Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=O.S(Cl)(Cl)=O.CN(C=O)C.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[NH:27][C:28](=[O:35])[C:29](=[CH:33][CH:34]=2)[C:30]([OH:32])=[O:31])=[CH:22][CH:21]=1.C(N(CC)CC)C.Cl[Si](C)(C)C>ClCCl>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[NH:27][C:28](=[O:35])[C:29](=[CH:33][CH:34]=2)[C:30]([OH:32])=[O:31])=[CH:24][CH:25]=1)=[O:9]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CC[C@@H](C(=O)Nc2ccc(-c3ccc(C(=O)O)c(=O)[nH]3)cc2)N1
Reaction time: 1.17 h

Procedure:
A solution of 2.3 g (5.75 m mol) of the above enamine and 20 ml of DMF is stirred at room temperature and 2.3 g (14.2 m mol) of carbonyldiimidazole is added. The solution is stirred at 50°-60° for 1 hr and then at room temperature overnight. The DMF is evaporated under vacuum and the residue dissolved in 40 ml of dichloromethane. The solution is diluted with 100 ml of ethyl acetate and 100 ml of ether. The precipitated solid is filtered, washed with 1:1 ethyl acetate ether and ether and dried to give 2.2 g of imidazolide. L. A mixture of 19.37 g (0.15 mol) of L-pyroglutamic acid, 11.0 ml (0.15 mol) of thionyl chloride, 11.6 ml (0.15 mol) of DMF, and 350 ml of dichloromethane is stirred at 0°-5° for 70 min. This solution is then added to a cold solution of the silylated derivative of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid prepared by the method of Starting Material I from 23 g (0.1 mol) of the acid, 42 ml (0.3 mol) of triethylamine, 38 ml (0.3 mol) of chlorotrimethylsilane, and 750 ml of dichloromethane. The reaction mixture is stirred at 0°-5° for 1 hr 45 min and then evaporated to dryness. Methanol is added to the residue and evaporated again. Next 500 ml of methanol and 500 ml of water are added and the solid is collected by filtration, washed with warm methanol and with ether. Drying gives 27.84 g of 6-[4-(L-pyroglutamylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid; [α]D23 +15.2 (cl, DMSO).
Reaction SMILES: C(OC([N:8]1C(C(O)=O)C[C:15]2[CH:14]=[C:13]3OC[C@H](C4C=CC(OCC5C=CC(Cl)=C(Cl)C=5)=CC=4)O[C:12]3=[CH:11][C:10]=2[CH2:9]1)=O)(C)(C)C.[C:41]([O:45][C:46]([N:48]1[CH:57]([C:58](=[O:68])[NH:59][C@H:60]([C:64]([O:66][CH3:67])=[O:65])[CH2:61][C:62]#[CH:63])[CH2:56][C:55]2[CH:54]=[C:53]3[O:69][CH2:70][C@H:71]([C:73]4[CH:78]=[CH:77][C:76]([O:79][CH2:80][C:81]5[CH:86]=[CH:85][C:84]([Cl:87])=[C:83]([Cl:88])[CH:82]=5)=[CH:75][CH:74]=4)[O:72][C:52]3=[CH:51][C:50]=2[CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42].IC1C=CC(C#N)=CC=1>>[C:41]([O:45][C:46]([N:48]1[CH:57]([C:58](=[O:68])[NH:59][C@H:60]([C:64]([O:66][CH3:67])=[O:65])[CH2:61][C:62]#[C:63][C:13]2[CH:12]=[CH:11][C:10]([C:9]#[N:8])=[CH:15][CH:14]=2)[CH2:56][C:55]2[CH:54]=[C:53]3[O:69][CH2:70][C@H:71]([C:73]4[CH:74]=[CH:75][C:76]([O:79][CH2:80][C:81]5[CH:86]=[CH:85][C:84]([Cl:87])=[C:83]([Cl:88])[CH:82]=5)=[CH:77][CH:78]=4)[O:72][C:52]3=[CH:51][C:50]=2[CH2:49]1)=[O:47])([CH3:44])([CH3:42])[CH3:43]
Reactant: C#CC[C@H](NC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3)C(=O)OC
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2CC1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: N#Cc1ccc(I)cc1
Product: COC(=O)[C@H](CC#Cc1ccc(C#N)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Yield: 40.3 %

