Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]([CH3:8])=[CH:6][CH:7]=1)#[CH:2].C(NC(C)C)(C)C.I[C:17]1[CH:22]=[CH:21][C:20](/[C:23](/[C:40]2[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=2)=[CH:24]\[CH2:25][O:26][C:27]2[CH:38]=[CH:37][C:30]([O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[C:29]([CH3:39])[CH:28]=2)=[CH:19][CH:18]=1>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:39][C:29]1[CH:28]=[C:27]([O:26][CH2:25]/[CH:24]=[C:23](\[C:20]2[CH:19]=[CH:18][C:17]([C:2]#[C:1][C:3]3[S:4][C:5]([CH3:8])=[CH:6][CH:7]=3)=[CH:22][CH:21]=2)/[C:40]2[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=2)[CH:38]=[CH:37][C:30]=1[O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34]
Reactant: C#Cc1ccc(C)s1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#Cc3ccc(C)s3)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Temperature: 25 °C
Reaction time: 19 h

Procedure:
2-Ethynyl-5-methylthiophene (161 mg, 1.32 mmol) and diisopropylamine (0.43 mL, 3.10 mmol) were added to a solution of methyl (Z)-[4-[3-(4-iodophenyl)-3-(4-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]acetate (384 mg, 0.659 mmol; example 4) in tetrahydrofuran (10 mL). The mixture was degassed and copper(I) iodide (10 mg, 0.053 mmol) and bis(triphenylphosphine)palladium(II) dichloride (23 mg, 0.033 mmol) were added. The reaction mixture was stirred at ambient temperature for 19 h and subsequently evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 15:1-12:1) yielding methyl (E)-[2-methyl-4-[3-[4-[(5-methylthiophen-2-yl)ethynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]phenoxy]acetate as brown oil.
Reaction SMILES: C(O)C(F)(F)F.[O:7]=[C:8]([N:22]1[CH2:27][CH2:26][N:25]2[C:28]([C:31]([F:34])([F:33])[F:32])=[N:29][N:30]=[C:24]2[CH2:23]1)/[CH:9]=[C:10](\[NH2:21])/[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[F:20]>>[O:7]=[C:8]([N:22]1[CH2:27][CH2:26][N:25]2[C:28]([C:31]([F:34])([F:33])[F:32])=[N:29][N:30]=[C:24]2[CH2:23]1)[CH2:9][C@H:10]([NH2:21])[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[F:20]
Reactant: N/C(=C\C(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Solvent: OCC(F)(F)F
Product: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a flask was charged [Rh(cod)2]OTf (0.1 mmol) and (S)-Cy2-p-Tol-Biphemp (Ligand E) (0.1 mmol) under a nitrogen atmosphere. Degassed trifluoroethanol was then added (20 mL) and the mixture was stirred at room temperature for 1 h. Into a hydrogenator was charged the enamine amide 2-4 (1 mmol) and then degassed. The catalyst solution was then transferred to the hydrogenator under nitrogen. After degassing three times, the enamine amide was hydrogenated under 100 psig hydrogen gas at 20° C. for 20 h (94% assay yield, 98% ee).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.C(O)(=O)C.C([O-])(=O)C.[NH4+].[N+:22]([CH3:25])([O-:24])=[O:23]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:25][N+:22]([O-:24])=[O:23])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1OC
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(C=C[N+](=O)[O-])cc1OC
Temperature: 25 °C
Yield: 53.7 %

