Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=O)[CH:2]([CH3:4])[CH3:3].S(Cl)(Cl)(=O)=O.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22]([C:25](=[S:27])[NH2:26])=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[CH3:3][CH:2]([C:1]1[N:26]=[C:25]([C:22]2[CH:21]=[CH:20][C:19]([C:18]([F:28])([F:17])[F:29])=[CH:24][CH:23]=2)[S:27][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:4]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.1 %

Procedure:
Ethyl isobutyrylacetate (XI-3a) (3.006 g, 19.0 mmol) was dissolved in chloroform (20 mL). Sulfuryl chloride (1.70 mL, 21.2 mmol) was added and the solution was stirred at RT for 18 hours, then was concentrated. The residue was dissolved in ethanol (50 mL). 4-(Trifluoromethyl)benzenethioamide (4.234 g, 20.6 mmol) was added and the solution was heated to reflux for 24 hours. The mixture was cooled to RT and filtered. The solid was washed with cold ethanol and dried to provide the title product (2.68 g, 32%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J=8.1 Hz, 2H), 7.69 (d, J=8.1 Hz, 2H), 4.35 (q, J=7.1 Hz, 2H), 3.99 (qu, J=6.8 Hz, 1H), 1.39 (t, J=7.1 Hz, 3H), 1.35 (d, J=6.8 Hz, 6H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.[F:12][C:13]([F:35])([F:34])[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21]/[N:22]=[CH:23]/[C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)=[CH:17][CH:16]=1>C(Cl)Cl>[Cl:1][C:23](=[N:22][NH:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:13]([F:34])([F:35])[F:12])=[CH:16][CH:17]=1)[C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(/C=N/Nc2ccc(OC(F)(F)F)cc2)cc1
Solvent: ClCCl
Solvent: CSC
Product: COC(=O)c1ccc(C(Cl)=NNc2ccc(OC(F)(F)F)cc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a magnetically stirred solution of N-chlorosuccinimide (0.59 g, 4.43 mmoL) in CH2Cl2 (8 mL) at 0° C. was added dimethyl sulfide (0.85 mL, 8.87 mmoL) and the reaction mixture was stirred for 15 minutes (min) and then cooled to −78° C. To this solution was added (E)-methyl 4-((2-(4-(trifluoromethoxy)-phenyl)hydrazono) methyl)benzoate dissolved in 8 mL of CH2Cl2 and the reaction mixture was stirred at this temperature for 1 hour (h), warmed to room temperature and stirred for 2 h. The solution was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (15 mL) and added to a silica gel (SiO2) loading cartridge and purified via flash column chromatography (Gradient EtOAc/hexanes). The title compound was obtained as a yellow solid as a mixture of E and Z isomers: mp 159-162° C.; 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 8.07 (d, J=8.8 Hz, 2H), 7.98 (d, J=8.8 Hz, 2H), 7.20 (s, 4H), 3.95 (s, 3H); 19F NMR (376 MHz, CDCl3) δ−58.32; ESIMS m/z 372 ([M+H])+.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]([OH:11])=O.CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.Cl.[NH2:42][CH:43]1[CH:50]2[CH2:51][CH:46]3[CH2:47][CH:48]([CH2:52][CH:44]1[CH2:45]3)[CH2:49]2>ClCCl.CN(C=O)C.O>[CH:44]12[CH2:52][CH:48]3[CH2:47][CH:46]([CH2:51][CH:50]([CH2:49]3)[CH:43]1[NH:42][C:9]([C:3]1[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=1[Cl:1])=[O:11])[CH2:45]2
Reactant: Cc1nn(C)c(Cl)c1C(=O)O
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nn(C)c(Cl)c1C(=O)NC1C2CC3CC(C2)CC1C3
Reaction time: 1 h
Yield: 58.5 %

Procedure:
5-Chloro-1,3-dimethyl-1H-pyrazole-4-carboxylic acid (69 mg, 0.4 mmol, CAS#: 27006-82-2, purchased from Maybridge) was dissolved in a mixture of dry dichloromethane (3.2 mL) and dry DMF (0.8 mL). DIPEA (0.28 mL, 1.6 mmol) and TSTU (145 mg, 0.4 mmol) were added to the above mixture. After the mixture was stirred for 1 h, the appearance of active ester was detected by LC-MS. Then 2-aminoadamantane hydrochloride (75 mg, 0.4 mmol) was added. After another 2 hours water was added and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane. The combined organic phases were dried under vacuum and purified by C-18 reversed phase HPLC with a gradient of 10-100% acetonitrile/water to give 5-chloro-1,3-dimethyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (72 mg, 58%). Mass spectrum: m/z: 308.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].S(OC)(O[CH3:20])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:20][O:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CC(C)=CCOc1ccc(C=O)c(O)c1
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(OCC=C(C)C)ccc1C=O

