Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)=[C:4]([F:19])[CH:3]=1.Cl.[CH2:21]([O:23][C:24](=[O:28])[CH2:25][NH:26][CH3:27])[CH3:22].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[CH2:21]([O:23][C:24](=[O:28])[CH2:25][N:26]([C:11](=[O:13])[C:10]1[CH:14]=[CH:15][CH:16]=[C:8]([CH2:7][O:6][C:5]2[CH:17]=[CH:18][C:2]([Br:1])=[CH:3][C:4]=2[F:19])[CH:9]=1)[CH3:27])[CH3:22]
Reactant: O=C(O)c1cccc(COc2ccc(Br)cc2F)c1
Reactant: CCOC(=O)CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN(C)C(=O)c1cccc(COc2ccc(Br)cc2F)c1

Procedure:
A solution of 3-(4-bromo-2-fluoro-phenoxymethyl)-benzoic acid (5.21 g, 16.02 mmol), N-methyl glycine ethyl ester hydrochloride (4.9 g, 32.05 mmol), DIEA (14 mL, 80.01 mmol), EDCI (6.1 g, 32.05 mmol) and HOAT (4.4 g, 32.05 mmol) in methylene chloride (300 mL) was stirred at room temperature for 12 h. The mixture was evaporated and the residue was purified by column (0-50% EtOAc in hexane) to give {{[3-(4-bromo-2-fluoro-phenoxymethyl)-benzoyl]-methyl-amino}-acetic acid ethyl ester, 4.5 g (66%). LC-MS (ES) calculated for C19H19BrFNO4, 423; found m/z 424 [M+H]+.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([CH3:59])([CH3:58])[C@H:16]3[C@:29]([CH3:32])([CH2:30][CH:31]=2)[C@@H:28]2[C@:19]([CH3:57])([C@@:20]4([CH3:56])[C@H:25]([CH2:26][CH2:27]2)[C@H:24]2[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:23]2([CH2:39][NH:40][CH2:41][CH2:42][N:43]2[CH2:48][CH2:47][N:46](C(OC(C)(C)C)=O)[CH2:45][CH2:44]2)[CH2:22][CH2:21]4)[CH2:18][CH2:17]3)=[CH:10][CH:9]=1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:56][C@:20]12[C@@:19]3([CH3:57])[C@@H:28]([C@:29]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:58])([CH3:59])[C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:6]([OH:7])=[O:5])=[CH:9][CH:10]=3)=[CH:31][CH2:30]4)[CH2:27][CH2:26][C@@H:25]1[C@H:24]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:23]1([CH2:39][NH:40][CH2:41][CH2:42][N:43]1[CH2:44][CH2:45][NH:46][CH2:47][CH2:48]1)[CH2:22][CH2:21]2
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCCN3CCN(C(=O)OC(C)(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)[C@@H]1CC[C@]2(CNCCN3CCNCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 5 h
Yield: 16.2 %

Procedure:
To a solution of tert-butyl 4-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(tert-butoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-yl)methylamino)ethyl)piperazine-1-carboxylate (136 mg, 0.167 mmol) in DCM (1 ml) was added TFA (0.4 ml, 5.19 mmol). The mixture was stirred at rt for 5 h then was concentrated under reduced pressure. The residue was dissolved in dioxane and MeOH and was purified by prep. HPLC. The fractions containing the expected product were combined and concentrated under reduced pressure. HPLC showed some impurities were still present, so the reaction was repurified by prep. HPLC. The fractions were concentrated under reduced pressure to give the title compound as a white solid (18 mg, 0.027 mmol, 16.43% yield). LCMS: m/e 656.6 (M+H)+, 2.24 min (method 6). 1H NMR (500 MHz, Acetic) δ ppm 8.03 (d, J=8.24 Hz, 2H),7.30 (d, J=8.24 Hz, 2H), 5.37 (d, J=4.58 Hz, 1H), 4.79 (s, 1H), 4.68 (s, 1H), 3.50-3.67 (m, 6H), 3.40 (d, J=12.82 Hz, 1H), 3.22-3.29 (m, 6H), 2.99 (d, J=13.12 Hz, 1H), 2.49-2.58 (m, 1H), 1.76 (s, 3H), 1.19 (s, 3H), 1.16-2.23 (m, 22H), 1.10 (s, 3H), 1.08 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:12]([CH3:34])[CH2:13][CH2:14][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1.[N:35]1[CH:40]=[CH:39][C:38]([CH:41]=O)=[CH:37][CH:36]=1.[H-].[Na+]>CS(C)=O.O1CCCC1>[CH3:11][O:10][C:8]1[CH:7]=[C:6]([CH:12]([CH3:34])[CH2:13][CH:14]=[CH:41][C:38]2[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=2)[CH:5]=[C:4]([O:3][CH3:2])[CH:9]=1
Reactant: O=Cc1ccncc1
Reactant: COc1cc(OC)cc(C(C)CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1cc(OC)cc(C(C)CC=Cc2ccncc2)c1
Reaction time: 1 h
Yield: 70.8 %