Procedure:
(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester (59 mg) was coupled with (S)-propargyl-glycinemethylester hydrochloride (20 mg) according to General Procedure A. The resulting (S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-8-((S)-1-methoxycarbonyl-but-3-ynylcarbamoyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (26 mg) was reacted with 4-iodobenzonitrile (7 mg) according to General Procedure S to give (S)-8-[(S)-4-(4-cyano-phenyl)-1 methoxycarbonyl-but-3-ynylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (12 mg).
Reaction SMILES: [OH-].[Na+].C(OC([O-])=O)(O[C:6](C)([CH3:8])[CH3:7])=O.C1C2[CH:21]=[C:22]([OH:25])[CH:23]=CC=2CCCN1.[C:26]([O:29][CH2:30][CH3:31])(=[O:28])[CH3:27]>C(Cl)(Cl)Cl.O>[C:26]([O:29][CH2:30][CH3:31])(=[O:28])[CH3:27].[CH:6]([O:25][CH:22]([CH3:21])[CH3:23])([CH3:8])[CH3:7]
Reactant: Oc1ccc2c(c1)CNCCC2
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)OC(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2 N sodium hydroxide (40 ml) and t-butyl dicarbonate were added at 0° C. to a solution of 2,3,4,5-tetrahydro-1H-2-benzazepin-8-ol hydrobromate (12.0 g, 49.2 mm) in chloroform (40 ml) and water (40 ml), and the mixture was stirred at room temperature for 16 hours. Ethyl acetate was added to the resulting mixture which was then washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the resultant residues were formed into powder with ethyl acetate-isopropyl ether, to give the title compound (7.99 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[S:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[C:23]1[C:31](Cl)=[O:32]>>[S:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[C:23]1[C:31]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)=[O:32]
Reactant: O=C(Cl)c1cc2ccccc2s1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C(=O)c3cc4ccccc4s3)CC1)O2

Procedure:
Compound 51 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 1-benzothiophene-2-carbonyl chloride and conditions outlined in procedure N. M.p.=110-112° C.; 300 MHz 1H NMR (DMSO-d6) δ 8.20 (m, 1H), 7.93 (m, 3H), 7.77 (m, 2H), 7.58 (t, 1H), 7.45 (m, 2H), 4.22 (brm, 2H), 3.41 (brm, 2H), 3.15 (s, 2H), 2.17 (m, 2H), 1.88 (m, 2H); LCMS: 462 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[O:17][N:16]=[C:15]([CH2:18][OH:19])[CH:14]=1)=[C:5]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[O:17][N:16]=[C:15]([CH:18]=[O:19])[CH:14]=1)=[C:5]2[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)c1-c1cc(CO)no1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CC#N
Product: O=Cc1cc(-c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)on1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
To a solution of 6-chloro-3-(3-hydroxymethyl-isoxazol-5-yl)-4-phenyl-1H-quinolin-2-one (822 mg, 2.33 mmol) in CH3CN (8 mL), Dess-Martin periodinane (1.05 g, 2.47 mmol) was added. The resulting mixture was stirred at RT for 3 hr and concentrated. Water (20 mL) was then added and the product was extracted with (5% MeOH: CH2Cl2 3×50 mL). The organic layer was dried (Na2SO4) and concentrated. The residue was chromatographed on silica (30-80% EtOAc:Hexane) to obtain partially pure 5-(6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl)-isoxazole-3-carboxaldehyde. Yield 66%: 1H-NMR (CDCl3; 400 MHz) δ 13.15 (s,1H), 10.09 (s, 1H), 7.57-7.47 (m, 8H), 6.97 (s,1H).
Reaction SMILES: [NH2:1][C:2]1[CH2:3][C@@H:4]2[C@@H:11]([C@H:12]([OH:14])[CH3:13])[C:10](=[O:15])[N:5]2[C:6]=1[C:7]([O-:9])=[O:8].[Na+:16].C(=O)(O)[O-].[Na+].[C:22](Cl)(=[O:24])[CH3:23].S(=O)(=O)(O)O>O.O1CCOCC1>[C:22]([NH:1][C:2]1[CH2:3][C@@H:4]2[C@@H:11]([C@H:12]([OH:14])[CH3:13])[C:10](=[O:15])[N:5]2[C:6]=1[C:7]([O-:9])=[O:8])(=[O:24])[CH3:23].[Na+:16]
Reactant: CC(=O)Cl
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(N)C[C@H]12
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)NC1=C(C(=O)[O-])N2C(=O)[C@H]([C@@H](C)O)[C@H]2C1

