Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl.N1C=CC=CC=1>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:3][C:2]=1[NH:1][S:14]([CH3:13])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)Cc1ccc(Cl)c(N)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Cc1ccc(Cl)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1-(3-Amino-4-chloro-phenyl)-propan-2-one (Intermediate D) (0.5 g, 2.73 mmol) in DCM (2 ml) and pyridine (1 ml) is added drop wise methanesulfonyl chloride (0.34 g, 0.23 ml, 3.0 mmol) at 0° C. (ice-bath). The reaction mixture is allowed to warm to room temperature and stirred for 3 days. The solvents are removed in vacuo and the residue is dissolved in EtOAc and washed with water, the organic portion is dried over MgSO4, filtered and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica eluting with EtOAc affords the title compound.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:25])[C@@H:6]([CH3:24])[CH2:7][CH:8]([NH2:23])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:12][CH:11]=1)[CH3:3].[O:26]1[C:30](=[O:31])[CH2:29][CH2:28][C:27]1=[O:32].N1C=CC=CC=1.Cl>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:25])[C@H:6]([CH3:24])[CH2:7][C@H:8]([NH:23][C:30](=[O:31])[CH2:29][CH2:28][C:27]([OH:32])=[O:26])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:12][CH:11]=1)[CH3:3]
Reactant: O=C1CCC(=O)O1
Reactant: CCOC(=O)[C@@H](C)CC(N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)CCC(=O)O
Reaction time: 2 h
Yield: 21.6 %

Procedure:
To a stirred solution of (S)-4-Amino-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester hydrochloric acid salt (200 mg, 0.52 mmol) and dihydrofuran-2,5-dione (68 mg, 0.68 mmol) in 8 ml CH2Cl2 was added pyridine (0.17 ml, 2.1 mmol) and the solution was stirred for 2 hours. The reaction mixture was acidified to pH=3 with 1M HCl. Solvent was removed under reduced pressure and the residue was purified by preparatory HPLC (DAICEL CHIRALCEL OD-H 21×250 mm column, 18 ml/min, 90% heptane 10% EtOH+0.1% TFA), collected a peak at 3.9 minutes, to give 50 mg (2R,4S)-4-(3-carboxy-propionylamino)-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester. MS m/z 446.3 (M+H), 444.3 (M−H). LC/MS (Condition A): 1.52 min. 1H NMR (400 MHz, DMSO-d6): 1.04-1.05 (d, J=7.07 Hz, 3H), 1.09-1.13 (t, J=7.07 Hz, 3H), 1.34-1.42 (m, 1H), 1.72-1.79 (m, 1H), 2.24-2.29 (m, 2H), 2.36-2.40 (m, 21-9, 2.64-2.74 (m, 2H), 3.33 (s, 1H), 3.86-3.93 (m, 1H), 3.95-4.01 (q, J=7.33 Hz, 14.40 Hz, 2H), 7.25-7.27 (m, 2H), 7.39-7.41 (m, 1H), 7.46-7.50 (t, J=7.58 Hz, 1H), 7.61-7.64 (m, 3H), 7.70 (t, J=1.77 Hz, 1H), 7.75-7.77 (d, J=8.59 Hz, 1H), 12.08 (br s, 2H).
Reaction SMILES: CS([C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH2:8])(=O)=O.[CH3:15][S:16](Cl)(=[O:18])=[O:17].[C:20]([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH3:20][C:5]1[CH:6]=[C:7]([NH:8][S:16]([CH3:15])(=[O:18])=[O:17])[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)c1cc(N)cc([N+](=O)[O-])c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1cc(NS(C)(=O)=O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43 %

Procedure:
3-methylsulfonyl-5-nitro-aniline (0.26 g; 1.2 mmol) was dissolved in pyridine (10 ml). A solution of methanesulfonylchloride (0.2 mL; 2.4 mmol) in 2 mL of pyridine was added and the reaction mixture was stirred for 12 hours at ambient temperature. NaHCO3 solution was added and the mixture extracted with dichloromethane. The aqueous phase was acidified and extracted with ethyl acetate. The organic phase was dried and concentrated. 0.12 g (0.5 mmol; 43% yield) of N-(3-methyl-5-nitro-phenyl)-methylsulfonamide were obtained as a yellow solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[H-].[Na+].[N+:16]([C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][Cl:22])([O-:18])=[O:17].Cl>CO.CCOCC>[ClH:22].[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N+:16]([O-:18])=[O:17])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccccc1CCl
Reactant: Oc1ccc(Cc2ncc[nH]2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: O=[N+]([O-])c1ccccc1COc1ccc(Cc2ncc[nH]2)cc1