Procedure:
In a 250 mL flask was placed 42.45 g of 3,4-dimethoxybenzaldehyde (0.255 mole, 1 eq.), 64 mL of glacial acetic acid (4.0 M), 9.83 g of ammonium acetate (0.128 mole, 0.5 eq), and 15.2 mL of nitromethane (0.281 mole, 1.1 eq.). The mixture was stirred well and heated to reflux for 1.5 hour and allowed to cool to room temperature. The reaction mass solidified and was dissolved in methylene chloride (500 mL) and washed with water (2×400 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated on a rotary evaporator to provide 56.33 g of crude product. Crystallization of the product from ethanol (240 mL) and acetone (100 mL) provided 28.66 g of 2-(3,4-dimethoxypheny)-nitroethene (0.137 mole), 53.7% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:6]1[C:7]([OH:9])=O)[CH3:2].S(Cl)(Cl)=O.[CH2:19]([O:22][C:23]1[C:24]([Cl:31])=[CH:25][C:26]([F:30])=[C:27]([CH:29]=1)[NH2:28])[CH:20]=[CH2:21].Cl>C(Cl)Cl.C(N(CC)CC)C.N1C=CC=CC=1>[CH2:19]([O:22][C:23]1[C:24]([Cl:31])=[CH:25][C:26]([F:30])=[C:27]([NH:28][C:7]([CH:6]2[CH2:10][CH2:11][CH2:12][CH2:13][CH:5]2[C:4]([O:3][CH2:1][CH3:2])=[O:14])=[O:9])[CH:29]=1)[CH:20]=[CH2:21]
Reactant: CCOC(=O)C1CCCCC1C(=O)O
Reactant: C=CCOc1cc(N)c(F)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: C=CCOc1cc(NC(=O)C2CCCCC2C(=O)OCC)c(F)cc1Cl
Temperature: 25 °C

Procedure:
In 20 ml of methylene chloride, 1.20 g of 1,2,3,4,5,6-hexahydrophthalic acid monoethyl ester was dissolved. To this solution 0.47 g of pyridine and 0.71 g of thionyl chloride were added and the resulting mixture was stirred at room temperature. Two hour later, 1 20 g of 5-allyloxy-4-chloro-2-fluoroaniline and 0.61 g of triethylamine were added and the resulting mixture was stirred at room temperature for 5 hours. After completion of the reaction, 10% hydrochloric acid was added to the reaction mixture to make the same acidic and was extracted twice with methylene chloride. The extract was washed with saturated aqueous sodium hydrogen carbonate and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate =5/1 (v/v)) to obtain 1.5 g of light brown crystal.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][CH:15]=1)=[O:12].CN1C2C(=CC=CC=2)C=C1C(O)=O.CC1(C)C(C)(C)OB(C2C=CC(N)=CC=2)O1.Br[C:59]1[N:60]=[C:61]([C@H:69]2[CH2:74][CH2:73][C@H:72]([N:75]3[CH2:80][CH2:79][N:78]([CH3:81])[CH2:77][CH2:76]3)[CH2:71][CH2:70]2)[N:62]2[CH:67]=[CH:66][N:65]=[C:64]([CH3:68])[C:63]=12>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:59]2[N:60]=[C:61]([C@H:69]3[CH2:74][CH2:73][C@H:72]([N:75]4[CH2:80][CH2:79][N:78]([CH3:81])[CH2:77][CH2:76]4)[CH2:71][CH2:70]3)[N:62]3[CH:67]=[CH:66][N:65]=[C:64]([CH3:68])[C:63]=23)=[CH:16][CH:15]=1)=[O:12]
Reactant: Cn1c(C(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc2ccccc21
Reactant: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](N2CCN(C)CC2)CC1
Agent: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: Cn1c(C(=O)O)cc2ccccc21
Product: Cc1nccn2c1c(-c1ccc(NC(=O)c3cc4ccccc4n3C)cc1)nc2[C@H]1CC[C@H](N2CCN(C)CC2)CC1

Procedure:
Reaction of 1-methyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-indole-2-carboxamide (29 mg), prepared from 1-methyl-1H-indole-2-carboxylic acid which was transformed into its acid chloride first and then reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, and 1-bromo-8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine (30 mg) according to the procedure described in example 4 step 4c and purification by column chromatography (silica gel; dichloromethane with gradient 0 to 20% of methanol) gave 1-methyl-N-(4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1H-indole-2-carboxamide (12 mg)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]#[C:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.[Cu](C#N)[C:15]#[N:16]>CN1CCCC1>[CH3:11][C:10]([CH3:13])([CH3:12])[C:9]#[C:8][C:5]1[N:4]=[CH:3][C:2]([C:15]#[N:16])=[CH:7][N:6]=1
Reactant: CC(C)(C)C#Cc1ncc(Br)cn1
Reactant: N#C[Cu]C#N
Agent: CN1CCCC1
Product: CC(C)(C)C#Cc1ncc(C#N)cn1
Temperature: 200 °C
Yield: 67.5 %