Procedure:
A solution of sodium (5R,6S)-2-amino-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate (23 mg, 0.1 mmol) in water (2.5 ml) is cooled in an ice-bath, stirred, and treated with sodium bicarbonate (84 mg, 1 mmol) and dioxane. The resulting solution is stirred in the cold while a solution of acetyl chloride (11 μl, 0.15 mmol) in dioxane (0.5 ml) is added dropwise over 10 minutes. After stirring an additional 30 minutes, the solution is acidified to pH 6.8 with 1M sulfuric acid and extracted with diethyl ether (3×10 ml). The aqueous phase is layered with ethyl acetate (2.5 ml) and vigorously stirred in an ice-bath while acidifying to pH 2.3 with 1M sulfuric acid. The aqueous phase is separated and extracted with more ethyl acetate (2×2 ml). The combined ethyl acetate solution is washed with brine, then layered with water (5 ml) and stirred vigorously in an ice-bath while the pH is brought to 7 with 1N sodium hydroxide. The aqueous phase is separated, concentrated under vacuum, and lyophilized to yield sodium (5R,6S)-2-acetamido-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate (32).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][C:7]([CH3:14])([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=O.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)(Cl)Cl>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][CH2:1][C:3]2[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=2)[O:6][C:7]([CH3:14])([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(C)(C)Oc1cccc(C=O)c1
Reactant: NCc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(C)Oc1cccc(CNCc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Ethyl 2-(3-formylphenoxy)-2-methylpropionate (25 g, 105.8 mmol) was dissolved in 1,2-dichloroethane (300 mL). Subsequently, 4-chlorobenzylamine (15.44 mL, 127.0 mmol) and acetic acid (7.26 mL, 127.0 mmol) were added thereto, and the resultant mixture was stirred for 20 minutes at 0° C. Subsequently, sodium (triacetoxy)borohydride [NaBH(OAc)3 (26.91 g, 127.0 mmol)] was added thereto, and the mixture was stirred for five hours at room temperature. After completion of reaction, chloroform was added. Washing was performed sequentially with aqueous saturated sodium bicarbonate, water, and saturated brine, followed by drying over magnesium sulfate. The reaction mixture was subjected to filtration, concentration under reduced pressure, and purification by silica gel column chromatography (chloroform/methanol=10/1), whereby a yellow oil was obtained (35.27 g, 92%).
Reaction SMILES: [C:1]([C:3]1[C:9](=O)[C:8](Cl)=[C:7](Cl)[C:5](=O)[C:4]=1[C:13]#N)#N.[C:15]1([CH3:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:1]1[C:8]2[CH:9]=[CH:3][C:4]3=[C:5]4[C:13]=2[C:4]2[C:5]5[C:16]6[C:17]4=[C:18]([CH:19]=[CH:20][C:15]=6[CH2:21][C:7]=5[CH:8]=[CH:9][C:3]1=2)[CH2:13]3
Reactant: Cc1ccccc1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Product: c1cc2c3c4c1Cc1ccc5c(c14)c1c(ccc(c31)C2)C5
Temperature: 110 °C
Yield: 67 %

Procedure:
First, a double-necked flask of 10 mL was subjected to vacuum and dried by heat, and subsequently, its volume was displaced with argon. Next, a solution obtained by solving hexahydrosumanene (0.0 11 mmol, 3 mg) into 2 mL of toluene was added into the flask by using a syringe, and DDQ (0.0385 mmol, 9 mg) further was added therein, and subsequently, the system was heated at 110° C. for 20 hours. After the reaction, the solvent was evaporated under a reduced pressure, and residues were separated by thin layer chromatography (hexane), thereby obtaining Sumanene (yield: 2 mg, isolation yield: 67%) as an objective compound. Physical properties of this compound will be described below. In addition, UV-VIS absorption spectrograms of this compound will be shown in FIGS. 1 to 5. Used solvents are cyclohexylamine (CHA) in FIG. 1, tetrahydrofuran (THF) in FIG. 2, acetonitrile (CH3CN) in FIG. 3 and dichloromethane (CH2Cl2) in FIG. 4, where concentrations of all the solutions are 1.0×10−4 M. Moreover, FIG. 5 is a view showing all of the spectrograms of FIGS. 1 to 4 in one.
Reaction SMILES: C1(C(C2(O)CCCCC2)=[O:8])C=CC=CC=1.O[C:17]1[C:30]2[C:29](=[O:31])[C:28]3[C:23](=[C:24]([OH:32])[CH:25]=[CH:26][CH:27]=3)[C:22](=[O:33])[C:21]=2[CH:20]=[CH:19][CH:18]=1.C1(C(=O)CC(C2C=CC=CC=2)=O)C=CC=CC=1>>[OH:32][C:24]1[CH:25]=[CH:26][C:27]2[C:22](=[O:33])[C:21]3[C:30](=[CH:17][CH:18]=[C:19]([OH:8])[CH:20]=3)[C:29](=[O:31])[C:28]=2[CH:23]=1
Reactant: O=C1c2cccc(O)c2C(=O)c2cccc(O)c21
Reactant: O=C(c1ccccc1)C1(O)CCCCC1
Agent: O=C(CC(=O)c1ccccc1)c1ccccc1
Product: O=C1c2ccc(O)cc2C(=O)c2ccc(O)cc21