Procedure:
Analogously to Example 1, a crude ether is obtained from 1.74 g. of 4-(1-imidazolylmethyl)-phenol, 300 mg. of sodium hydride suspension, and 1.72 g. of 2-nitrobenzyl chloride. This crude ether is dissolved in methanol and combined with an excess of methanol which contains hydrogen chloride until the mixture shows an acidic reaction. After the solvent has been removed by evaporation under vacuum, the residue is dissolved in methylene chloride and mixed with ether until the onset of crystallization, thus obtaining 925 mg. of [4-(1-imidazolylmethyl)-phenyl]-(2-nitrobenzyl)-ether, hydrochloride, which melts at 156°-158° after another recrystallization from isopropanol.
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5]([O:8]C)O1.Cl.[CH2:11]1[N:16]([CH2:17][CH2:18][NH2:19])[CH2:15][CH2:14][O:13][CH2:12]1.[CH2:20]([C:27](O)=O)[C:21](CC(O)=O)=O.[OH-].[Na+]>O>[O:13]1[CH2:14][CH2:15][N:16]([CH2:17][CH2:18][N:19]2[CH:7]3[CH2:3][CH2:27][CH:20]2[CH2:21][C:5](=[O:8])[CH2:6]3)[CH2:11][CH2:12]1
Reactant: NCCN1CCOCC1
Reactant: COC1CCC(OC)O1
Reactant: O=C(O)CC(=O)CC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1CC2CCC(C1)N2CCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 16.2 ml of 2,5-dimethoxytetrahydrofuran in 50 ml of water was added 6 ml of conc. hydrochloric acid. The mixture was stirred at room temperature for 20 minutes. Thereafter, 150 ml of water, 25 ml of 1-(2-aminoethyl)morpholine, 20 ml of conc. hydrochloric acid and 20.1 g of 1,3-acetonedicarboxylic acid were successively added to the reaction mixture. Furthermore, a solution of 8.8 g of Na2HPO4 and 2.5 g of sodium hydroxide in 100 ml of water was added to the mixture. Thereafter the pH was adjusted to the range of 2 to 3. After stirring overnight at room temperature, the reaction solution was washed with chloroform. Potassium carbonate was added to the mixture to render alkaline, followed by extraction with chloroform. The organic layer was washed with water and then dried over anhydrous sodium sulfate. The solvent was then distilled off. The residue was purified by silica gel column chromatography (chloroform:NH3 -saturated methanol=20:1) to give 26.7 g of 8-(2-morpholinoethyl)-8-azabicyclo[3.2.1]octan-3-one.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH+:2]=1.[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:16][CH:17]=1.[CH3:22]O>>[C:12]1([CH3:11])[CH:13]=[CH:14][C:15]([S:18]([O-:21])(=[O:19])=[O:20])=[CH:16][CH:17]=1.[CH2:22]([N+:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: C1=[NH+]CCc2ccccc21
Reactant: CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCCC[N+]1=Cc2ccccc2CC1
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
3,4-Dihydroisoquinolinium (1.31 g, 10.0 mmol) was dissolved in 3 ml MeOH in a 3-neck 25 mi round bottom flask fitted with a condenser, drying tube and stirrer bar, and cooled in an ice bath. n-Octyt p-toluenesulfonate (2.84 g, 10.0 mmol)*, dissolved in 7.0 ml methanol, was added dropwise over about 7 minutes via an addition funnel. The ice bath was removed and replaced with an oil bath and the colorless clear solution heated to reflux for at least 8 hours during which time the reaction solution lo turned yellow. Removal of the methanol in vacuo gave slightly colored solid product which was triturated with about 7.5 ml acetone. The acetone insoluble solids were filtered, washed with more acetone and dried in a vacuum desiccator. Yield of colorless solids was 1.91 g. A second batch of solids was recovered from the acetone flitrate/washing and filtered, washed with acetone and dried to give 0.31 gm colorless solids. 1H NMR (CDCl3, 200 MHz) δ 9.70 (1H, s, C1), 7.00-8.10 (8H, m), 4.20 (2H, t) 4.00 (2H, t), 3.25 (2H, t), 2.30 (3H, s), 1.80 (2H, m), 1.20 (10H, m), 0.87 (3H, t)
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([CH2:19][CH3:20])[CH:17]=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>>[CH2:9]([N:8]([C@H:16]([C@H:17]([OH:18])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])[CH2:19][CH3:20])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Reactant: CCCCCCCCCCCCCCCBr
Product: CCCCCCCCCCCCCCC[C@@H](O)[C@H](CC)N(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 6 (1.0 g, 3.7 mmol) and 1-bromopentadecane (6.55 g, 22.5 mmol), alcohol 56 was obtained as a colorless oil (800 mg, 45% yield).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[C:7]([N:11]1[C:17](=[O:18])[C:16]2[CH:19]=[C:20](I)[CH:21]=[CH:22][C:15]=2[NH:14][C:13](=[O:24])[CH2:12]1)([CH3:10])([CH3:9])[CH3:8].C(OCC)(=O)C>C(N(CC)CC)C.[Cu]I.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>[C:7]([N:11]1[C:17](=[O:18])[C:16]2[CH:19]=[C:20]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:21]=[CH:22][C:15]=2[NH:14][C:13](=[O:24])[CH2:12]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)N1CC(=O)Nc2ccc(I)cc2C1=O
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)N1CC(=O)Nc2ccc(C#C[Si](C)(C)C)cc2C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.8 %

