Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:7]=1.[CH:24]([Sn](CCCC)(CCCC)CCCC)=[CH2:25].N#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH:24]([C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:7]=1)=[CH2:25]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=[N+]([O-])c1ccc(Br)cc1NC1CCN(C2CCOCC2)CC1
Agent: [Pd]
Agent: N#N
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc([N+](=O)[O-])c(NC2CCN(C3CCOCC3)CC2)c1
Temperature: 130 °C
Yield: 67 %

Procedure:
To a mixture of N-(5-bromo-2-nitrophenyl)-1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine D24 (1.8 g, 0.0047 mol) and vinyl tri(n-butyl)tin (1.58 mL, 0.0054 mol) in toluene (70 mL) was added, under a positive flow of N2, triphenyl phosphine (0.295 g, 1.125 mmol) and bis(dibenzylidene acetone)palladium (0) (0.338 g, 0.675 mmol). The mixture was put under a N2 atmosphere and heated at 130° C. for 1.5 hours (LC/MS was used to monitor the reaction). After the reaction was completed the reaction mixture was cooled to room temperature, filtered through a celite pad, and washed with dichloromethane. The filtrate was washed with 10% of aqueous NH4OH solution (3×50 mL), H2O (3×50 mL), and dried with Na2SO4, and concentrated in vacuo. The resulting residue was redissolved in acetonitrile. 416 mg of the title compound was crystallized out and the resulted solution was purified by using a Gilson preparative HPLC system with a Waters Xterra (C-18) column 100 mm by 50 mm ID, eluting with 10% B to 90% B in 10 min, where A=H2O and B=CH3CN pumped at 150 mL/min to yield additional 578 mg of the title compound (overall 994 mg, 67% yield). MS (ESI): 332 [M+H]+; 1H NMR (400 MHz, CDCl3): δ 1.67 (6H, m), 2.11 (2H, d), 2.47 (3H, m), 2.90 (2H, m), 3.39 (2H, t), 3.61 (1H, m), 4.03 (2H, dd), 5.47 (1H, d), 5.88 (1H, d), 6.66 (1H, dd), 6.75 (2H, m), 8.14 (1H, d), 8.23 (1H, d).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([N:13]([CH:22]([CH3:24])[CH3:23])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[O:12])[C:6]2[CH:25]=[CH:26][CH:27]=[CH:28][C:5]=2[N:4](CC2C=CC(OC)=CC=2)[C:3]1=[O:38].[N+]([O-])([O-])=O.[NH4+]>C(#N)C.O>[NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([N:13]([CH:22]([CH3:24])[CH3:23])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[O:12])[C:6]2[CH:25]=[CH:26][CH:27]=[CH:28][C:5]=2[NH:4][C:3]1=[O:38]
Reactant: COc1ccc(CN2C(=O)C(N)C(=O)N(CC(=O)N(c3ccc(OC)cc3)C(C)C)c3ccccc32)cc1
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(N(C(=O)CN2C(=O)C(N)C(=O)Nc3ccccc32)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
To a stirred solution of 2-[3-Amino-5-(4-methoxybenzyl)-2,4-dioxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxyphenyl)-acetamide (2.63 g, 5.09 mmol) in acetonitrile/H2O (9:1, 70 mL) at ambient temperature was added cerric ammonium nitrate (10.05 g, 18.3 mmol) portionwise over one hour. The solution was stirred overnight at room temperature. The solution was concentrated in vacuo, chased with toluene (2×50 mL) and the residue was extracted with CH2Cl2 (3×50 mL), filtered and concentated to an orange glass. The crude product was purified by flash chromatography on silica gel (100 g) eluting successively with CH2 Cl2 /CH3OH (15:1, 1.5 L) and CH2Cl2 /CH3OH (10:1, 1.3 L). Appropriate fractions were combined and concentrated under reduced pressure to give the title compound (1.97 g, 4.97 mmol) as a brown foam: 1H NMR (300 MHz, DMSO-d6): d 10.68 (br s, 1H), 7.39-6.98 (m, 8H), 5.75 (s, 1H), 4.76 (m, 1H), 4.16-3.92 (m, 4H), 3.7 (s, 3H), 3.15 (m, 2H), 0.97 (m, 6H); TLC (CH2Cl2 /CH3OH (13:1)): Rf =0.21.