Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].CO>C(OCC)(=O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:26]3[CH2:27][CH2:28][CH:23]([C:20]4[CH:21]=[CH:22][C:17]([C:16]([F:15])([F:29])[F:30])=[CH:18][CH:19]=4)[CH2:24][CH2:25]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: FC(F)(F)c1ccc(C2CCNCC2)cc1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2ccc(C(F)(F)F)cc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(4-trifluoromethylphenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 34% overall yield. FDMS m/e=419 (M+ of free base). α[D]589 =-10.15 (c=0.47, methanol).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([O:13][CH3:14])[C:10](Cl)=[O:11].[Cl:15][C:16]1[CH:17]=[C:18]([N:23]2[C:27](=[O:28])[CH2:26][NH:25][C:24]2=[O:29])[CH:19]=[C:20]([Cl:22])[CH:21]=1>O1CCCC1>[CH3:14][O:13][N:9]([CH3:8])[C:10]([N:25]1[CH2:26][C:27](=[O:28])[N:23]([C:18]2[CH:17]=[C:16]([Cl:15])[CH:21]=[C:20]([Cl:22])[CH:19]=2)[C:24]1=[O:29])=[O:11]
Reactant: O=C1CNC(=O)N1c1cc(Cl)cc(Cl)c1
Reactant: CON(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CON(C)C(=O)N1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Temperature: 20 °C

Procedure:
At about 20° C, 10.5 parts of triethylamine and subsequently 12.4 parts of methylmethoxycarbamoyl chloride are added to a suspension of 24.5 parts of 3-(3,5-dichlorophenyl)-hydantoin in 250 parts of dry tetrahydrofuran. After all has been added, the mixture is refluxed for 3 hours. After the mixture has been cooled to 20° C, the precipitated triethylamine hydrochloride is removed by suction filtration. The filtrate is concentrated. The residue is dissolved in a 1:1 mixture of n-pentane and ether, suction filtered, dried and recrystallized from toluene.
Reaction SMILES: [Sn].C[Sn](C)(C)[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH3:14].C(Cl)[Cl:18]>>[Cl:18][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH3:14]
Reactant: ClCCl
Reactant: Cc1ccc2ccccc2c1[Sn](C)(C)C
Agent: [Sn]
Product: Cc1ccc2ccccc2c1Cl
Reaction time: 8 h
Yield: 80 %

Procedure:
To the tin compound 20 (1 g, 3.3 mmole) in CH2Cl2 (50 ml) was added N-chlorosuccimimide NCIS (931 mg, 7 mmole). The mixture was stirred overnight. The mixture was washed with saturated solution of NaHCO3, water, brine, dried with anhydrous magnesium sulfate, and concentrated in vacuo to yield 0.7 g of a crude yellowish semi-solid. The crude yellow semi-solid was purified by column chromatography (silica, 100% hexane) to afford 1.2 g of 21 (80%) as a white powder. A simple component was detected by TLC (100%) hexane) Rf, 0.69; NMR (CDCl3) d 2.3 (3H, S, CH3), d 7.2-8.2 (m, 6H, naphthyl).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11].[OH-].[Na+].[CH3:14][C:15]1[O:19][N:18]=[C:17]([CH:20]=O)[CH:16]=1.Cl>CCO.O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])/[CH:9]=[CH:20]/[C:17]2[CH:16]=[C:15]([CH3:14])[O:19][N:18]=2)=[CH:4][C:3]=1[CH3:11]
Reactant: CC(=O)c1ccc(O)c(C)c1
Reactant: Cc1cc(C=O)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(/C=C/C(=O)c2ccc(O)c(C)c2)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of commercially available 4′-hydroxy-3′-methylacetophenone (700 mg, 4.66 mmol) and NaOH (365 mg, 9.1 mmol) in 10 mL of absolute EtOH was added commercially available 5-methylisoxazole-3-carbaldehyde (518 mg, 4.66 mmol). The reaction mixture was stirred at room temperature for 18 hr. 5 mL of water was added and the reaction mixture was acidified with concentrated HCl to pH 5-6. The precipitate was filtered, washed with water and dried to give (E)-1-(4-hydroxy-3-methylphenyl)-3-(5-methylisoxazol-3-yl)prop-2-en-1-one. MS (EI) for C14H13NO3: 244 (MH+).
Reaction SMILES: [OH-].[Na+].[CH2:3](OCC)C.CN(N=O)C(N[N+]([O-])=O)=N.[OH:18][C@H:19]([CH2:23][C:24]1[CH:32]=[C:31]([CH3:33])[C:30]2[C:26](=[CH:27][N:28]([CH2:34][O:35][CH3:36])[N:29]=2)[CH:25]=1)[C:20]([OH:22])=[O:21]>ClCCl>[OH:18][C@H:19]([CH2:23][C:24]1[CH:32]=[C:31]([CH3:33])[C:30]2[C:26](=[CH:27][N:28]([CH2:34][O:35][CH3:36])[N:29]=2)[CH:25]=1)[C:20]([O:22][CH3:3])=[O:21]
Reactant: COCn1cc2cc(C[C@@H](O)C(=O)O)cc(C)c2n1
Reactant: CCOCC
Agent: CN(N=O)C(=N)N[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COCn1cc2cc(C[C@@H](O)C(=O)OC)cc(C)c2n1
Reaction time: 0.25 h

