Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.[C:16]1([CH:22]2[CH2:26][CH2:25][NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:24]1[CH2:25][CH2:26][CH:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:23]1)=[O:15]
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Reactant: c1ccc(C2CCNC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cnoc1-c1ccccc1Cl)N1CCC(c2ccccc2)C1
Temperature: 25 °C

Procedure:
5-(2-chlorophenyl)-isoxazole-4-carboxylic acid (51.6 mg, 0.231 mmol), 3-phenylpyrrolidine (40 mg, 0.271 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (92.6 mg, 0.288 mmol) and diisopropylethylamine (49.7 mg, 0.384 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature over night. Solvent was evaporated in vacuo (0.5-1.0 mL) and the residue was taken up in dichloromethane (1 mL), filtered and purified by normal-phase chromatography (20-50% EtOAc:petroleum ether). The combined fractions were partitioned between H2O/Acetic acid (pH 4) and ethyl acetate. The organic fractions were washed with H2O/brine and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C20H17ClN2O2: 352.0979, found 352.0980.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C:10](=[CH2:13])[C:9]2=[O:14])=[CH:4][CH:3]=1.[CH3:15][O:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:22]3[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][O:16][CH3:15])[CH2:20][CH2:21]3)[C:9]2=[O:14])=[CH:4][CH:3]=1
Reactant: C=C1CCN(c2ccc(Cl)cc2)C1=O
Reactant: COCCN1CCNCC1
Solvent: CC#N
Product: COCCN1CCN(CC2CCN(c3ccc(Cl)cc3)C2=O)CC1
Yield: 76.4 %

Procedure:
0.85 g of 1-(4-chlorophenyl)-3-methylene-2-pyrrolidinone and 0.71 g of 4-(2-methoxyethyl)piperazine were mixed with 3 ml of acetonitrile. The mixture was refluxed for 3.5 hours. The reaction mixture was concentrated to dryness. The residue was purified by silica gel column chromatography using a mixed solvent (chloroform/methanol=20/1) to obtain 1.1 g of 1-(4-chlorophenyl)-3-[4-(2-methoxyethyl)piperazine-1-yl]methyl-2-pyrrolidinone.
Reaction SMILES: COC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC(OC)=O)C=CC=1OC.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:41]=[CH:42][C:43]=1[O:44][CH3:45])[C:32]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)=O.C(OP([CH2:54][C:55]#[N:56])(=O)OCC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:32]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[CH:54][C:55]#[N:56])[CH:41]=[CH:42][C:43]=1[O:44][CH3:45]
Reactant: COc1ccc(C(=O)c2ccc(F)cc2)cc1OC
Reactant: CCOP(=O)(CC#N)OCC
Agent: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COc1ccc(C(=CC#N)c2ccc(F)cc2)cc1OC

Procedure:
3-(3,4-Dimethoxyphenyl)-3-(4'-fluorophenyl)acrylonitrile was prepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3,4-dimethoxy-4'-fluorobenzophenone (1.3 g, 5 mmol), diethylcyanomethylphosphonate (0.91 mL, 5.5 mmol) and lithium hexamethyldisilazide (5.5 mL, 5.5 mmol, 1M) with a reaction time of 22 hours at room temperature. The crude product was purified by chromatography (silica gel, 1% ethyl acetate/methylene chloride) to afford 2.38 g (55%) of a mixture of the E and Z isomers as a white solid: mp 100-102° C.; 1H NMR (CDCl3) δ 7.54-6.74 (m, 14 H), 5.67 (s, 1 H), 5.57 (s, 1 H), 3.94 (s, 3 H), 3.92 (s, 3 H), 3.87 (s, 3 H), 3.83 (s, 3 H), 13C NMR (CDCl3) δ 166.0, 165.6, 162.0, 161.6, 151.3, 150.7, 148.9, 148.7, 135.4, 135.4, 133.2, 133.1, 131.7, 131.6, 131.3, 130.7, 130.5, 129.2, 123.1, 122.1, 118.1, 118.0, 115.8, 115.8, 115.5, 115.4, 112.6, 111.0, 110.8, 93.4, 93.2, 56.0, 56.0, 55.9; Anal. Calcd for C17H14FNO2. Theoretical: C, 72.07; H, 4.98; N, 4.94. Found: C, 71.91; H, 4.98; N, 4.79.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1C(=O)C2=CC=CC=C2C1=O.C(Cl)(Cl)Cl>C(O)C.O.NN>[Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH2:10]
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(I)cc1Cl
Agent: NN
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCO
Product: NCc1ccc(I)cc1Cl
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 143.5 %