Procedure:
A mixture of 5-bromo-2-(3,3-dimethylbut-1-ynyl)pyrimidine (2.5 g, 0.010 mol) and copper cyanide (1.4 g, 0.016 mol) in N-methyl pyrrolidine was heated in a sealed tube at 200° C. for 24 hours. The mixture was allowed to cool to room temperature and filtered through Celite® and the filtrate was concentrated under vaccum. The residue was purified by column chromatography on silica gel with an ethyl acetate: hexane (0-50% gradient) to give the product (1.25 g).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:30]=[CH:31][CH:32]=1)[C:9]([C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[C:14]([C:25]([O:27]CC)=[O:26])=[CH:13][N:12]=1)=[O:10])[CH2:2][CH2:3][CH3:4]>C(O)C.C1COCC1.[OH-].[Na+]>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:30]=[CH:31][CH:32]=1)[C:9]([C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[C:14]([C:25]([OH:27])=[O:26])=[CH:13][N:12]=1)=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cccc(C(=O)c2ncc(C(=O)OCC)c3cc(OC)c(OC)cc23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCOc1cccc(C(=O)c2ncc(C(=O)O)c3cc(OC)c(OC)cc23)c1
Yield: 96 %

Procedure:
The above intermediate, 1-(3-butoxybenzoyl)-6,7-dimethoxy-4-ethoxycarbonyl-isoquinoline (390 mg, 0.89 mmol) was dissolved in a solution of ethanol (10 ml), THF (5 ml) and 4N sodium hydroxide (1 ml). The mixture was refluxed until all starting material was consumed. Solvents were evaporated and 25 ml of water was added. The solution was washed with ethyl ether (2×10 ml). The aqueous phase was neutralized by the addition of 4 ml of 1.0 N hydrochloric acid. The milky mixture was extracted with two 25 ml portions of ethyl acetate. The organic layer was washed with brine. The organic extracts were dried over sodium sulfate, filtered and evaporated to give 350 mg of yellow solid which was stirred in 25 ml of ethyl ether. The solid was filtered and washed with cold ethyl ether to produce 310 mg of the carboxylic acid as a yellow solid 1-(3-Butoxy-benzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1C1CCCCC=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29](B(O)O)[CH:28]=1>>[C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:29]1[CH:28]=[N:27][C:36]2[C:31]([CH:30]=1)=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2ccccc2c(C2=CCCCC2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: OB(O)c1cnc2ccccc2c1
Product: Cc1cc2ccccc2c(-c2cnc3ccccc3c2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-Butoxy-2-(3-methyl-1-(quinolin-3-yl)naphthalen-2-yl)acetic acid (16) was prepared following the procedure to make (S)-2-tert-butoxy-2-(1-cyclohexenyl-3-methylnaphthalen-2-yl)acetic acid of Example 6, using quinolin-3-ylboronic acid instead of cyclohexenylboronic acid. The compound is an atropisomer mixture. 1H-NMR: 400 MHz, (CD3OD) δ: 9.20-8.50 (m, 2H), 8.18 (m, 1H), 8.08 (m, 1H), 7.95 (m, 1H), 7.80 (m, 3H), 7.40 (t. 1H), 7.25 (t, 1H), 7.06 (m, 1H), 5.19 (s, 1H), 2.62 (d, 3H), 0.95, 0.86 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C26H26NO3: 400.48. found: 400.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:15][C:16]([NH:18][CH2:19][CH2:20]C1C2C=C(OC)C=CC=2NC=1)=[O:17]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([N:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:20][CH2:19][NH:18][C:16](=[O:17])[CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2[nH]cc(CCNC(C)=O)c2c1
Reactant: Brc1cccc(Nc2ccccc2)c1
Solvent: C1CCOC1
Product: CC(=O)NCCN(c1ccccc1)c1cccc(Br)c1