Procedure:
(Trimethylsilyl)acetylene (1.18 mL, 8.4 mmol), copper(I) iodide (0.05 g, 0.28 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.1 g, 0.14 mmol) are added sequentially to a degassed suspension of 4-tert-butyl-3,4-dihydro-7-iodo-1H-1,4-benzodiazepine-2,5-dione (2.5 g, 7.0 mmol) in triethylamine. The reaction mixture is stirred at room temperature for 5 hours and filtered. The filtrate is diluted with ether and concentrated in vacuo to obtain a solid. Chromatography of the solid using silica gel and 15% to 20% ethyl acetate in hexanes solutions gives the title product as a light brown solid (1.33 g, mp 243°-244° C.).
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[O:11][C:12]([CH2:15][NH:16][C:17]([NH2:19])=[S:18])=[CH:13][CH:14]=2)[N:9]=1)[NH2:3].[CH3:20][I:21]>CO>[IH:21].[NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[O:11][C:12]([CH2:15][N:16]=[C:17]([NH2:19])[S:18][CH3:20])=[CH:13][CH:14]=2)[N:9]=1)[NH2:3]
Reactant: CI
Reactant: NC(=S)NCc1ccc(-c2csc(N=C(N)N)n2)o1
Solvent: CO
Product: CSC(N)=NCc1ccc(-c2csc(N=C(N)N)n2)o1
Product: I
Temperature: 25 °C
Reaction time: 34 h
Yield: 87.9 %

Procedure:
A suspension of 2-(diaminomethyleneamino)-4-(5-thioureidomethylfuran-2-yl)thiazole (1.0 g) and methyl iodide (600 mg) in methanol was stirred at room temperature for 34 hours. The solvent was removed under reduced pressure to afford 2-(diaminomethyleneamino)-4-[5-(2-methyl-3-isothioureido)methylfuran-2-yl]thiazole hydriodide (1.3 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[N:13]([C:14]3[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[N:12]=[C:11]([C:22]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH:10]=2)[CH:4]=1)#N.[OH-:30].[Na+].C[OH:33]>O1CCCC1>[CH3:21][O:20][C:17]1[N:16]=[CH:15][C:14]([N:13]2[C:9]([C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][N:6]=3)[C:1]([OH:33])=[O:30])=[CH:10][C:11]([C:22]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)=[O:23])=[N:12]2)=[CH:19][CH:18]=1
Reactant: CO
Reactant: COc1ccc(-n2nc(C(=O)N3CCCCC3)cc2-c2cc(C#N)ccn2)cn1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C(=O)N3CCCCC3)cc2-c2cc(C(=O)O)ccn2)cn1
Yield: 52 %