Procedure:
1-hydroxycyclohexyl phenyl ketone; 1,5-dihydroxyanthraquinone; 1,3-diphenyl-1,3-propanedione;
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: O=C(CCCCO)N1CCCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OCCCCCN1CCCc2ccccc21

Procedure:
The 1-(5-hydroxypentanoyl)-1,2,3,4-tetrahydroquinoline (2.0 g) was refluxed for 8 hours in ether (250 ml) containing lithium aluminium hydride (1.0 g). The solution was cooled, water was added, and the ethereal solution was extracted with dilute hydrochloric acid. The extract was basified with sodium hydroxide and extracted with ether. The ethereal solution was dried and evaporated to afford the title compound as an oil.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:15](=[O:17])[CH3:16])[S:10][C:11]=2[CH2:12][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([CH3:28])[C:26]=1[OH:27])[CH:22]=O>C(O)C.Cl.C(O)(C)C.O>[OH:27][C:26]1[C:25]([CH3:28])=[CH:24][C:21]([CH2:22][CH2:16][C:15]([C:9]2[S:10][C:11]([CH2:12][CH2:13][CH3:14])=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=2)=[O:17])=[CH:20][C:19]=1[CH3:18]
Reactant: CCCc1sc(C(C)=O)cc1-c1ccccc1
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Solvent: O
Product: CCCc1sc(C(=O)CCc2cc(C)c(O)c(C)c2)cc1-c1ccccc1
Reaction time: 16 h
Yield: 79 %

Procedure:
A solution of 1-(4-phenyl-5-propyl-thiophen-2-yl)-ethanone (450 mg, 1.84 mmol) and 3,5-dimethyl-4-hydroxybenzaldehyde (331 mg, 2.21 mmol) in ethanol (4 mL) and 5 N HCl in isopropanol (2 mL) is stirred at rt for 18 h. The dark solution is diluted with water and extracted with EA. The organic extract is evaporated, dissolved in methanol (5 mL) and THF (5 mL) and treated with Pd/C (100 mg, 10% Pd). The slurry is stirred under 1.8 bar of H2 for 16 h. The mixture is filtered, the solvent of the filtrate is removed in vacuo and the crude product is purified by CC prep. TLC plates with heptane:EA 2:1 to give 3-(4-hydroxy-3,5-dimethyl-phenyl)-1-(4-phenyl-5-propyl-thiophen-2-yl)-propan-1-one (550 mg) as a colourless oil; LC-MS: tR=1.13 min; [M+1]+=379.20, 1H NMR (CDCl3): δ 7.56 (s, 1H), 7.45-7.28 (m, 5H), 6.85 (s, 2H), 4.48 (s, 1H), 3.17-3.10 (m, 2H), 2.96-2.89 (m, 2H), 2.87-2.80 (m, 2H), 2.21 (s, 6H), 1.74-1.64 (m, 2H), 0.94 (t, J=7.0 Hz, 3H).
Reaction SMILES: NC1C=CC(OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=NC=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[CH2:41][CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[C:37]([O:42][C:43]4[CH:48]=[CH:47][C:46]([N+:49]([O-])=O)=[CH:45][N:44]=4)[CH:38]=3)[O:33]2)=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[CH2:41][CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[C:37]([O:42][C:43]4[N:44]=[CH:45][C:46]([NH2:49])=[CH:47][CH:48]=4)[CH:38]=3)[O:33]2)=[CH:28][CH:27]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccc(F)cc2)O3)nc1
Agent: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccc(F)cc2)O3)nc1