Procedure:
10.6 g (206 mmol) of 2-hydroxy-4-(3methylbut-2-enyloxy)benzaldehyde and 5.4 ml of dimethyl sulfate were dissolved in 102 ml of distilled acetone, the solution was added 25.5 g of potassium carbonate, and the resulting mixture was refluxed for 5 hours. The mixture was filtered and the filtrate concentrated in vacuo to give 8.3 g of an yellow oil from which 5.4 g of 2-methoxy-4-(3-methylbut-2-enyloxy)benzaldehyde was isolated by column chromatography over silica gel 60 (Merck 0.063-0.200 mm, 400 g) using petroleum ether-ethyl acetate (9:1, 1000 ml), (4:1, 500 ml) as eluents.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH2:14][CH:15]=[CH2:16])=[CH:11][CH:10]=[CH:9][CH:8]=2)=O.[BH4-].[Li+].Cl.C(=O)(O)[O-].[Na+]>O1CCCC1.O>[CH2:14]([C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH2:3][OH:2])[CH:15]=[CH2:16]
Reactant: C=CCc1c(C(=O)OC)[nH]c2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCc1c(CO)[nH]c2ccccc12
Yield: 98.3 %

Procedure:
The mixture of 3-allyl-2-indolecarboxylic acid methyl ester (13.1 g) and lithium borohydride (2.65 g) in tetrahydrofuran (100 ml) was refluxed for 3 hours. After cooling, the reaction mixture was diluted with chilled water, made acidic with 2N-hydrochloric acid. The mixture was neutralized with aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give 3-allyl-2-hydroxymethylindole (11.2 g) as an oil. The oil was used in the next reaction without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[N:15][C:14]([CH2:17][NH:18][CH:19]3[CH2:22][CH2:21][CH2:20]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:23]([C:27]1[CH:28]=[C:29]2[C:34](=[C:35]([F:37])[CH:36]=1)[C:33](=[O:38])[N:32]([C:39]1[CH:49]=[CH:48][CH:47]=[C:46](B3OC(C)(C)C(C)(C)O3)[C:40]=1[CH2:41][O:42]C(=O)C)[N:31]=[CH:30]2)([CH3:26])([CH3:25])[CH3:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[OH-].[Na+]>C(O)CCC.O>[C:23]([C:27]1[CH:28]=[C:29]2[C:34](=[C:35]([F:37])[CH:36]=1)[C:33](=[O:38])[N:32]([C:39]1[CH:49]=[CH:48][CH:47]=[C:46]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[CH:16]=[N:15][C:14]([CH2:17][NH:18][CH:19]5[CH2:22][CH2:21][CH2:20]5)=[CH:13][N:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=3)[C:40]=1[CH2:41][OH:42])[N:31]=[CH:30]2)([CH3:26])([CH3:24])[CH3:25]
Reactant: Cn1nc(Cl)cc(Nc2cnc(CNC3CCC3)cn2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: Cn1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2cnc(CNC3CCC3)cn2)c1=O
Temperature: 110 °C
Reaction time: 3 h
Yield: 25.9 %

Procedure:
In a 15 mL microwave reaction vial was added 6-chloro-4-(5-cyclobutylaminomethyl-pyrazin-2-ylamino)-2-methyl-2H-pyridazin-3-one (71 mg, 221 μmol, Eq: 1.00) in 7 mL n-butanol and 1.4 mL water. Argon was bubbled through the reaction mixture. To the reaction was added acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester (218 mg, 309 μmol, Eq: 1.39), potassium phosphate tribasic (103 mg, 487 μmol then X-PHOS (15.8 mg, 33.2 μmol, Eq: 0.15). The mixture was purged with argon and (dibenzylideneacetone)palladium (9.55 mg, 16.6 μmol, Eq: 0.075) was added. The tube was sealed and heated at 110° C. (bath temp) for 3 hrs. The reaction mixture was allowed to cool to room temperature, a solution of NaOH (189 mg) in water (1.5 mL) was added and the mixture was stirred in an oil bath at 37° C. for 3 hrs. The crude reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (3×10 mL). The organic phase was concentrated and chromatographed on silica gel eluting with 5-10% (10% in NH4OH in MeOH) in (1/1) EtOAc/n-heptane to give a pure fraction (pale yellow) and mixed fractions (yellow). The pure fraction was concentrated and dissolved in DCM. Methanol was added to make a 10% solvent mixture of MeOH in DCM. Heptane was added which resulted in immediate precipitation of solid. The suspension was allowed to sit at room temperature overnight and the resultant solid was filtered, washed with n-heptane and dried to afford 35 mg (25%) of the title compound as an off-white solid. mp: 163-167° C.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22]C)[CH:18]=3)[C:13]=2[O:24][C:25]2[CH:39]=[CH:38][C:28]([O:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:27][CH:26]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>ClCCl.CO.C(OCC)(=O)C.[Cl-].[Na+].O>[CH3:2][S:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[C:13]([O:24][C:25]3[CH:39]=[CH:38][C:28]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:27][CH:26]=3)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15]3)=[CH:10][CH:11]=1)(=[O:5])=[O:4]
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Temperature: 3 °C
Reaction time: 0.08 h
Yield: 84.6 %