Procedure:
A mixture of 3-(3,5-dimethoxyphenyl)butyl triphenylphosphonium bromide (19.0 g., 35.4 mmoles) in dimethylsulfoxide (50 ml.) is added to 4-pyridinecarboxaldehyde (3.79 g., 35.4 mmoles) in tetrahydrofuran (40 ml.). The resulting mixture is then added dropwise to a slurry of 50% sodium hydride (1.87 g., 39 mmoles) in tetrahydrofuran (20 ml.) under a nitrogen atmosphere at 0°-5° C. Following completion of addition, the mixture is stirred for one hour at 0°-5° C. and then concentrated under reduced pressure. The concentrate is diluted with water (200 ml.) and then acidified with 6N HCl. The aqueous acid solution is extracted with benzene (4×50 ml.). It is then made basic and extracted with ethyl acetate (3×50 ml.). Evaporation of the combined extracts after drying (MgSO4) affords 4-(3,5-dimethoxyphenyl)-1-(4-pyridyl)-1-pentene (7.1 g., 70%) as an oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:20]I.[C:22]([C:26]1[CH:27]=[C:28]([C:37]2[O:38][CH:39]=[C:40]([CH2:42][CH2:43]O)[N:41]=2)[CH:29]=[C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:31]=1[OH:32])([CH3:25])([CH3:24])[CH3:23].N1C=CN=C1>C(Cl)Cl>[C:22]([C:26]1[CH:27]=[C:28]([C:37]2[O:38][CH:39]=[C:40]([CH2:42][CH2:43][I:20])[N:41]=2)[CH:29]=[C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:31]=1[OH:32])([CH3:25])([CH3:24])[CH3:23]
Reactant: II
Reactant: CC(C)(C)c1cc(-c2nc(CCO)co2)cc(C(C)(C)C)c1O
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)c1cc(-c2nc(CCI)co2)cc(C(C)(C)C)c1O
Yield: 96.1 %

Procedure:
A solution of triphenylphosphine (118.8 mmole, 31.12 g), in methylene chloride (460 ml) was treated with iodine (approximately 30.17 g) until a dull yellow color persisted. The reaction stirred fifteen minutes, then a solution of 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-(2-hydroxyethyl)oxazole (79.2 mmole, 25.10 g) and imidazole (158.3 g, 10.77 g) in methylene chloride (300 ml) was added over a ten minute period. At 3.0 hours the reaction was concentrated in vacuo then taken up into methylene chloride and subjected to flash silica gel filtration. Desired product was eluted with 1:1 ethyl acetate:hexane, collecting 500 ml fractions. Desired fractions were combined, washed with 1×250 ml 1N sodium thiosulfate and 1×250 ml brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 32.53 g (96%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH2:15][NH:14][C:13]1=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([O:28][C:29]([NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]1[CH:44]=[CH:43][C:42]([CH2:45]O)=[CH:41][CH:40]=1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH2:15][N:14]([CH2:45][C:42]2[CH:41]=[CH:40][C:39]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH2:32][NH:31][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])=[CH:44][CH:43]=2)[C:13]1=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CO)cc1
Reactant: O=C(N[C@@H]1Cc2ccccc2CNC1=O)OCc1ccccc1
Product: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CN2Cc3ccccc3C[C@@H](NC(=O)OCc3ccccc3)C2=O)cc1

