Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:10])=[N:4][C:5]([CH3:9])=[N:6][C:7]=1Cl.[NH2:11][CH2:12][C:13]1[CH:14]=[C:15]([Br:19])[CH:16]=[N:17][CH:18]=1.CO>C(COC)OC>[Br:19][C:15]1[CH:14]=[C:13]([CH2:12][NH:11][C:7]2[NH:6][C:5]([CH3:9])=[N:4][C:3](=[O:10])[C:2]=2[Cl:1])[CH:18]=[N:17][CH:16]=1
Reactant: Cc1nc(O)c(Cl)c(Cl)n1
Reactant: NCc1cncc(Br)c1
Solvent: CO
Solvent: COCCOC
Product: Cc1nc(=O)c(Cl)c(NCc2cncc(Br)c2)[nH]1

Procedure:
A stirred mixture of 5,6-dichloro-2-methyl-4-pyrimidinol (1.20 g, 6.70 mmol) and 5-aminomethyl-3-bromopyridine (3.65 g, 19.5 mmol) in dimethoxyethane (25 mL) was heated at reflux for 14 hours. The mixture was then concentrated in vacuo and diluted with water. The precipitate was isolated by filtration with aqueous rinse, recrystallized twice from ethyl acetate, and then recrystallized a third time, but from methanol, to provide the title compound as a pure product (1.07 g, 3.25 mmol, 48%): mp 274°-275° C.; Rf 0.59 (20% MeOH in EtOAc); 1H NMR (DMSO-D6, 400 MHz)δ11.9 (br s, 1H), 8.57 (d, J=2 Hz, 1H), 8.49 (s, 1H), 7.93 (s, 1H), 7.46 (t, J=6 Hz, 1H), 4.56 (d, J=6.1 Hz, 2H), 2.18 (s, 3H); IR (KBr) 3300 (NH), 2790-3000 (CH), 1660, 1615, 2590 (C=C, C=N); mass spectrum m/e 329.8 (M+, 70%), 292.9 (M+ -Cl, 32%).
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=[CH2:23]>O1CCOCC1>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH3:15])[CH2:23][CH2:22][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Reactant: C=Cc1ccccn1
Solvent: C1COCCO1
Product: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)CCc1ccccn1

Procedure:
A solution containing 2,2-diphenyl-5-methylaminopentanamide (2.0 g--see Preparation 3) and 2-vinylpyridin (1.1 ml) in dioxan (15 ml) was heated under reflux for 48 hours. The mixture was concentrated in vacuo and the residue partitioned between dichloromethane (50 ml) and water (50 ml). The dichloromethane layer was dried (MgSO4) and concentrated in vacuo to give a solid which was purified by column chromatography eluting with hexane containing dichloromethane (50% up to 100%) and then with dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as an oil which was crystallised from acetonitrile, yield 0.5 g, m.p. 134°-136°.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[O:9])[CH:3]=1.[CH:20]1([NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[NH:16][N:15]=[CH:14]4)=[O:9])[CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(Nc1ccc2[nH]ncc2c1)c1cc(Cl)ncn1
Reactant: CC(C)CNC1CCCC1
Product: CC(C)CN(c1cc(C(=O)Nc2ccc3[nH]ncc3c2)ncn1)C1CCCC1
Yield: 78 %

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-pyrimidine-4-carboxylic acid (1H-indazol-5-yl)-amide (Intermediate 16) and cyclopentyl-isobutyl-amine (Intermediate 27), the title compound was obtained as a white solid in 78% yield.
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14](OC)=[O:15])[CH2:3]1.[Li+].[BH4-]>C1COCC1>[F:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([CH2:14][OH:15])[CH2:3]1
Reactant: COC(=O)[C@@H]1C[C@H](F)CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a THF (20 mL) solution of 1-tert-butyl 2-methyl (2S,4S)-4-fluoro-1,2-pyrrolidinedicarboxylate (950 mg, 3.9 mmol) at 0° C., 5.8 mL 2M LiBH4 (11.6 mmol, 3 eq) was added slowly. The resulting mixture was left stirring overnight while allowing the temperature to warm up to room temperature.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:29])[N:7]([CH2:19][C@@H:20]([OH:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[N:22]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)([CH3:4])[CH3:3].[Sn](Cl)Cl.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>CO>[CH3:4][C:2]([O:5][C:6](=[O:29])[N:7]([CH2:19][C@@H:20]([OH:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[N:22]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc([N+](=O)[O-])cc1)C[C@@H](O)c1cccc(Cl)n1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCc1ccc(N)cc1)C[C@@H](O)c1cccc(Cl)n1
Temperature: 25 °C
Yield: 54.9 %