Procedure:
Dissolve the product of Example 2 (6.45 g, 11.4 mmol) in dichloromethane (200 mL) and cool to 3° C. in an ice bath. Treat this solution with neat BBr3 (5.4 mL, 57 mmol), dropwise over 5 minutes, and stir for 3 hours at 0 to 10° C. Slowly pour the reaction mixture into a 1-liter separatory funnel containing saturated aqueous NaHCO3 (300 mL) and ice. Dilute the two-phase mixture with a solution of 7.5% MeOH in ethyl acetate (EtOAc, 400 mL) and brine (100 mL). Separate the layers and back extract the aqueous layer with 5% MeOH in EtOAc (2×150 mL). Wash the combined organic layers with brine (100 mL), dry (Na2SO4), filter and evaporate to obtain 5.3 g of crude product. Chromatograph the residue on a SiO2 column eluting the material with methanol in dichloromethane (2.5 to 12%) to give 4.99 grams of the title compound (85%). Dry at 45° C. (<2 mm of Hg) for 18 hours: mass spectrum (ion spray): m/z=518.3 (M+H).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[F:12][C:13]1[CH:14]=[C:15]([CH:32]=[CH:33][CH:34]=1)[O:16][C:17]1[C:18]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[C:19]2[CH:25]=[N:24][NH:23][C:20]2=[N:21][CH:22]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:57]([O:61][C:62]([N:64]([CH:77]([CH3:79])[CH3:78])[CH2:65][C@H:66]([C:70]1[CH:75]=[CH:74][C:73]([Cl:76])=[CH:72][CH:71]=1)[C:67](O)=[O:68])=[O:63])([CH3:60])([CH3:59])[CH3:58]>C(Cl)Cl>[Cl:76][C:73]1[CH:74]=[CH:75][C:70]([C@H:66]([C:67]([N:29]2[CH2:30][CH2:31][N:26]([C:18]3[C:17]([O:16][C:15]4[CH:32]=[CH:33][CH:34]=[C:13]([F:12])[CH:14]=4)=[CH:22][N:21]=[C:20]4[NH:23][N:24]=[CH:25][C:19]=34)[CH2:27][CH2:28]2)=[O:68])[CH2:65][N:64]([CH:77]([CH3:78])[CH3:79])[C:62](=[O:63])[O:61][C:57]([CH3:59])([CH3:58])[CH3:60])=[CH:71][CH:72]=1
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: Fc1cccc(Oc2cnc3[nH]ncc3c2N2CCNCC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(Oc3cccc(F)c3)cnc3[nH]ncc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
DIEA (0.0271 mL, 0.155 mmol) was added to 5-(3-fluorophenoxy)-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (0.015 g, 0.0388 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.0150 g, 0.0466 mmol) and (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.0133 g, 0.0388 mmol, see Example B) in DCM (1 mL) and stirred at room temperature for 30 minutes. The reaction was then concentrated to dryness. The resulting residue was dissolved in THF/MeOH (2 mL, 1:1), and an aqueous LiOH solution (1 mL, 2M) was added. The reaction was stirred for 30 minutes, and then ether (20 mL) was added. The organic layer was separated, washed with brine (10 mL), and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by column chromatography (hexane:ethyl acetate, 1:1) to give (S)-tert-butyl 2-(4-chlorophenyl)-3-(4-(5-(3-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate as a solid. The solid was dissolved in DCM (1 mL), and TFA (0.4 mL) was added. The reaction was stirred at room temperature for 30 minutes and concentrated to dryness. The residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The resulting solid was collected by filtration to give (S)-2-(4-chlorophenyl)-1-(4-(5-(3-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (0.006 g, 25%). MS APCI (+) m/z 537.3 detected.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Cl:11][C:12]1[CH:13]=[C:14]([S:19](Cl)(=[O:21])=[O:20])[CH:15]=[C:16]([Cl:18])[CH:17]=1.O.C(OCC)(=O)C>N1C=CC=CC=1>[Cl:18][C:16]1[CH:15]=[C:14]([S:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)(=[O:20])=[O:21])[CH:13]=[C:12]([Cl:11])[CH:17]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(Nc1ccc2[nH]ccc2c1)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.5 g 5-aminoindole are dissolved in 25 ml of pyridine. To this are added 4.64 g of 3,5-dichlorophenylsulphonyl chloride and the mixture is stirred for 4 hours at ambient temperature. The solvent is eliminated in vacuo and the residue is divided between water and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 10:1 to 1:5).
Reaction SMILES: [CH2:1]([OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C([OH:19])(C)C>CC(C)=O.OS(O)(=O)=O>[C:1]([OH:19])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCC#CCCCCCCO
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CCCCCCC#CCCCCCC(=O)O
Reaction time: 30 h

