Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=O)[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.[CH2:14]([NH2:18])[CH2:15][CH2:16][CH3:17].C(O)C>O>[OH:1][C:2]1[CH:3]=[C:4]2[C:11](=[O:13])[N:18]([CH2:14][CH2:15][CH2:16][CH3:17])[C:6](=[O:8])[C:5]2=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(O)cc1C(=O)O
Reactant: CCCCN
Solvent: CCO
Solvent: O
Product: CCCCN1C(=O)c2ccc(O)cc2C1=O

Procedure:
In a 250-ml round bottom flask were placed 20.5 g (112.6 mmols) of 4-hydroxyphthalic acid, 8.2 g (112.6 mmols) of n-butylamine and 100 ml of absolute ethanol. After mixing, the resulting mixture generated heat gently. The mixture was sufficiently stirred until the solids were completely dissolved. The alcohol was distilled off under reduced pressure, after which the viscous liquid thus obtained was heated at 180° C. for about 3 hours with continuous extraction of water. After cooling, the residue was solidified. The solidified residue was dissolved in an ethyl acetatebenzene (1:1 by volume) mixed solvent, and the resulting solution was washed with water, an aqueous sodium carbonate solution and then water. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and then cooled to obtain powder crystals having a slightly yellowish white color. The crystals were collected by suction filtration and dried. Yield: 18.5 g (75%), m.p. 126°-127° C. The product was determined to be 4-hydroxy-N-n-butylphthalimide by investigation of its structure by NMR and infrared absorption spectrum.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][N:5]=1.BrCC1CCCCO1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:20]1=[O:40]>>[F:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]3([C:39]4[C:30](=[CH:31][C:32]5[O:37][CH2:36][CH2:35][O:34][C:33]=5[CH:38]=4)[O:29][CH2:28]3)[C:20]2=[O:40])=[N:5][CH:6]=1
Reactant: Fc1ccc(CCl)nc1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Agent: Cl
Product: O=C1N(Cc2ccc(F)cn2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(chloromethyl)-5-fluoropyridine hydrochloride (Cai, Z. et al. US 2007/0072831) to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-[(5-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (99%) as a colorless solid: mp 174-176° C.; 1H NMR (300 MHz, CDCl3) δ 8.40 (d, J=2.7 Hz, 1H), 7.41-7.11 (m, 4H), 7.01 (t, J=7.4 Hz, 1H), 6.89 (d, J=7.8 Hz, 1H), 6.48 (s, 1H), 6.25 (s, 1H), 5.16 (d, J=15.7 Hz, 1H), 4.98-4.88 (m, 2H), 4.65 (d, J=8.9 Hz, 1H), 4.20-4.07 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.5, 160.2, 157.2, 155.3, 151.5, 151.5, 144.7, 142.0, 138.3, 137.8, 137.5, 132.2, 128.8, 124.1, 123.9, 123.8, 123.6, 122.9, 122.8, 121.0, 111.6, 109.4, 99.4, 80.1, 64.5, 63.9, 58.1, 45.4; MS (ES+) m/z 404.9 (M+1).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:20]([C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1)#[CH:21]>>[C:20]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:24][CH:23]=1)#[CH:21]
Reactant: C#Cc1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: C#Cc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-ethynylbenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-ethynylphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([CH:14]3[CH2:16][CH2:15]3)[O:12][C:11](=[O:17])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C([Li])CCC.CCCCCC.[CH:29]1[C:34]([N+:35]([O-:37])=[O:36])=[CH:33][CH:32]=[C:31]([Cl-]C([O-])=O)[CH:30]=1.[C:42](=O)([OH:44])[O-:43].[Na+]>C1COCC1>[N+:35]([C:34]1[CH:29]=[CH:30][C:31]([O:44][C:42]([N:10]2[CH:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=3)[CH:13]([CH:14]3[CH2:15][CH2:16]3)[O:12][C:11]2=[O:17])=[O:43])=[CH:32][CH:33]=1)([O-:37])=[O:36]
Reactant: O=C1NC(c2ccc(F)c(F)c2)C(C2CC2)O1
Reactant: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1C(=O)OC(C2CC2)C1c1ccc(F)c(F)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-(3,4-difluorophenyl)-5-cyclopropyl-oxazolidin-2-one (2 g, 8.3 mmol) in 100 mL THF was added a solution of n-butyllithium in hexane (9.1 mmol) dropwise via a syringe under an argon atmosphere at −78° C. The resulting yellow solution was stirred at −78° C. for 10 min. To this solution was then added dropwise via syringe 4-nitrophenylchloroformate (1.03 g, 5.1 mmol) in 20 mL of THF. The reaction was stirred at −78° for 10 min. The reaction mixture was poured into saturated sodium bicarbonate and extracted with ethyl acetate (2×200 mL). The organic extracts were washed with brine, and the organic layer was dried over Na2SO4. The solvent was removed after filtration, and the residue was purified by column chromatography on silica gel 30% ethyl acetate hexane. The material was rechromatographed on silica gel eluting with 2% acetone/methylene chloride ti) give 1.2 g the product as a thick syrup which solidified upon standing.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:17](Cl)(=[O:25])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCOCC1.C1(C)C=CC=CC=1>[C:19]1([O:18][C:17]([N:7]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[NH:11][C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:6]2=3)=[O:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: O=C1Nc2cccnc2N(C(=O)Oc2ccccc2)c2ccccc21

