Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH3:29][O:30][C:31](=[O:49])[C@H:32]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=1)[NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>O>[CH3:29][O:30][C:31](=[O:49])[C@@H:32]([NH:33][C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:6]=2)=[CH:44][CH:43]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: BrCCOc1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(OCCOc2ccc(Oc3ccccc3)cc2)cc1)NC(=O)OC(C)(C)C
Yield: 64.6 %

Procedure:
To a solution of 1-(2-Bromo-ethoxy)-4-phenoxy-benzene (2.5 g, 8.53 mmol), potassium carbonate (3.21 g, 23.3 mmol), and N,N-Dimethylformamide (150 mL) was added Boc-L-Tyrosine methyl ester (2.3 g, 7.75 mmol). The mixture was poured into 200 mL water solution and extracted with ethyl acetate (EtOAc) (3×100 mL). The combined organic layers were washed with brine (40 mL) and dried over anhydrous Na2SO4. The organic layer was concentrated in vacuo to obtain the crude mixture, which was purified by of silica gel flash chromatography, using EtOAc/hexane (gradient system), to obtain the product (2.54 g, 59%): 1H NMR (400 MHz, CDCL3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:11]=[N:10][CH:9]([CH3:12])[N:5]2[C:6](=[O:8])[N:7]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH3:18]>O1CCOCC1>[Cl:1][C:2]1[N:7]([CH2:16][CH2:17][CH3:18])[C:6](=[O:8])[N:5]2[C:9]([CH3:12])=[N:10][CH:11]=[C:4]2[CH:3]=1
Reactant: CC1N=Cc2cc(Cl)nc(=O)n21
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCCn1c(Cl)cc2cnc(C)n2c1=O
Temperature: 0 °C

Procedure:
To a mixture of 2.0 g (10.9 mmole) of 7-chloro-3-methylimidazo[1,5-c]pyrimidin-5-one (from Example 4, Part B) in 50 ml of dioxane was added 0.52 g (13 mmole) of 60% sodium hydride in oil. After ten minutes of stirring, 1.6 g (13 mmole) of 3-bromopropane was added and the mixture was stirred for 16 hours at 50° C. The solution was poured into 100 ml of an ice water mixture. The resulting solution was extracted four times with 75 ml portions of chloroform. The extracts were washed twice with water, dried, and evaporated. The residue was dissolved in 80 ml of chloroform, washed with six 100 ml portions of water, dried and evaporated. The residue was recrystallized with treatment with decolorizing charcoal from cyclohexane to provide 7-chloro-3-methyl-6-n-propylimidazo[1,5-c]pyrimidin-5-one, m.p. 125°-126° C. Analysis: Calculated for C10H12ClNO: %C, 53.2 ; %H, 5.4; %N, 18.6; Found: %C, 53.5; %H, 5.3; %N, 18.6.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:9][Si:10]([O:13][CH2:14][CH3:15])([CH3:12])[CH3:11].[Cl-]>>[CH:1]1([NH:7][CH2:9][Si:10]([O:13][CH2:14][CH3:15])([CH3:12])[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CCO[Si](C)(C)CCl
Agent: [Cl-]
Product: CCO[Si](C)(C)CNC1CCCCC1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
In a 500 ml three-necked flask having a reflux condenser, KPG stirrer and thermometer, 317 g of dry cyclohexylamine were heated to 130° C., and 122 g of (chloromethyl)ethoxydimethylsilane were added in the course of 45 min with stirring. After the end of the addition, stirring was effected for a further 30 min at 130° C. and excess cyclohexylamine was distilled off under reduced pressure. Thereafter, the mixture was cooled to 30° C. and 150 ml of isohexane were added. Thereafter, the suspension was filtered using a pressure filter, and the precipitate was rinsed with two 80 ml portions of isohexane. Filtrate and wash solutions were combined and were freed from the solvent under reduced pressure. The subsequent fractional distillation gave 163 g (yield 95%) of (N-cyclohexyl-aminomethyl)ethoxydimethylsilane with a chloride content of <20 ppm. When 1% of ammonia was added before the distillation of the product and any precipitate which separated out was filtered off, a product having a chloride content of <10 ppm was obtained in the same yield.
Reaction SMILES: [C:1]([O:4]CC)(=[O:3])[CH3:2].[C:7]1([CH3:13])[CH:12]=CC=[CH:9][CH:8]=1>>[CH3:12][CH:7]([CH3:13])[CH2:8][CH2:9][CH2:2][C:1]([OH:4])=[O:3]
Reactant: Cc1ccccc1
Reactant: CCOC(C)=O
Product: CC(C)CCCC(=O)O
Temperature: 250 °C