Procedure:
Prepared from 4(R)-benzyloxycarbonylamino-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one (Step H) and 2'-[(t-butoxycarbonylamino)methyl]-1,1'-biphenyl-4-methanol, methanesulfonate ester (Step F) by the procedure described in Example 1, Step E. 1H NMR (400 MHz, CDCl3): δ1.40 (s, 9H), 3.02 (dd; 12, 16 Hz; 1H), 3.55 (dd; 5, 16 Hz; 1H), 3.87 (d, 18 Hz, 1H), 4.18 (d, 6 Hz, 2H), 4.43 (d, 15 Hz, 1H), 4.60 (br t, 6 Hz, 1H), 4.95 (d, 15 Hz, 1H), 5.07 (d, 18 Hz, 1H), 5.13 (s, 2H), 5.29 (dd; 5, 12 Hz; 1H), 6.25 (d, 6 Hz, 1H), 6.87 (d, 8 Hz, 1H), 7.04 (t, 8 Hz, 1H), 7.10 (d, 8 Hz, 1H), 7.13-7.45 (m, 14 H). FAB-MS: calculated for C37H39N3O5 605; found 612 (M+Li,100%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6](O)=O.[NH2:15][NH:16][C:17]([NH2:19])=[S:18].P(Cl)(Cl)(Cl)=O>O1CCOCC1>[Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[O:4][CH:5]([C:6]1[S:18][C:17]([NH2:19])=[N:16][N:15]=1)[CH3:9]
Reactant: NNC(N)=S
Reactant: CC(Oc1ccc(Cl)cc1Cl)C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CC(Oc1ccc(Cl)cc1Cl)c1nnc(N)s1
Temperature: 90 °C

Procedure:
A 250 milliliter, 3-neck flask adapted with a Claisen adaptor, paddle stirrer, thermometer, an addition funnel and condenser, was charged with 28.2 grams (0.120 mole) of 2-(2,4-dichlorophenoxy)propanoic acid, (10.9 grams, 0.120 mole) of thiosemicarbazide and 90 milliliters of dioxane. The slurry was heated to 90° C. and the addition funnel was charged with phosphorous oxychloride (POCl3). The POCl3 (20.2 grams, 0.13 mole) was slowly added (for 38 minutes) while maintaining the temperature within 90°-95° C. The resulting mixture was refluxed for 115 minutes, and then evacuated by using a water aspirator to remove volatiles (HCl, POCl3 and some dioxane). One hundred (100) milliliters of water was added and 50 percent NaOH solution was also added until the pH of the solution was 10. An oil formed, which was extracted with a mixture of CH2Cl2, CHCl3 and diethyl ether, and the organic phase was dried over anhydrous MgSO 4, filtered and topped on a roto-vac at 70° C. to a grey sludge. Upon addition of diethylether, a first crop of crystals formed which were removed by filtration and then dried in a vacuum oven at 80° C. to crystals containing 5-[1-(2,4-dichlorophenoxy)ethyl-2-amino-1,3,4-thiadiazole (9.7 grams). Addition of hexane to the filtrate produced a second crop of crystals which were filtered off, dried in a vacuum oven at 80° C. to 10.1 grams of crystals. The first and second crop of crystals were combined, and recrystallized from the minimum amount of an ethanol water mixture, suction filtered, and dried in a vacuum oven at 80° C. to 17.1 grams of a grey powder of 5-[1-(2,4-dichlorophenoxy)ethyl]-2-amino-1,3,4-thiadiazole. (Melting point 119°-123° C.).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@@H:2]([C:10]([NH:12][C@@H:13]([C:26]([O:28][CH3:29])=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][CH:16]=1)=[O:11])[C@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[H][H]>CO.[Pd]>[NH2:1][C@@H:2]([C:10]([NH:12][C@@H:13]([C:26]([O:28][CH3:29])=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][CH:16]=1)=[O:11])[C@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: [H][H]
Reactant: COC(=O)[C@@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@H](NC(=O)OCc1ccccc1)[C@H](C)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@H](N)[C@H](C)OC(C)(C)C
Reaction time: 4 h
Yield: 95 %