Procedure:
To a solution of 1.00 g (2.37 mmol) of (R)-N-[2-(4-nitrophenyl)ethyl]-2-hydroxy-2-(6-chloro-2-pyridyl)ethylcarbamic acid 1,1-dimethylethyl ester in 60 mL of methanol under an atmosphere of nitrogen was added 1.35 g (7.12 mmol) of tin(II) chloride. The mixture was heated at reflux for 5 h then cooled to room temperature. Saturated aqueous sodium bicarbonate solution was added followed by ethyl acetate. The resulting emulsion was filtered through Celite and the organic phase separated. The aqueous phase was re-extracted twice with ethyl acetate. The combined organic phase was washed twice with water, brine, dried over magnesium sulfate and the solvent removed in vacuo. Biotage chromatography (40M column, 30, 35% ethyl acetate-hexanes) afforded 510 mg (55%) of (R)-N-[2-(4-aninophenyl)ethyl]-2-hydroxy-2-(6-chloro-2-pyridyl)ethylcarbamic acid 1,1-dimethylethyl ester.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=2[F:36])[O:7][C:8]=1[C:9]1[CH:28]=[CH:27][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)(=[O:3])[NH2:2].Cl.O1CCOCC1.C([O-])=O>C(Cl)Cl>[F:35][C:34]1[CH:33]=[CH:32][CH:31]=[C:30]([F:36])[C:29]=1[C:6]1[O:7][C:8]([C:9]2[CH:10]=[CH:11][C:12]([CH2:13][N:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)=[CH:27][CH:28]=2)=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3oc(-c4c(F)cccc4F)nc3C(N)=O)cc2)CC1
Agent: Cl
Agent: O=C[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(CN2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of tert-butyl 4-(4-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-yl)benzyl)piperazine-1-carboxylate (0.100 g, 0.2 mmol) in DCM (3 mL) was added 4M HCl in dioxane (2 mL, 8.0 mmol) and the resulting mixture stirred at room temperature overnight. The solvent was removed in vacuo. The residue was purified by preparative HPLC to afford 2-(2,6-difluorophenyl)-5-(4-(piperazin-1-ylmethyl)phenyl)oxazole-4-carboxamide (0.043 g, 0.1 mmol, 50%) as a white solid as the formate salt. 1H NMR (DMSO) 2.44 (4H, m), 2.88 (4H, m), 3.55 (2H, s), 7.40 (2H, t), 7.47 (2H, d), 7.75 (3H, m), 8.19 (2H, d), 8.32 (1H, s). LCMS (2) Rt: 2.63 min; m/z (ES+) 399.
Reaction SMILES: C(OC([S:6][C:7]1[CH:8]=[C:9]([C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:11][C:12]=1[F:13])=S)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[F:13][C:12]1[CH:11]=[CH:10][C:9]([C:14]([F:15])([F:16])[F:17])=[CH:8][C:7]=1[SH:6]
Reactant: CCOC(=S)Sc1cc(C(F)(F)F)ccc1F
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Fc1ccc(C(F)(F)F)cc1S
Reaction time: 3 h