Procedure:
A solution of 7-tetradecyne-1-ol (2.10 g) in acetone (100 ml) was added dropwise to a vigorously stirred solution of 20 ml of 1M CrO3 in 10N H2SO4 cooled in ice. The addition took 30 hours after which 5 ml of isopropyl alcohol was added and the reaction mixture was filtered. The filtrate was diluted with 50 ml of water and extracted five times with ether. The combined organic phases were washed with water and saturated NaCl solution. The ether solution was then washed two times with 2N NaOH. The combined basic washes were extracted again with ether and acidified with 6 N HCl. Extraction with CHCl3 (3 times), drying (MgSO4) and removal of solvent under reduced pressure gave 1.95 g of 7-tetradecynoic acid as a yellow oil, which solidified on standing.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:10]=[C:9]([Cl:11])[C:6]([CH2:7]Cl)=[C:5]([NH2:12])[CH:4]=1.Cl[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(Cl)(Cl)Cl.CO.Cl>ClC1C=CC=CC=1.C(O)C>[Cl:11][C:9]1[CH:10]=[C:3]([Cl:2])[CH:4]=[C:5]2[C:6]=1[CH2:7][N:15]1[CH:14]=[CH:19][CH:18]=[CH:17][C:16]1=[N:12]2
Reactant: Nc1cc(Cl)cc(Cl)c1CCl
Reactant: Clc1ccccn1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1
Solvent: CCO
Product: Clc1cc(Cl)c2c(c1)N=C1C=CC=CN1C2

Procedure:
Five grams of the above solid 4,6-dichloro-2-aminobenzyl chloride hydrochloride was heated with 10 mL of 2-chloropyridine in 25 mL of chlorobenzene. The reaction was followed by TLC (300:20:1 chloroform/methanol/28% aqueous ammonia). When the reaction was complete, the reaction mixture was concentrated in vacuo (cold trap). The residue was basified with saturated aqueous potassium carbonate and distributed between 50 mL of chloroform and 50 mL of water. The chloroform layer was separated, dried with anhydrous potassium carbonate and concentrated in vacuo. The brown residue was chromatographed using the above solvent system and the appropriate fractions were concentrated in vacuo to give a yellow solid. This was treated with one equivalent of 4N hydrochloric acid and coevaporated with 50 mL of absolute ethanol. The residue was recrystallized from absolute ethanol-ethyl acetate mixture to give the hydrochloride of 1,3-dichloro-11H-pyrido[2,1-b]quinazoline.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([O-:13])=O)=[N:9][CH:10]=1)=[O:4].[K+].S(Cl)(Cl)=O.[CH:19]([N:22]([CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:24][NH2:25])([CH3:21])[CH3:20].C(N(CC)CC)C>ClC(Cl)C.C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:6]=[CH:7][C:8]([C:11](=[O:13])[NH:25][CH2:24][CH2:23][N:22]([CH:26]([CH3:28])[CH3:27])[CH:19]([CH3:21])[CH3:20])=[N:9][CH:10]=1
Reactant: COC(=O)c1ccc(C(=O)[O-])nc1
Reactant: CC(C)N(CCN)C(C)C
Agent: [K+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)NCCN(C(C)C)C(C)C)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74 %