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=2)[N:8]=1.[C:24]1([NH2:31])[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH2:30].CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl>C(#N)C>[NH2:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[NH:31][C:19](=[O:21])[C:18]1[CH:17]=[CH:16][C:15]([CH2:14][NH:13][C:9]2[N:8]=[C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)[CH:12]=[CH:11][N:10]=2)=[CH:23][CH:22]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)c1ccc(CNc2nccc(-c3cnccn3)n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1ccccc1NC(=O)c1ccc(CNc2nccc(-c3cnccn3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.8 %

Procedure:
To a solution of 25a (1 g, 3.3 mmol) in dry acetonitrile (35 mL) was added 1,2-phenylenediamine (0.88 g, 8.1 mmol) followed by Et3N (2.7 mL, 19.1 mmol), HOBt.H2O (803 mg, 5.9 mmol) and EDCI.HCl (1.89 g, 9.9 mmol). The mixture was stirred at room temperature for 16 h to form a suspension which was collected by filtration, washed successively with MeCN, water and again MeCN, triturated with MeOH, filtered and dried to afford the title compound 26a (730 mg, 1.84 mmol, 55% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.57 (s, 1H), 9.43 (s, 1H), 8.75 (d, J=4.8 Hz, 2H), 8.49 (d, J=5.2 Hz, 1H), 8.11 (t, J=5.2 Hz, 1H), 7.91 (d, J=8.4 Hz, 2H), 7.59-7.37 (m, 2H), 7.44 (d, J=5.2 Hz, 1H), 7.12 (d, J=7.6 Hz, 1H), 6.94 (td, J=7.6, 1.6 Hz, 1H), 6.75 (dd, J=8.0, 1.2 Hz, 1H), 6.57 (t, J=7.2 Hz, 1H), 4.86 (s, 2H), 4.66 (d, J=5.2 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][C:7]=1[Cl:15].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:43][CH2:44][C:45]1[C:46]([OH:53])=[N:47][C:48]([CH3:52])=[CH:49][C:50]=1[CH3:51]>O.ClCCl.C(N(CC)CC)C>[Br:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:43][CH2:44][C:45]2[C:46]([OH:53])=[N:47][C:48]([CH3:52])=[CH:49][C:50]=2[CH3:51])=[O:12])=[CH:8][C:7]=1[Cl:15]
Reactant: N#Cc1c(Br)cccc1Oc1ccc(C(=O)O)cc1Cl
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2ccc(Oc3cccc(Br)c3C#N)c(Cl)c2)c(O)n1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
A mixture of 4-(3-bromo-2-cyanophenoxy)-3-chlorobenzoic acid (1 g, 2.8 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.08 g, 5.7 mmol), N-hydroxybenzotriazole (769 mg, 5.7 mmol), triethylamine (0.1 mL) and dichloromethane (5 mL) was stirred at 25° C. for half an hour. And then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (430 mg, 2.8 mmol) was added. The mixture was stirred at 25° C. for 12 hours. To the mixture, water (10 mL) was added and the mixture was extracted with dichloromethane (10 mL×3). The combined organic phase was dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give 4-(3-bromo-2-cyanophenoxy)-3-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide as a white solid (1.1 g, 83%). LRMS (M+H+) m/z: calcd 485.01. found 485. 