Procedure:
The above-obtained 3-ethoxythiocarbonylthio-4-fluorobenzotrifluoride was dissolved in 100 ml of tetrahydrofuran without further purification. The solution was added dropwise to a suspension of 4.4 g of lithium aluminum hydride in 100 ml of tetrahydrofuran. The reaction mixture was stirred for 3 hours, followed by addition of diluted hydrochloric acid to adjust the pH to 1, and the mixture was extracted with ethyl acetate, giving 13 g of 4-fluoro-3-mercaptobenzotrifluoride.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[S:12][C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[C:4]=2[N:3]=1.[Cl:20]C1C=C2C(C3OC4C=CC=CC=4C=3N=C2O)=CC=1>>[Cl:20][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[S:12][C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[C:4]=2[N:3]=1
Reactant: Oc1nc2c3ccccc3oc2c2ccc(Cl)cc12
Reactant: Oc1nc2c3ccc(F)cc3sc2c2ccccc12
Product: Fc1ccc2c(c1)sc1c3ccccc3c(Cl)nc21

Procedure:
The procedure was similar to step S19C, while the starting material was 29B in stead of 19B.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:24])[C:12]([CH3:23])([S:14]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])[CH3:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:25]([N-]C(C)C)(C)C.[Li+].CI>C1COCC1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:24])[C:12]([CH3:13])([S:14]([C:17]2([CH3:25])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)(=[O:15])=[O:16])[CH3:23])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)no1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2(C)CCOCC2)no1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 14.9 %

Procedure:
To a solution of 202 mg (0.56 mmol) of N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionamide (prepared according to Method E) in anhydrous THF (10 mL) at −78° C. under nitrogen atmosphere were added 0.8 mL (1.4 mmol) of lithium diisopropylamide (1.8 M solution in THF/heptane/ethylbenzene) and the reaction was stirred at −78° C. for 0.5 h. Then 0.1 mL (1.6 mmol) of methyl iodide were added in one portion and stirring was continued for further 0.5 h at −78° C., before the reaction was warmed to room temperature. After 18 h at room temperature the reaction was quenched by the addition of saturated aqueous NH4Cl solution (25 mL). The mixture was extracted with ethyl acetate (3×25 mL). The organic extracts were combined, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue purified by mass-triggered preparative LCMS to afford 31 mg of N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-2-(4-methyl-tetrahydro-pyran-4-sulfonyl)-propionamide.
Reaction SMILES: I(O)(=O)(=O)=O.[Cl:6][CH2:7][C:8]([OH:25])([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])CO.C(OCC)(=O)C.CCCCCC>CCOCC>[Cl:6][CH2:7][C:8](=[O:25])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCC(O)(CO)CCl
Agent: [O-][I+3]([O-])([O-])O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCCCCCCCCCCCCC(=O)CCl
Yield: 91.2 %

Procedure:
Periodic acid (excess) was added to a solution of 2-chloromethylhexadecan-1,2-diol (23a, 0.021 g, 0.068 mmole) in wet ether (15 ml). The progress of the reaction was followed by TLC (30% ethyl acetate-hexane) and within 70 minutes, the diol 23a was completely transformed to a new, nonpolar product. Additional ether (15 ml) was added and the organic solution was washed with water (2×) and brine. The ether layer was dried (MgSO4), filtered, and concentrated, leaving 0.017 g (0.062 mmole, 91%) of a crystalline material. Recrystallization from methanol gave 0.009 g of 1-chlorohexadecan-2-one (25), mp. 52.5°-53.5° C. (lit.16 mp., 52°-52.5° C.).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C@H:15]([C:17]1[N:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[N:18]=1)[CH3:16])(C)(C)C>C(Cl)Cl>[N:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[N:25]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[N:18]=[C:17]1[C@@H:15]([NH2:14])[CH3:16]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccnc2n1-c1ccccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1nc2cccnc2n1-c1ccccn1
Reaction time: 0.5 h
Yield: 18.7 %

