Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3]Br.[CH3:5][O:6][C:7](=[O:23])[C@H:8]([CH2:17][C:18]1[N:22]=[CH:21][NH:20][CH:19]=1)[NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:13]([O:12][C:10]([NH:9][C@@H:8]([CH2:17][C:18]1[N:22]=[CH:21][N:20]([CH2:1][CH2:2][CH3:3])[CH:19]=1)[C:7]([O:6][CH3:5])=[O:23])=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OC(C)(C)C
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCn1cnc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)c1

Procedure:
n-propyl bromide (0.17 ml, 1.85 mmol) was added to a mixture of Nα-Boc-L-histidine methyl ester (500 mg, 1.85 mmol) and potassium carbonate (200 mg, 1.85 mmol) in acetonitrile (20 ml), and the mixture was heated under reflux for 18 hours. TLC analysis showed starting material remaining, so additional n-propyl bromide (0.17 ml, 1.85 mmol) and potassium carbonate (200 mg, 1.85 mmol) were added, and the mixture was heated for a further 8 hours. The cooled mixture was concentrated under reduced pressure. The residue was dissolved in water and the solution was extracted with ethyl acetate (3×20 ml). The combined organic extracts were washed with brine (3×20 ml), dried (Na2SO4) and evaporated under reduced pressure. The residual orange oil was purified by column chromatography on silica gel using an elution gradient of hexane:ethyl acetate (100:0 to 0:100) to afford the title compound as a colourless oil, 200 mg. 1H-NMR (CDCl3, 300 MHz) δ: 0.90 (t, 3H), 1.42 (s, 9H), 1.78 (m, 2H), 3.03 (m, 2H), 3.68 (s, 3H), 3.80 (t, 2H), 4.56 (m, 1H), 5.92 (m, 1H), 7.37 (s, 1H). LRMS: m/z (TSP+) 312.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:19][C:20]([CH3:27])=[C:21]([C:23]([O:25]C)=[O:24])[N:22]=3)=[CH:14][CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:19][C:20]([CH3:27])=[C:21]([C:23]([OH:25])=[O:24])[N:22]=3)=[CH:14][CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)OC)c(C)o3)cc2)nc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)O)c(C)o3)cc2)nc1Cl
Yield: 79.3 %

Procedure:
The same operation as in Example (91d) was performed using methyl 2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}phenyl)-5-methyl-1,3-oxazole-4-carboxylate obtained in Example (97e) (0.14 g, 0.36 mmol), 2 N lithium hydroxide (2 mL, 4 mmol), methanol (3 mL) and tetrahydrofuran (5 mL), to obtain 107 mg of the title compound as a light pink solid (79%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.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>[NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:13]2[CH:14]=[CH:15][C:10]([OH:9])=[CH:11][CH:12]=2)=[CH:4][N:3]=1
Reactant: Nc1cnc(Br)cn1
Reactant: OB(O)c1ccc(O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1cnc(-c2ccc(O)cc2)cn1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 2-amino-5-bromopyrazine (366 mg) in dimethoxyethane (20 mL) was added 4-hydroxyphenylboronic acid (320 mL), 1.5N sodium carbonate aqueous solution (2.5 mL) and tetrakis(triphenylphosphine)palladium (0) (54 mg). The mixture was stirred at 80° C. for 3 hours. To the reaction mixture was added water (20 mL) and the whole was extracted with ethyl acetate (50 mL×3). The extract was washed with saturated saline solution, then dried over anhydrous Na2SO4. The removal of the solvent provided crystal residue, which was washed with diethyl ether (10 mL) to give the subject compound (305 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[NH2:11].[CH3:21][N:22]([CH3:27])[C:23](=[O:26])[CH:24]=[CH2:25].C(N(CC)CC)C>C1COCC1>[NH2:11][C:7]1[C:6]2[C:10](=[C:2](/[CH:25]=[CH:24]/[C:23]([N:22]([CH3:27])[CH3:21])=[O:26])[CH:3]=[CH:4][C:5]=2[C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[NH:9][N:8]=1
Reactant: C=CC(=O)N(C)C
Reactant: Nc1n[nH]c2c(Br)ccc(-c3ccc([N+](=O)[O-])cc3)c12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)/C=C/c1ccc(-c2ccc([N+](=O)[O-])cc2)c2c(N)n[nH]c12