Procedure:
To a heterogeneous mixture of 5 M sodium hydroxide (20 mL) and diethyl ether (60 mL) at 0° C. was added N-methyl-N′-nitro-N-nitrosoguanidine (1.17 g, 7.95 mmol) in small portions with swirling (no stirbar). After addition was complete, the mixture was allowed to stand at 0° C. for 15 min with occasional swirling. The ethereal was transferred in portions to a suspension of (R)-2-hydroxy-3-(2-(methoxymethyl)-7-methyl-2H-indazol-5-yl)propanoic acid (1.40 g, 5.30 mmol) in dichloromethane (20 mL) until the solid had all dissolved and a yellow color persisted. The reaction was allowed to rest at room temperature for ca. 5 min. before bubbling nitrogen through the solution to remove unreacted diazomethane. The reaction was concentrated and purified by column chromatography (50%→75% ethyl acetate/hexanes) to give 1.47 g (100%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 1.60 (bs, 1H), 2.58 (s, 3H), 2.95 (dd, J=13.9, 7.0, 1H), 3.14 (dd, J=13.9, 4.0, 1H), 3.36 (s, 3H), 3.76 (s, 3H), 4.46 (bm, 1H), 5.65 (s, 2H), 6.90 (s, 1H), 7.31 (s, 1H), 7.99 (s, 1H). Mass spec.: 279.11 (MH)+.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].Cl[C:9]1[N:18]=[CH:17][C:16]2[C:11](=[CH:12][C:13]([O:19]C)=[CH:14][CH:15]=2)[N:10]=1>C(Cl)Cl>[CH2:1]([S:3][C:9]1[N:18]=[CH:17][C:16]2[C:11](=[CH:12][C:13]([OH:19])=[CH:14][CH:15]=2)[N:10]=1)[CH3:2]
Reactant: CCS
Reactant: COc1ccc2cnc(Cl)nc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCSc1ncc2ccc(O)cc2n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
To a solution of ethanthiol (30 ml) in DCM (50 ml) was added AlCl3 (6 eq). The reaction mixture was cooled to 0° C. and stirred for 10 min under N2 atmosphere. A solution of 2-chloro-7-methoxyquinazoline (1 eq) in DCM (20 ml) was added dropwise to it. The reaction mixture was warmed to room temperature and stirred for 2 h. The solvent was evaporated and residue was partitioned between EtOAc and satd. NaHCO3. The insoluble material was filtered, washed and dried to provide title product as a yellow solid (yield, 60%). The ethyl acetate layer was separated from basic layer, washed with brine and dried over sodium sulfate. Filtration, evaporation and drying under vacuum provide additional amount of product. (yield, 38%). ES/MS m/z 207.0 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([Br:12])=[CH:4][N:3]=1.[C:13]1([CH:19]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Br:12][C:5]1[C:6]([N:24]2[CH2:25][CH2:26][N:21]([CH:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:20])[CH2:22][CH2:23]2)=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Reactant: CC(c1ccccc1)N1CCNCC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1ccccc1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Temperature: 45 °C
Reaction time: 20 h