Procedure:
In a solution of 2.9 g of N-[(2-chloro-4-iodophenyl)methyl]phthalimide in 60 mL of ethanol, 3.0 mL of 80% hydrazine monohydrate aqueous solution was added, and stirred at 70° C. for 30 minutes. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, 100 mL of chloroform was added therein and insoluble substance was filtered off, and the solvent was distilled off under reduced pressure. The procedure comprising adding 30 mL of chloroform in the residue, filtering off insoluble material and distilling off the solvent under reduced pressure was repeated twice to obtain 2.8 g of the aimed product as yellow oily substance.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1.[C-:14]#[N:15].[Na+]>CN(C=O)C.O>[N:13]1[C:12]2[NH:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:3][CH2:2][C:14]#[N:15]
Reactant: ClCCc1ccc2c(n1)NCCC2
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCc1ccc2c(n1)NCCC2
Temperature: 85 °C
Yield: 21 %

Procedure:
7-(2-chloroethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (500 mg) and NaCN (150 mg) were dissolved in DMF (in 15 mL) and the mixture was heated at 85° C. for 6 hrs. Cooled to 25° C. and the reaction was diluted with H2O, extracted with CHCl3, and the solution was washed with H2O, dried with MgSO4. The solution was concentrated to a yellow oil. Column purification (Ethyl acetate: Hexane=1:1) to yield a yellow solid 100 mg (8.9%). 1H NMR (DMSO-d6) δ 7.06 (d, 1H), 6.45 (m, 2H), 3.33 (1, 2H), 2.75 (m, 4H), 2.63 (t, 2H), 1.75 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>CN(C)C(=O)C>[C:12]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH2:1])=[N:3][C:4]=2[Cl:11])(=[O:14])[CH3:13]
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(=O)n1cnc2c(Cl)nc(N)nc21
Temperature: 55 °C
Reaction time: 4 h
Yield: 99.3 %

Procedure:
2-Amino-6-chloropurine (150 g, 0.89 mol) and acetic anhydride (108 g, 1.06 mol) were added to N,N-dimethylacetamide (350 ml), and the mixture was heated to 50-60° C. and stirred for 4 hr. The reaction mixture was cooled and filtrated. The obtained crystals were washed with isopropanol (400 ml) and dried at 80° C. under reduced pressure to give 9-acetyl-2-amino-6-chloropurine as a pale-yellow powder (187 g, yield 99.0%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]2[CH2:7][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][C:3]=12.CC[O-].[Na+].CO[CH:23](OC)[CH2:24][C:25](=O)[CH3:26]>C(O)C>[CH3:26][C:25]1[CH:24]=[CH:23][N:6]2[N:5]=[C:4]3[CH2:7][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][C:3]3=[C:2]2[N:1]=1.[CH3:26][C:25]1[N:6]2[N:5]=[C:4]3[CH2:7][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][C:3]3=[C:2]2[N:1]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1Cc2n[nH]c(N)c2C1
Reactant: COC(CC(C)=O)OC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccn2nc3c(c2n1)CN(C(=O)OC(C)(C)C)C3
Product: Cc1ccnc2c3c(nn12)CN(C(=O)OC(C)(C)C)C3
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 448 mg (2 mmol) of the product from Step A and 80 □L (1 mmol) of NaOEt (21 wt % in ethanol), in 10 mL of anhydrous ethanol, was added 297 □L (2.4 mmol) of 4,4-dimethoxy-2-butanone. The reaction mixture was stirred at ambient temperature for 10 min, then refluxed for 16 h. The mixture was cooled to ambient temperature and the solvent evaporated in vacuo to afford the title compound as an 8:1 mixture with tert-butyl 4-methyl-7H-pyrrolo[3′,4′:3,4]pyrazolo[1,5-a]pyrimidine-8(9H)-carboxylate and was used without purification. LC/MS 275.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.IC.[C:25](=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH3:25]
Reactant: O=C([O-])O
Reactant: Cc1cccc(-n2[nH]c3c(c2=O)[C@H]2CC[C@]3(C)C2(C)C)c1C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cccc(-n2c(=O)c3c(n2C)[C@]2(C)CC[C@H]3C2(C)C)c1C
Temperature: 105 °C
Reaction time: 1.5 h
Yield: 49 %