Procedure:
A mixture of Example 84B (165 mg), N,N-dimethylacrylamide (0.102 mL), triethylamine (0.207 mL), and Pd(o-tol3P)2Cl2 (30 mg) in THF (2 mL) in a sealed tube was heated in a Smith Synthesizer microwave oven (at 300 W) to 150° C. and concentrated. The residue was purified by flash column chromatography on silica gel with 3% methanol/dichloromethane to provide 163 mg of the desired product. MS (ESI(+)) m/e 352 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)=[CH:15][C:14]=2[F:30])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](O)=[O:6].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:43][O:44][CH2:45][CH2:46][OH:47]>>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)=[CH:15][C:14]=2[F:30])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:43][O:44][CH2:45][CH2:46][OH:47])=[O:6]
Reactant: NOCCO
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(C#CCCOC2CCCCO2)cc1F
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(C#CCCOC2CCCCO2)cc1F

Procedure:
The title compound was prepared by reaction of 3,4-difluoro-2-{2-fluoro-4-[4-(tetrahydro-2H-pyran-2-yloxy)-1-butynyl]anilino} benzoic acid with CDI and 2-(aminooxy)ethanol by the general procedure of Example 1, Step E, then purified by column chromatography on silica gel (50% EtOAc/PE as eluant) to give 3,4-difluoro-2-{2-fluoro-4-[4-(tetrahydro-2H-pyran-2-yloxy)-1-butynyl]anilino}-N-(2-hydroxyethoxy)benzamide as a viscous transparent oil which was immediately dissolved in EtOH and treated with 1 M HCl according to the general procedure of Example 10, Step D. Purification of the resulting oil was carried out by filtration through a plug of silica gel (EtOAc as eluant) to give 3,4-difluoro-2-[2-fluoro-4-(4-hydroxy-1-butynyl)anilino]-N-(2-hydroxyethoxy)benzamide as a pale yellow crystalline solid (51%); m.p. (EtOAc/Et2O) 126-129° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.82 (br s, 1 H), 8.85 (br s, 1 H), 7.45-7.39 (m, 1 H), 7.25-7.17 (m, 2 H), 7.07 (dd, J=8.3, 1.4 Hz, 1 H), 6.78 (dd, J=8.8, 8.8,4.7 Hz, 1 H), 4.88 (t, J=5.6 Hz, 1 H), 4.73 (br s, 1 H), 3.85 (t, J=4.8 Hz, 2 H), 3.59-3.53 (m, 4 H), 2.53 (t, J=6.9 Hz, 1 H). Anal. calcd. for C19H17F3N2O4.0.25Et2O: C, 58.2; H, 4.8; N, 6.8. Found C, 58.1; H, 4.8; N, 7.1.
Reaction SMILES: [Br:1][C:2]1(O)[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1.[C:9](=O)([O-])[O-:10].[K+].[K+].IC>CC(C)=O>[Br:1][C:2]1[C:7]([O:10][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OC1(Br)C=CC=CN1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cccnc1Br
Temperature: 70 °C
Yield: 76.7 %

Procedure:
2-Bromo-2-pyridinol (15 g, 86 mmol) in acetone (500 ml) was treated with potassium carbonate (23.8 g, 172 mmol) and iodomethane (8.1 ml, 130 mmol) and the suspension was refluxed at 70° C. for 16 hours. Once cooled, the mixture was filtered and the filtrate concentrated in vacuo. The residue was then purified by silica wet flash chromatography to give the product as yellow crystals (12.4 g, 66 mmol, 77% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[C:10]([O:15][CH2:16][CH3:17])(=[O:14])[C:11]([CH3:13])=O>>[CH2:16]([O:15][C:10](=[O:14])[C@H:11]([CH3:13])[NH:5][C:4]1[CH:6]=[CH:7][C:8]([F:9])=[C:2]([F:1])[CH:3]=1)[CH3:17]
Reactant: CCOC(=O)C(C)=O
Reactant: Nc1ccc(F)c(F)c1
Product: CCOC(=O)[C@H](C)Nc1ccc(F)c(F)c1