1H NMR (300 MHz, d6-DMSO): δ 11.44 (s, 1H), 8.52 (s, 1H), 8.12 (s, 1H), 7.90-7.87 (m, 1H), 7.61-7.52 (m, 2H), 7.37 (d, J=6.0 Hz, 1H), 6.86 (d, J=6.3 Hz, 1H), 5.82 (s, 1H), 4.25 (s, 2H), 2.45 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[NH:15][C:14]4[CH:16]=[CH:17][CH:18]=[C:19]([CH2:20][O:21][CH3:22])[C:13]=4[N:12]=3)=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:25][Si:26]([CH2:29][CH2:30][O:31][CH2:32]Cl)([CH3:28])[CH3:27]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:15]([CH2:32][O:31][CH2:30][CH2:29][Si:26]([CH3:28])([CH3:27])[CH3:25])[C:14]4[CH:16]=[CH:17][CH:18]=[C:19]([CH2:20][O:21][CH3:22])[C:13]=4[N:12]=3)=[N:9][N:8]([CH2:32][O:31][CH2:30][CH2:29][Si:26]([CH3:28])([CH3:27])[CH3:25])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COCc1cccc2[nH]c(-c3n[nH]c4ncc(Br)cc34)nc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1cccc2c1nc(-c1nn(COCC[Si](C)(C)C)c3ncc(Br)cc13)n2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-bromo-3-(4-methoxymethyl-1H-benzoimidazol-2-yl)-1H-pyrazolo[3,4-b]pyridine Compound 11 (1.2 g, 4.19 mmol) was dissolved in dry THF (20 mL). The solution was cooled to 0° C. before sodium hydride (0.37 g, 60% in mineral oil, 9.25 mmol) was added in portions. The suspension was stirred at 0° C. for additional 15 minutes before (trimethylsilyl)ethoxymethyl chloride (1.78 mL, 10.06 mmol) was added. The reaction was warmed to room temperature and stirred overnight. Solvent was removed and the residue was purified by silica gel chromatography (10% to 50% ethyl acetate in hexanes) to yield 5-bromo-3-[4-methoxymethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine Compound 12a (1.59 g, 77%) as amber oil. 1H NMR (300 MHz, CDCl3) δ 9.35 (d, 1H, J=2.4 Hz), 8.84 (d, 1H, J=2.4 Hz), 7.74 (d, 1H, J=5.4 Hz), 7.57 (m, 2H), 6.45 (s, 2H), 6.09 (s, 2H), 5.26 (s, 2H), 3.86 (m, 4H), 3.77 (s, 3H), 1.13 (t, 2H, J=7.2 Hz), 1.05 (t, 2H, J=7.8 Hz), 0.14 (s, 9H), 0.03 (s, 9H); MS (ESI) m/z: 619 (M+H+).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH2:1]([NH:8][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzylamine (0.125 mmol) in 5 mL of THF is added diisopropylethyl amine (0.15 mmol) and benzoylchloride (0.10 mmol). The reaction mixture is stirred at room temperature for 1 hour or until TLC analysis shows consumption of the benzoyl chloride. To this mixture is added perfluorsulfonic acid resin prepared in example 8 (3 g, 0.3 mmol/g loading) and the slurry is gently agitated for 1 hour. The slurry is filtered and the resin washed with dichloromethane. The combined filtrates are combined and the solvent removed under reduced pressure to afford N-benzylbenzamide as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[CH:28]#[C:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(Cl)Cl.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.[Cu]I>[C:28]([C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=1)#[C:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1
Reactant: C#CCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC#Cc1cncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