Procedure:
Trifluoroacetic acid (20 mL) was added to a solution of [(S)-1-(3-pyridin-2-yl-3H-imidazo[4,5-b]pyridin-2-yl)ethyl]carbamic acid tert-butyl ester (1.10 g, 3.24 mmol) in DCM (10 mL) and stirred for 30 min. The reaction mixture was concentrated in vacuo and the residue purified by chromatography (SiO2 0-10% (2M ammonia in methanol) in DCM) to give the title compound (0.145 g, 19%). LCMS (method H): Rt 0.26 min, [M+H]+ 240.
Reaction SMILES: C(Cl)Cl.Cl[CH:5]1[NH:10][CH:9]=[CH:8][N:7]2[C:11]([CH:30]3[CH2:33][CH2:32][CH2:31]3)=[N:12][C:13]([C:14]3[CH:23]=[C:22]4[C:17]([N:18]=[CH:19][C:20]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[N:21]4)=[CH:16][CH:15]=3)=[C:6]12.[N:34]#N.N>CC(O)C>[CH:30]1([C:11]2[N:7]3[CH:8]=[CH:9][N:10]=[C:5]([NH2:34])[C:6]3=[C:13]([C:14]3[CH:23]=[C:22]4[C:17](=[CH:16][CH:15]=3)[N:18]=[CH:19][C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:21]4)[N:12]=2)[CH2:33][CH2:32][CH2:31]1
Reactant: N#N
Reactant: ClC1NC=Cn2c(C3CCC3)nc(-c3ccc4ncc(-c5ccccc5)nc4c3)c21
Agent: N
Solvent: ClCCl
Solvent: CC(C)O
Product: Nc1nccn2c(C3CCC3)nc(-c3ccc4ncc(-c5ccccc5)nc4c3)c12
Temperature: 100 °C

Procedure:
DCM solution of 7-(8-chloro-3-cyclobutyl-7,8-dihydroimidazo[1,5-a]pyrazin-1-yl)-2-phenylquinoxaline (61 mg, 0.15 mmol) was evaporated to dryness by passing a stream of N2. The residue was suspended in anh. i-PrOH (4 mL) and the suspension was saturated with gaseous NH3 at 0° C. (2 min). The reaction vessel was sealed and heated to 100° C. (external temperature) for 63 h. Then the reaction was cooled to rt, concentrated under reduced pressure and purified by flash chromatography (silica gel, 0-5% MeOH in DCM) and then preparative TLC (4% MeOH in CH3CN) to afford the title compound as a light yellow solid; 1H NMR (400 MHz, CDCl3) δ 9.36 (d, J=4 Hz, 1H), 8.43 (s, 1H), 8.30-8.25 (m, 4H), 7.65-7.50 (m, 3H), 7.15 (m, 2H), 5.26 (br, 2H), 3.86 (quintet, J=8 Hz, 1H), 2.75-2.60 (m, 2H), 2.60-2.45 (m, 2H), 2.20 (q, J=8 Hz, 1H), 2.07 (br, 1H). MS (ES+): m/z 393.1 (100) [MH+]; HPLC: tR=2.30 min (OpenLynx, polar—5 min).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C)C=O>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]2[C:6](=[CH:7][N:8]([CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[N:9]=2)[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2nn(CCN3CCCCC3)cc2c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-Nitroindazole (1.00 g, 6.13 mmol) and and potassium carbonate (2.50 g, 18.1 mmol) in 20 mL of N,N-dimethylformamide was stirred for 30 minutes and then 1-(2-chloro-ethyl)-piperidine hydrochloride (1.74 g 9.45 mmol) was added. The mixture was heated to 60° C. for 6 hours, cooled to room temperature, filtered through a plug of silica gel and rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under vacuo and the residue purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30). 1H NMR (300 MHz, DMSO-d6) ppm 1.13–1.15 (m, 6H) 2.40 (m, 4H), 2.82 (t, 2H, J=6.44) 4.61 (t, 2H, J=6.44), 7.78 (m, 1H), 8.00 (m, 1H), 8.81 (s, 1H), 8.90 (d, 1H); MS (DCI/NH3) m/z 275 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:6]([CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:5]2[CH2:18][CH:19]=[CH:20][CH:21]=[C:4]2[O:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(Cl)[Cl:29].CCOCC.Cl>CCOCC>[ClH:29].[CH3:17][N:15]([CH3:16])[CH2:14][CH2:13][C:6]([C:5]1[CH:18]=[CH:19][CH:20]=[CH:21][C:4]=1[OH:3])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:2][OH:1]
Reactant: ClCCl
Reactant: CN(C)CCC1(c2ccccc2)C(=O)OC2=CC=CCC21
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CN(C)CCC(CO)(c1ccccc1)c1ccccc1O
Reaction time: 0.5 h