Procedure:
Following General Procedure AA above and using 3,4-difluoroaniline (Aldrich) and ethyl pyruvate (Aldrich), the title compound was prepared. The reaction was monitored by tlc on silica gel (Rf=0.4 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: Cl.[F:2][C:3]([F:21])([F:20])[C:4]1[N:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][NH:11]2)=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.[C:31](Cl)(=[O:34])[O:32][CH3:33]>C(Cl)Cl>[F:21][C:3]([F:2])([F:20])[C:4]1[N:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][N:11]2[C:31]([O:32][CH3:33])=[O:34])=[CH:6][CH:5]=1
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(c2ccc(C(F)(F)F)nc2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(C(F)(F)F)nc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
Methyl 2-(6-(trifluoromethyl)pyridin-3-yl)piperidine-4-carboxylate hydrochloride (3 g, 9.24 mmol) was dissolved in DCM (50 mL) and DIPEA (4.03 mL, 23.10 mmol). Methyl carbonochloridate (1.019 mL, 12.93 mmol) was added dropwise to the solution. The mixture was stirred at room temperature for 10 minutes. The mixture was washed with 0.1 M HCl (2×100 mL) and satd NaHCO3 (100 mL), then dried through a phase-separator and evaporated yielding crude dimethyl 2-(6-(trifluoromethyl)pyridin-3-yl)piperidine-1,4-dicarboxylate (3 g, 94%) as a dark brown oil. MS m/z 347 (M+H)+
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[S:16][CH:17]=[C:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[N:19]=3)[CH:6]=[CH:5][C:4]1=2.[OH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=O>>[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[S:16][CH:17]=[C:18]([CH:20]4[CH2:25][CH2:24][N:23]([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][OH:27])[CH2:22][CH2:21]4)[N:19]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: O=CCCCCO
Reactant: CC1(C)CCC(C)(C)c2cc(-c3nc(C4CCNCC4)cs3)ccc21
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3nc(C4CCN(CCCCCO)CC4)cs3)ccc21

Procedure:
The preparation was carried out as already described via a reductive amination starting from 100 mg (0.28 mmol) of 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-4-yl]piperidine hydrochloride (preparation already described above) and 58 mg (0.56 mmol) of 5-hydroxypentanal. The product was purified by means of preparative HPLC and is in the form of the hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[N+:3]([O-])=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.P(Cl)(Cl)([Cl:23])=O.N>C(Cl)(Cl)Cl>[Cl:23][CH2:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1ccc(-c2oc(-c3ccccc3)c(C)[n+]2[O-])cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2nc(CCl)c(-c3ccccc3)o2)cc1
Temperature: 0 °C

