Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=2[N:7]=1.Cl.[O:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1.C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:33][CH:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccncc2)c2c(Cl)nc(Cl)nc21
Reactant: NC1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOCn1cc(-c2ccncc2)c2c(NC3CCOCC3)nc(Cl)nc21
Temperature: 120 °C
Yield: 34 %

Procedure:
To a solution of 2,4-dichloro-5-(pyridin-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv) in 1,4-dioxane (0.4 M) in a sealable vessel was added tetrahydro-2H-pyran-4-amine hydrochloride (1.5 equiv) and triethylamine (3 equiv). The resulting mixture was heated at 120° C. for 2 h under nitrogen atmosphere. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (0-30% ethyl acetate in petroleum ether) to afford the desired product (34% yield) as a yellow solid. MS (ESI) m/z 460.2 [M+1]+.
Reaction SMILES: [Cl:1][CH:2]1[CH:9]=[CH:8][CH:5]([C:6]#[N:7])[CH:4]([C:10]#[N:11])[CH2:3]1.BrBr>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]#[N:11])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7]
Reactant: N#CC1C=CC(Cl)CC1C#N
Agent: BrBr
Solvent: Clc1ccccc1
Product: N#Cc1ccc(Cl)cc1C#N
Temperature: 135 °C

Procedure:
To a 1-l three-necked flask, equipped with a mechanical stirrer, a condenser with a gas outlet and an equa-pressured addition funnel, is charged 166.5 g (1 mole) of 4-chlorotetrahydrophthalonitrile and 75 g of chlorobenzene. The mixture is heated to 100°-110° C. with stirring. Bromine, 320 g (2 moles), is added dropwise into the mixture in a sub-surface manner. The red color of bromine dissipates quickly and a gas evolution starts. After about 240 g of bromine is added, the pot temperature is heated to 135° C. The addition of bromine continues until completion. The pot temperature is then raised to 165°-170° C. for 2-4 hours. During this period an additional amount of bromine, such as about 10 to 15 g, may be added to complete the conversion of 4-chlorotetrahydro-phthalonitrile. A good yield of 4-chlorophthalonitrile can be obtained by distilling out the chlorobenzene.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[N:9]([CH2:18][C:19]#[C:20][CH3:21])[C:10]2[C:15](=[O:16])[NH:14][N:13]=[CH:12][C:11]=2[N:17]=1.Cl[CH2:23][C:24]1[N:33]=[C:32]([CH3:34])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1>CN(C)C=O.O>[Br:7][C:8]1[N:9]([CH2:18][C:19]#[C:20][CH3:21])[C:10]2[C:15](=[O:16])[N:14]([CH2:23][C:24]3[N:33]=[C:32]([CH3:34])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)[N:13]=[CH:12][C:11]=2[N:17]=1
Reactant: CC#CCn1c(Br)nc2cn[nH]c(=O)c21
Reactant: Cc1nc(CCl)nc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCn1c(Br)nc2cnn(Cc3nc(C)c4ccccc4n3)c(=O)c21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
489 mg (1.5 mmol) of caesium carbonate were added to a solution of 300 mg (1.12 mmol) of 2-bromo-3-(but-2-ynyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one and 260.1 mg (1.35 mmol) of 2-chloromethyl-4-methyl-quinazoline in 4.0 ml of dimethylformamide and this mixture was stirred for 2 hours under an argon atmosphere at 80° C. Then it was diluted with 10 ml of water and stirred for 30 minutes at ambient temperature. The crude product precipitated was suction filtered and purified by column chromatography (silica gel; eluant:petroleum ether with 20–50% ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:21]=1/[CH:30]=[CH:31]/[C:32](O)=[O:33]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:32](=[O:33])/[CH:31]=[CH:30]/[C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([F:28])([F:27])[F:29])[C:20]=3[F:19])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1cccc(C(F)(F)F)c1F
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3cccc(C(F)(F)F)c3F)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2-fluoro-3-trifluoromethyl-phenyl)-acrylic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C([Li])(CC)C.[CH3:14][Si:15]([CH3:22])([CH3:21])[C:16]#[C:17][C:18](=[O:20])[CH3:19]>CCOCC>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:18]([OH:20])([C:17]#[C:16][Si:15]([CH3:22])([CH3:21])[CH3:14])[CH3:19])=[N:3][CH:4]=1
Reactant: CC(=O)C#C[Si](C)(C)C
Reactant: Fc1ccc(Br)nc1
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: CC(O)(C#C[Si](C)(C)C)c1ccc(F)cn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
To a stirred solution of 2-bromo-5-fluoropyridine (1.76 g, 10.00 mmol) in ether (20 mL) maintained under nitrogen at −78° C. was added a solution of s-butyllithium (1.3M in hexane, 10 mL, 13.00 mmol) dropwise. The reaction mixture was then stirred at −78° C. for 1 hr and 4-(trimethylsilyl)but-3-yn-2-one (1.54 g, 10.98 mmol) was added to the reaction mixture dropwise with stirring at −78° C. The resulting solution was stirred at −78° C. for 2 hr and then quenched by the addition of saturated ammonium chloride solution (5 mL) and water (10 mL). The resulting solution was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified on a silica gel column with ethyl acetate/petroleum ether (1:3) to give 1 g (42%) of the title compound as a yellow oil: LC-MS: m/z=+238 (M+H)+.
Reaction SMILES: [Cl-].[NH4+].O.[N+:4]([C:7]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]1)=[O:23])([O-])=O>C(O)C.[Fe]>[NH2:4][C:7]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:21][C:22]([N:24]1[CH2:25][CH2:26][CH:27]([OH:30])[CH2:28][CH2:29]1)=[O:23]
Reactant: O=C(Cc1cccc(Oc2ccccc2F)c1[N+](=O)[O-])N1CCC(O)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1c(CC(=O)N2CCC(O)CC2)cccc1Oc1ccccc1F
Yield: 100.7 %