Procedure:
The crude ester prepared in example 1, is added to a mixture of ethyl acetate and toluene, and heated to 80° C. (range 400 to 100° C.) until dissolution. The solution is cooled to 2° C. (range 0° to 20° C.) to get a yellowish solid of (S)-3-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)carbonyl)methyl)-5-methylhexanoic acid (Fenchyl ester), which is filtered from the mixture.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20](O)[CH2:21][CH2:22][CH3:23])=[CH:16][CH:15]=1.B(F)(F)F.CCOCC>O1CCOCC1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[CH:20]([C:17]1[CH:16]=[CH:15][C:14]([CH3:13])=[CH:19][CH:18]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCC(O)c1ccc(C)cc1
Reactant: O=c1cc(O)c2ccccc2o1
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCCC(c1ccc(C)cc1)c1c(O)c2ccccc2oc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
To a flame-dried flask containing a mixture of 650 mg of 4-hydroxycoumarin and 980 mg of 1-(4-methylphenyl)-butan-1-ol of Preparation 20 in 20 mL of dioxane under an argon atmosphere is added 2.5 mL of boron trifluoride etherate. The resulting yellow solution is left to stir at room temperature overnight. The volatiles are removed and the residue is partioned between diethyl ether and 1N sodium hydroxide. The basic aqueous phase is washed with diethyl ether and acidified to pH=1 with 6N hydrochloric acid. The resulting precipitant is repeatedly extracted with dichloromethane (methanol-chloroform co-solvents). The combined dichloromethane extracts are washed once with dilute sodium bicarbonate to remove most of the unreacted 4-hydroxycoumarin, then brine, dried (magnesium sulfate), and finally concentrated under reduced pressure. The residue is adsorbed onto silica and flash column chromatographed with 40% to 50% ethyl acetate in hexane to yield 660 mg of the title product as a white solid.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[Cl:44][C:45]1[CH:68]=[CH:67][C:48]([C:49]([N:51]2[C:59]3[C:54](=[CH:55][C:56]([O:60][CH3:61])=[CH:57][CH:58]=3)[C:53]([CH2:62][C:63](O)=[O:64])=[C:52]2[CH3:66])=[O:50])=[CH:47][CH:46]=1>C(#N)C>[CH:1]1([N:7]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[C:63](=[O:64])[CH2:62][C:53]2[C:54]3[C:59](=[CH:58][CH:57]=[C:56]([O:60][CH3:61])[CH:55]=3)[N:51]([C:49](=[O:50])[C:48]3[CH:47]=[CH:46][C:45]([Cl:44])=[CH:68][CH:67]=3)[C:52]=2[CH3:66])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: c1csc(NC2CCCCC2)n1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)c(CC(=O)N(c1nccs1)C1CCCCC1)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a suspension of 2 g (0.02 mol) of N-Cyclohexyl-N-thiazol-2-yl amine in 20 mL of acetonitrile at rt was added 6.1 mL (0.044 mol) of triethylamine and 10.24 g (0.022 mol) of PyBroP [bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (Aldrich or NovaBiochem)]. To the reaction mixture was then added 3.93 g (0.01 mol) of 1-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid and the reaction mixture was heated at 100° C. for 4 h. The reaction mixture was then cooled to 0° C. and the white precipitate was isolated by filtration. The filtrate was concentrated to ˜10 mL, recooled to 0° C., refiltered and the filtrate was concentrated to an oil. The residue was dissolved in 100 mL of dichloromethane and the solution was washed twice with 1N HCl, and once with 1N NaHCO3 solution. The organic phase was dried (Na2SO4) filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 0-50% EtOAc in heptane) to give the title compound. 1H NMR (CDCl3) δ 7.74 (1H, d), 7.66 (2H, d), 7.50 (2H, d), 7.40 (1H, d), 6.95 (1H, bs), 6.82 (1H, d), 6.67 (1H, dd), 4.59 (1H, bt), 3.84 (3H, s), 3.61 (2H, s), 2.22 (3H, s), 0.9-2.0 (10H, m)
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12]4([CH2:25][CH2:26][C:5]=3[C:4]=2[CH:3]=1)[CH2:17][CH2:16][N:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:14][CH2:13]4.[CH3:27][N:28]=[C:29]=[O:30]>ClCCl.[Cu]Cl>[CH3:11][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([O:1][C:29]([NH:28][CH3:27])=[O:30])=[CH:3][C:4]=2[C:5]2[CH2:26][CH2:25][C:12]3([CH2:13][CH2:14][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:16][CH2:17]3)[C:6]1=2
Reactant: CN=C=O
Reactant: Cn1c2c(c3cc(O)ccc31)CCC21CCN(Cc2ccccc2)CC1
Agent: Cl[Cu]
Solvent: ClCCl
Product: CNC(=O)Oc1ccc2c(c1)c1c(n2C)C2(CC1)CCN(Cc1ccccc1)CC2
Yield: 70.7 %