Procedure:
From 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and phenyl chlorocarbonate in a mixture of dioxan and toluene, 5,11-dihydro-11-phenyloxycarbonyl-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one was obtained.
Reaction SMILES: [NH2:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[CH:3][C:4]#[N:5].[Br:19][C:20]1[CH:21]=[C:22]([C:26](=O)[CH2:27][C:28](OCC)=[O:29])[CH:23]=[CH:24][CH:25]=1>O>[Br:19][C:20]1[CH:21]=[C:22]([C:26]2[NH:1][C:2]([C:6]3[CH:11]=[CH:10][C:9]([O:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:8][CH:7]=3)=[C:3]([C:4]#[N:5])[C:28](=[O:29])[CH:27]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: N#CC=C(N)c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)CC(=O)c1cccc(Br)c1
Solvent: O
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)[nH]c(-c2cccc(Br)c2)cc1=O
Temperature: 25 °C
Yield: 21.9 %

Procedure:
A mixture of 3-amino-3-(4-phenoxyphenyl)acrylonitrile (0.553 g, 2342 mmol) and ethyl 3-(3-bromophenyl)-3-oxopropanoate (2.540 g, 9.37 mmol) was microwaved at 230° C. for 20 min. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate (100 mL). The ethyl acetate phase was washed with saturated ammonium chloride, brine, dried (MgSO4), and concentrated. Silica gel chromatography, eluting with 0-80% ethyl acetate in hexanes, gave 6-(3-bromophenyl)-4-oxo-2-(4-phenoxyphenyl)-1,4-dihydropyridine-3-carbonitrile as brown solid (0.909 g, 88% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.81 (1H, br. s), 7.70 (2H, δ, J=8.28 Hz), 7.62 (2H, δ, J=7.28 Hz), 7.35 (3H, t, J=7.40 Hz), 7.18 (1H, t, J=7.28 Hz), 7.03 (4H, dd, J=11.92, 8.66 Hz), 6.68 (1H, br. s); MS (ES+) m/z: 443,445 (M+H); LC retention time: 4.361 min (analytical HPLC Method A).
Reaction SMILES: [C:1]([C@@:18]1([N:26]2[C:36]3[N:35]=[C:33]([NH2:34])[NH:32][C:30](=[O:31])[C:29]=3[N:28]=[CH:27]2)[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([OH:21])[CH2:19]1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[SH:37]C1N(C2N=C(N)NC(=O)C=2N=1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O.O.[C@@H]1(N2C3N=C(N)NC(=O)C=3N=C2)O[C@H](CO)[C@@H](O)C1>>[C:1]([C@@:18]1([N:26]2[C:36]3[N:35]=[C:33]([NH2:34])[NH:32][C:30](=[O:31])[C:29]=3[N:28]=[C:27]2[SH:37])[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([OH:21])[CH2:19]1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)[C@]1(n2cnc3c(=O)[nH]c(N)nc32)C[C@H](O)[C@@H](CO)O1
Reactant: Nc1nc2c(nc(S)n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)[C@]1(n2c(S)nc3c(=O)[nH]c(N)nc32)C[C@H](O)[C@@H](CO)O1