Procedure:
A suspension of 1.1 g (5 mmol) potassium 5-methoxycarbonyl-pyridine-2-carboxylate, 0.9 ml (12 mmol) thionyl chloride and 0.1 ml DMF in 5 ml dichloroethane was heated at reflux for 2 h. To the reaction mixture 5 ml CH2Cl2 were added and the solvent was evaporated. This procedure was repeated three times. The residue was suspended in 5 ml CH2Cl2 and a solution of 9.95 ml (5.5 mmol) 2-diisopropylaminoethylamine, 0.97 ml (7 mmol) triethylamine, 0.1 ml DMF in 5 ml CH2Cl2 was added under ice-cooling. After stirring for 12 h at rt the organic phase was extracted with water, 5% citric acid and aqueous NaHCO3 and dried over magnesium sulfate. After evaporation of the solvent the residue was subjected to silica gel chromatography (20% MeOH and 1% triethylamine in ethyl acetate) to yield 1.15 g (3.7 mmol) 6-(2-diisopropylamino-ethylcarbamoyl)-nicotinic acid methyl ester; exact MW [M+H] calcd: 308.20; MW .found [M+H]: 308.20.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][C:12]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[N:13][C:14]#[N:15].[Na].ClC1C=CC=CC=1NC(NC#N)=S.OC1C([N+:46]([O-:48])=[O:47])=CC=CC=1N.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CC(C)=O.C(Cl)(Cl)Cl>[OH:1][C:2]1[CH:7]=[C:6]([N+:46]([O-:48])=[O:47])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[N:13][C:14]#[N:15]
Reactant: Nc1cccc([N+](=O)[O-])c1O
Reactant: N#CN=C(Nc1ccccc1Cl)Nc1cccc([N+](=O)[O-])c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N#CNC(=S)Nc1ccccc1Cl
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: N#CN=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Sodium (1.64 g, 71.3 mmol) was dissolved in ethanol until all gas evolution had ceased. Then cyanamide (1.685 g, 40 mmol) was added. The reaction mixture was stirred for 15 min, 2-chlorophenylisothiocyanate (7.21 g, 42.66) was added and the mixture kept at reflux for 6 hr. The reaction was cooled and diluted with methylene chloride. A white solid precipitated which was filtered and dried to give the sodium salt of N-(2-chlorophenyl)-N″-cyanothiourea. ( 8.26 g, 87.5%). MS(ES+) m/e 210,212 [M+H]+b) N-(2-Hydroxy-3-nitrophenyl)-N′-(2-chlorophenyl)-N″-cyanoguanidine To a stirred solution of the sodium salt of N-(2-chlorophenyl)-N′-cyanothiourea (234 mg, 1 mmol) and 2-hydroxy-3-nitro-aniline(156 mg, 1 mmol) in 2 ml dry DMF was added EDC hydrochloride (384 mg, 2 mmol) under Ar and the reaction stirred at rt for 4 d. The reaction mixture was partitioned between EtOAc and 1 N HCl and the organic extracts were washed with water and brine. After drying (Na2SO4) and evaporation of the solvent under reduced pressure, a red oil was isolated. Chromatography (silica gel, 3% acetone/CHCl3) afforded a bright yellow solid.(30 mg, 9%) which was recrystallized from t-butylmethylether to afford the title compound. 1H NMR(400 MHz, CDCl3) δ 10.93 (s, 1H), 8.53 (s, 1H), 7.92 (d, J=7.8 Hz, 1H),7.61 (d, J=7.8 Hz, 2H), 7.38-7-50 (m, 2H), 7.22 (s, 1H), 7.08 (t, 1H); IR(KBr) 2181 cm−1; MS(ES−) m/e 330[M−H]−; mp. 163-164°.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([OH:29])=O)[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[C:51]([O:55][C:56](=[O:59])[CH2:57][NH2:58])([CH3:54])([CH3:53])[CH3:52]>CN(C=O)C.C(Cl)CCl>[C:51]([O:55][C:56](=[O:59])[CH2:57][NH:58][C:27]([C:18]1[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@H:8]2[C:6](=[O:7])[NH:5][CH:1]2[CH2:2][CH2:3][CH2:4]2)=[O:30])[N:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:19]=1)=[O:29])([CH3:54])([CH3:53])[CH3:52]
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reaction time: 12 h

Procedure:
To a solution of 920 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 46 ml DMF were added 342 mg HOBt, 428 mg EDC, 0.78 ml DIPEA and 374 mg glycine tert-butyl ester hydrochloride. After stirring for 12 h it was concentrated and the residue dissolved in dichloromethane. It was extracted with aqueous LiCl (4% w/w), aqueous NaHCO3 and 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated to furnish the crude coupling product as colorless oil.