Procedure:
To a solution of 1-[5-(4-cyano-2-pyridyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]piperidine (0.418 g) obtained in Example 98 in a mixture of methanol (8.4 mL) and tetrahydrofuran (8.4 mL), 1N aqueous sodium hydroxide (5.38 mL) was added at room temperature. The resultant mixture was stirred at 80° C. for 7 hours, and then cooled in air. The reaction mixture was partitioned between water and chloroform. The aqueous layer was neutralized to pH 6 with 1N aqueous hydrochloric acid. Chloroform was added for partitioning to the aqueous layer. The aqueous layer was further extracted with chloroform. The organic layers were combined and dried over sodium sulfate anhydrate. After filtration, the solvent was removed under reduced pressure, to thereby give the title compound as a solid (0.239 g, 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:22]([F:25])([F:24])[F:23])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[C:26]([O:30][C:31]([NH:33][CH2:34][C:35](OC1C=CC([N+]([O-])=O)=CC=1)=[O:36])=[O:32])([CH3:29])([CH3:28])[CH3:27].[F-].[K+].C1OCCOCCOCCOCCOCCOC1.CCN(C(C)C)C(C)C>C(#N)C.C(Cl)Cl>[Cl:9][C:6]1[CH:5]=[C:4]([CH:10]([C:22]([F:24])([F:23])[F:25])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:35](=[O:36])[CH2:34][NH:33][C:31](=[O:32])[O:30][C:26]([CH3:27])([CH3:28])[CH3:29])[CH:17]=[CH:16]3)[CH:3]=[C:2]([Cl:1])[C:7]=1[F:8]
Reactant: Fc1c(Cl)cc(C(/C=C/c2ccc3[nH]ccc3c2)C(F)(F)F)cc1Cl
Reactant: CC(C)(C)OC(=O)NCC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCC(=O)n1ccc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indole (0.1 g, 0.258 mmol) in acetonitrile (5.0 mL) was added 4-nitrophenyl 2-(tert-butoxycarbonylamino)acetate (0.114 g, 0.387 mmol), potassium fluoride (0.03 g, 0.516 mmol), 18-crown-6-ether (0.075 g, 0.283 mmol) and DIEA (0.0332 g, 0.258 mmol) and the reaction was stirred at RT for 16 h. The reaction mixture was concentrated to obtain a residue which was diluted with DCM and washed with water and brine solution. The separated DCM layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude title compound as a light brown gummy material which was used in the next step without further purification (0.1 g): ESIMS m/z 545.23 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:13]2[N+:14]([O-])=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N:4][C:5]([CH2:8][O:9][C:10](=[O:12])[CH3:11])=[CH:6][CH:7]=1.P(Cl)(Cl)Cl.O>C1C=CC=CC=1>[CH3:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:4][C:5]([CH2:8][O:9][C:10](=[O:12])[CH3:11])=[CH:6][CH:7]=1
Reactant: CC(=O)OCc1ccc(C)c(-c2cccc[n+]2[O-])n1
Solvent: c1ccccc1
Solvent: ClP(Cl)Cl
Solvent: O
Product: CC(=O)OCc1ccc(C)c(-c2ccccn2)n1
Temperature: 23 °C

Procedure:
2.1 g (8.1 mmols) of 3-methyl-6-acetoxymethyl-2,2'-bipyridine 1'-oxide are dissolved in 20 ml of benzene at 45° C., and 1.43 g (10.4 mmols) of phosphorus trichloride are added dropwise under an atmosphere of nitrogen. Subsequently, the mixture is boiled under reflux for 30 minutes. After cooling to 23° C., 35 ml of water are added and the benzene phase is separated off. The water phase is washed with twice 15 ml of ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. After distillation in a bulb tube oven at 125° C./0.13 Pa, 1.51 g (77% of theory) of 3-methyl-6-acetoxymethyl-2,2'-bipyridine are obtained in the form of a colourless oil.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.CC1(C)C(C)(C)OB([C:40]2[CH:48]=[CH:47][C:43]3[N:44]=[CH:45][S:46][C:42]=3[CH:41]=2)O1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[S:46]1[C:42]2[CH:41]=[C:40]([C:2]3[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:3]=3)[CH:48]=[CH:47][C:43]=2[N:44]=[CH:45]1
Reactant: CC1(C)OB(c2ccc3ncsc3c2)OC1(C)C
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: COCCOC
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2ncsc2c1
Yield: 39.3 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.08 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 mg; 0.025 mmol), N,N-diisopropylethylamine (0.173 mL; 1 mmol) and intermediate 19 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (0.098 g; 0.5 mmol) in DME-water (1 mL) for 20 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (5-40%) in heptane furnished 0.041 g (39%) of the title compound.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Cl[CH2:14][C:15]1[N:16]=[C:17]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C)C=O>[C:1]1(=[O:11])[N:5]([CH2:14][C:15]2[N:16]=[C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:18][C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCc1nc(-c2ccccc2)oc1-c1ccccc1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1nc(-c2ccccc2)oc1-c1ccccc1