Procedure:
This compound was prepared using the procedure for palmitoyl-2'-deoxyguanosine, substituting the appropriate amount of 8-mercaptoguanosine for 2'-deoxyguanosine monohydrate.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:10]([Br:11])=[CH:9][C:8]([Br:12])=[CH:7][C:5]=2[N:6]=1.[CH3:13][O:14][S:15]([O:18]C)(=[O:17])=[O:16]>>[CH3:13][O:14][S:15]([OH:18])(=[O:17])=[O:16].[CH3:1][CH:2]1[N:6]([CH3:13])[C:5]2[CH:7]=[C:8]([Br:12])[CH:9]=[C:10]([Br:11])[C:4]=2[O:3]1
Reactant: COS(=O)(=O)OC
Reactant: Cc1nc2cc(Br)cc(Br)c2o1
Product: CC1Oc2c(Br)cc(Br)cc2N1C
Product: COS(=O)(=O)O

Procedure:
A mixture of 2.9 g. of 2-methyl-5,7-dibromo-benzoxazole and 2.5 ml. of dimethyl-sulfate were heated at 150° C. for 5 minutes. By cooling, a solid cake was obtained. It was then ground in a mortar by washing repeatedly with ethyl ether. The product was employed without further purification for the dye synthesis.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:7]([C:6]2[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[N+:11]([O-:13])=[O:12])=[O:9])=[N:16][CH:17]=1
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: Nc1ccc(Br)cn1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(Nc1ccc(Br)cn1)c1cc(F)ccc1[N+](=O)[O-]
Yield: 68.1 %