To a solution of 5-bromo-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from Example 54b (180 mg, 0.48 mmol), bis(triphenylphosphine)palladium(II) chloride (7 mg, 0.05 mmol), copper (I) iodide (2 mg) and triethylamine (1.0 mL) in CH2Cl2 (3 mL) was added 1-hexyne (8.3 mL, 0.72 mmol). The mixture was refluxed overnight and cooled to room temperature. The solvent was removed, and the residue was chromatographed on a silica gel column, eluting with EtOAc:hexane 1:1 to afford the title compound (102 mg, 56% yield). MS (CI/NH3) m/z 379 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 0.96 (t, J=6.6 Hz, 3H), 1.43 (s, 9H), 1.46-1.69 (m, 4H), 2.20-2.40 (m, 2H), 2.44-2.56 (m, 2H), 3.83-3.92 (m, 2H), 4.06-4.15 (m, 1H), 4.26-4.38 (m, 1H), 4.45-4.57 (m, 1H), 7.34 (br s, 1H), 7.51-7.58 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Cl:15])=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.[OH-].[K+].CCCCCCCC(C([NH3+])(C(CCCCCCC)=O)C(CCCCCCC)=O)=O.[Cl-].Br[CH2:49][CH2:50][CH:51]([CH3:58])[CH2:52][CH2:53][CH2:54][CH:55]([CH3:57])[CH3:56]>C(Cl)Cl>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Cl:15])=[CH:9][CH:10]=3)[N:5]([CH2:49][CH2:50][CH:51]([CH3:58])[CH2:52][CH2:53][CH2:54][CH:55]([CH3:57])[CH3:56])[C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)[nH]c1cc(Cl)ccc12
Reactant: CC(C)CCCC(C)CCBr
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)CCCC(C)CCn1c2cc(Cl)ccc2c2ccc(Cl)cc21
Temperature: 85 °C

Procedure:
2,7-Dichlorocarbazole (synthesized according to the procedure by Leclerc et al: Morin, Jean-Francois; Leclerc, Mario; Macromolecules (2001), 34(14), 4680–4682) (10.7 g, 45.3 mmol) was added to a 50% w/w aqueous solution of potassium hydroxide (75 ml) and Aliquat-336 (0.5 ml). 1-Bromo-3,7-dimethyloctane (12.0 g, 54.3 mmol) was added dropwise and the reaction mixture was heated at 85° C. for 12 h. After cooling to room temperature, methylene chloride was added. The reaction mixture was transferred to a separation funnel and the organic layer was removed. The aqueous layer was extracted with methylene chloride (3×) and the combined organic layers were dried over magnesium sulfate. After removal of the solvent in vacuo, the crude product was purified by column chromatography (silica gel, hexane) to yield 13.5 g of the product as colorless solid.
Reaction SMILES: F[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=O.O.[NH2:23][NH2:24].CCOC(C)=O.Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[C:3]3[C:2](=[C:7]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:5][CH:4]=3)[NH:24][N:23]=2)=[CH:15][CH:16]=1
Reactant: NN
Reactant: COc1ccc(C(=O)c2cccc(C(F)(F)F)c2F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
(2-Fluoro-3-trifluoromethyl-phenyl)-(4-methoxy-phenyl)-methanone (59.6 mg, 0.2 mmol) was dissolved in 1 ml of pyridine. Hydrazine hydrate (97 μl, 2 mmol) and 4-(dimethylamino)-pyridine (24.4 mg, 0.2 mmol) were added. The reaction mixture was stirred overnight at 100° C. After cooling to room temperature, EtOAc and 1M HCl were added. The organic phase was washed three times with brine, dried over MgSO4 and concentrated under vacuum. Purification of the crude product by flash column chromatography on silica gel (n-heptane/ethyl acetate, 85:15) afforded 56 mg of the analytically pure product.