Procedure:
A mixture of (4S,7R)-2-(2,3-dimethyl-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 16; 4.07 g, 13.8 mmol) and iodomethane (1.5 mL, 24.1 mmol) in N,N-dimethylformamide (60 mL) in a sealed tube was heated to 105° C. and stirred for 1.5 h. The reaction mixture was allowed to cool and saturated sodium bicarbonate solution (200 mL) was added. A solid precipitated. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with brine (300 mL), concentrated and purified by chromatography, eluting with 60-100% ethyl acetate/dichloromethane. Fractions containing the product were combined, evaporated, and recrystallized from ethyl acetate/hexanes to give (4S,7R)-2-(2,3-dimethyl-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (2.12 g 49%) as a white solid. ES(+)-MS (M+H) 311.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[C:25](O)(=[O:30])/[C:26](=[CH:28]/[CH3:29])/[CH3:27].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:25]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)(=[O:30])/[C:26](=[CH:28]/[CH3:29])/[CH3:27]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: C/C=C(\C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C/C=C(\C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Yield: 98.9 %

Procedure:
The same procedures as in Example 146 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), tiglic acid (1.4 g), WSC.HCl (2.7 g), and methylene chloride (80 mL), to give the captioned compound (3.5 g, 99%) as an oily product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl.[C:49]1([CH:55]([OH:59])[CH2:56][CH2:57][CH3:58])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38](=[O:40])[O:59][CH:55]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:56][CH2:57][CH3:58])=[CH:18][CH:17]=1
Reactant: CCCC(O)c1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCC(OC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1)c1ccccc1
Temperature: 25 °C
Yield: 62.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (78 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepared a solution. A solution of triphosgene (118 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 1-phenyl-1-butanol (59 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (78 mg, yield 58%).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]1[C:14](=[O:26])[C@@H:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH3:17])=O.[CH3:27][S:28][CH2:29][CH2:30][NH2:31].ClCCl>CO.C(OCC)C>[CH3:27][S:28][CH2:29][CH2:30][NH:31][C:3]([C@@H:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]1[C:14](=[O:26])[C@@H:15]([NH:18][C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:16][CH3:17])=[O:2]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccccc2C[C@H]1C(=O)OC
Reactant: CSCCN
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccccc2C[C@H]1C(=O)NCCSC
Temperature: 60 °C
Reaction time: 48 h