Procedure:
A mixture of iron powder (2.7 g.), ammonium chloride (0.3 g.), ethanol (20 ml.) and water (10 ml.) and a solution of 1-[2-{2-nitro-3-(2-fluorophenoxy)phenyl}acetyl]-4-hydroxypiperidine (2.7 g.) in ethanol (5 ml.) were treated in a similar manner to that of Example 1-(1) to give oily 1-[2-{2-amino-3-(2-fluorophenoxy)phenyl}acetyl]-4-hydroxypiperidine (2.5 g.). Thus obtained compound was dissolved in ethanol containing hydrochloric acid and evaporated under reduced pressure. The residue was crystallized with a mixture of ethanol and ethyl acetate to give white needles of the captioned compound (2 g.). mp 160° to 161° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:19]C)=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[S:7][C:6]=2[C:17]=1[Cl:18].Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[C:3]([OH:19])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[S:7][C:6]=2[C:17]=1[Cl:18]
Reactant: COc1cc2cc(-c3ccccc3Cl)sc2c(Cl)c1Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Oc1cc2cc(-c3ccccc3Cl)sc2c(Cl)c1Cl
Yield: 72.4 %

Procedure:
A mixture of 26.8 g of 6,7-dichloro-2-(2'-chlorophenyl)-5-methoxybenzo[b]thiophene and 260 g of pyridine hydrochloride is heated at 190°-200° for 4.5 hrs. To the cooled mixture is addded 800 ml of water and the aqueous mixture is extracted with three 400-ml portions of ethyl ether. The organic layers are collected, washed with 400 ml of 2N hydrochloric acid and with 200 ml of water. The organic layer is dried over anhydrous magnesium sulfate, decolorized (charcoal) overnight and the solvent is removed. Recrystallization from acetone-hexane gives 18.6 g of 6,7-dichloro-2-(2'-chlorophenyl)-5-hydroxybenzo[b]thiophene, mp 174°-175°.
Reaction SMILES: [Na].I[CH2:3][CH2:4][C:5]1[O:9][CH:8]=[N:7][C:6]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:16]([O:19]CC)(=[O:18])C>CS(C)=O>[C:10]1([C:6]2[N:7]=[CH:8][O:9][C:5]=2[CH2:4][CH2:3][C:16]([OH:19])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ICCc1ocnc1-c1ccccc1
Reactant: CCOC(C)=O
Agent: [Na]
Solvent: CS(C)=O
Product: O=C(O)CCc1ocnc1-c1ccccc1
Temperature: 0 °C