Procedure:
A solution of 5-fluoro-2-nitrobenzoic acid (10.0 g, 54 mmol, 1.0 equiv), 2-amino-5-bromopyridine (12.2 g, 1.3 equiv), in 80 mL of pyridine was treated with phosphorous oxychloride (25.3 g, 3.0 equiv) for 30 min. The volatile was evaporated and the residue was redissolved into EtOAc, washed with 1N HCl, saturated aqueous NaHCO3 and saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered, and evaporated. The volatile was evaporated, and the product was triturated with diethyl ether to give N-(5-bromo-2-pyridinyl)-(2-nitro)-5-fluorophenylcarboxamide (12.5 g, 68%). MS found for C12H7BrFN3O3 (M+H)+: 340, 342.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH:11]1([N:15]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13][CH2:12]1>>[ClH:1].[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:18]2[CH2:19][CH2:20][CH2:21][N:15]([CH:11]3[CH2:12][CH2:13][CH2:14]3)[CH2:16][CH2:17]2)=[O:7])=[CH:9][CH:10]=1
Reactant: C1CC(N2CCCNCC2)C1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: Cl
Product: O=C(c1ccc(Cl)nc1)N1CCCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-Chloronicotinic acid chloride (25.0 g, 137.8 mmol, 1 eq) was dissolved in 2-methyl-THF (328.0 g). A solution of 1-cyclobutyl-[1,4]diazepane (prepared as in Example 13 above, 24.1 g, 147.8 mmol, 1.05 eq) in 2-methyl-THF (164.0 g) was then added to the reaction mixture, while maintaining the temperature of the reaction mixture at less than 35° C. (about 45 min-1.5 hours). The resulting suspension was stirred at room temperature for 16 hours, then cooled to about 0-5° C. and maintained at 0° C. for 2 hours. The title compound was isolated by filtration, washed with 2-methyl-THF (2×45.0 g), then dried in vacuo at 60° C., to yield the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](N(OC)C)=[O:10])[CH:5]=[CH:6][CH:7]=1.OS([O-])(=O)=O.[K+]>CCOCC.O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)Cc1cccc(Cl)c1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: O=CCc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of LiAIH4 (1.90 g, 51 mmol) in anhydrous ether (250 mL) was stirred at room temperature tinder nitrogen for about 1 hour. The suspension was cooled to about 45° C. To it was added drops of a solution of 2-(3-chlorophenyl)-N-methoxy-N-methyl-acetamide (8.19 9, 38.3 mmol, see Preparation 1) in 10 mL of anhydrous tetrahydrofuran (THF). The mixture was warmed to about 0° C. and stirred for about 3 hours. The solution was then cooled to about 45° C. To this solution was slowly added a solution of KHSO4 (13 g) in water (about 30 mL) the resulting mixture was filtered through CELITE®. The filtrate was concentrated in vacuo, the resulting solution was diluted with DCM and washed with 1N HCl aqueous solution (2 times), and brine (2 times) dried over anhydrous MgSO4, filtered and concentrated in vacuo. The title compound was obtained as a liquid (5.80 g), which was used immediately in the next step without further purification. Rf=0.71 (silica, EtOAc/hexane 1:3).
Reaction SMILES: [N:1]([CH:4]([C:11]1([CH2:15][F:16])[CH2:14][O:13][CH2:12]1)[C:5]1[O:6][C:7]([CH3:10])=[CH:8][CH:9]=1)=[N+]=[N-].[H][H]>C(O)C.[Pd]>[CH3:10][C:7]1[O:6][C:5]([CH:4]([NH2:1])[C:11]2([CH2:15][F:16])[CH2:12][O:13][CH2:14]2)=[CH:9][CH:8]=1
Reactant: Cc1ccc(C(N=[N+]=[N-])C2(CF)COC2)o1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(C(N)C2(CF)COC2)o1
Yield: 100.4 %

Procedure:
A solution of 2.25 g (10 mmol, 1 eq) of 2-[azido-(3-fluoromethyloxetan-3-yl)methyl]-5-methylfuran in 40 ml of ethanol in the presence of 378 mg (17% by weight) of palladium on carbon at 10% was stirred at hydrogen atmospheric pressure for two and a half hours. The reaction medium was filtered and the filtrate was evaporated. 2.0 g of C-(5-methylfuran-2-yl)-C-(3-fluoromethyloxetan-3-yl)methylamine were obtained in the form of a grayish oil. Yield=100%. TLC SiO2/Heptane:EtOAc (70/30), developing with KMnO4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:34]1[CH:39]=[N:38][CH:37]=[CH:36][N:35]=1)CCC>CN(C=O)C.[Cl-].[Na+].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>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([NH2:18])=[N:9][C:8]2([C:4]1[CH:3]=[CH:2][CH:7]=[C:6]([C:34]2[CH:39]=[N:38][CH:37]=[CH:36][N:35]=2)[CH:5]=1)[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: NC1=NC(c2cccc(Br)c2)(c2ccnc(C(F)(F)F)c2)c2cccc(F)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NC1=NC(c2cccc(-c3cnccn3)c2)(c2ccnc(C(F)(F)F)c2)c2cccc(F)c21
Temperature: 180 °C
Yield: 13.8 %