Procedure:
6-[2-(4-Fluorophenyl)chroman-6-yloxy]pyridin-3-ylamine was prepared as described for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine in Example 26 starting from 3.04 g of 2-[2-(4-fluorophenyl)chroman-6-yloxy]-5-nitropyridine (Example 75(d)). 1H NMR (400 MHz, d6-DMSO) δ: 7.52-7.47 (m, 3H), 7.24 (m, 2H), 7.05 (dd, 1H, J 8.6, 3.0 Hz), 6.84-6.68 (m, 4H), 5.09 (dd, 1H, J 10.2, 2.1 Hz), 5.00 (bs, 2H), 2.93 (m, 1H), 2.69 (m, 1H), 2.13 (m, 1H), 1.98 (m, 1H).
Reaction SMILES: CC(O)([C:4]#[C:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[CH:7]=1)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[NH2:12][C:8]1[CH:7]=[C:6]([C:5]#[CH:4])[CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(O)C#Cc1cccc(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C#Cc1cccc(N)c1
Yield: 104.7 %

Procedure:
2 grams of 2-methyl-4-(3-aminophenyl)-3-butyn-2-ol were dissolved in 15 ml of toluene containing one pellet (0.1 grams) of sodium hydroxide which had been crushed to a powder. The mixture was charged to a 100 ml, round-bottom flask equipped with a Dean-Stark trap and condenser. The mixture was refluxed for one hour, and the accetone byproduct was removed periodically through the Dean-Stark trap. The reaction product was then cooled, and the mixture filtered to remove particles of caustic. After the solvent was stripped, a quantitative yield of 3-aminophenylacetylene (1.4 grams) of greater than 98% purity as analyzed by gas chromatography was obtained; refractive index, nD20, 1.686.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][N:7]2[CH:21]=1)(=O)[NH2:2].COC(OC)[N:25]([CH3:27])C>C(COC)OC>[CH:4]([N:5]1[C:1]([C:4]2[N:5]=[C:6]3[C:12]4[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:11]=4[O:10][CH2:9][CH2:8][N:7]3[CH:21]=2)=[N:2][CH:27]=[N:25]1)([CH3:21])[CH3:1]
Reactant: COC(=O)c1ccc2c(c1)OCCn1cc(C(N)=O)nc1-2
Reactant: COC(OC)N(C)C
Solvent: COCCOC
Product: COC(=O)c1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Temperature: 90 °C

Procedure:
Alternatively, methyl 2-carbamoyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (370 mg, 1.3 mmol) in dimethoxyethane (3 mL) was treated with 1,1-dimethoxy-N,N-dimethylmethanamine (1 mL, 7.5 mmol) and heated to 90° C. for 0.5 h. LC/MS indicated major desired product. After cooling, the reaction was concentrated to give the crude acylamidine and then suspended in acetic acid (2.3 mL), treated with isopropylhydrazine hydrochloride (0.29 g, 2.5 mmol). The mixture was heated at 75° C. for 30 min., cooled to room temperature and concentrated. Purification by ISCO using 100% EtOAc gave 184 (0.32 g, 70% yield). 1H NMR (400 MHz, DMSO) δ 8.54 (d, J=8.4, 1H), 8.02 (s, 1H), 7.93 (s, 1H), 7.70 (dd, J=8.4, 1.7, 1H), 7.57 (d, J=1.7, 1H), 5.85 (dq, J=13.3, 6.6, 1H), 4.57 (q, J=6.0, 4H), 3.87 (s, 3H), 1.49 (d, J=6.6, 6H).
Reaction SMILES: O.Cl.Cl.[CH2:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[NH:13][C:14]1[N:15]=[CH:16][C:17]2[CH2:22][NH:21][CH2:20][C:18]=2[N:19]=1.C(N(CC)CC)C.[Cl:30][CH2:31][C:32](Cl)=[O:33]>ClCCl>[Cl:30][CH2:31][C:32]([N:21]1[CH2:22][C:17]2[CH:16]=[N:15][C:14]([NH:13][CH:5]3[CH2:4][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH2:6]3)=[N:19][C:18]=2[CH2:20]1)=[O:33]
Reactant: c1ccc2c(c1)CC(Nc1ncc3c(n1)CNC3)C2
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Temperature: -30 °C
Yield: 83.5 %