Procedure:
Sodium cyannide (1.18 g) was dissolved in dimethyl sulfoxide (40 ml) and, under stirring, a solution of 5-(2-iodoethyl)-4-phenyloxazole (6.0 g) in dimethyl sulfoxide (20 ml) was added dropwise. The mixture was stirred for 2 hours, followed by addition of ice-water and extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residual crude 4-phenyloxazole-5-propionitrile was dissolved in a mixture of ethanol (40 ml) and 2N sodium hydroxide (40 ml) and the solution was refluxed under stirring for 2 hours. The reaction mixture was concentrated, diluted with water and washed with dichloromethane. The aqueous layer was adjusted to pH 2 with hydrochloric acid and the resulting crystalline precipitate was collected by filtration and recrystallized from ethyl acetate and then from ethanol to give 4-phenyloxazole-5-propionic acid as prisms, yield 0.95 g (21.8%), m.p. 142°-143° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:15](Br)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].O1[CH2:38][CH2:37]OCC1.O>CCOC(C)=O.C1C=CC([P]([Pd]([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)=CC=1>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:15]([C:2]4[CH:3]=[N:4][CH:5]=[CH:37][CH:38]=4)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Reactant: C1COCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1C(c2cccnc2)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Temperature: 25 °C
Yield: 64 %

Procedure:
To a microwave reaction vial, 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one (1.0 g, 2.5 mmol) obtained in Step 6,3-pyridinylboronic acid (470 mg, 3.8 mmol, 1.5 eq), Pd(PPh3)4 (180 mg, 6 mol %), Na2CO3 (800 mg, 3.0 eq), and dioxane/H2O (4:1, 5 mL) were sequentially charged. The reaction vial was placed into a microwave reactor and irradiated at 150° C. for 20 min. After cooling to room temperature, the reaction was diluted with EtOAc and dried over MgSO4. The mixture was filtered through a Celite pad while rinsing with EtOAc and then concentrated in vacuo. The residue was purified by prep HPLC (CH3CN/H2O=1:1) to afford the desired product (640 mg, 64%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([OH:16])=[O:15])=[CH:7][C:6]=2[CH:17]=1.S(=O)(=O)(O)O.[CH3:23]O>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:23])=[O:15])=[CH:7][C:6]=2[CH:17]=1
Reactant: CO
Reactant: O=C(O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Agent: O=S(=O)(O)O
Product: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1

Procedure:
To a solution of 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (856 mg) in methanol (10 ml) was added sulfuric acid (0.1 ml), and the resulting mixture was heated at reflux for 23 hours. After concentration under reduced pressure, the reaction mixture was mixed with water and was then extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (848 mg) as light yellow crystals.
Reaction SMILES: COCCOC[O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[F:16][C:17]([F:32])([F:31])[C:18]1[CH:19]=[C:20]([CH2:28][C:29]#[N:30])[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1>>[F:16][C:17]([F:31])([F:32])[C:18]1[CH:19]=[C:20](/[C:28](=[CH:12]/[C:11]2[CH:10]=[CH:9][C:8]([OH:7])=[CH:15][CH:14]=2)/[C:29]#[N:30])[CH:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=1
Reactant: COCCOCOc1ccc(C=O)cc1
Reactant: N#CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: N#C/C(=C\c1ccc(O)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 17.1 %

Procedure:
4-Methoxyethoxymethoxybenzaldehyde (420 mg) and 3,5-bis(trifluoromethyl)phenylacetonitrile (506 mg) were subjected to condensation in accordance with process A of (production process 2), and the resultant product was subjected to deprotection in accordance with (production process 3), to thereby produce the target product (122 mg, yield: 17%).
Reaction SMILES: [F:1][C:2]([F:19])([CH3:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][C:29]=2[O:40][CH3:41])[C:24]([Cl:42])=[CH:23][N:22]=1>>[Cl:42][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:30][C:29]=2[O:40][CH3:41])=[N:26][C:21]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][C:2]([F:1])([F:19])[CH3:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:22][CH:23]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CC(C)(F)F)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N4CCOCC4)cc3OC)n1)CCN(CC(C)(F)F)CC2