Reaction SMILES: C(OC([NH:8][CH:9]([CH:17]([OH:28])[CH2:18][CH:19]([NH2:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[NH2:8][CH:9]([CH:17]([OH:28])[CH2:18][CH:19]([NH2:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)CC(N)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(Cc1ccccc1)CC(O)C(N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(2RS,3RS,5RS)-2-tert-Butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexane obtained in Example 39 (A) was dissolved in methylene chloride (1 ml), and trifluoroacetic acid (0.5 ml) was added at room temperature. After the mixture was stirred at room temperature for 3 hours, a 10% aqueous sodium hydroxide was added. After being extracted with methylene chloride, the mixture was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure to give the desired compound as a colorless solid (3.2 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.Br[C:16]1[S:17][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:20]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:10]([O:9][C:8]([NH:7][CH:4]1[CH2:3][CH2:2][N:1]([C:16]2[S:17][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:20]=2)[CH2:6][CH2:5]1)=[O:14])([CH3:11])([CH3:13])[CH3:12]
Reactant: COC(=O)c1cnc(Br)s1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnc(N2CCC(NC(=O)OC(C)(C)C)CC2)s1
Temperature: 130 °C

Procedure:
tert-Butyl piperidin-4-ylcarbamate (4.5 g, 22 mmol), methyl 2-bromo-1,3-thiazole-5-carboxylate (5.0 g, 22 mmol), and diisopropylethylamine (3.8 ml, 22 mmol) were suspended in anhydrous DMF and heated to an external temperature of 130° C. for 1.5 hours. The DMF was removed and the solid was partitioned with EtOAc and water. The combined organic extracts were washed with brine, dried with MgSO4 and concentrated to a yellow solid (7.05 g, 94%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9]O.CC(C)(O)[C:13]#[N:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1.CCCCCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:13]#[N:14]
Reactant: OCCc1ccccc1Br
Reactant: CC(C)(O)C#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCCCCC
Product: N#CCCc1ccccc1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of commercially available 2-(2-bromophenyl)ethanol (1 eq.) in Benzene (0.064M) at room temperature was added acetone cyanohydrin (1.5 eq), 1-1′(Azodicarbonyl)dipiperidine (1.5 eq) then dropwise over 5 min triphenyl phosphine (1.5 eq). The mixture was stirred at room temperature for 12 h, diluted with hexane (0.03M) and filtered on pad of silica gel. Fractions containing the desired material were combined and concentrated. A second purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (0 to 30%, in 30 min) afforded the desired compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[C:5]([C:16]#[N:17])=[C:4]([SH:18])[N:3]=1.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[S:24][CH:25]=1.C(=O)(O)[O-].[Na+].NC1C(C#N)=C(C2CCCCO2)C(C#N)=C(SCC2N=C(C3C=CC(Cl)=CC=3)SC=2)N=1>CN(C=O)C>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([C:23]2[S:24][CH:25]=[C:21]([CH2:20][S:18][C:4]3[C:5]([C:16]#[N:17])=[C:6]([CH:10]4[CH2:15][CH2:14][CH2:13][CH2:12][O:11]4)[C:7]([C:8]#[N:9])=[C:2]([CH3:1])[N:3]=3)[N:22]=2)=[CH:31][CH:30]=1
Reactant: Cc1nc(S)c(C#N)c(C2CCCCO2)c1C#N
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Agent: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1C1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(C2CCCCO2)c1C#N

Procedure:
50 mg (0.14 mmol) of the compound from Example 41A, 40 mg (0.16 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 45 mg (0.54 mmol) of sodium bicarbonate are reacted in 2.8 ml of dry DMF analogously to the preparation of the compound of Example 14.
Reaction SMILES: [CH2:1](I)[CH3:2].[C:4]1([C:10]2[NH:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CI.CN1C=C(C(F)(F)F)N=C1C1C=CC=CC=1>>[CH2:1]([N:11]1[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=[C:10]1[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCI
Reactant: FC(F)(F)c1c[nH]c(-c2ccccc2)n1
Agent: Cn1cc(C(F)(F)F)nc1-c1ccccc1
Solvent: CI
Product: CCn1cc(C(F)(F)F)nc1-c1ccccc1

Procedure:
By substituting equivalent amounts of ethyl iodide and 2-phenyl-4-trifluoromethylimidazole for the methyl iodide and 2-(2-pyridyl)-4(5)-trifluoromethylimidazole of Example 57 and following substantially the procedure described therein there is obtained 1-ethyl-2-phenyl-4-trifluoromethylimidazole, b.p., 160°-165° C. at 0.5 mm.