Procedure:
To a solution of 1,4-dihydro-7-hydroxy-4-methyl-1'-phenylmethylspiro[cyclopent[b]indole-3(2H), 4'-piperidine] (0.25 g) and copper (I) chloride (0.01 g) in dichloromethane (10 ml) was added methyl isocyanate (0.04 g), under nitrogen, with stirring. The reaction mixture was stirred for 24 hrs. The mixture was flash chromatographed (neutral alumina) and eluted with 25% ethyl acetate/dichloromethane. The appropriate fractions were collected and concentrated to give 0.2 g (69%) of product, mp 189-190° C.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.Br[C:18]1[C:24]([OH:25])=[CH:23][C:21]([NH2:22])=[C:20]([F:26])[CH:19]=1>C(O)(C)C>[ClH:2].[Cl:1][C:18]1[C:24]([OH:25])=[CH:23][C:21]([NH:22][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][N:4]=2)=[C:20]([F:26])[CH:19]=1
Reactant: Nc1cc(O)c(Br)cc1F
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3cc(O)c(Cl)cc3F)c2cc1OC
Yield: 46.9 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxyquinazoline hydrochloride (2.1 g, 8 mmol), (prepared as described for the starting material in Example 1 but without the aqueous work up), and 4-chloro-2-fluoro-5-hydroxyaniline (1.43 g, 8.9 mmol), (as described in EP 61741 A2), in isopropanol (150 ml) was heated at reflux for 2 hours. The mixture was allowed to cool, the solid product collected by filtration, washed with isopropanol and dried to give 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6,7-dimethoxyquinazoline hydrochloride (1.45 g, 47%).
Reaction SMILES: [CH3:1][C@@H:2]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH2:3][N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5]1.[CH:22]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[CH3:1][C@@H:2]([N:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[C:28]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:29])[CH2:3][N:4]1[CH2:5][CH:6]=[C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH2:8][CH2:9]1
Reactant: C[C@H](CN1CC=C(c2cccs2)CC1)Nc1ccccn1
Reactant: O=C(Cl)C1CCCCC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: C[C@H](CN1CC=C(c2cccs2)CC1)N(C(=O)C1CCCCC1)c1ccccn1
Yield: 82.4 %