Procedure:
4.03 g of Z-D-Thr(tBu)-D-Tyr(tBu)-OMe (7.45 mmoles) were dissolved in 250 ml of CH3OH. After addition of 850 mg of 10% Pd on activated charcoal (Fluka, cat. No 75990) a hydrogen stream was blown on the solution at room temperature under shaking for 4 h. The hydrogenation reaction was monitored by TLC. After removal of the catalyst by filtration and evaporation of the filtrate, 2.88 g (7.08 mmoles, yield 95%) of H-D-Thr(tBu)-D-Tyr(tBu)-OMe were obtained in the form of pure oil (TLC).
Reaction SMILES: C1C2C3=C4C(=CC=2)C=CC=C4C=CC3=CC=1.[C:17]1([C:36](O)=[O:37])[C:26]2[C:25]([C:27]([OH:29])=[O:28])=[CH:24][CH:23]=[C:22]([C:30]([OH:32])=[O:31])[C:21]=2[C:20]([C:33]([OH:35])=[O:34])=[CH:19][CH:18]=1>>[C:17]12[C:36](=[O:37])[O:35][C:33](=[O:34])[C:20]([C:21]3[C:22]([C:30]([OH:32])=[O:31])=[CH:23][CH:24]=[C:25]([C:27]([OH:29])=[O:28])[C:26]=31)=[CH:19][CH:18]=2
Reactant: O=C(O)c1ccc(C(=O)O)c2c(C(=O)O)ccc(C(=O)O)c12
Agent: c1cc2ccc3cccc4ccc(c1)c2c34
Product: O=C(O)c1ccc(C(=O)O)c2c3ccc(c(=O)oc3=O)c12

Procedure:
The 1,3,6,8-tetrabromopyrene is obtained in an amount of 564 parts and a purity of about 83%, which corresponds to a yield of about 2% of theory, based on 100% pure pyrene, which on further processing to naphthalene-1,4,5,8-tetracarboxylic acid gives 258 parts of naphthalene-1,4,5,8-tetracarboxylic 1,4-monoanhydride.
Reaction SMILES: [NH2:1][C:2]1[C:3](OP(N2CCOCC2)(N2CCOCC2)=O)=[N:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:9][C:8]([Cl:18])=[CH:7][CH:6]=2.[Na].[CH3:35][SH:36]>O1CCCC1>[NH2:1][C:2]1[C:3]([S:36][CH3:35])=[N:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:9][C:8]([Cl:18])=[CH:7][CH:6]=2
Reactant: CS
Reactant: Nc1c(OP(=O)(N2CCOCC2)N2CCOCC2)nc2ccc(Cl)cc2c1-c1ccccc1
Agent: [Na]
Solvent: C1CCOC1
Product: CSc1nc2ccc(Cl)cc2c(-c2ccccc2)c1N
Temperature: 25 °C

Procedure:
To a stirred solution of 488.9 mg (1.0 mmole) of 3-amino-6-chloro-2-(dimorpholino)phosphinyloxy-4-phenylquinoline in 30 ml of dry tetrahydrofuran was added 4 ml of a 1M solution of sodium salt of methyl mercaptan in cellusolve. The reaction mixture was heated to reflux for 2 hrs. The resulting suspension was then allowed to cool to room temperature at which time the insoluble salts were removed by filtration. The filtrate was concentrated to an oily gum. The gum was separated by preparative thin-layer chromatography (six 20 cm×20 cm×1.5 mm silica gel plates developed in a 1:9 (v/v) mixture of ether and benzene. The desired product was isolated and crystallized from ether-hexane. The product consisted of light yellow prisms were collected, mp 115°-117°. This material was found to be identical to that of an authentic sample (mp 115°-117°) by tlc and mixture mp.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9](CO)[OH:10])[OH:8])[OH:6])[OH:4].O=C(O)[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[Ca]>>[O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Ca]
Product: O=C[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The aerobic fermentation of D-glucose may be replaced by a modification consisting of passing by oxidation of D-glucose into D-gluconic acid which, in the calcium salt form, can be decarboxylated by the so-called RUFF method to give D-arabinose, as described in U.S. Pat. No. 3,755,294. The D-arabinose is then hydrogenated in manner known in itself to produce D-arabitol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]2[N:18]=[CH:19][C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-])=O)[CH:23]=4)=[CH:21][C:12]3=2)=[CH:5][CH:4]=1.CO>C1COCC1.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]2[N:18]=[CH:19][C:20]([C:22]4[CH:23]=[C:24]([NH2:28])[CH:25]=[CH:26][CH:27]=4)=[CH:21][C:12]3=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc3[nH]c4ncc(-c5cccc([N+](=O)[O-])c5)cc4c3c2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3[nH]c4ncc(-c5cccc(N)c5)cc4c3c2)cc1
Reaction time: 16 h
Yield: 77.8 %