Procedure:
To a mixture of 2-amino-5-bromo-4-chloro-3-nitropyridine (0.252 g, 1.00 mmol) and isopropanol (18 ml) was added 1-(1-phenylethyl)piperazine (0.209 g, 1.10 mmol) followed by diisopropylethylamine (0.20 ml, 1.15 mmol). The reaction mixture was stirred at 45° C. for 20 h, then allowed to cool to room temperature and diluted with isopropanol (10 ml). The resulting precipitate was collected by filtration, washed with isopropanol (3×5 ml), diethyl ether (3×5 ml), and dried. The title compound was obtained as a yellow solid (0.300 g, 74%). 1H-NMR (500 MHz, DMSO-d6) 1.30 (d, J=6.7 Hz, 3H, CHCH3), 2.42 (m, 2H) and 2.54 (m, 2H) (piperazine N(CH2)2), 3.03 (br s, 4H, piperazine N(CH2)2), 3.45 (q, J=6.7 Hz, 1H, CHCH3), 6.95 (s, 2H, NH2), 7.23 (m, 1H) and 7.32 (m, 4H) (PhH), 8.13 (s, 1H, pyridine 6-H);
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]\[C:5]1[CH2:6][S:7][C@@H:8]2[CH:28]([NH:29][C:30](=[O:69])/[C:31](=[N:57]\[O:58][C:59]([CH3:68])([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH3:60])/[C:32]3[N:33]=[C:34]([NH:37][C:38]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[S:35][CH:36]=3)[C:27](=[O:70])[N:9]2[C:10]=1[C:11]([O:13][CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[I-:71].[Na+]>CC(C)=O.C(OCC)(=O)C>[I:71][CH2:2]/[CH:3]=[CH:4]/[C:5]1[CH2:6][S:7][C@@H:8]2[CH:28]([NH:29][C:30](=[O:69])/[C:31](=[N:57]\[O:58][C:59]([CH3:68])([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH3:60])/[C:32]3[N:33]=[C:34]([NH:37][C:38]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[S:35][CH:36]=3)[C:27](=[O:70])[N:9]2[C:10]=1[C:11]([O:13][CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C\CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
A mixture of diphenylmethyl 3-[(Z)-3-chloro-1-propen-1-yl]-7-[(Z)-2-(1-methyl-1-t-butoxycarbonylethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxy-late (IXa) (488 mg, 0.5 mmol) and sodium iodide (225 mg, 1.5 mmol) in acetone (5 ml) was stirred at room temperature for 2 hours and diluted with ethyl acetate. The organic layer was washed with an aqueous sodium thiosulfate, dried over anhydrous MgSO4 and concentrated to afford 546 mg (yield, quantitative) of the title product.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:13])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[N:6]1.[C:14](=O)(OC1C=CC=CN=1)[O:15]C1C=CC=CN=1>ClCCl>[N+:10]([C:7]1[CH:8]=[CH:9][N:5]([CH2:4][C@H:3]2[O:13][C:14](=[O:15])[NH:1][CH2:2]2)[N:6]=1)([O-:12])=[O:11]
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Reactant: NC[C@H](O)Cn1ccc([N+](=O)[O-])n1
Solvent: ClCCl
Product: O=C1NC[C@@H](Cn2ccc([N+](=O)[O-])n2)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.6 %

Procedure:
To a solution of (S)-1-amino-3-(3-nitro-pyrazole-1-yl)-propan-2-ol (0.65 g, 3.49 mmol) in dichloromethane (15 mL) was added di-2-pyridyl carbonate (0.76 g, 3.49 mmol). The reaction mixture was stirred at room temperature for 2 h and then diluted with dichloromethane. The organic layer was washed with a saturated sodium chloride solution and dried over magnesium sulfate. The crude product obtained after concentration, was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% to 10% methanol/dichloromethane) to afford (S)-5-(3-nitro-pyrazol-1-ylmethyl)-oxazolidin-2-one (0.36 g, 49%) as a clear colorless oil: HR-ES-MS m/z calculated for C7H8N4O4 [M]+ 212, observed 213 [M+H]+.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C>[C:10]1([C:2]2[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(O)c1ccc(Br)o1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(-c2ccccc2)o1
Temperature: 150 °C
Yield: 55.5 %