Procedure:
The title compound was prepared from (R)-[1-methyl-2-(4-thiophen-2-yl-3,6-dihydro-2H-pyrid-1-yl)-ethyl]-pyrid-2-yl-amine (2.4 g, 8 mmol) and cyclohexanecarbonyl chloride (1.173 g, 8 mmol) in the manner described in Example 5 above to yield 2.7 g of title compound as the dihydrochloride, m.p. 103°-6° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=O)[CH3:2].S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([Cl:16])=[O:13])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCc1ccccc1CCC(=O)O
Solvent: Cc1ccccc1
Product: CCc1ccccc1CCC(=O)Cl

Procedure:
A mixture of 3-(2-ethylphenyl)propanoic acid (prepared in 3 steps from 1-ethyl-2-iodobenzene, 4.24 g, 23.8 mmole), thionyl chloride (9.50 ml, 130 mmol) and toluene (100 ml) was refluxed for 2 hours. Concentration in vacuo gave 3-(2-ethylphenyl)propanoyl chloride which was taken up in methylene chloride and used in the next step as a crude.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[NH:14][C:15]([NH2:24])=[C:16]2[C:20]([N:21]=1)=[N:19][C:18]([O:22][CH3:23])=[N:17]2)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:34][CH2:33][O:32][CH2:31]1>>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:34][CH2:33][O:32][CH2:31]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: BrCCCCC1CCOC1
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCOC3)c2n1

Procedure:
Prepared similarly to Intermediate 216 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 3-(4-bromobutyl)tetrahydrofuran.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][N:22]=[N+]=[N-])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]>CO.[Pd]>[CH2:1]([C:3]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH2:22])=[CH:18][CH:19]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCN=[N+]=[N-])cc1
Agent: [Pd]
Solvent: CO
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCN)cc1
Reaction time: 4 h
Yield: 93.5 %

Procedure:
To a solution of 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl azide (step 8, 2.35 g, 7.3 mmol) in methanol (50 mL) was added 10% Pd—C (200 mg). The resulting mixture was stirred for 4 h under hydrogen atmosphere. The mixture was filtered through a pad of Celite and the filtrate was concentrated. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane/methanol/triethylamine (100:5:1) to afford 2.01 g (94%) of the title compound as white solids: 1H-NMR (CDCl3) δ 7.39 (2H, d, J=8.4 Hz), 7.32 (2H, d, J=8.4 Hz), 6.90 (1H, s), 3.05 (2H, t, J=7.3 Hz), 2.88-2.78 (4H, m), 2.65 (3H, s), 2.51 (3H, s), 1.28 (3H, t, J=7.6 Hz).
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[CH2:11][C:12]([C:14]1[CH2:18][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:16][N:15]=1)=O>CN1CCCC1=O>[C:19]1([CH:17]2[O:16][N:15]=[C:14]([C:12]3[N:9]=[C:1]([C:2]4[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=4)[S:8][CH:11]=3)[CH2:18]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NC(=S)c1ccncc1
Reactant: O=C(CCl)C1=NOC(c2ccccc2)C1
Solvent: CN1CCCC1=O
Product: c1ccc(C2CC(c3csc(-c4ccncc4)n3)=NO2)cc1
Temperature: 100 °C
Yield: 63.3 %

Procedure:
To a solution of thioisonicotinamide (0.5 g, 3.6 mmol) in 1-methyl-2-pyrrolidinone (25 mL) was added 2-chloro-1-(4,5-dihydro-5-phenyl-3-isoxazolyl)ethanone (0.807 g, 3.6 mmol), at room temperature. The reaction mixture was then heated to 100° C. for 3 h. Then the reaction mixture was cooled to room temperature, quenched with water (100 mL), extracted with ethyl acetate (50 mL×2). The reaction mixture was diluted with water (50 mL) and brine (50 mL), and the organic layer was concentrated under reduced pressure and purified by medium-pressure liquid chromatography using 2% of methanol in chloroform as eluant to give 0.7 g of the title compound as a brown solid.
Reaction SMILES: C(OC([N:8]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([C:22]3[O:23][C:24]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:25][C:26](=[O:28])[CH:27]=3)[C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:29]1([C:24]2[O:23][C:22]([C:17]3[C:16]4[S:15][C:14]5[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=5)[NH:8][C:21]=4[CH:20]=[CH:19][CH:18]=3)=[CH:27][C:26](=[O:28])[CH:25]=2)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1c2ccccc2Sc2c(-c3cc(=O)cc(N4CCOCC4)o3)cccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1cc(-c2cccc3c2Sc2ccccc2N3)oc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.1 %