Procedure:
6.4 g of 4-methyl-5-phenyl-2-p-tolyloxazole 3-oxide are dissolved in 50 ml of chloroform, 2.4 ml of phosphorus oxychloride are added and the mixture is, under reflux, heated at the boil for 30 minutes. The reaction mixture is cooled to 0° C., the pH is made slightly alkaline using ammonia and the mixture is extracted three times with in each case 100 ml of ethyl acetate. The combined organic phases are washed with water and dried over MgSO4, and the solvent then removed under reduced pressure. This gives 5.4 g of 4-chloromethyl-5-phenyl-2-p-tolyloxazole as a yellow solid. C17H14CINO (283.76), MS(ESI)=284 (M+H+), Rf(n-heptane:ethyl acetate)=7:1)=0.41.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][CH:14]=[CH2:15])[C:10](O)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(=O)C([Cl:19])=O.CN(C)C=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][CH:14]=[CH2:15])[C:10]([Cl:19])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=CCC(C(=O)O)c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCC(C(=O)Cl)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
To a soln of 2-(3,4-dichlorophenyl)pent-4-enoic acid (2.34 g, 9.53 mmol) in methylene chloride (25.0 mL) was added oxalyl chloride (1.61 mL, 19.0 mmol) followed by N,N-dimethylformamide (73.8 uL, 0.953 mmol) After 1 hr of stirring at rt, the solution was concentrated to provide 2-(3,4-dichlorophenyl)pent-4-enoyl chloride as a yellow oil (2.70 g, quantitative). 1H NMR (400 MHz, CDCl3) δ 7.49-7.42 (d, J=8.3 Hz, 1H), 7.40-7.36 (d, J=2.2 Hz, 1H), 7.17-7.10 (dd, J=8.3, 2.2 Hz, 1H), 5.73-5.57 (ddt, J=17.1, 10.2, 6.9 Hz, 1H), 5.15-5.06 (m, 2H), 4.06-3.97 (t, J=7.6 Hz, 1H), 2.97-2.83 (m, 1H), 2.61-2.49 (m, 1H).
Reaction SMILES: [C:1]1([CH:7]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][NH:11][CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[C:1]1([CH:7]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:8]2[CH2:9][CH2:10]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2NCCNCc3ccccc32)cc1
Reactant: O=Cc1ccccc1
Solvent: CCO
Product: c1ccc(C2c3ccccc3CN3CCN2C3c2ccccc2)cc1
Yield: 85 %

Procedure:
A mixture of 2 g (8.4 mmol) of 1,2,3,4,5,6-hexahydro-1-phenyl-2,5-benzodiazocine and 1.0 g (9.2 mmol) of benzaldehyde in 40 mL of ethanol was refluxed for 30 min, cooled on ice and the product filtered off. There was obtained 2.33 g of 3,4-dihydro-1,11-diphenyl-2,5-methano-1H,6H-2,5-benzodiazocine, mp 175°-176°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[S:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([N+:44]([O-:46])=[O:45])=[C:39]([CH:43]=1)[C:40](Cl)=[O:41]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:40](=[O:41])[C:39]3[CH:43]=[C:35]([Cl:34])[CH:36]=[CH:37][C:38]=3[N+:44]([O-:46])=[O:45])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Reactant: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OC(=O)c2cc(Cl)ccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
1.86 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and 1 ml of triethylamine are dissolved in 15 ml of methylene chloride, and 1.27 g of 5-chloro-2-nitrobenzoyl chloride are added thereto. The mixture is stirred at room temperature for one hour. After the reaction, the mixture is poured into ice-water and then extracted with ethyl acetate. The extract is washed with an aqueous sodium bicarbonate solution, water and an aqueous sodium chloride solution, successively. Then, the extract is evaporated to remove solvent, and the residue is crystallized with ethanol. 2.45 g of (+)-cis-2-(4-methoxyphenyl)-3-(5-chloro-2-nitrobenzoyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are thereby obtained as colorless prisms. Yield: 88.1%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][NH2:15])([O-:3])=[O:2].[CH:16](O)=[O:17]>O>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:5]=1[N:14]([CH:16]=[O:17])[NH2:15])([O-:3])=[O:2]
Reactant: NNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: O=CO
Solvent: O
Product: NN(C=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 98 %