Procedure:
A solution of nitrile 4f (1.16 mmol), prepared according to the method previously described for the preparation of 4a, but starting with N-(3-bromophenyl)-aniline (3f) [yield (4f): 37%; oil; 1H-NMR (CDCl3): δ 4.50 (s, 2H), 6.87 (m, 1H), 7.08-7.46 (m, 8H)] in dry THF (6 mL), was hydrogenated according to the procedure previously described for the preparation of 5a to provide the title compound 5f. The crude product was purified by flash-chromatography on silica gel (dichloromethane/acetone, 95:5 as eluent). Yield (5f): 20%; 1H-NMR (CDCl3): δ 1.90 (s, 3H), 3.48 (m, 2H), 3.85 (m, 2H), 6.03 (brs, 1H), 6.81-7.41 (m, 9H).
Reaction SMILES: [C:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:9]2[N:13]=[CH:12][N:11]([CH2:14][CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[N:10]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][N:38]2[C:46](=[O:47])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]2=[O:48])=[CH:32][CH:31]=1>>[OH:8][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[N:13]=[CH:12][N:11]([CH2:14][CH:15]2[CH2:16][CH2:17][N:18]([CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([CH2:36][CH2:37][N:38]4[C:46](=[O:47])[C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[C:39]4=[O:48])=[CH:34][CH:35]=3)[CH2:19][CH2:20]2)[N:10]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1ccc(CCBr)cc1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ncn(CC2CCNCC2)n1
Product: O=C1c2ccccc2C(=O)N1CCc1ccc(CCN2CCC(Cn3cnc(C(O)(c4ccccc4)c4ccccc4)n3)CC2)cc1
Yield: 71 %

Procedure:
The title compound was prepared from diphenyl[1-(piperidin-4-ylmethyl)-1H-1,2,4-triazol-3-yl]methanol (Preparation 26, 778 mg, 2.23 mmol) and 2-{2-[4-(2-bromoethyl)phenyl]ethyl}-1H-isoindole-1,3(2H)-dione (Preparation 11, 800 mg, 2.23 mmol) using the same method as described in preparation 12, to give a white solid, in 71% yield, 1.00 g.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.C[O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26]Br)[CH:21]=1>>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:26][C:22]2[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=2)[C:19]([OH:28])=[O:18])=[CH:3][CH:4]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(O)cc1
Reactant: COC(=O)c1cccc(CBr)c1
Product: O=C(O)c1cccc(COc2ccc(-c3ccccc3[N+](=O)[O-])cc2)c1

Procedure:
3-(2′-Nitro-biphenyl-4-yloxymethyl)-benzoic acid was prepared using general procedure A from 4-hydroxy-2′-nitrobiphenyl (available from TCI America, Portland, Oreg.) and 3-(bromomethyl)benzoic acid methyl ester (available from Lancaster Synthesis Ltd., Morcambe, Lancashire, UK). Yield: 82 mg. Mass spectrum (ES) MH+=350.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[N:8]2[N:9]=[C:10]([CH2:12][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:11]=[C:7]2[C:6]([CH3:32])=[N:5][CH:4]=1.[CH2:33]([N:35]1[C:39]([CH:40]=O)=[N:38][C:37]([N:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)=[N:36]1)[CH3:34].N12CCCN=C1CCCCC2>O1CCCC1>[CH2:33]([N:35]1[C:39]([CH:40]=[CH:12][C:10]2[N:11]=[C:7]3[C:6]([CH3:32])=[N:5][CH:4]=[C:3]([CH3:2])[N:8]3[N:9]=2)=[N:38][C:37]([N:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)=[N:36]1)[CH3:34]
Reactant: Cc1ncc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Reactant: CCn1nc(N2CCCC2)nc1C=O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1nc(N2CCCC2)nc1C=Cc1nc2c(C)ncc(C)n2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.2 %