Procedure:
6-(4-methoxyphenyl)-3-(3-nitrophenyl)-9H-pyrido[2,3-b]indole (35 mg, 0.09 mmol, 1 equiv.), is dissolved in anhydrous THF (1 ml), MeOH (8 ml), and palladium on charcoal (10 mg, 0.009 mmol, 0.1 equiv.), are then added in an autoclave which is flushed with argon and then pressurized with H2 (10 bar). The reaction is carried out at room temperature for 16 hours. The mixture is then filtered over Mite and washed with AcOEt. The green solid obtained is washed with methanol to afford the product as a slightly green solid (26 mg, 0.07 mmol), in 79% yield.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1(C)C=CC(S(O[CH2:25][C:26]2([CH2:32]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:7][O:6][C:4]([C:3]1[C:2]2[O:1][CH2:32][C:26]3([CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH2:25][O:12][C:11]=2[C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:5]
Reactant: Cc1ccc(S(=O)(=O)OCC2(COS(=O)(=O)c3ccc(C)cc3)CCOCC2)cc1
Reactant: COC(=O)c1ccc(OC)c(O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(OC)c2c1OCC1(CCOCC1)CO2

Procedure:
Following the general procedure, dialkylation of compound 513 (95 mg, 0.48 mmol) with compound 519 (240 mg, 0.53 mmol) in DMSO (3 mL) in the presence of K2CO3 (166 mg, 1.2 mmol) afforded compound 520 as a white solid material after purification by column chromatography (45-65% EtOAc in light petroleum). LC-MS: RT=2.40 min.; 1H NMR (DMSO-d6): δ 7.34 (1H, d, J 8.8), 6.78 (1H, d, J 8.8), 3.99 (4H, s), 3.80 (3H, s), 3.76 (3H, s), 3.61 (4H, t, J 5.5), 1.54 (4H, t, J 5.5).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CN(C(O[N:35]1[N:43]=[N:42][C:37]2[CH:38]=[CH:39][CH:40]=[N:41][C:36]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.ClCCO>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([O:26][N:35]4[C:36]5=[N:41][CH:40]=[CH:39][CH:38]=[C:37]5[N:42]=[N:43]4)=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Agent: F[P-](F)(F)(F)(F)F
Agent: OCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)On3nnc4cccnc43)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
To a DMF (1 mL) suspension of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation B, 0.1 g, 0.28 mmol) and HATU (0.128 g, 0.336 mmol) was added DIEA (0.146 ml, 0.840 mmol), followed by 2-chloroethanol (0.0270 g, 0.336 mmol). After stirring at ambient temperature for 30 minutes, the reaction was directly purified by reverse phase column chromatography (Biotage SP4 system C18 25+M, 5 to 65% acetonitrile/water) to obtain the intermediate (R)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl 5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate as white solid (94.7 mg, 71% yield). This isolated intermediate was dissolved in excess chloroethanol (1 mL), followed by addition of drops of DIEA at ambient temperature and stirred overnight to reach completion. The reaction was directly purified by reverse phase column chromatography (Biotage SP4 system C18 25+M, acetonitrile/water 5 to 73) to obtain the titled product as white foamy solid (56 mg, 48% yield). MS (apci) m/z=419.9 (M+H).
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]([OH:15])=O)[C:10]=2[CH3:12])[S:5](=[O:17])(=[O:16])[CH2:4][CH2:3]1.[CH2:18]([N:20]1[C:24]([OH:25])=[CH:23][CH:22]=[N:21]1)[CH3:19].C1(N=C=NC2CCCCC2)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)(CC)(C)C>[OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]([C:23]3[CH:22]=[N:21][N:20]([CH2:18][CH3:19])[C:24]=3[OH:25])=[O:15])[C:10]=2[CH3:12])[S:5](=[O:17])(=[O:16])[CH2:4][CH2:3]1
Reactant: Cc1c(C(=O)O)ccc2c1C(O)CCS2(=O)=O
Reactant: CCn1nccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Product: CCn1ncc(C(=O)c2ccc3c(c2C)C(O)CCS3(=O)=O)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.2 %