Procedure:
64 g of 2-nitro-4-trifluoromethylphenylhydrazine [prepared as described in: J. Org. Chem. 42, 542 (1977)] were heated with 200 ml of 85% formic acid in a water bath for 90 minutes. After cooling down, the yellow solution was poured into 250 ml of water. The crystalline precipitate was filtered by suction, washed with water and dried at 80° C. to yield 72 g (98%) of 2-nitro-4-trifluoromethyl-N-formylphenylhydrazine, m.p.: 152°-153° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[CH3:7][CH:8]([CH2:10][CH2:11][CH2:12][C@H:13]([C@@H:15]1[C@:33]2([CH3:34])[C@H:18]([C@H:19]3[C@H:30]([CH2:31][CH2:32]2)[C@:28]2([CH3:29])[C:22]([CH2:23][C@H:24]([CH2:26][CH2:27]2)[OH:25])=[CH:21][CH2:20]3)[CH2:17][CH2:16]1)[CH3:14])[CH3:9].N1C=CC=CC=1>C(Cl)Cl>[Cl:6][CH2:5][O:4][C:2]([C@:24]1([OH:25])[CH2:26][CH2:27][C@@:28]2([CH3:29])[C:22](=[CH:21][CH2:20][C@@H:19]3[C@@H:30]2[CH2:31][CH2:32][C@@:33]2([CH3:34])[C@H:18]3[CH2:17][CH2:16][C@@H:15]2[C@H:13]([CH3:14])[CH2:12][CH2:11][CH2:10][CH:8]([CH3:9])[CH3:7])[CH2:23]1)=[O:3]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(Cl)OCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@](O)(C(=O)OCCl)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 24 h

Procedure:
Chloromethyl chloroformate (1.96 g, 15.2 mmol) and cholesterol (5.0 g, 12.9 mmol) was dissolved in CH2Cl2 (10 ml). The solution was cooled. Pyridine (1.21 g, 15.3 mmol) was dripped into the stirred solution over 5 minutes. Heat was produced and the reaction gave a clear solution from a somewhat unclear starting solution. After 24 hours at room temperature, the mixture was diluted with CH2Cl2 (50 ml), washed with 0.5M HCl (50 ml) and water (3×25 ml). After treatment with MgSO4, the solution was evaporated to dryness.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[Br:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[CH2:23]Br>>[Br:12][C:13]1[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[CH:15][C:14]=1[CH2:23][N:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=Cc1ccc2[nH]ncc2c1
Reactant: FC(F)(F)c1ccc(CBr)c(Br)c1
Product: O=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2Br)c1

Procedure:
1-(2-Bromo-4-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde was prepared from 1H-indazole-5-carbaldehyde and 2-bromo-1-bromomethyl-4-trifluoromethyl-benzene following General Procedure A.
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([CH:15]=O)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[Br:17][C:18]1[N:19]=[CH:20][C:21]([NH2:24])=[N:22][CH:23]=1>ClCCCl.CC(O)=O>[Br:17][C:18]1[N:19]=[CH:20][C:21]([NH:24][CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([CH3:2])=[CH:4][CH:5]=2)=[N:22][CH:23]=1
Reactant: Nc1cnc(Br)cn1
Reactant: Cc1ccc(-c2ccccc2C=O)cc1
Agent: [Na]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1ccc(-c2ccccc2CNc2cnc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
Sodium tiracetoxyl borohydride (215 mg, 1.02 mmol) was added to the solution of 4′-methyl-biphenyl-2-carbaldehyde and 5-bromo-pyrazin-2-ylamine in 5 ml of DCE, 0.1 ml of HOAc was added and the mixture was stirred overnight at room temperature, followed by addition of 5 ml of DCE. The organic phase was washed with water, and purified with column (silica gel, hexane:EtOAc 6:1) to give 100 mg of (5-bromo-pyrazin-2-yl)-(4′-methyl-biphenyl-2-ylmethyl)-amine, yield 55%.
Reaction SMILES: Cl.[Cl:2]C1C(Cl)=C(C)NC=1C(NC1CCNCC1)=O.[Br:19][C:20]1[CH:21]=[C:22]([C:26]([NH:28][CH:29]2[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]2)=[O:27])[NH:23][C:24]=1[CH3:25]>>[ClH:2].[Br:19][C:20]1[CH:21]=[C:22]([C:26]([NH:28][CH:29]2[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]2)=[O:27])[NH:23][C:24]=1[CH3:25]
Reactant: Cc1[nH]c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)cc1Br
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Agent: Cl
Product: Cc1[nH]c(C(=O)NC2CCNCC2)cc1Br