Procedure:
To a stirred solution of 4-(6-Morpholin-4-yl-4-oxo-4H-pyran-2-yl)-phenothiazine-10-carboxylic acid tert-butyl ester (3.65 g, 7.63 mmol), in CH2Cl2 (30 ml) was added trifluoroacetic acid in a single portion. The mixture was stirred at room temperature for 20 hours whereupon the reaction was concentrated in vacuo to give a thick syrup that was basified in a dropwise fashion with saturated NaHCO3 (40 ml). The dark green mixture was then stirred at room temperature for 18 hours. The mixture was filtered and the filtrant retained, washed with water and dried to give the title compound as a dark green solid (2.89 g, 83.74% over 3 steps) m/z (LC-MS, ESP): 479 [M+H]+, R/T=4.05 mins
Reaction SMILES: [NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[O:7])=[C:4]([OH:20])[CH:3]=1.[H-].[Na+].Cl[CH2:24][C:25](=[O:27])[CH3:26]>CN(C=O)C>[NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][CH:9]2[CH:14]3[CH2:13][CH2:12][N:11]([CH2:16][CH2:15]3)[CH2:10]2)=[O:7])=[C:4]([O:20][CH2:24][C:25](=[O:27])[CH3:26])[CH:3]=1
Reactant: Nc1cc(O)c(C(=O)NC2CN3CCC2CC3)cc1Cl
Reactant: CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)COc1cc(N)c(Cl)cc1C(=O)NC1CN2CCC1CC2
Reaction time: 5 h

Procedure:
When the starting benzamide intermediate from Example 74 is first reacted with one equivalent of sodium hydride in DMF and then to this is added on equivalent of chloroacetone and the mixture stirred for 5 h followed by heating to 50° for 30 min and workup, the title compound is isolated.
Reaction SMILES: OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:6].[CH3:16][O:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]2[N+:29]([O-:30])=[N:28][C:27]([NH:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])=[N:26][C:25]=2[CH:37]=1.FC(F)(F)C(O)=O>C(Cl)Cl.N>[CH3:16][O:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]2[N+:29]([O-:30])=[N:28][C:27]([NH:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])=[N+:26]([O-:6])[C:25]=2[CH:37]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: COCCOc1ccc2c(c1)nc(NCCN(C)C)n[n+]2[O-]
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCOc1ccc2c(c1)[n+]([O-])c(NCCN(C)C)n[n+]2[O-]
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 48.1 %