Reaction SMILES: [NH:1]=[C:2]1[C:6]([CH3:13])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5][C:4](=[S:14])[N:3]1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.N[OH:24]>CO>[OH:24][N:1]=[C:2]1[C:6]([CH3:13])([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[S:5][C:4](=[S:14])[N:3]1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC1(c2ccccc2)SC(=S)N(Nc2ccccc2)C1=N
Reactant: NO
Agent: Cl
Solvent: CO
Product: CC1(c2ccccc2)SC(=S)N(Nc2ccccc2)C1=NO
Yield: 52.2 %

Procedure:
A solution of 4-imino-5-methyl-5-phenyl-3-phenylaminothiazolidine-2-thione (0.31 g) and hydroxylamine hydrochloride (0.16 g) in methanol (15 ml) was refluxed for 6 hrs followed by solvent evaporation. The residue was purified by column chromatography (ethyl acetate-n-hexane, ⅓) to yield 4-hydroxyimino-5-methyl-5-phenyl-3-phenylamino-thiazolidine-2-thione (0.17 g) having a melting point of 83-84° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([OH:9])=O.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:43][C:44]1[C:48]2[CH2:49][NH:50][CH2:51][CH2:52][C:47]=2[S:46][C:45]=1[C:53]([O:55][CH2:56][CH3:57])=[O:54]>CN(C)C=O>[CH3:43][C:44]1[C:48]2[CH2:49][N:50]([C:7]([C:3]3[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=3)=[O:9])[CH2:51][CH2:52][C:47]=2[S:46][C:45]=1[C:53]([O:55][CH2:56][CH3:57])=[O:54]
Reactant: CCOC(=O)c1sc2c(c1C)CNCC2
Reactant: Cn1cccc1C(=O)O
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: CCOC(=O)c1sc2c(c1C)CN(C(=O)c1cccn1C)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-methylpyrrole-2-carboxylic acid (12.5 mg, 0.1 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.048 g, 0.11 mmol) and N,N-diisopropylethylamine (52.2 μL, 0.3 mmol) in N,N-dimethylformamide (1 mL, 12.9 mmol) was stirred at room temperature for 15 minutes. A solution of ethyl 3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (22.5 mg, 0.1 mmol) in N,N-dimethylformamide (1 mL) was then added and the reaction was further stirred at room temperature overnight. The solution was evaporated to dryness and the residue obtained was partitioned between DCM (2 mL) and half-saturated aqueous sodium bicarbonate solution (2 mL). Upon separation of the layers, the aqueous layer was extracted with additional DCM (2 mL) and the combined organic layers were concentrated to dryness.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:7]2=[N:6][C:5]=1[CH3:17].CC(O)C.Cl.[H][H]>[Pd].CO>[ClH:1].[Cl:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH:12]([O:15][CH3:16])[CH2:13][CH2:14][C:7]2=[N:6][C:5]=1[CH3:17]
Reactant: COc1ccc2nc(C)c(CCCl)c(=O)n2c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: COC1CCc2nc(C)c(CCCl)c(=O)n2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A mixture of 10 parts of 3-(2-chloroethyl)-7-methoxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 40 parts of 2-propanol saturated with hydrogen chloride and 160 parts of methanol was hydrogenated at normal pressure and at room temperature with 2.0 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off over diatomaceous earth and the filtrate was evaporated. The oily residue was taken up in 80 parts of 2-propanol and 2,2'-oxybispropane. After stirring overnight at room temperature, the precipitated product was filtered off, washed with a mixture of 2-propanol and 2,2'-oxybispropane and dried in vacuo at 50° C., yielding 7.5 parts (64.0%) of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-7-methoxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride; mp. 170° C. (intermediate 4)