Procedure:
Stir a suspension of N-(2,3-dihydro-1H-inden-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride hydrate (14.4 g, 41.9 mmol) and triethylamine (14.3 g, 19.7 mL, 141.4 mmol) in dichloromethane (200 mL) at 23° C. for 10 minutes, then cool to −30° C. Add 2-chloroacetyl chloride (5.49 g, 3.86 mL, 48.6 mmol) over two minutes and warm to 23° C. over 10 minutes. Add methanol (5 mL) and remove the solvent in vacuo. Slurry the crude reaction mixture in methanol (30 mL), add 50 g silica gel and remove solvent in vacuo. Load the resulting residue onto a loading column and purify via silica gel column chromatography (gradient elution: 50% ethyl acetate in hexanes to ethyl acetate to 10% methanol in ethyl acetate) to give the title compound (11.5 g, 84%). MS (m/z): 329(M+1).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH:13]=O)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[CH3:21][NH:22][C:23]1([CH3:30])[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:22]([CH3:21])[C:23]3([CH3:30])[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24]3)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1
Reactant: CNC1(C)CCS(=O)(=O)C1
Reactant: Cn1c(CC=O)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(CCc1nc2c(N3CCOCC3)nc(Cl)nc2n1C)C1(C)CCS(=O)(=O)C1
Reaction time: 23 h
Yield: 27.7 %

Procedure:
A mixture of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (210 mg, 0.71 mmol), methyl-(3-methyl-1,1-dioxotetrahydrothiophen-3-yl)amine (116 mg, 0.71 mmol), sodium triacetoxyborohydride (301 mg, 1.42 mmol) and 4 Å powdered molecular sieves (280 mg) in DCE (15 mL) was stirred for 23 h. The reaction mixture was filtered through Celite® and the filtrate loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH/DCM. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%) affording the title compound as a pale yellow solid (87 mg, 28%). LCMS (method H): RT 2.01 min [M+H]+ 443.2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.[CH3:11][N:12]1[C:21]2[CH2:20][CH2:19][CH2:18][C:17](=O)[C:16]=2[CH:15]=[CH:14][C:13]1=[O:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH:17]2[CH2:18][CH2:19][CH2:20][C:21]3[N:12]([CH3:11])[C:13](=[O:23])[CH:14]=[CH:15][C:16]2=3)=[CH:4][CH:3]=1
Reactant: Cn1c2c(ccc1=O)C(=O)CCC2
Reactant: NCCc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cn1c2c(ccc1=O)C(NCCc1ccc(Cl)cc1)CCC2
Temperature: 25 °C
Reaction time: 40 h
Yield: 66.6 %

Procedure:
A mixture of 2-(4-chlorophenyl)ethylamine (5.8 g), 5,6,7,8-tetrahydro-1-methyl-5-oxo-2(1H)-quinolinone (5.5 g), and a catalytic amount of para-toluenesulfonic acid was heated in refluxing toluene (90 ml), with azeotropic removal of water, for 40 hrs. The solution was cooled and concentrated in vacuo. Sodium borohydride (1.1 g) was added to a solution of the residue in ethyl alcohol (90 ml), and the mixture was stirred at room temperature for 2 hrs. The mixture was concentrated in vacuo, the residue was quenched with water, and the mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. Recrystallization of the residue from ethyl acetate/hexanes provided 6.55 g (67%) of product, mp 110°-112° C.
Reaction SMILES: [F:1][C:2]([F:14])([C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])[C:3]([O:5]C)=[O:4].C[Si](C)(C)[O-].[Na+:20]>CCOCC>[F:1][C:2]([F:14])([C:7]([F:12])([F:13])[C:8]([F:9])([F:10])[F:11])[C:3]([O-:5])=[O:4].[Na+:20]
Reactant: COC(=O)C(F)(F)C(F)(F)C(F)(F)F
Agent: C[Si](C)(C)[O-]
Agent: [Na+]
Solvent: CCOCC
Product: O=C([O-])C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 8 h
Yield: 84 %

Procedure:
Methyl perfluorobutyrate (12.81 g, 56 mmol) was added dropwise to a stirred solution of sodium trimethylsilanolate (6.3 g, 56 mmol) in dry ether (300 mL) at room temperature under nitrogen. The reaction mixture was stirred overnight. The solid was filtered under nitrogen, washed with dry ether, and dried under a stream of nitrogen to afford sodium perfluorobutyrate (11.1 g, 84% yield) as a white solid: 19F NMR (D2O) δ -79.6 (t, J=8 Hz, CF3 --, 3F), -117.2 (q, J=8 Hz, CF3CF2CF2 --, 2F), -126.2 ppm (s, CF3CF2 --, 2F). Anal. Calcd. for C4F7NaO2 : C, 20.36; F, 56.35; Na, 9.74. Found: C, 20.84, 20.61, 20.58; F, 56.68, 53.24; Na, 9.89, 9.65.