Procedure:
1-(3-Bromophenyl)-4-fluoro-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-3-amine (131 mg, 0.29 mmol), 2-(tributylstannyl)pyrazine (0.096 mL, 0.31 mmol) and Pd(Ph3P)4 (33.6 mg, 0.03 mmol) were dissolved in DMF (2 mL) and the reaction mixture was heated in a microwave reactor at 180° C. for 15 min. Brine was added and the mixture was extracted with EtOAc (3×). The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo. Purification by preperative HPLC afforded the title compound 18 mg (14% yield).
Reaction SMILES: [Si:1]([O:8][CH:9]([C:22]1[O:23][CH:24]=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CN(C)[C:29](=[O:31])[CH3:30]>>[Si:1]([O:8][CH:9]([C:22]1[O:23][C:24]([C:29](=[O:31])[CH3:30])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncco1
Reactant: CC(=O)N(C)C
Product: CC(=O)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Yield: 24 %

Procedure:
The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)oxazole (50 mg, 0.134 mmol) and N,N-dimethylacetamide following General Procedure K. Flash chromatography (2-10% EtOAc/hexanes) yielded the title compound as a clear oil (14 mg, 24%): 1H NMR (CDCl3, 600 MHz) δ 7.69 (s, 1H), 7.27-7.25 (m, 2H), 7.17-7.15 (m, 3H), 4.83 (t, 1H, J=7.0 Hz), 2.58 (t, 2H, J=7.5 Hz), 2.48 (s, 3H), 1.91-1.84 (m, 2H), 1.61-1.57 (m, 2H), 1.43-1.32 (m, 6H), 0.87 (s, 9H), 0.07 (s, 3H), −0.02 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 186.7, 169.5, 150.5, 143.6, 134.2, 129.2, 129.1, 126.5, 69.5, 37.2, 36.8, 32.2, 30.0, 30.0, 27.6, 26.5, 25.8, 19.1, −4.2, −4.3.
Reaction SMILES: [S:1]([NH:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22](=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:17]2)[C:7]=1[C:8]#[N:9])(=[O:4])(=[O:3])[NH2:2].[OH-].[Na+]>CCO>[NH2:9][C:8]1[C:7]2[C:10]([O:14][CH2:15][C@H:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22](=[O:27])[CH2:23][CH:24]([CH3:25])[CH3:26])[CH2:17]3)=[CH:11][CH:12]=[CH:13][C:6]=2[NH:5][S:1](=[O:3])(=[O:4])[N:2]=1
Reactant: CC(C)CC(=O)N1CCC[C@H](COc2cccc(NS(N)(=O)=O)c2C#N)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CC(=O)N1CCC[C@H](COc2cccc3c2C(N)=NS(=O)(=O)N3)C1
Temperature: 65 °C
Yield: 90.8 %