Procedure:
A solution of 5-bromofuran-2-carboxylic acid (381 mg, 2 mmol), phenylboronic acid (488 mg, 4 mmol) in DMF (3 ml) was place in a microwave reaction tube and treated with a 2 M K3PO4(aq) (2 ml, 4 mmol). The solution was purged with nitrogen for 10 minutes before adding Pd(PPh3)4 (1.5 mg) catalyst. The mixture was again purged with nitrogen for 5 minutes before the reaction tube was sealed. The mixture was heated in a microwave oven at 150° C. for 30 minutes. The reaction mixture was filtered and the filtrate poured into 1N HCl (100 ml) with stirring. The precipitate was filtered and air-dried to give 209 mg of 5-phenylfuran-2-carboxylic acid. MS (ES−) found: (M−H)−=187.13.
Reaction SMILES: C([N:8]1[C@@H:13]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH3:19])(OC(C)(C)C)=O>FC(F)(F)C(O)=O.ClCCl>[CH3:19][C@H:9]1[CH2:10][CH2:11][CH2:12][C@H:13]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[NH:8]1
Reactant: CC(C)CC[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC[C@H]1CCC[C@H](C)N1

Procedure:
To a stirred solution of trans-N-Boc-2-methyl-6-isopentylpiperidine (1.5 g, 5.56 mmol) in 15% trifloroacetic acid (35 mL) in dichloromethane was stirred for 2 h at room temperature, and the reaction mixture was quenched with 90 mL saturated NaHCO3 solution. The mixture was extracted with ether *5 and the combined extracts were dried over K2CO3 and then concentrated to give trans-2-methyl-6-isopentylpiperidine as an oil. The crude oil was immediately dissolved in a small amount of ether, and ether saturated with HCl (g) was added slowly via pipette. This solution was allowed to stand for 10 minutes, and the solvent was evaporated. More ether was added and the flask was swirled constantly until crystallization occured. The solid was collected via filtration, and dried in vacuo to give the piperidinium hydrochloride as a white solid. mp 134.1-134.7° C.; 1H NMR (250 MHz) 67 9.36 (s, 2H), 3.53 (s, 1H), 3.25 (s, 1H), 1.96-1.1 (m, 14H), 0.88-0.82 (d, 6H); 13C NMR (62.7 MHz) δ51.9 (s), 47.8 (s), 34.7 (s), 28.9 (s), 28.4 (s), 27.8 (s), 26.0 (s), 22.7 (s), 22.1 (s), 17.3 (s), 16.9 (s). FT-IR (neat): 3422, 2949, 1636, 1602, 1587, 1500, 1422, 1384, 1230, 1105, 1030, 998, 895. Elemental Analysis for C11H24NCl: C, 64.20%; H, 11.78%; N, 6.80%. Found: C, 64.08%; H, 11.72%; N, 6.78%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH:6]([CH3:9])[CH2:7][NH2:8].[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][CH2:26]OS(C1C=CC(C)=CC=1)(=O)=O.C(N(CC)CC)C.O>C(S(CC)=O)C>[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][CH2:26][NH:8][CH2:7][CH:6]([O:5][C:4]1[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=1[O:2][CH3:1])[CH3:9]
Reactant: COc1ccccc1OC(C)CN
Reactant: Cc1ccc(S(=O)(=O)OCCCc2c[nH]c3ccc(F)cc23)cc1
Agent: CCS(=O)CC
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccccc1OC(C)CNCCCc1c[nH]c2ccc(F)cc12
Temperature: 90 °C
Reaction time: 8 h
Yield: 23.4 %

Procedure:
A solution of 2-(2-methoxy-phenoxy)propylamine (0.26 g, 1.2 mmol), 5-fluoro-3-(3-p-toluenesulfonyloxypropyl)indole (0.26 g, 0.81 mol) and triethylamine (0.13 g, 1.2 mmol) in anhydrous diethylsulfoxide (20 ml) was allowed to stir for 8 hours at 90° C. The mixture was poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The organic layer was washed with water (3×100 ml), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. Chromatography (10% methanol-methylene chloride plus ammonium hydroxide) afforded 0.1 g (36%) of product of product as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[O:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1.[CH3:17][Si:18]([CH3:25])([CH3:24])[CH2:19][CH2:20][O:21][CH2:22]Cl.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH3:17][Si:18]([CH3:25])([CH3:24])[CH2:19][CH2:20][O:21][CH2:22][O:15][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([O:4][C:3](=[O:16])[O:2][CH3:1])[CH:14]=1
Reactant: COC(=O)Oc1cc(O)c2ccccc2c1
Reactant: C[Si](C)(C)CCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Oc1cc(OCOCC[Si](C)(C)C)c2ccccc2c1
Temperature: 2 °C
Reaction time: 48 h
Yield: 75.4 %