Procedure:
A solution of 28.6 g (102 mmole) 2-(2-oxo-3-phenyl-3-dihydrobenzofuranyl)-N,N-dimethylethylamine in 300 ml anhydrous Et2O was added to 7.74 g (204 mmole) LiAlH4 in 150 ml Et2O at ice bath temperature and this mixture stirred at that temperature for 30 minutes. After further stirring for 2 hours at room temperature, the reaction mixture was quenched with saturated Na2SO4, filtered, and the solids washed with excess EtOAc (4×350 ml). The combined organics were washed with saturated Na2CO3 (300 ml) and saturated NaCl (200 ml), and dried over Na2SO4. Filtration and evaporation gave 28 g of a crude oil which solidified on standing. A solution of 5 g of this material in a minimum amount of CH2Cl2 was added to excess Et2O/HCl. Filtration of the precipitated salt gave 5.5 g of a solid which was recrystallized from EtOH to give 3.2 g (57%) of crystals, m.p. 199°-201°.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[C:13]([F:18])[CH:12]=2)[N:8]=[C:7]([C:19]([O:21][CH3:22])=[O:20])[C:6]=1[Cl:23])(=O)C.C(Cl)(=O)C>CO>[NH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[C:13]([F:18])[CH:12]=2)[N:8]=[C:7]([C:19]([O:21][CH3:22])=[O:20])[C:6]=1[Cl:23]
Reactant: COC(=O)c1nc(-c2ccc(Br)c(F)c2)cc(NC(C)=O)c1Cl
Solvent: CO
Solvent: CC(=O)Cl
Product: COC(=O)c1nc(-c2ccc(Br)c(F)c2)cc(N)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.1 %

Procedure:
To a 100-mL round bottom flask, equipped with a stir bar, was added methyl 4-acetamido-6-(4-bromo-3-fluorophenyl)-3-chloropicolinate (0.411 g, 1.023 mmol), methanol (5.12 mL) and acetyl chloride (1.45 mL, 20.5 mmol). The reaction was allowed to stir at room temperature for 18 hours. The solvent was removed with a rotary evaporator. The resulting solid was dissolved in 1 N NaHCO3 and extracted with ethyl acetate (3×75 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated to afford the title compound as a white solid (0.324 g, 88%).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:13]=[CH:14][N:15]=2)[CH:5]=[C:6]([C:8]([O:10]CC)=[O:9])[CH:7]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CO.O.C(O)CC>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[C:3]3[N:4]([CH:13]=[CH:14][N:15]=3)[CH:5]=[C:6]([C:8]([OH:10])=[O:9])[CH:7]=2)=[CH:19][CH:18]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1cc(Br)c2nccn2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: CCCO
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)cn3ccnc23)cc1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A degassed solution of n-propanol (40 mL) and water (10 mL) was added to a mixture of ethyl 8-bromoimidazo[1,2-a]pyridine-6-carboxylate (1.0 g, 3.72 mmol), (4-methylphenyl)boronic acid (0.66 g, 4.83 mmol), (tetrakistriphenylphosphine) palladium(0) (0.22 g, 0.19 mmol) and potassium carbonate (1.54 g, 11.2 mmol). The mixture was heated to 90° C. After 18 h, sodium hydroxide (3N in water; 3 mL) and methanol (20 mL) was added. The mixture was stirred at 90° C. for another 48 h. The mixture was cooled to ambient temperature and filtered with Celite. The filtrate was concentrated. The water was azeotropically removed with repeated concentration from acetonitrile. The crude mixture was taken up in methanol and small amount of water and loaded onto a 25 g pre-equilibrated SCX column. The column was washed with 5× column volumes of methanol to remove impurities. The column was then washed with 3× column volumes of 2 M ammonia/methanol to elude the titled product (0.90 g): LC-MS [M+1]=253.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:10]#[N:11])=[CH:4][CH:3]=1.P(Cl)(Cl)Cl.[NH2:23][NH2:24]>C(#N)C>[NH2:11][C:10]1[NH:24][N:23]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1
Reactant: NN
Reactant: N#CC(C(=O)c1ccc(Cl)cc1)c1ccncc1
Solvent: ClP(Cl)Cl
Solvent: CC#N
Product: Nc1[nH]nc(-c2ccc(Cl)cc2)c1-c1ccncc1
Yield: 54.3 %