Procedure:
Hydrogen peroxide (70%, 0.44 mL, ca. 8.7 mmol) was added dropwise to a stirred solution of trifluoroacetic anhydride (1.23 mL, 8.7 mmol) in DCM (20 mL) at 5° C. The mixture was stirred at 5° C. for 5 min, warmed to 20° C., stirred for 10 min, and cooled to 5° C. The mixture was added to a stirred solution of 1-oxide 13 (268 mg, 0.9 mmol) and trifluoroacetic acid (0.34 mL, 4.4 mmol) in DCM (20 mL) at 5° C. and the mixture stirred at 20° C. for 6 h. The solution was carefully diluted with dil. aq. NH3 solution (2.0 mL) and the mixture extracted with CHCl3 (5×50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 14 (140 mg, 50%) as a red solid, mp (MeOH/DCM) 146-149° C.; 1H NMR δ 8.21 (d, J=9.6 Hz, 1 H, H-8), 7.52 (d, J=2.6 Hz, 1 H, H-5), 7.48 (br s, 1 H, NH), 7.10 (dd, J=9.6, 2.6 Hz, 1 H, H-7), 4.31-4.36 (m, 2 H, CH2O), 3.81-3.84 (m, 2 H, CH2O), 3.61-3.65 (m, 2 H, CH2N), 3.47 (s, 3 H, OCH3), 2.62 (br t, J=6.0 Hz, 2 H, CH2N), 2.31 [s, 6 H, (CH3)2]; 13C NMR δ 165.2, 150.2, 140.2, 125.7, 123.5, 120.5, 95.6, 70.3, 68.8, 59.2, 57.5, 45.0 (2), 38.9. Anal. Calcd for C14H21N5O4¼CH2Cl2: C, 50.1; H, 6.2; N, 20.2. Found: C, 50.1; H, 6.1; N, 20.6%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:20])[CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.O.O.O.[F:24][C:25]([F:33])([F:32])[C:26]([C:28]([F:31])([F:30])[F:29])=[O:27]>C1(C)C=CC=CC=1>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[CH:11]=[C:10]([C:26]([C:28]([F:31])([F:30])[F:29])([C:25]([F:33])([F:32])[F:24])[OH:27])[N:9]([CH3:20])[C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:14][CH:15]=1
Reactant: Cn1ccc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1c(C(O)(C(F)(F)F)C(F)(F)F)cc(-c2ccc(F)cc2)c1-c1ccc(F)cc1

Procedure:
A mixture of 4.0 g (0.015 mole) of 2,3-bis(4-fluorophenyl)-1-methyl-1H-pyrrole and 3.7 g (0.017 mole) of hexafluoroacetone trihydrate in 75 ml toluene was heated at reflux overnight. Another 3.7 g of hexafluoroacetone trihydrate was added and the mixture was heated at reflux overnight again. An additional 2.0 g of hexafluoroacetone trihydrate was added and the mixture was heated at reflux another eight hours. The mixture was washed twice with water, then the organic layer was dried and concentrated. The crude product was purified by chromatography on silica gel, eluting with hexane/toluene mixtures to give, after recrystallization from hexane, 4.8 g of product, m.p. 130°-131°.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]=[CH:8][C:9](=[O:17])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1.C(O)C.[H][H]>[Ni].O>[CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][C:9](=[O:17])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCC(=O)C=Cc1ccc(C)o1
Reactant: [H][H]
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCC(=O)CCc1ccc(C)o1
Temperature: 70 °C

Procedure:
For the hydrogenation reaction, 10 g of ethyl 6-(5-methylfuran-2-yl)-4-oxohex-5-enoate, 1 g of 10% wet weight basis Raney Nickel, 100 mL of ethanol, and 5 mL of water were combined in a Parr Bottle. The mixture was pressurized to 50 psi with hydrogen gas and heated to 70° C. The mixture was stirred until hydrogen uptake stopped. The mixture was cooled to ambient temperature, filtered, and washed with ethanol. The filtrate was rotary evaporated to yield ethyl 6-(5-methylfuran-2-yl)-4-oxohexanoate. The ethyl 6-(5-methylfuran-2-yl)-4-oxohexanoate (9.9 g) was then dissolved in hexanes solvent (Aldrich) and dried with sodium sulfate. The solids were filtered, and washed with hexanes. The hexane was combined with the liquid extract and evaporated to an oil. The oil was dissolved in 100 mL isopropyl alcohol (IPA) and added to a Parr bottle containing IPA-washed Raney Nickel (5.0 g wet weight). The reaction mixture was pressurized to 50 psi with hydrogen gas and heated to 70° C. The reaction mixture was stirred until hydrogen uptake stopped. The Raney Nickel was filtered off and washed with IPA. The IPA was then combined with the liquid extract and evaporated to produce ethyl 4-hydroxy-6-(5-methyltetrahydrofuran-2-yl)hexanoate.