Procedure:
To a solution of 1-(N-t-butoxycarbonyl-2(S)-aminobutyryl)-indoline-2(S)-carboxylic acid methyl ester (0.5 g, 1.4 mmol) in methanol (2 ml), was added 2-methylthioethylamine (3 ml) under nitrogen, and the resulting solution was stirred at 60° C. for 48 hours. The solution was poured into dichloromethane (20 ml), and washed with 1M potassium hydrogen sulphate, the aqueous layer was extracted with dichloromethane (3×15 ml). The combined organic layers were dried over Na2SO4, and then the solvent was evaporated. A white solid was obtained after column chromatography on silica gel using diethyl ether as eluent.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH3:14][C@@H:15]1[NH:20][CH2:19][CH2:18][N:17]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:16]1=[O:30]>C(#N)C>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:20]2[CH2:19][CH2:18][N:17]([CH2:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)[C:16](=[O:30])[C@@H:15]2[CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: C[C@@H]1NCCN(CCCN2CCCCC2)C1=O
Solvent: CC#N
Product: C[C@H]1C(=O)N(CCCN2CCCCC2)CCN1C(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 60 °C
Yield: 83 %

Procedure:
3-(Trifluoromethyl)phenyl isocyanate (30 mg, 0.15 mmol) was added to a solution of (S)-3-methyl-1-(3-piperidin-1-yl-propyl)-piperazin-2-one (intermediate 20; 30 mg, 0.13 mmol) in acetonitrile (1 ml). The solution was heated at 60° C. for 15 min under microwave irradiation, then evaporated. Chromatography (SiO2; dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) produced the title compound (46 mg, 86%). Colorless gum, MS (ISP)=427.3 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:16]CC[CH2:13]2)=[NH:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:17][S:18](Cl)(=[O:20])=[O:19]>>[CH3:13][N:12]([CH3:16])[C:10](=[N:11][S:18]([CH3:17])(=[O:20])=[O:19])[C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: N=C(c1ccc([N+](=O)[O-])cc1)N1CCCC1
Reactant: CS(=O)(=O)Cl
Product: CN(C)C(=NS(C)(=O)=O)c1ccc([N+](=O)[O-])cc1

Procedure:
Part B: According to the procedure described Example 57, part C, 1.14 g (5.9 mmol) of (4-nitrophenyl)(pyrrolidin-1-yl)methanimine were reacted with methane sulfonyl chloride to yield N,N-dimethyl-N′-(methylsulfonyl)-4-nitrobenzamidine (890 mg).
Reaction SMILES: CO[C:3](=O)[N:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15]3[CH:16]=[C:17]([F:27])[CH:18]=[C:19]4[C:25](=[O:26])[NH:24][CH2:23][CH2:22][C:21]=2[C:20]=34)=[CH:9][CH:8]=1)C.C(CN)O.[OH-].[Na+]>Br.C(O)(=O)C>[F:27][C:17]1[CH:18]=[C:19]2[C:25](=[O:26])[NH:24][CH2:23][CH2:22][C:21]3=[C:13]([C:10]4[CH:9]=[CH:8][C:7]([CH2:6][NH:4][CH3:3])=[CH:12][CH:11]=4)[NH:14][C:15]([CH:16]=1)=[C:20]23
Reactant: COC(=O)N(C)Cc1ccc(-c2[nH]c3cc(F)cc4c3c2CCNC4=O)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: NCCO
Solvent: CC(=O)O
Product: CNCc1ccc(-c2[nH]c3cc(F)cc4c3c2CCNC4=O)cc1
Temperature: 25 °C
Reaction time: 46 h
Yield: 87.6 %