Procedure:
A solution of potassium phthalimide (10 g, 54 mmoles) and 4-chloromethyl-2,5-diphenyloxazole (10.4 g, 40 mmoles) in 80 cc of dimethylformamide was heated at 100° C. for 2 hours. When the solution was cooled to room temperature 300 cc of water was added. The solution was extracted with chloroform several times. The combined chloroform solution was washed with 20-30 ml of 0.2N sodium hydroxide and finally with water. After drying over sodium sulfate the chloroform was concentrated. The product precipitated out.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:22][C:23](=[O:31])[CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@H:14](OS(C)(=O)=O)[CH2:13]1)[CH:6]=[CH:5]2.[CH3:32][NH2:33]>C(O)C>[Cl:1][C:2]1[C:3]([NH:22][C:23](=[O:31])[CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@@H:14]([NH:33][CH3:32])[CH2:13]1)[CH:6]=[CH:5]2
Reactant: CS(=O)(=O)O[C@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Reactant: CN
Solvent: CCO
Product: CN[C@@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Temperature: 80 °C

Procedure:
To a 10 mL vial was added N-[6-Chloro-2-[(3S)-3-[(methylsulfonyl)oxy]-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide (Example 33(a)) (225 mg) and 8M methylamine in ethanol (6 mL). The vial was sealed and heated at 80° C. for 120 minutes within a microwave. The solvent was removed under vacuum and purified (SiO2, ammonia:methanol:dichloromethane, 1:2:97 as eluant) to afford the titled compound (0.033 g).
Reaction SMILES: [CH:1]1[C:6]2=[C:7]3[C:16](=[CH:17][CH:18]=[C:5]2[CH:4]=[CH:3][N:2]=1)[N:15]=[C:14]1[C:9]([C:10]([C:19](O)=[O:20])=[CH:11][CH:12]=[CH:13]1)=[N:8]3.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH:26][C:19]([C:10]1[C:9]2[C:14](=[N:15][C:16]3[C:7]([N:8]=2)=[C:6]2[CH:1]=[N:2][CH:3]=[CH:4][C:5]2=[CH:18][CH:17]=3)[CH:13]=[CH:12][CH:11]=1)=[O:20]
Reactant: O=C(O)c1cccc2nc3ccc4ccncc4c3nc12
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)c1cccc2nc3ccc4ccncc4c3nc12

Procedure:
Pyrido [3,4-α]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide was prepared from pyrido[3,4-α]phenazine-11-carboxylic acid (II.2) and N,N-dimethylethylenediamine
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[CH:2]1.Cl.[CH2:15](OCC)[CH3:16]>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([O:13][CH2:15][CH3:16])=[O:12])=[CH:2]1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: CCOCC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cc1c[nH]c2ccccc12
Yield: 158.3 %

Procedure:
Indole-3-acetic acid (3.5 g, 20 mmol) was dissolved in ethanol (70 Cm3) and a solution of hydrogen chloride in diethyl ether (12 cm3, 12 mmol) was added. The reaction was heated to reflux for 5 hand upon cooling the solvent was removed under reduced pressure to provide ethyl indole-3-acetate (4 g, 19 mmol, 98%) as a yellow oil.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([OH:41])[CH2:27][CH2:26][N:25]([C:28]3[CH:29]=[CH:30][C:31]4[N:32]([C:34]([C:37]([F:40])([F:39])[F:38])=[N:35][N:36]=4)[N:33]=3)[CH2:24][CH2:23]2)=[CH:18][CH:17]=1.[CH3:42][N:43]1[C:47]([CH2:48][CH2:49]OC2C=CC(C3CCN(C4CCC5N(C(C(F)(F)F)=NN=5)N=4)CC3)=CC=2)=[CH:46][CH:45]=[N:44]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:42][N:43]1[C:47]([CH2:48][CH2:49][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3([OH:41])[CH2:27][CH2:26][N:25]([C:28]4[CH:29]=[CH:30][C:31]5[N:32]([C:34]([C:37]([F:40])([F:39])[F:38])=[N:35][N:36]=5)[N:33]=4)[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)=[CH:46][CH:45]=[N:44]1
Reactant: Oc1ccc(C2(O)CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: Cn1nccc1CCOc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1nccc1CCOc1ccc(C2(O)CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.1 %

Procedure:
DIAD (0.311 mL, 1.58 mmol) was added dropwise to 4-(4-hydroxyphenyl)-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol (500 mg, 1.32 mmol), 2-(1-methyl-1H-pyrazol-5-yl)ethanol (obtained as described in Example 15, preparation of starting materials) (249 mg, 1.98 mmol) and triphenylphosphine (519 mg, 1.98 mmol) in THF (10 mL) under nitrogen. The resulting suspension was stirred at ambient temperature for 16 hours then the solvents were evaporated to give crude product. The crude product was purified by flash silica chromatography, eluting with EtOAc then a gradient of 3 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to give a solid which was triturated with ether, filtered and dried to give 4-[4-[2-(1-methyl-1H-pyrazol-5-yl)ethoxy]phenyl]-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol (464 mg, 72.2%) as a solid.