Procedure:
A solution of 3-(4-chlorophenyl)-3-oxo-2-(pyridin-4-yl)propanenitrile (3.50 g, 13.6 mmol) in 40 mL acetonitrile and phosphorous trichloride (14.2 ml, 163 mmol) was stirred at 100° C. for 5 hours. The reaction mixture was concentrated in vacuo, and the residue taken up in toluene and concentrated again. The residue was then taken up in ethanol (150 mL) and treated with anhydrous hydrazine (1.71 mL, 54.4 mmol). The reaction mixture was heated to reflux for 3 hours, cooled, and concentrated in vacuo. The residue was triturated with a mixture of ethanol and dichloromethane (1:4), and filtered. The solid was washed with the ethanol/dichloromethane mixture, and dried to give 5-amino-3-(4-chlorophenyl)-4-(pyridin-4-yl)-pyrazole (2.0 g, 54%): m.p. >300° C. 1H NMR (DMSO/300 MHz) δ 8.40 (d, 2H), 7.40 (d, 2H), 7.29 (d, 2H), 7.11 (d, 2H), 5.05 (s, 2H). ESLRMS m/z 271 (M+H). ESHRMS m/z 271.0752 (M+H, C14H11N4Cl requires 271.0750).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=2[O:2]1.[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](O)=[O:22])([O-:17])=[O:16].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(Cl)CCl>[CH2:1]1[O:2][C:3]2[C:8](=[CH:7][C:6]([C:21](=[O:22])[C:20]3[CH:24]=[CH:25][CH:26]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=3)=[C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:4]=2)[O:9]1
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCCl
Product: COC(=O)Cc1cc2c(cc1C(=O)c1cccc([N+](=O)[O-])c1)OCO2

Procedure:
The title compound was prepared from methyl 3,4-methylenedioxyphenylacetate (368 mg, 1.89 mmol) in ClCH2CH2Cl (8 mL), 3-nitrobenzoic acid (393 mg, 2.35 mmol) and P2O5 (3.2 g) as a yellow oil (500 mg, 1.46 mmol, 77%). 1H NMR (CDCl3) 8.60 (s, 1H), 8.43 (d, J=7.8, 1H), 8.13 (d, J=7.8, 1H), 7.68 (t, J=7.8, 1H), 6.86 (s, 1H), 6.82 (s, 1H), 6.07 (s, 2H), 3.87 (s, 2H), 3.63 (s, 3H).
Reaction SMILES: [ClH:1].Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:32][C:33]([O:35]CC)=[O:34])[C:10]([C:12]1[CH:13]=[CH:14][C:15]2[S:19][C:18]([CH2:20][NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[NH:30])[NH2:29])=[CH:24][CH:23]=3)=[N:17][C:16]=2[CH:31]=1)=[O:11].[OH-].[Na+]>>[ClH:1].[ClH:1].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:32][C:33]([OH:35])=[O:34])[C:10]([C:12]1[CH:13]=[CH:14][C:15]2[S:19][C:18]([CH2:20][NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[NH:29])[NH2:30])=[CH:24][CH:23]=3)=[N:17][C:16]=2[CH:31]=1)=[O:11]
Reactant: CCOC(=O)CN(C(=O)c1ccc2sc(CNc3ccc(C(=N)N)cc3)nc2c1)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N=C(N)c1ccc(NCc2nc3cc(C(=O)N(CC(=O)O)c4ccccn4)ccc3s2)cc1

Procedure:
Prepared analogously to Example 10 from 2-[N-(4-amidinophenyl)aminomethyl]benzothiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)amide dihydrochloride and sodium hydroxide solution.