Procedure:
Lactam 14 (14.42 g, 0.038 mol) was dissolved in hydrobromic acid in acetic acid (30%-32%, 140 ml). The reaction solution was stirred for 46 hours at room temperature in a 500 ml flask that was connected to an ethanolamine scrubber system. HPLC analysis indicated the completion of the reaction. Ice (30 g) was added to the reaction solution followed by addition of aqueous NaOH (327 ml, 10 M, 3.27 mol) while the temperature was maintained between 25° C. and 35° C. When addition of NaOH was complete, the pH was 10. The resulting solid was collected by filtration, washed with water (2×50 ml). The filter cake was then suspended in water (125 ml) and stirred for 2 hours. The solid was collected by filtration, washed with water (2×25 ml) and dried to afford 10.76 g of product (88% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.577 (s, 3H), 3.053 (m, 2H), 3.406 (m, 2H), 4.159 (s, 2H), 7.36 (dd, 1H, J=2.4 Hz and J=9.3 Hz), 7.44 (dd, 1H, J=2.4 Hz and J=11.1 Hz), 7.63 (d, 2H, J=8.1 Hz), 7.70 (d, 2H, J=8.1 Hz), 8.265 (t, 1H, J=5.7 Hz), 11.77 (s, 1H). Exact mass calculated for C19H19FN3O: 324.1512. Found: 324.1497.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:24]2[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=2)[C:27]([O:29]C)=O)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)=[N:6]2.[NH4+:34]>CO>[CH3:1][C:2]1[N:3]=[C:4]([C:24]2[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=2)[C:27]([NH2:34])=[O:29])[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH:11][C:12]1[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=1)=[N:6]2
Reactant: COC(=O)c1cccc(-c2nc(C)c3cnc(Nc4cc(OC)c(OC)c(OC)c4)nn23)c1
Reactant: [NH4+]
Solvent: CO
Product: COc1cc(Nc2ncc3c(C)nc(-c4cccc(C(N)=O)c4)n3n2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
To methyl 3-{5-methyl-2-[(3,4,5-trimethoxyphenyl)amino]imidazo[5,1-f][1,2,4]triazin-7-yl}benzoate (Example 12) (0.020 g, 0.044 mmol) was added 7N ammonium in methanol (5 mL). The solution was heated in a sealed tube for 18 hours. After cooling to room temperature, the volatiles were removed under reduced pressure to give 3-{5-methyl-2-[(3,4,5-trimethoxyphenyl)amino]imidazo[5,1-f][1,2,4]triazin-7-yl}benzamide (0.015 g) as a yellow solid. 1H NMR (CDCl3): δ9.41 (s, 1H), 9.16 (s, 1H), 8.73 (d, J=7.3 Hz, 1H), 8.27 (d, J=7.6 Hz, 1H), 8.23-8.17 (m, 1H), 7.75-7.59 (m, 3H) 7.26 (s, 2H), 3.98 (s, 3H), 3.92 (s, 3H), 3.72 (s, 3H), 2.71 (s, 3H). MS m/z 435 (M+1).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10](CCCCO)[O:9]N=2)C=CC=C[CH:2]=1.[OH:17][N:18]=[C:19](Cl)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)CCC#C>>[C:21]1([CH2:20][C:19]2[CH:2]=[C:1]([CH2:7][CH2:11][CH2:10][OH:9])[O:17][N:18]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ON=C(Cl)Cc1ccccc1
Reactant: OCCCCc1cc(-c2ccccc2)no1
Agent: C#CCCCO
Product: OCCCc1cc(Cc2ccccc2)no1

Procedure:
Synthesised as with 4-(3-phenyl-5-isoxazolyl)-1-butanol, using N-hydroxy-2-phenylethanimidoyl chloride (253 mg, 1.5 mmol) and 4-pentyn-1-ol (139 mg, 1.65 mmol). Yield 61 mg of pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH:63]([C@@H:76]1[CH2:80][CH2:79][CH2:78][NH:77]1)([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>CS(C)=O>[CH:63]([C@@H:76]1[CH2:80][CH2:79][CH2:78][N:77]1[C:12]([C:11]1[CH:10]=[C:9]2[C:4]([C:5]([NH:15][CH:16]([C:18]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=4[N:19]=3)[CH3:17])=[N:6][CH:7]=[N:8]2)=[CH:3][C:2]=1[Cl:1])=[O:13])([C:70]1[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=1)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: c1ccc(C(c2ccccc2)[C@@H]2CCCN2)cc1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCC[C@H]3C(c3ccccc3)c3ccccc3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (S)-2-benzhydryl-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: [Br:1][C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:12].Cl.[CH3:14]O>>[Br:1][C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[CH:4][C:3]=1[OH:12]
Reactant: CO
Reactant: O=C(O)c1cc(O)c(Br)c(O)c1
Agent: Cl
Product: COC(=O)c1cc(O)c(Br)c(O)c1