Procedure:
4.62 g (21.2 mmol) of carbonic acid 4-hydroxy-naphthalen-2-yl ester methyl ester [Journal of Agricultural and Food Chemistry (1994), 42(12), 2970-2] was dissolved in 150 ml of MeCl2, 4.95 ml=4.71 g (25.4 mmol) of 2-(trimethylsilyl)-ethoxymethylchloride was added and this mixture cooled down to 2° C. 11.1 ml=8.38 g (63.5 mmol) of N-ethyl-diisoproylamine was added drop by drop and then, reaction was warmed up to ambient temperature. After 48 hours, it was poured into crashed ice and extracted twice with MeCl2; the organic phases were washed with water, dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (SiO2, gradient of n-heptane/MeCl2) to give 5.57 g of carbonic acid methyl ester 4-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-yl ester as colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16]Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:19]=[N+:20]=[N-:21].[Na+]>C(Cl)Cl.O.[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-]>[N:19]([CH2:16][C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)=[O:18])=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: [N-]=[N+]=NCC(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 4 h
Yield: 94.5 %

Procedure:
To a mixture of 1-(4-benzyloxy-phenyl)-2-bromo-ethanone (28.55 g; 93.6 mmol) in CH2Cl2 (300 mL) and water (30 mL) was added nBu4NBr (1.51 g; 4.7 mmol) and NaN3 (6.69 g; 102.9 mmol) in one portion. After 4 h at RT, the layers were separated. The organic layer was washed water, dried (Na2SO4), filtered and concentrated in vacuo to afford 2-azido-1-(4-benzyloxy-phenyl)-ethanone (23.64 g).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:9]([OH:13])(=[O:12])[CH:10]=[CH2:11].S(=O)(=O)(O)O>>[C:9]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:12])[CH:10]=[CH2:11]
Reactant: C=CC(=O)O
Reactant: C=CCCCCCC
Agent: O=S(=O)(O)O
Product: C=CC(=O)OCCCCCCCC

Procedure:
To 1.00 g (0.00891 mole, 1 eq) of 1-octene heated to 50° C. was added a solution of 0.706 g (0.00980 mole, 1.1 eq) of acrylic acid and 2.00 g of a 96 wt-% solution of sulfuric acid (18 M, 0.0196 mole, 2.2 eq). After 15 minutes at 70° C. all the olefin was consumed but only 30% of the product was the desired acrylate.
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[C:5]2[C:6]3[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]=3[CH:14]=[CH:15][CH:16]=2>C(O)(=O)C>[Br:3][C:4]1[C:5]2[C:6]3[C:10](=[C:11]([Br:1])[CH:12]=1)[NH:9][C:8](=[O:13])[C:7]=3[CH:14]=[CH:15][CH:16]=2
Reactant: BrBr
Reactant: O=C1Nc2ccc(Br)c3cccc1c23
Solvent: CC(=O)O
Product: O=C1Nc2c(Br)cc(Br)c3cccc1c23
Yield: 66.5 %

Procedure:
A solution of bromine (3.8 g) in glacial acetic acid (15 mL) was added dropwise to a suspension of 6-bromo-benz[cd]indol-2(1H)-one[4 g, 16.1 mmol, described by H. Goldstein and P. Francey, Helv., 15, 1366 (1932)] in glacial acetic acid (30 mL) for 3-4 hr. The precipitate was collected by filtration, washed, dried (any coloration caused by the excess of bromine could be removed by washing with a diluted sodium thiosulfate solution), and crystallized from ethanol-water to give the title compound (3.5 g): mp 280°-290° C.; Anal. Calcd for C11H5Br2NO: C, 40.41% H, 1.54% N, 4.28% and Found: C, 40.52% H, 1.51% N, 4.43%; IR (mineral oil) 3140 and 1700 cm-1 ; UV max (methanol) 345 (ε4370), 329 (2910), 264 (27,680), and 212 nm (30,920); and NMR (DMSO-d6)δ 8.0 (m, 4H), and 11.3 (s, 1H).
Reaction SMILES: [C:1]([C:4](=[C:9]([NH2:14])[C:10]([F:13])([F:12])[F:11])[C:5]([O:7][CH3:8])=[O:6])(=[O:3])[CH3:2].[C:15](OC(=O)C)(=O)C.C(OC)(OC)OC.[H-].[Na+]>COCCOC>[OH:3][C:1]1[CH:2]=[CH:15][N:14]=[C:9]([C:10]([F:12])([F:13])[F:11])[C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(C(C)=O)=C(N)C(F)(F)F
Reactant: CC(=O)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: COC(OC)OC
Product: COC(=O)c1c(O)ccnc1C(F)(F)F
Temperature: 27.5 °C
Reaction time: 18 h
Yield: 18.5 %