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-propyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to Example 61e. Product isolated as an off-white solid (0.047 g, 57%). MP: 215-220° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 8.23 (d, 1H, J=8.8 Hz), 8.10 (s, 1H), 8.01 (s, 1H), 7.51 (s, 1H), 7.44 (s, 1H), 6.62 (s, 1H), 6.54 (d, 1H, J+2.3 Hz), 6.50 (dd, 1H, J=8.8 Hz and 2.0 Hz), 3.91 (s, 3H), 3.90-3.87 (m, 4H), 3.86 (s, 3H), 3.18-3.12 (m, 4H), 2.90-2.76 (m, 10H), 1.68 (t, 3H, J=18.7 Hz). MS: 589 (MH)+.
Reaction SMILES: [F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[C:19]([CH3:30])[C:18]=2[OH:31])=[C:13]([F:32])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].[Li+].[OH-].O.Cl>C1COCC1>[F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[C:19]([CH3:30])[C:18]=2[OH:31])=[C:13]([F:32])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)cc(C)c2O)c1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2cccc(F)c2)cc(CNc2c(F)ccc(OCC(=O)O)c2F)c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of ethyl 2-[2,4-difluoro-3-[[5-(3-fluorophenyl)-2-hydroxy-3-methyl-phenyl]methylamino]phenoxy]acetate (90 mg, 0.20 mmol, 1.0 eq) in THF (3 mL) was added a solution of LiOH (2M aqueous solution, 3 mL, 6 mmol, 30 eq). The reaction was stirred at room temperature for 3 h. Water was added and the mixture acidified to pH 4-5 with diluted HCl then extracted with EtOAc. The combined organic extracts were washed with water and brine, dried and evaporated in vacuo to give the title compound (as a white solid (73 mg, 86%).
Reaction SMILES: [CH3:1][C:2]1O[CH:7]=[CH:6][C:4](=[O:5])[C:3]=1[OH:9].CC(C)=O.[CH3:14][NH2:15]>O>[CH3:14][N:15]1[CH:7]=[CH:6][C:4](=[O:5])[C:3]([OH:9])=[C:2]1[CH3:1]
Reactant: CN
Reactant: Cc1occc(=O)c1O
Solvent: O
Solvent: CC(C)=O
Product: Cc1c(O)c(=O)ccn1C
Reaction time: 6.5 h
Yield: 53 %

Procedure:
Maltol (i.e. 2-methyl-3-hydroxypyran-4-one) 250 g) was dissolved in 25% aqueous methylamine (750 ml) and water (125 ml). The solution was pumped through the CMR (18 ml/min; 160°-2° C.; 900 kPa) and the hot reaction mixture passed directly into acetone (2.5 liters), cooled in an ice water bath. The crystalline product (146 g; 53% yield) was collected by filtration, and washed with acetone (2×250 ml). The corresponding literature method17 involved 6.5 hours at reflux, followed by laborious work up.
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]/[C:4]([C:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]=[CH:8][C:7]=1[CH3:14])=[O:5].C(N(CC)CC)C.[CH3:22][SH:23]>CCOCC>[CH3:22][S:23][CH:2]([CH3:1])[CH2:3][C:4]([C:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]=[CH:8][C:7]=1[CH3:14])=[O:5]
Reactant: CS
Reactant: C/C=C/C(=O)C1=C(C)C=CCC1(C)C
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CSC(C)CC(=O)C1=C(C)C=CCC1(C)C
Temperature: 10 °C
Reaction time: 1 h

Procedure:
In a 50 ml, three-necked, round-bottom flask equipped with a magnetic stirring assembly, a tube submerged for the introduction of gas, an immersion thermometer and a dry ice isopropanol condenser, the outlet of which leads through a 50% alkali trap to the hood sink, is placed 8.3 grams of beta-damascenone and approximately 1 gram of triethylamine. Gaseous methyl mercaptan is introduced into the stirred reaction mixture which is maintained at 10° C. Addition is continued for approximately one hour and then stopped. The stirred reaction mix is allowed to attain room temperature, and the reaction mix is stirred overnight at room temperature. The next morning the light yellow reaction mix is transferred to 50 ml of ether in a separatory funnel and washed twice with dilute sulfuric acid, twice with saturated sodium bicarbonate solution, and then with saturated saline solution until the wash is neutral. The dried ether layer is stripped of solvent on a `rotovap` and GLC of the residue on an 1/8'×10" stainless steel, 5% carbowax 20 M column isothermally at 190° C. shows one major late eluting peak which is trapped for infra-red and nuclear magnetic resonance/mass spectral analyses. Infra-red analysis suggests that the cyclohexadienyl ring structure is intact and in conjugation with the side chain ketone which is, however, now out of cross conjugation. Therefore, reaction appears to have occurred at the side chain olefinic site. Mass spectral analysis shows a molecular weight of 238, and the proper fragmentation for the proposed structure. The mass spectral analysis also is a satisfactory match with the scan for peak "A" as set forth in Example I. This peak has an IE on SE-30 of 13.00. A trap of the synthetic material is run for IE and the IE on SE-30 is 13.08.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:13]([C:28]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][N:29]=2)[NH:14][C:15](=[O:27])[C:16]2[CH:21]=[C:20]([N+:22]([O-])=O)[C:19]([O:25][CH3:26])=[CH:18][N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].CCOC(C)=O>[Ni].CO>[NH2:22][C:20]1[C:19]([O:25][CH3:26])=[CH:18][N:17]=[C:16]([C:15]([NH:14][C@@H:13]([C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]([F:10])([F:11])[F:12])=[C:2]([F:1])[CH:3]=2)[C:28]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][N:29]=2)=[O:27])[CH:21]=1
Reactant: COc1cnc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cnc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)cc1N
Reaction time: 2 h

Procedure:
To a stirred suspension of Raney Nickel (0.4 g, Monarch, India) in MeOH (10 mL) was added (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-methoxy-4-nitropicolinamide (700 mg, 0.0014 mol) at rt. The reaction mixture was stirred under a hydrogen balloon for 2 h. After completion of the reaction, monitored by TLC (TLC eluent: 50% EtOAc in petroleum ether), the reaction mixture was filtered through Celite® brand filter agent and concentrated. The resulting product was triturated with petroleum ether to give the title compound as a white solid. MS (ESI, positive ion) m/z: 455.2 (M+H).
Reaction SMILES: [P:1]([O-:18])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C[Al](C)C.[CH2:23]=[C:24]([CH2:35][CH2:36][C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>ClCCl>[CH2:3]([O:2][P:1]([CH2:23][CH:24]([CH2:35][CH2:36][C:37]([O:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:38])[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Reactant: C=C(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: C[Al](C)C
Solvent: ClCCl
Product: O=C(CCC(CP(=O)(OCc1ccccc1)OCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
Dibenzyl phosphite (9.5 g, 36 mmol) in 350 mL of dichloromethane was cooled to 0° C. To this stirring solution was added trimethyl aluminum (18.2 mL, 2.0 M solution in hexane, 36.4 mmol). After 30 minutes, dibenzyl 2-methylenepentanedioate (2)(6.0 g, 37 mmol) in 90 mL of dichloromethane was added dropwise over 10 minutes. The clear and colorless solution was then warmed to room temperature and left to stir overnight. The mixture was then quenched by the slow addition of 5% HCl. After stirring an additional 1.5 hours the lower organic layer was removed and the aqueous layer extracted once with 100 mL of dichloromethane. The organics were combined, dried (MgSO4), and evaporated to give a clear light golden liquid. The liquid was chromatographed on silica gel (4 cm×30 cm) and eluted with a gradient (4:1-1:1) solvent system (Hexane/EtOAc). The fractions containing the desired product were combined and evaporated to yield dibenzyl 2-[[bis(benzyloxy)phosphoryl]methyl]pentanedioate (7.1 g, 42%) as a clear and colorless liquid. The liquid was then distilled on a Kughleror apparatus at 0.5 mm Hg and 195-200° C. The distillate was discarded and the remaining light golden oil was chromatographed on silica gel (1:1, Hexane/EtOAc) to give 2.9 g of dibenzyl 2-[[bis(benzyloxy)phosphoryl]-methyl]pentanedioate as a clear and colorless oil. TLC Rf 0.5 (1:1 Hexane/EtOAc).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]4[CH2:25][CH2:26][CH2:27][CH:18]34)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]>CN(C=O)C>[CH:38]([O:37][C:35]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([N:17]3[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]4[CH2:25][CH2:26][CH2:27][CH:18]34)(=[O:16])=[O:15])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1)=[O:36])([CH3:40])[CH3:39]
Reactant: Nc1ccc(-c2ccc(S(=O)(=O)N3C(C(=O)O)CC4CCCC43)cc2)cc1
Reactant: CC(C)OC(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)OC(=O)Nc1ccc(-c2ccc(S(=O)(=O)N3C(C(=O)O)CC4CCCC43)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
500 mg (1.30 mmol) of 1-(4′-aminobiphenyl-4-sulfonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid were dissolved in 3 ml of DMF, after which the solution was cooled down to 0° C. in an ice bath and 2.6 mmol of pyridine were added. After the mixture had been stirred at 0° C. for 15 min, 2 mmol of isopropyl chloroformate in 3 ml of DMF were added. The reaction solution was then stirred at RT for a further 2 h. The crude product was purified using chromatographic methods.