Procedure:
In a 2.0-liter egg plant-type flask, a hydrochloric acid/methanol solution (500 mL) of 4-bromo-3,5-dihydroxybenzoic acid (50 g, 0.21 mol) was stirred with heating under reflux for 6 hours. Methanol was removed under reduced pressure to obtain a crude crystal. This was washed with hexane and chloroform to obtain the title compound as a colorless solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[C:19]2[C:14](=[CH:15][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=4)[CH2:23][CH2:22]3)=[CH:17][CH:18]=2)[CH:13]=[CH:12]1>>[CH3:36][CH:35]([CH3:37])[C:34]([NH:33][C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([CH:24]2[CH2:23][CH2:22][N:21]([CH2:20][C:16]3[CH:15]=[C:14]4[C:19](=[CH:18][CH:17]=3)[N:11]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N+:8]([O-:10])=[O:9])[CH:12]=[CH:13]4)[CH2:26][CH2:25]2)[CH:28]=1)=[O:38]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Reactant: O=[N+]([O-])c1ccccc1I
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4c(ccn4-c4ccccc4[N+](=O)[O-])c3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-2-nitrobenzene and N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 497.2 (M+H)+.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[OH:10])[CH:3]=[CH:2]1.[Br:11]Br>C(O)(=O)C>[Br:11][C:7]1[C:8]([OH:10])=[C:9]2[S:1][CH:2]=[CH:3][C:4]2=[N:5][CH:6]=1
Reactant: Oc1ccnc2ccsc12
Reactant: BrBr
Solvent: CC(=O)O
Product: Oc1c(Br)cnc2ccsc12
Temperature: 110 °C
Yield: 115.2 %

Procedure:
To a solution of thieno[3,2-b]pyridin-7-ol (1, 2.55 g, 16.87 mmol) in acetic acid (50 mL) was added bromine (1.7 mL, 32.72 mmol). The mixture was heated at 110° C. for 1 h, cooled and the resultant precipitate was separated by filtration, to afford the title compound 270 (4.47 g, crude) as a dark brown powder, which was used in next step without further purification. M/S (m/z): 231.9 (M+H) (found).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:9][C:10]1([C:15](O)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:27]([O:29][C:30](=[O:37])[C@H:31]([CH2:33][CH2:34][S:35][CH3:36])[NH2:32])[CH3:28].C(N(CC)CC)C.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH2:27]([O:29][C:30](=[O:37])[C@H:31]([CH2:33][CH2:34][S:35][CH3:36])[NH:32][C:15]([C:10]1([CH2:9][CH:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:16])[CH3:28]
Reactant: CCOC(=O)[C@@H](N)CCSC
Reactant: CC(C)(C)OC(=O)C(CCc1ccccc1)CC1(C(=O)O)CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](CCSC)NC(=O)C1(CC(CCc2ccccc2)C(=O)OC(C)(C)C)CCCC1
Reaction time: 18 h

Procedure:
Combine the product of Step 1 (1.50 g, 4.33 mmol) with (S)-methionine ethyl ester hydrochloride (0.92 g, 4.33 mmol), triethylamine (0.65 g, 6.5 mmol), hydroxybenzotriazole (HOBT) (0.66 g, 4.33 mmol), and 1-(3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (DEC) (0.91 g, 4.8 mmol) in 25 ml dimethylformamide (DMF). Stir 18 h., partition between EtOAc-H20, wash with 1N NaHCO3 and concentrate. Chromatograph the resultant residue on silica, eluting with hexane-ether 1:1 to obtain an oil, [α]D26 =-17.4° (EtOH).