Procedure:
To a stirred solution of (S)-2-sulfamoylamino-6-((1-(3-methylbutanoyl)piperidin-3-yl)methoxy)benzonitrile (Example 5a, 19.5 g, 49.4 mmol) in EtOH (130 mL) was added 2N NaOH solution (84 mL) at room temperature. The reaction mixture was then heated at 65° C. until LC/MS confirmed that the starting material was consumed approximately 18 hours. The mixture was concentrated to remove ethanol, diluted with water (500 mL) and washed with ethyl acetate (50 mL×2). Ethanol (100 mL) was added to the aqueous phase and the mixture was acidified with 1M aq. HCl solution until pH=3. The precipitate that formed was collected by vacuum filtration to give a white solid that was further suspended in Ethanol (300 mL) and the solution was heated to reflux for 1 hr then cooled to 0° C. The precipitate was collected and dried under vacuum to give the title compound as an off-white solid (17.7 g, 82% yield). This material was combined with several other batches synthesized following the same procedure. A suspension of the combined batches (73.6 g, 186.57 mmol) in water (1500 mL) was treated with a solution of NaHCO3 (39.18 g, 466.43 mmol, 2.5 equivalents) in water (500 mL) and heated to 98° C. for 12 hrs until complete dissolution. The hot solution was then filtered to remove undissolved fine particles and the filtrate was cooled to room temperature and treated dropwise with 0.3M HCl until neutral pH, followed by 2M HCl until pH 3 and the solution was further stirred for 30 minutes. The precipitate that formed was collected by vacuum filtration, washed with water, and dried under vacuum to afford the title compound as an off-white powder (72.44 g). 1H NMR (400 MHz, DMSO-d6, 80° C.) δ 0.89 (d, 6H, J=4.0 Hz), 1.37-1.47 (m, 2H), 1.67-1.72 (m, 1H), 1.86-1.91 (m, 1H), 1.94-2.19 (m, 4H), 2.96 (br. s, 2H), 3.55-4.14 (m, 4H), 6.66 (d, 1H, J=4.0 Hz), 6.75 (d, 1H, J=8.0 Hz), 7.45 (t, 1H, J=8.0 Hz), 7.78 (br. s, 1H) 8.00 (br. s, 1H), 10.69 (s, 1H). MS 395 (MH+). Mp 237-238.
Reaction SMILES: [C:1]1(/[C:7](=[N:9]/[NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(O)(=O)=O.O.COC(OC)(C)C.[H][H]>CC(C)=O>[C:1]1([CH:7]([NH:9][NH:10][C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: C/C(=N\NC(=O)c1ccccc1)c1ccccc1
Agent: CS(=O)(=O)O
Solvent: COC(C)(C)OC
Solvent: CC(C)=O
Solvent: O
Product: CC(NNC(=O)c1ccccc1)c1ccccc1

Procedure:
In a 120 mL high-pressure autoclave were charged (E)-N′-(1-phenylethylidene)benzohydrazide (119 mg) [mw. 238.28, 0.5 mmol], [Rh(cod) (S,S)-ptbp-skewphos)]OTf (5.1 mg) [mw. 1025.08, 5.0 μmol, s/c 100], and methanesulfonic acid (0.5 mg) [mw. 96.11, 5.0 μmol, 0.01 eq.]. The system was argon-substituted 7 times. 10 mL Schlenk flask was substituted with argon, and pure water (9 mg) [mw. 18.02, 0.5 mmol, 1.0 eq.], 2,2-dimethoxypropane (0.18 mL) [mw. 104.15, d=0.85, 1.5 mmol, 3.0 eq.] and dehydrated acetone for organic synthesis (5 mL) were added. The solution was fed into an autoclave by argon pressure supply. The system was substituted with hydrogen gas, and the mixture was stirred with hydrogen gas pressurization at 1.0 MPa for 2 hr. The system was depressurized, and analyzed by high performance liquid chromatography to find that the starting material, (E)-N′-(1-phenylethylidene)benzohydrazide, remained by 38%, and the resultant product, N′-(1-phenylethyl)benzohydrazide was produced by 59%, and the decomposed product, acetophenone, was produced by 1%.
Reaction SMILES: [CH3:1][C@H:2]1[C:7](=O)[CH2:6][C@H:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH2:3]1.[CH3:12]COCC>>[CH3:1][CH:2]1[CH2:3][CH2:4][CH:5]([C:9]([CH3:11])=[CH2:10])[CH2:6][C:7]1=[CH2:12]
Reactant: CCOCC
Reactant: C=C(C)[C@@H]1CC[C@@H](C)C(=O)C1
Product: C=C1CC(C(=C)C)CCC1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
BDAM (2.60 grams) was combined with ether (2 milliliters) and TMAL (1.0 milliliter) as described in Example 4, after which 1.50 grams of (+) dihydrocarvone were added. As in Example 4, a noticeably exotherm was observed. After 3 hours of stirring at room temperature, the reaction mixture was hydrolyzed as in Example 1. After the usual work up and column separation, 1.40 grams of 4-methyl-3-methylene-1-isopropenyl cyclohexane were isolated (95% yield).