Procedure:
2.0 Grams (7.8 mmol) of 4-hydroxy-6-carboxy-5-methylthiochroman-1,1-dioxide was dissolved in 10 ml of t-amyl alcohol, and 1.0 g (8.6 mmol, 1.1 eq.) of 1-ethyl-5-hydroxypyrazole and 1.8 g (8.6 mmol, 1.1 eq.) of N,N'-dicyclohexylcarbodiimide were added. The mixture was stirred at room temperature for 3 hours. Then, 0.8 g (5.9 mmol) of potassium carbonate was added. The mixture was heated at 80° C. for 6 hours. After the completion of the reaction, the solvent was distilled off. The remaining oil was dissolved in ethyl acetate, and end product was extracted with a 5 wt % sodium hydrogencarbonate aqueous solution. The resultant aqueous solution was adjusted to a pH of 1 in an ice bath by adding 2N hydrochloric acid, and extracted with ethyl acetate. An organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and the solvent was distilled off to give 2.0 g (yield 73%) of 4-hydroxy-5-methyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide.
Reaction SMILES: [N+:1]([C:4]1[CH:45]=[C:44]([CH3:46])[C:7]([O:8][C:9]2[CH:43]=[CH:42][C:12]([C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([CH3:41])([CH3:40])[C:23]4[CH:28]=[CH:27][C:26]([O:29][C:30]5[C:35]([CH3:36])=[CH:34][C:33]([N+:37]([O-])=O)=[CH:32][CH:31]=5)=[CH:25][CH:24]=4)[CH:17]=3)([CH3:15])[CH3:14])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)(C)C>[NH2:37][C:33]1[CH:34]=[C:35]([CH3:36])[C:30]([O:29][C:26]2[CH:25]=[CH:24][C:23]([C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([C:13]([CH3:15])([CH3:14])[C:12]4[CH:42]=[CH:43][C:9]([O:8][C:7]5[C:44]([CH3:46])=[CH:45][C:4]([NH2:1])=[CH:5][CH:6]=5)=[CH:10][CH:11]=4)[CH:17]=3)([CH3:41])[CH3:40])=[CH:28][CH:27]=2)=[CH:31][CH:32]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1Oc1ccc(C(C)(C)c2cccc(C(C)(C)c3ccc(Oc4ccc([N+](=O)[O-])cc4C)cc3)c2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: Cc1cc(N)ccc1Oc1ccc(C(C)(C)c2cccc(C(C)(C)c3ccc(Oc4ccc(N)cc4C)cc3)c2)cc1
Yield: 82 %

Procedure:
Successively, to a reduction vessel equipped with a thermometer, reflux condenser and stirrer, 120 g (0.195 mol) of 1,3-bis[4-(4-nitro-6-methylphenoxy)-α, α-dimethylbenzyl]benzene, 400 g of isopropyl alcohol and 5 g of 5%-Pd/c having a moisture content of 50% were charged and reacted at 70°~80° C. for 4 hours in a hydrogen atmosphere. After finishing the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to obtain 89.0 g (82% yield) of 1,3-bis[4-(4-amino-6-methylphenoxy)-α, α-dimethylbenzyl]benzene as a light yellow crystal having a melting point of 118.1~118.2.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8](C(=O)C)=[CH:7][CH:6]=1.P(Cl)(Cl)(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)=O.[Na].N.[CH2:31](OCC)[CH3:32]>[Cl-].[NH4+].O>[F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([C:31]#[CH:32])[CH:8]=[CH:9][CH:10]=1
Reactant: CCOCC
Reactant: CC(=O)c1ccc(Oc2ccccc2F)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: N
Agent: [Cl-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: C#Cc1cccc(Oc2ccccc2F)c1
Reaction time: 8 h

Procedure:
A mixture of 34.5 g of 4'-(2-fluorophenoxy)acetophenone, 41.6 g of phosphorus pentachloride, and 80 ml of phosphorus oxychloride was heated at 60° for 20 hours. The reaction mixture was cooled and volatile materials were distilled in vacuo. The crude 4-(2-fluorophenoxy)-α-chlorostyrene which remained was diluted with benzene which was removed by distillation; the dilution-distillation procedure was repeated three times. The residue then was dissolved in tetrahydrofuran. The resulting solution was added dropwise to a solution of sodium amide in ammonia prepared by adding 23 g of sodium to 750 ml of liquid ammonia containing several mg of ferric chloride. The reaction solution was agitated overnight after adding 375 ml of diethyl ether. The reaction solution then was diluted successively with 150 ml of saturated aqueous ammonium chloride solution and 100 ml of water. The resulting mixture was poured onto ice. The organic layer was separated and the aqueous layer extracted successively with diethyl ether and ethyl acetate. The organic layer and organic extracts were combined and washed successively with water, five percent aqueous hydrochloric acid, and water, and dried over anhydrous sodium sulfate. The organic solvents were distilled under reduced pressure and the residue was vacuum distilled to give [3-(2-fluorophenoxy)phenyl]acetylene, bp 93°-96°/0.2 mm. The following elemental analysis was obtained: