Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][C:13](OC(C)=O)=[O:14]>CN(C1C=CN=CC=1)C>[CH3:10][C:8]([O:11][C:13](=[O:14])[CH3:12])([C:7]1[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[CH3:9]
Reactant: Cc1ncccc1C(C)(C)O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Product: CC(=O)OC(C)(C)c1cccnc1C
Temperature: 100 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
2-(2-methyl-pyridin-3-yl)-propan-2-ol (1.30 g, 8.61 mmol) and DMAP (30 mg) were combined in Ac2O (8 mL) and stirred at 100° C. for 16 hours. Following removal of the solvent under reduced pressure, the brown residue was quenched with saturated NaHCO3 (50 mL) and extracted with CH2Cl2 (5×60 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to afford a yellow oil. Purification via column chromatography on silica gel (CH2Cl2:MeOH, 95:5, v/v) afforded acetic acid 1-methyl-1-(2-methyl-pyridin-3-yl)-ethyl ester as a white crystalline solid (1.25 g, 75%). 1H NMR (CDCl3) δ 1.80 (s, 3H), 2.05 (s, 3H), 2.66 (s, 3H), 7.12 (dd, 1H, J=9.0, 6.0 Hz), 7.62 (dd, 1H, J=9.0, 3.0 Hz), 8.39 (dd, 1H, J=6.0, 3.0 Hz).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:14])=[C:4]([O:12][CH3:13])[C:5]([C:8](=[CH2:11])[CH2:9][CH3:10])=[CH:6][CH:7]=1.[F:15][C:16]([F:25])([F:24])[C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>ClCCl.FC(F)(F)CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:9][CH3:10])[CH2:11][C@:17]([OH:23])([C:16]([F:24])([F:25])[F:15])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:4]([O:12][CH3:13])[C:3]=1[CH3:14]
Reactant: C=C(CC)c1ccc(F)c(C)c1OC
Reactant: CCOC(=O)C(=O)C(F)(F)F
Agent: [Pd]
Solvent: ClCCl
Solvent: OCC(F)(F)F
Product: CCOC(=O)[C@](O)(CC(CC)c1ccc(F)c(C)c1OC)C(F)(F)F
Temperature: 0 °C
Reaction time: 16 h
Yield: 34.1 %

Procedure:
5.7 g (29.3 mmol) of 3-fluoro-2-methyl-6-(1-methylenepropyl)anisole, 7.7 ml (170 mmol) of ethyl trifluoropyruvate and 15 g of molecular sieve are admixed dropwise at 0° C. over 30 minutes with 0.76 g (0.88 mmol) of [Cu(R,R)-2,2-bis(4,5-dihydro-4-tert-butyloxazolin-2-yl)propane)(H2O)2]((SbF6)2, in 38 ml of dichloromethane. The reaction mixture is stirred at 0° C. for 16 hours and the reaction mixture is purified by means of column chromatography on silica gel (hexane/ethyl acetate 0-20%). This gives 8.7 g of ethyl (R)-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-hydroxy-2-(trifluoromethyl)hex-4-enoate as an E/Z mixture with an enantiomeric excess of greater than 80%, and in this way 13.9 of crude E/Z-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-(trifluoromethyl)hex-4-ene-1,2-diol. 4.0 g (11 mmol) of ethyl (2R,4E/Z)-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-hydroxy-2-(trifluoromethyl)hex-4-enoate are dissolved in 180 ml of 2,2,2-trifluoroethanol and the solution is admixed with 400 mg of palladium on carbon (10%). The suspension is shaken under a hydrogen atmosphere at 100 bar until reaction is complete. The mixture is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. The concentrated crude product is purified by column chromatography on silica gel (hexane/ethyl acetate 15%) to give 3.7 g (10 mmol) of ethyl (2R,4R/S)-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-hydroxy-2-(trifluoromethyl)hexanoate as a diastereomer mixture. 3.7 g (10 mmol) of ethyl (2R,4R/S)-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-hydroxy-2-(trifluoromethyl)hexanoate are cooled to −15° C. in 132 ml of diethyl ether and admixed over 10 minutes with solid lithium aluminum hydride, 1.03 g (27.3 mmol), in portions. The mixture is stirred at −10° C. for 3 hours, and ethyl acetate and water are added cautiously. The suspension is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[CH:18]=[C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[C:36](Cl)(=[O:39])[CH:37]=[CH2:38]>CN(C1C=CN=CC=1)C.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[CH:18]=[C:17]([N:19]([CH2:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:36](=[O:39])[CH:37]=[CH2:38])[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(Nc2ncnc3cnc(NCCCN4CCOCC4)cc23)c1
Reactant: C=CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)N(CCCN1CCOCC1)c1cc2c(Nc3cccc(Br)c3)ncnc2cn1
Reaction time: 1 h

Procedure:
To a stirred solution of 4-[(3-bromophenyl)amino]-6-[(3-morpholinopropyl)amino]pyrido[3,4-d]pyrimidine (400 mg, 0.90 mmol), (prepared from 4-[(3-bromophenyl)amino]-6-fluoropyrido[3,4-d]pyrimidine and 3-morpholinoprop-1-ylamine) DMAP (40 mg) and Et3N (excess, 2.0 mL) at 0° C. under N2 was added acryloyl chloride (1.2 mol eq., 1.08 mmol, 89 μL). After 1 hour stirring, a further two portions of acid chloride (89 μL each) were added over the next 2 hours, and the reaction was then stirred at 20° C. for 1 hour, diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure before being chromatographed on silica gel eluting with MeOH/EtOAc (1:9) to MeOH/EtOAc (1:5) to give N-[4-[(3-bromophenyl)amino]pyrido[3,4-d]pyrimidin-6-yl]-N-[3-morpholinopropyl]acrylamide](142 mg, 32%) as a cream powder, mp (CH2Cl2/hexane) 178-180° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:7]2[C:12]([C:13](=[O:26])[C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:25])[CH2:23]Br)=[CH:18][CH:17]=1)=[CH:11][CH:10]=[C:9]([CH3:27])[N:8]=2)=[O:4].C([O-])=[O:35].[Na+]>CCO>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:7]2[C:12]([C:13](=[O:26])[C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:25])[CH2:23][OH:35])=[CH:18][CH:17]=1)=[CH:11][CH:10]=[C:9]([CH3:27])[N:8]=2)=[O:4]
Reactant: O=C[O-]
Reactant: COC(=O)c1c(Cc2ccc(C(=O)CBr)cc2)c(=O)c2ccc(C)nc2n1-c1ccccc1
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1c(Cc2ccc(C(=O)CO)cc2)c(=O)c2ccc(C)nc2n1-c1ccccc1
Temperature: 80 °C
Yield: 42.2 %

Procedure:
A mixture of 3-[4-(2-bromo-acetyl)-benzyl]-7-methyl-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester (38 mg, 0.075 mmol) and sodium formate (25.5 mg, 5 eq.) in EtOH (15 mL) was heated at 80° C. overnight. The reaction mixture was concentrated under reduced pressure and filtered. The crude residue was purified by preparative TLC (EtOAc/hexane, 60/40) to afford 14 mg of 3-[4-(2-hydroxy-acetyl)-benzyl]-7-methyl-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester as an off-white powder. MS=443 [M+H]+; MP=189.9-192.9° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[C:11]([CH3:14])([CH3:13])[CH2:10][CH2:9][C:8]([CH3:16])([CH3:15])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:17][NH:18][C:19]([C:21]1[CH:32]=[CH:31][C:24]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:23][CH:22]=1)=[O:20].N1C=CC=CC=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>O>[C:39]([O:1][CH2:2][C:3]1[C:12]2[C:11]([CH3:13])([CH3:14])[CH2:10][CH2:9][C:8]([CH3:15])([CH3:16])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:17][NH:18][C:19]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:31][CH:32]=1)=[O:20])(=[O:41])[CH3:40]
Reactant: C=CCOC(=O)c1ccc(C(=O)NCc2ccc3c(c2CO)C(C)(C)CCC3(C)C)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: C=CCOC(=O)c1ccc(C(=O)NCc2ccc3c(c2COC(C)=O)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
395 mg (0.9 mmol) of allyl 4-[α-hydroxymethyl-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)methylcarbamoyl]benzoate, 15 ml of pyridine and 200 μl (1.8 mmol) of acetic anhydride were introduced into a round-bottomed flask. The mixture was stirred at room temperature for 8 hours, the reaction medium was poured into water, and extracted with ethyl ether. The organic phase was decanted off, washed with water, dried over magnesium sulfate and evaporated. 435 mg (100%) of the expected compound were recovered in the form of a colorless oil.
Reaction SMILES: O.ON1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2N=N1.C(N(C(C)C)[CH:15]([CH3:17])[CH3:16])C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH2:16]1[C:7]2[C:6](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:17][CH2:15]1
Reactant: On1nnc2ccccc21
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: c1ccc2c(c1)CCC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1-Hydroxybenzotriazole hydrate (0.3 eq.) and N-ethyl-diisopropylamine (4 eq.) were added to a solution of (G) (1.5 eq.) in methylene chloride. The reaction mixture was cooled to 0° C. and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 eq.) was then added. The mixture was stirred at this temperature for 15 min, before the amine (1 eq.) was finally added. The reaction mixture was then stirred at room temperature overnight. For working up, the reaction mixture was washed 3× with 0.5 M KOH solution and the organic phase was dried over MgSO4, filtered and concentrated. The crude product was either purified by column chromatography (silica; methylene chloride/methanol or aluminium oxide; methylene chloride/methanol) or recrystallized from methylene chloride to obtain the product (H) in a pure form.
Reaction SMILES: [CH3:1][N:2]([CH2:19][C:20]([OH:22])=[O:21])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].C(N1C=CN=C1)(N1[CH:29]=[CH:28]N=C1)=O.C(O)C>O1CCCC1>[CH2:28]([O:21][C:20](=[O:22])[CH2:19][N:2]([CH3:1])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:13][CH2:14][C:15](=[O:18])[CH2:16][CH2:17]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:29]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(CC(=O)O)S(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CN(C)S(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Reaction time: 0.75 h
Yield: 134 %

Procedure:
A solution of 0.53 g (1.6 mmol) {methyl-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-amino}-acetic acid in 8 mL anhydrous tetrahydrofuran was treated with 0.32 g (2.0 mmol) 1,1′-carbonyl-diimidazole. After stirring for 45 minutes, 1 mL of ethanol was added. The resulting mixture was then permitted to stir overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The organics were washed twice with saturated sodium bicarbonate, twice with water, dried over sodium sulfate and concentrated in vacuo. After drying via high vacuum overnight, 0.76 g of the title compound was isolated as a red solid; 1H NMR (CDCl3) δ 1.23-1.29 (m, 3H), 2.59 (t, J=6.15 Hz, 4H), 2.87 (s, 1H), 3.76 (t, J=6.09 Hz, 4H), 3.96 (s, 2H), 4.11-4.18 (m, 2H), 6.89-6.96 (m, 2H), 7.67-7.75 (m, 2H); MS (ES) m/z 355.3 (MH+); HRMS for C16H22N2O5S: 355.1332.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@@H:9]([C:13]1[CH:26]=[CH:25][C:16]([O:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:15][CH:14]=1)[C@@H:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:7][CH2:6]2.C(OCC1C=CC=CC=1)C1C=CC=CC=1>[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]1[CH:26]=[CH:25][C:16]([O:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:15][CH:14]=1)[CH:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CC[C@H](c1ccccc1)[C@@H]2c1ccc(OCCN2CCCC2)cc1
Agent: [Pd]
Solvent: c1ccc(COCc2ccccc2)cc1
Product: COc1ccc2c(c1)CCC(c1ccccc1)C2c1ccc(OCCN2CCCC2)cc1

Procedure:
The synthesis begins with bromination1 of 2-bromo-5-methoxy-toluene to provide the benzyl bromide 1-Bromo-2-bromomethyl-4-methoxy-benzene. Alkylation of ethyl benzoylacetate2 with the benzyl bromide followed by decarboxylation leads to the ketone 3-(2-Bromo-5-methoxy-phenyl)-1-phenyl-propan-1-one, which is protected3 as the ketal 2-[2-Bromo-5-methoxy-phenyl)-2-phenyl-[1,3]dioxolane. Metal-halogen exchange of ketal 2-[2-Bromo-5-methoxy-phenyl)-2-phenyl-[1,3]dioxolane provides an aryl-lithium species, which adds readily to either 4-benzyloxy-benzoate or 4-benzoxy-benzontrile4 and furnishes the diketone 3-[2-(4-Benzyloxy-benzoyl)-5-methoxy-phenyl]-1-phenyl-propan-1-one upon acidic work-up. The diketone undergoes a titanium mediated McMurry type coupling5 to provide the alkene 4-(4-Benzyloxy-phenyl)-7-methoxy-3-phenyl-1,2-dihydro-naphthalene, which possesses the carbon framework of cis-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine with all the functional groups in place. A palladium catalyzed hydrogenation achieves the reduction of the olefinic double bond and deprotection of the benzyl ether in one pot. The introduction of the N-ethyl-pyrrolidino side-chain is achieved under Mitsunobu conditions to afford 1-{2-[4-(6-Methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)-phenoxy]-ethyl}-pyrrolidine, the key precursor to cis-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine. This compound is converted to cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol with HBr as described in U.S. Pat. No. 5,552,241.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH:17]([F:19])[F:18])[N:5]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:3]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CC(C)=O>O>[F:18][CH:17]([F:19])[C:9]1[N:8]([C:6]2[N:5]=[C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:3]=[C:2]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:7]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1
Reactant: C1CNCCN1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Solvent: O
Solvent: CC(C)=O
Product: FC(F)c1nc2ccccc2n1-c1nc(N2CCNCC2)nc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
For example, a mixture of 6-chloro-2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-1,3,5-triazine (3.66 g, 10 mmol), piperazine (3.45 g, 40 mmol), and acetone (50 ml) was stirred at room temperature for 16 hours. The reaction mixture was poured into water, and precipitated crystals were filtered, and washed with methanol to afford 2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-(piperazin-1-yl)-1,3,5-triazine (3.87 g, 9.3 mmol) in a yield of 93% as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=2)=[C:8]([CH:14]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])([O-])=O.NC1C=CC=CC=1>C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=2)=[C:8]([CH:14]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1Oc1ccc(F)c(F)c1
Solvent: Nc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cc(N)ccc1Oc1ccc(F)c(F)c1
Yield: 97.2 %

Procedure:
Using the method of Example 17.3, ethyl 5-nitro-2-(3,4-difluorophenoxy)benzoate (0.76 g) in ethanol (8 mL) was converted to the corresponding aniline derivative which was obtained as an oil (0.67 g).
Reaction SMILES: [O:1]([CH:8]([CH3:12])[C:9]([O-:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[NH2:14][CH:15]1[C:26](=[O:27])[N:17]2[C:18]([C:23]([OH:25])=[O:24])=[C:19]([CH3:22])[CH2:20][S:21][C@H:16]12>>[O:1]([CH:8]([CH3:12])[C:9]([NH:14][CH:15]1[C:26](=[O:27])[N:17]2[C:18]([C:23]([OH:25])=[O:24])=[C:19]([CH3:22])[CH2:20][S:21][C@H:16]12)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CC(Oc1ccccc1)C(=O)[O-]
Agent: [Li+]
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(C)Oc3ccccc3)[C@H]2SC1

Procedure:
The procedure of Example 1 was repeated using 1.9 g of lithium α-phenoxypropionate and 2.14 g of 7-amino-3-methyl-3-cephem-4-carboxylic acid. 7-(α-Phenoxypropionamido)-3-methyl-3-cephem-4-carboxylic acid was obtained as a colorless crystalline product in a yield of 3.22 g (95%, mp. 145° C (dec.). This product showed the infra-red and ultra-violet absorption spectra which were entirely coincident with those of the authentic sample.
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1(=[O:29])[O:28][C:26](=[O:27])[CH:25]=[CH:24]1.Cl.O>[OH-].[Na+].C(O)C>[C:14]([C:12]1[CH:13]=[C:8]([N:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:23](=[O:29])/[CH:24]=[CH:25]\[C:26]([OH:28])=[O:27])[CH:9]=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=1[OH:18])([CH3:15])([CH3:16])[CH3:17]
Reactant: O=C1C=CC(=O)O1
Reactant: CC(C)(C)c1cc(Nc2ccccc2)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(N(C(=O)/C=C\C(=O)O)c2ccccc2)cc(C(C)(C)C)c1O
Temperature: 140 °C

Procedure:
Under a nitrogen atmosphere, a mixture of 2.97 g (0.01 mole) of 4-anilino-2,6-di-t-butylphenol and 4.90 g 0.05 mole) of maleic anhydride was heated at 140° C. for 2 hours. The cooled reaction mixture was suspended in 10% sodium hydroxide, and was then acidified with 10% hydrochloric acid. The resulting precipitate was collected, rinsed with water, air dried, and recrystallized from a mixture of ethyl acetate and hexane to give a yellow solid. This material was dissolved in hot ethanol. The ethanol solution was acidified with 6N hydrochloric acid, and then saturated with water. The resulting precipitate was collected, rinsed with water and air dried. This material was purified by silica gel chromatography, eluting with ethyl acetate, followed by recrystallization from a mixture of ethyl acetate and hexane to give 0.5 g of yellow crystalline N-(3,5-di-t-butyl-4-hydroxyphenyl)-N-phenylmaleamic acid, m.p. 154°-157° C. Analysis: Calculated for C25H29NO4 :% C, 72.9; % H, 7.9; % N, 3.5. Found: % C, 73.2; % H, 7.7; % N, 3.3.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:14][C:15]([NH:17][CH2:18][C:19]([OH:21])=O)=[O:16])([CH3:13])([CH3:12])[CH3:11].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[F:55][C:56]([F:60])([F:59])[CH2:57][NH2:58]>ClCCl>[C:10]([O:14][C:15](=[O:16])[NH:17][CH2:18][C:19](=[O:21])[NH:58][CH2:57][C:56]([F:60])([F:59])[F:55])([CH3:11])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NCC(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)NCC(F)(F)F
Reaction time: 24 h

Procedure:
DIPEA (15 ml) is added to a solution of N-(tert-butoxycarbonyl)glycine (5.0 g), PYBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, 16.3 g) and 2,2,2-trifluoroethylamine (2.47 ml) in dichloromethane (48 ml). After 24 hours at room temperature, the reaction is quenched with water and extracted three times with dichloromethane. The combined organic phases are washed with HOC (2M), Na2CO3 (1M) and a saturated aqueous solution of NaCl, dried over MgSO4 and concentrated in vacuo. The crude product is purified by column chromatography (450 g) eluting with a mixture of ethyl acetate and hexane (2:3 to 3:2) to yield [(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-carbamic acid tert-butyl ester (3.89 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[OH:12][C:13]1[C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]=2[CH:16]=[CH:15][CH:14]=1.[CH2:26](Br)[CH:27]=[CH2:28]>O>[CH2:28]([O:12][C:13]1[C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]=2[CH:16]=[CH:15][CH:14]=1)[CH:27]=[CH2:26]
Reactant: Oc1cccc2[nH]c3ccccc3c12
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1cccc2[nH]c3ccccc3c12

Procedure:
138 g of potassium carbonate was added to N,N-dimethylformamide (500 mL) solution of 121.9 g of 4-hydroxycarbazole. Under stirring, 88.6 g of allyl bromide was added thereto and the reaction mixture was stirred at 80° C. for 5 hours. The reaction mixture was allowed to cool, 3.5 L of water was added thereto, and extracted twice with 1 L of ethyl acetate. The combined organic layer was washed with 1 L of brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo. The residue was purified by NH silica gel chromatography (ethyl acetate:n-hexane=1:1), and 129 g of the subject compound was prepared.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][C:16]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[C:18]([C:31]([F:34])([F:33])[F:32])[N:17]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH3:15][C:16]1[CH:21]=[C:20]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=[C:18]([C:31]([F:33])([F:32])[F:34])[N:17]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(F)(F)F)n1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2nnc(N)nc2-c2ccccc2)cc(C(F)(F)F)n1
Yield: 90 %

Procedure:
6-bromo-5-phenyl-1,2,4-triazin-3-amine (1 molar eq.), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine (1 molar eq.) and K2CO3 (1.5 molar eq.) are suspended in a mixture of 1,4-dioxane and water (2:1; 10 mL of solvent per gram of bromotriazine). The resulting mixture is degassed, treated with dichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (2 mol %) and refluxed until full consumption of bromotriazine is observed by LCMS. The cooled reaction mixture is then diluted with water, extracted with DCM and passed through a phase separator. The organic phase is concentrated under reduced pressure and purified by gradient flash chromatography, eluting with mixtures of ethyl acetate and hexanes to afford 6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine (90%).
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH3:11][CH:12]([NH:14][CH:15]1[C:20]2=[C:21]([CH3:28])[C:22]3[C:27]([N:19]2[CH2:18][CH2:17][CH2:16]1)=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:13]>O1CCCC1>[CH3:28][C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]2[CH2:18][CH2:17][CH2:16][CH:15]([N:14]([CH:12]([CH3:13])[CH3:11])[CH:1]=[O:3])[C:20]=12
Reactant: O=CO
Reactant: Cc1c2n(c3ccccc13)CCCC2NC(C)C
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: Cc1c2n(c3ccccc13)CCCC2N(C=O)C(C)C
Temperature: 60 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
A mixture of formic acid (6 mL) and acetic anhydride (12 mL) was heated at 60° C. for 4 hours. A solution of 6,7,8,9-tetrahydro-N-(1-methylethyl)-10-methylpyrido[1,2-a]indol-9-amine (6 g, 24.7 mmol, described in Example 22) in tetrahydrofuran (60 mL) was added at once at 25° C. under exclusion of moisture. The reaction mixture was stirred at 25° C. for 12 hours, then poured into ice water (120 mL). The product was extracted with ether (3×80 mL), and the combined organic layer washed with 5% HCl, 10% NaHCO3, and water. The separated organic layer was dried over MgSO4, filtered, and evaporated to afford 6 g (90%) of the title compound as an amber oil.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:12][CH:13](O)[CH:14]=[CH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:12]([CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:8]1=[O:11])[CH:13]=[CH:14][CH3:15]
Reactant: Cc1ccc2c(c1)C(=O)CC2
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2ccc(C)cc2C1=O
Yield: 83 %

Procedure:
A solution of 14.2 g of 6-methyl-1-indanone, 20.1 ml of 3-buten-2-ol and 140 mg of p-toluenesulfonic acid in 140 ml of 2,2-dimethoxypropane was boiled under reflux for 69 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 5:1). 16.3 g (83%) of (RS)-2-(2-buten-1-yl)-6-methyl-1-indanone were obtained as a yellow oil.