Procedure:
A mixture of 105 g (0.5 mol) of methyl 2-acetyl-3-amino-4,4,4-trifluoro-2-butenoate (example 2 of U.S. Pat. No. 4,655,816), acetic anhydride (152 g), and trimethyl orthoformate (106 g) was held at reflux for 16 h then distilled to remove low boiling material (bp 65-90° C.). The remaining material was concentrated in vacuo and the residue was kugelrohr distilled at 2 torr (80-120° C.) to give 114 g of distillate. This distillate (44 g) was added dropwise to a mixture of 14.5 g of 60% sodium hydride oil dispersion in 100 ml of 1,2-dimethoxyethane (DME). The reaction mixture was maintained at 25-30° C. with an ice-water bath. The reaction mixture was stirred at room temperature for 18 h and poured into 300 ml of ice-water. The aqueous layer was extracted with ether and filtered. The aqueous layer was acidified with concentrated HCl. The oil precipitate was extracted into ether. The ether extract was extracted with 10% potassium carbonate. The potassium carbonate layer was acidified with concentrated HCl. The precipitate was filtered and air dried to give 20.4 g of the product, mp 78-82° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][C:11]([NH2:19])([CH2:12]3)[CH2:10]1)[CH2:16]2.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](O)=[O:27].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][C:11]([NH:19][C:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=4)=[O:27])([CH2:12]3)[CH2:10]1)[CH2:16]2
Reactant: NC12CC3CC(C1)CC(C#Cc1cnccn1)(C3)C2
Reactant: O=C(O)c1ccccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC12CC3CC(CC(C#Cc4cnccn4)(C3)C1)C2)c1ccccn1
Temperature: 25 °C
Yield: 116.2 %

Procedure:
To a solution of intermediate 11, 3-(pyrazin-2-ylethynyl)-1-adamantylamine (30 mg, 0.12 mmol) and picolinic acid (18 mg, 0.15 mmol) in DMF (2 mL) was added DIEA (50 mg, 0.38 mmol) and HATU (60 mg, 0.12 mmol) under N2. After stirring at room temperature for an hour, the reaction was quenched with brine and extracted with ethyl acetate (2×20 mL). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give a residue, which was purified by Prep HPLC to give 50 mg (95%) of the title compound, pyridine-2-carboxylic acid (3-pyrazin-2-ylethynyl-adamantan-1-yl)-amide, as an off-white solid. 1H NMR (500 MHz, CDCl3): δ 8.60-8.43 (m, 4H), 8.17 (d, J=8.0 Hz, 1H), 7.96 (s, 1H), 7.85-7.82 (m, 1H), 7.42-7.39 (m, 1H), 2.45 (s, 2H), 2.26-2.20 (m, 4H), 2.11-1.97 (m, 6H), 1.76-1.69 (m, 2H); ESI-MS m/z: 359 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CCN(C(C)C)C(C)C.[CH3:21][O:22][CH2:23]Cl>C(Cl)Cl>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([O:11][CH2:21][O:22][CH3:23])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COCCl
Reactant: COc1ccc(O)cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1ccc(OC)c(OC)c1
Reaction time: 17 h

Procedure:
To a stirred solution of 3,4-bis(methyloxy)phenol (Commercial eg Alfa Aesar) (1.0 g) and DIPEA (2.28 ml) in DCM (15 ml) was added chloromethyl methyl ether (0.74 ml) at 0 C. After stirring at 25-30 C for 17 h, the reaction was washed with dilute hydrochloric acid and saturated aqueous sodium bicarbonate. This was dried over sodium sulphate and purified through silica eluting with 0-5% ethyl acetate in hexane, to give the title compound, 0.80 g