Procedure:
A mixture of ((5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)triphenylphosphonium chloride (125 mg, 272 μmol, Eq: 1.00), 1-ethyl-3-(pyrrolidin-1-yl)-1H-1,2,4-triazole-5-carbaldehyde (52.9 mg, 272 μmol, Eq: 1.00) and 1,8-diazabicyclo[5.4.0]undec-7-ene (104 mg, 103 μl, 681 μmol, Eq: 2.5) in tetrahydrofuran (6 ml) was stirred for 18 hours at 25° C. under nitrogen atmosphere. The crude material was applied on silicagel and purified by flash chromatography over a 50 g silicagel column using ethyl acetate methanol 0-10% as eluent affording 2-[2-(2-ethyl-5-pyrrolidin-1-yl-2H-[1,2,4]triazol-3-yl)-vinyl]-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (37 mg/40.1%) as a bright yellow viscous oil. MS: m/e=339.5 (M+H+)
Reaction SMILES: [NH2:1][C:2]([CH3:32])([CH3:31])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([N:13]2[CH2:18][CH2:17][C@:16]([CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:15][C:14]2=[O:30])[CH3:12])=[CH:7][CH:6]=1.[CH3:33][N:34]=[C:35]=[O:36]>>[OH:29][C:26]([CH3:27])([CH3:28])[CH2:25][C@@:16]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:15][C:14](=[O:30])[N:13]([C@H:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]#[C:3][C:2]([NH:1][C:35]([NH:34][CH3:33])=[O:36])([CH3:31])[CH3:32])=[CH:6][CH:7]=2)[CH3:12])[CH2:18][CH2:17]1
Reactant: C[C@@H](c1ccc(C#CC(C)(C)N)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CN=C=O
Product: CNC(=O)NC(C)(C)C#Cc1ccc([C@H](C)N2CC[C@](CC(C)(C)O)(c3ccccc3)OC2=O)cc1

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 15 using (S)-3-((S)-1-(4-(3-amino-3-methylbut-1-ynyl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one and methyl isocyanate. LC-MS Method 1 tR=1.45 min, m/z=492, 434; 1H NMR (CDCl3) 1.13 (s, 3H), 1.19 (s, 3H), 1.49 (d, 3H), 1.64 (s, 6H), 2.10-2.50 (5H), 2.81 (m, 1H), 2.82 (s, 3H), 5.66 (q, 1H), 6.88 (d, 2H), 7.17 (d, 2H), 7.30-7.40 (5H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:10]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[CH:21]=[CH:22][O:23][CH2:24][CH3:25])CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:24]([O:23]/[CH:22]=[CH:21]/[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:10]=2)[CH:7]=1)[CH3:25]
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Reactant: CCOC(=O)c1cnc2ccc(Br)cn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCO/C=C/c1ccc2ncc(C(=O)OCC)n2c1
Temperature: 25 °C

Procedure:
To a stirring mixture of ethyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate (24s) (1 g, 3.72 mmol) and tetrakis(triphenylphosphine)palladium(0) (215 mg, 0.19 mmol) in anhydrous toluene (10 mL) under argon was added tributyl[2-ethoxyethenyl]stannane (1.7 g, 4.65 mmol). The reaction mixture was heated in a microwave sealed tube overnight at 90° C. The reaction was cooled to room temperature and was filtered through celite. The solvent was concentrated and the crude product was purified by silica chromatography to afford (E)-ethyl 6-(2-ethoxyvinyl)imidazo[1,2-a]pyridine-3-carboxylate (111). MS m/z 261.3 (M+1)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=O.[C:7]1([NH2:14])[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[NH2:1][CH2:5][CH2:4][CH2:3][C:2]1[NH:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:14]=1
Reactant: Nc1ccccc1N
Reactant: O=C1CCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: NCCCc1nc2ccccc2[nH]1

Procedure:
A mixture of 2-pyrrolidone (42.5 g; 0.5 mole) and o-phenylenediamine (54 g; 0.5 mole) was heated with p-toluenesulfonic acid (4.3 g) at 195°-207° for 6 hrs. while removing water (8.5 g) by distillation. A virtually quantitative yield of 2-(3-aminopropyl)benzimidazole was obtained.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([O:21][CH3:22])=[CH:13][C:14]=3[O:19][CH3:20])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.Cl.[CH3:24][S:25]([CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:27])=[O:26].CN(C)C(N(C)C)=N>CS(C)=O.C(OCC)(=O)C>[CH3:20][O:19][C:14]1[CH:13]=[C:12]([O:21][CH3:22])[CH:11]=[C:10]2[C:15]=1[C:16](=[O:18])[NH:17][C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([N:33]3[CH2:32][CH2:31][N:30]([CH2:29][CH2:28][S:25]([CH3:24])(=[O:26])=[O:27])[CH2:35][CH2:34]3)[N:7]=1)=[N:9]2
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(F)n3)nc2c1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(N4CCN(CCS(C)(=O)=O)CC4)n3)nc2c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 38.2 %

