 4.23 (t, 2H), 3.84 (s, 3H), 2.18 (m, 2H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH3:29])[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=3)=[CH:17][C:11]=2[N:10]([CH3:30])[C:9]1=[O:31])(=O)C.O[Li].O>C1COCC1.O.C(Cl)Cl>[OH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH3:29])[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=3)=[CH:17][C:11]=2[N:10]([CH3:30])[C:9]1=[O:31]
Reactant: CC(=O)OCCCn1c(=O)c2c(cc(-c3cccc(OC(F)(F)F)c3)n2C)n(C)c1=O
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1c(-c2cccc(OC(F)(F)F)c2)cc2c1c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
To a solution of 3-(1,5-dimethyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (30 mg, 0.068 mmol) in THF (5 mL) and water (5 mL) was added LiOH.H2O (5.73 mg, 0.136 mmol). The reaction was stirred at RT for 30 min then diluted with DCM (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 3-(3-hydroxypropyl)-1,5-dimethyl-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-dione (10 mg, 36.9% yield) as a white solid. 1H NMR (CDCl3) δ: 7.54 (t, J=7.9 Hz, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.32 (d, J=11.0 Hz, 2H), 6.03 (s, 1H), 4.29-4.17 (m, 2H), 3.98 (s, 3H), 3.72 (s, 1H), 3.54 (t, J=5.1 Hz, 2H), 3.50 (s, 3H), 1.99-1.84 (m, 2H). LCMS: MH+ 398 and TR=2.507 min.
Reaction SMILES: [F:1][CH:2](S(C1C=CC=CC=1)(=O)=O)[C:3]1([N:14]2[CH:18]=[C:17]([C:19]3[C:20]4[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:21]=4[N:22]=[CH:23][N:24]=3)[CH:16]=[N:15]2)[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1.P([O-])([O-])(O)=O.[Na+].[Na+].CO>CCOC(C)=O.[Na].[Hg]>[F:1][CH2:2][C:3]1([N:14]2[CH:18]=[C:17]([C:19]3[C:20]4[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:33])[CH3:34])[C:21]=4[N:22]=[CH:23][N:24]=3)[CH:16]=[N:15]2)[CH2:4][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CC(C(F)S(=O)(=O)c2ccccc2)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Agent: O=P([O-])([O-])O
Agent: [Hg]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(CF)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Temperature: -10 °C
Reaction time: 1 h
Yield: 49.2 %

Procedure:
To a mixture of tert-butyl 3-[fluoro(phenylsulfonyl)methyl]-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (0.312 g, 0.485 mmol) and disodium hydrogen phosphate (1.38 g, 9.71 mmol) in methanol (7.5 mL, 180 mmol) was added sodium mercury amalgam (2.17 g, 9.71 mmol), under nitrogen, at −20° C. The reaction was stirred at −20 to 0° C. for 1 h, diluted with EtOAc, then quenched with sat. ammonium chloride. The mixture was filtered through Celite and the solid collected was treated with elemental sulfur powder to destroy the mercury residue. The filtrate layers were separated and the organic layers were washed with brine, dried over sodium sulfate and evaporated. The residue was purified on silica gel, eluting with 0 to 80% EtOAc in hexane, to give the desired product (120 mg, 49.2%). LCMS calculated for C24H36FN6O3Si(M+H)+: m/z=503.3; Found: 503.2.