Procedure:
Title compound was synthesized by an analogous method to Intermediate 1, starting from tert-butyl 4-{[(4-bromo-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidine-1-carboxylate (Intermediate 52).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:28])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:28])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc(C#N)cc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1

Procedure:
A solution of tert-butyl{1-[2-(7-cyano-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 15) (6.57 g, 16.57 mmol) in dichloromethane (100 mL) was treated with trifluoroacetic acid (40 mL) at 0° C. for 30 minutes. The solvent was removed under reduced pressure and the residue codistilled once with dichloromethane, then taken up in dichloromethane (200 mL) and washed with saturated sodium hydrogencarbonate solution (50 mL, pH adjusted to 10 with sodium hydroxide). The aqueous phase was back-extracted three times with dichloromethane (3×100 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure to give the product as off-white solid, 5 g, mp 138° C.
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].Cl.[CH3:17][O:18][NH2:19].[OH-].[Na+].O>C(O)C>[CH3:17][O:18][N:19]=[C:2]([CH3:15])[CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14]
Reactant: CON
Reactant: CC(=O)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CON=C(C)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.7 %

Procedure:
1.33 g (6.55 mmol) of N-(2-oxopropyl)phthalimide was dissolved in 30 ml of ethanol and to the solution was added 1.64 g (19.7 mmol) of O-methylhydroxylamine hydrochloride. To this suspension was added 20 ml of 2N aqueous sodium hydroxide solution, followed by being stirred at room temperature for 12 hours. The reaction mixture was poured into 100 ml of water and extracted with chloroform (30 ml×3), and the combined organic layer was dried over magnesium sulfate. Chloroform was distilled off and the residual solids were washed with hexane to give 1.03 g (yield 68%) of the titled compound as colorless crystals.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[N:14]=[C:13]([Sn](CCCC)(CCCC)CCCC)[CH:12]=[CH:11][CH:10]=1.Br[C:29]1[N:33]2[N:34]=[C:35]([N:38]3[CH2:42][CH2:41][CH2:40][CH:39]3[C:43]3[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:44]=3[F:50])[CH:36]=[CH:37][C:32]2=[N:31][CH:30]=1>C1(C)C=CC=CC=1>[F:50][C:44]1[CH:45]=[CH:46][C:47]([F:49])=[CH:48][C:43]=1[CH:39]1[CH2:40][CH2:41][CH2:42][N:38]1[C:35]1[CH:36]=[CH:37][C:32]2[N:33]([C:29]([C:13]3[CH:12]=[CH:11][CH:10]=[C:9]([F:8])[N:14]=3)=[CH:30][N:31]=2)[N:34]=1
Reactant: Fc1ccc(F)c(C2CCCN2c2ccc3ncc(Br)n3n2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(F)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Fc1ccc(F)c(C2CCCN2c2ccc3ncc(-c4cccc(F)n4)n3n2)c1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
In step 5-1, triethylamine (0.045 mL, 0.29 mmol), tetrakis(triphenylphospine)palladium (0) (12 mg, 0.01 mmol), and 6-fluoro-2(tributylstannyl)pyridine (80 mg, 0.201 mmol) were added to a solution of 3-bromo-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (6-6) (53 mg, 0.13 mmol) in 3 mL of toluene. The reaction mixture was heated to 100° C. and stirred for 6 hours at 100° C. The reaction mixture was then cooled to room temperature and purified using flash chromatography (ethyl acetate and hexanes (1:1)) giving 6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-(6-fluoropyridin-2-yl)imidazo[1,2-b]pyridazine (5-1). 1H NMR (400 MHz, D3 acetonitrile) δ ppm 8.35-8.17 (m, 2H), 8.02-7.83 (m, 1H), 7.48-7.22 (m, 3H), 7.15-6.92 (m, 3H), 5.42 (br d, J=5.8 Hz, 1H), 4.12-3.99 (m, 1H), 3.81-3.72 (m, 1H), 2.70-2.56 (m, 1H), 2.30-2.06 (m, 3H). LCMS observed m/z 396.1