Procedure:
To a solution of 2-(6-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.200 g, 0.664 mmol) in DMSO (1.5 mL) under nitrogen was added 1-[2-(methylsulfonyl)ethyl]piperazine hydrochloride (0.265 g, 0.996 mmol) and 1,1,3,3-tetramethylguanidine. The reaction was stirred at 80° C. for 18 h. After that time the reaction was cooled to rt, diluted with ethyl acetate (50 mL), washed with water (2×20 mL), brine, dried over Na2SO4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 95:5 dichloromethane/methanol) to give 5,7-dimethoxy-2-(6-(4-(2-(methylsulfonyl)ethyl)piperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one (0.120 g, 38%) as a yellow solid: mp 243-244° C.; 1H NMR (400 MHz, CDCl3): δ 10.28 (br s, 1H), 7.88 (d, J=7.3 Hz, 1H), 7.73-7.66 (m, 1H), 6.87-6.81 (m, 2H), 6.49 (d, J=2.2 Hz, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 3.69-3.61 (m, 4H), 3.23 (t, J=6.4 Hz, 2H), 3.09 (s, 3H), 2.98 (t, J=6.4 Hz, 2H), 2.72-2.64 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].CCN(C(C)C)C(C)C.C1CCC(N=C=NC2CCCCC2)CC1.[C:48]([O:52][C:53](=[O:60])[CH2:54][CH2:55][CH2:56][C:57](O)=[O:58])([CH3:51])([CH3:50])[CH3:49]>C(#N)C.CN(C1C=CN=CC=1)C.C(O)(C(F)(F)F)=O>[CH3:23][O:22][C:10]1[CH:9]=[CH:8][C:7]2[CH2:20][C@H:19]3[N:2]([CH3:1])[CH2:3][CH2:4][C@:5]45[C:6]=2[C:11]=1[O:12][C@H:13]4[C:14]([O:15][C:57](=[O:58])[CH2:56][CH2:55][CH2:54][C:53]([O:52][C:48]([CH3:50])([CH3:49])[CH3:51])=[O:60])=[CH:16][CH2:17][C@@:18]35[OH:21]
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Reactant: CC(C)(C)OC(=O)CCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1ccc2c3c1O[C@H]1C(OC(=O)CCCC(=O)OC(C)(C)C)=CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.3 %

Procedure:
A suspension of oxycodone free base (100 mg, 0.317 mmol) in 1.5 mL of anhydrous acetonitrile was stirred for 20 min with DIEA (0.2 mL 1.15 mmol). DMAP (63 mg, 0.516 mmol) and DCC (112 mg, 0.545 mmol) were then added to the stirred suspension. After 5 min 1-2 (150 mg, 0.8 mmol) was added, the mixture stirred for 16 h at rt, and the resulting orange suspension concentrated to an oil under reduced pressure. The concentrated mixture was stirred with 6 mL of acetone for 10 min, and the precipitated DCU removed by filtration. The filtrate was concentrated to give a brown oil. HPLC analysis of the oil indicated that the primary reaction product was 1-3. The concentrated oil was subjected to reverse phase C-18 silica gel chromatography using a gradient of 25–40% acetonitrile in 0.07% aqueous TFA as eluent. Evaporation of the eluent from the fraction containing 1-3 gave 82 mg (53% yield) of a colorless oil which was greater than >99% pure 1-3 (HPLC).
Reaction SMILES: [CH3:1][NH2:2].C(O)C.Br[CH2:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:9]=1[C:10](OC)=[O:11]>C1COCC1>[CH3:1][N:2]1[CH2:7][C:8]2[C:9](=[C:14]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:16][CH:17]=2)[C:10]1=[O:11]
Reactant: CN
Reactant: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Solvent: CCO
Solvent: C1CCOC1
Product: CN1Cc2cccc([N+](=O)[O-])c2C1=O
Reaction time: 2 h
Yield: 78 %

Procedure:
A solution of methylamine in ethanol (10 mL, 80 mmol, 8M solution in ethanol) was added to a solution of methyl 2-(bromomethyl)-6-nitrobenzoate (8.1 g, 29.6 mmol) in THF (30 mL). After stirring for 2 h the reaction mixture was concentrated to dryness and water (30 mL) was added with rapid stirring. The solids produced were isolated by filtration and dried to give 4.35 g of 2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one (XXXVII, yield: 78%).