Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH3:13])[CH:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[N:20]2[N:21]=[C:22](F)[CH:23]=[CH:24][C:19]2=[N:18][CH:17]=1.C(N(CC)CC)C>C(O)(C)C>[C:1]([O:5][C:6](=[O:14])[N:7]([CH:8]1[CH2:12][CH2:11][N:10]([C:22]2[CH:23]=[CH:24][C:19]3[N:20]([C:16]([Br:15])=[CH:17][N:18]=3)[N:21]=2)[CH2:9]1)[CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc2ncc(Br)n2n1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNC1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc3ncc(Br)n3n2)C1
Temperature: 140 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
A mixture of methyl-pyrrolidin-3-yl-carbamic acid tert-butyl ester (1.2 g, 6 mmol), 3-bromo-6-fluoro-imidazo[1,2-b]pyridazine (648 mg, 3 mmol), and triethylamine (1.67 ml, 12 mmol) in isopropyl alcohol (3 ml) was heated in a microwave at 140° C. for 20 min. The reaction mixture was allowed to stand for overnight and the white solid was collected by filtration and washed with MeOH to give the titled compound (750 mg). The filtrate was concentrated and the residue was subjected to ISCO (40 g column), to give further titled compound (360 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.45-1.52 (m, 9H) 2.03-2.27 (m, 2H) 2.83 (s, 3H) 3.39-3.54 (m, 2H) 3.69-3.77 (m, 2H) 6.58 (d, J=9.92 Hz, 1H) 7.49 (s, 1H) 7.65 (d, J=9.70 Hz, 1H). LRMS (ESI) m/z 396.1 and 398 [(M+H)]+, calc'd for C16H22BrN6O2: 396.29.
Reaction SMILES: [CH2:1]([Sn:5]([Li])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].Cl[C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[CH2:1]([Sn:5]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:6][CH2:7][CH2:8][CH3:9])[C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [Li][Sn](CCCC)(CCCC)CCCC
Reactant: Clc1ncccn1
Product: CCCC[Sn](CCCC)(CCCC)c1ncccn1

Procedure:
Reaction of tri-n-butylstannyl lithium with 2-chloropyrimidine affords 2-(tributylstannyl)pyrimidine which can be condensed the an acid chloride such as 5 under palladium catalysis to afford these desired ketones.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12]N)=[CH:8][CH:7]=1.[CH3:14][C:15]1[CH:16]=[C:17]([C:22]2[NH:23][C:24]3[C:29]([C:30]=2CCNCCCCC2C=CC(NS(C)(=O)=O)=CC=2)=CC(C(N2CCOCC2)=O)=CC=3)[CH:18]=[C:19]([CH3:21])[CH:20]=1>>[CH3:14][C:15]1[CH:16]=[C:17]([C:22]2[NH:12][C:9]3[C:10]([C:30]=2[CH2:29][CH2:24][NH2:23])=[CH:11][C:6]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)=[CH:7][CH:8]=3)[CH:18]=[C:19]([CH3:21])[CH:20]=1
Reactant: NNc1ccc(-c2nccs2)cc1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)N4CCOCC4)cc3c2CCNCCCCc2ccc(NS(C)(=O)=O)cc2)c1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(-c4nccs4)cc3c2CCN)c1
Yield: 14 %

Procedure:
Reaction of (4-thiazol-2-ylphenyl)hydrazine and 3-chloropropyl 3,5-dimethylphenyl ketone (EXAMPLE 4) was carried out according to the procedure of Example 7.1, Step D to give a 14% yield of the title compound as a yellow, stiff foam, mp 98.5°-100.5° C.; homogeneous by TLC in 95:5 CH2Cl2-MeOH. 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (PB-NH3/CI): m/e=348.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:22]#[N:23])=[C:11]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[S:12][C:13]=1[CH:14]=O.C(O)(C)(C)C.[NH2:29][CH2:30][CH:31]([NH2:33])[CH3:32].II.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:22]#[N:23])=[C:11]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[S:12][C:13]=1[C:14]1[NH:29][CH2:30][CH:31]([CH3:32])[N:33]=1
Reactant: CC(N)CN
Reactant: N#Cc1c(N2CCOCC2)sc(C=O)c1-c1ccc(Cl)cc1Cl
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC1CNC(c2sc(N3CCOCC3)c(C#N)c2-c2ccc(Cl)cc2Cl)=N1
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
To 4-(2,4-dichlorophenyl)-5-formyl-2-morpholin-4-ylthiophene-3-carbonitrile (52.0 mg, 0.000142 mol) in tert-butyl alcohol (0.75 g, 0.010 mol) was added 1,2-diaminopropane (12.9 mg, 0.000174 mol) and the mixture was stirred for 30 min. Iodine (51 mg, 0.00020 mol) and potassium carbonate (65.7 mg, 0.000475 mol) was added the mixture was stirred at 70° C. for 3 hr. The reaction mixture was quenched by saturated sodium bicarbonate solution and brine. The organic layer was collected and purified by column chromatography to afford 4-(2,4-dichlorophenyl)-5-(4-methyl-4,5-dihydro-1H-imidazol-2-yl)-2-morpholinothiophene-3-carbonitrile (19 mg, 32%). LCMS: (FA) ES+ 421. 1H NMR (400 MHz, d1-chloroform) δ: 7.60 (s, 1H), 7.50-7.40 (m, 1H), 7.40-7.30 (m, 1H), 4.20-4.05 (m, 1H), 3.90-3.75 (m, 5H), 3.60-3.70 (m, 4H), 3.38-3.20 (m, 1H), 1.25 (s, 3H).
Reaction SMILES: [C:1]([CH:3]1[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1)#[CH:2].Br[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.C(N(CC)CC)C>C(OCC)C.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.[Cu]Br>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:2]#[C:1][CH:3]3[CH2:12][CH2:11][C:6]4([O:7][CH2:8][CH2:9][O:10]4)[CH2:5][CH2:4]3)=[CH:15][CH:16]=2)=[CH:25][CH:24]=1
Reactant: Fc1ccc(-c2ccc(Br)cc2)cc1
Reactant: C#CC1CCC2(CC1)OCCO2
Agent: [Cu]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Fc1ccc(-c2ccc(C#CC3CCC4(CC3)OCCO4)cc2)cc1
Reaction time: 4.5 h

Procedure:
A mixture of 1.03 g of 8-ethynyl-1,4-dioxaspiro[4.5]decane, 1.197 g 4-bromo-4'-fluorobiphenyl, 0.11 g of tetrakis(triphenylphosphine)palladium, 0.041 g of copper(I) bromide and 45 ml of triethylamine was heated to boiling for 4.5 hours. After cooling the mixture was diluted with diethyl ether, washed twice with water, dried over sodium sulphate, filtered and concentrated. The crude 8-[(4'-fluoro-4-biphenylyl)ethynyl]-1,4-dioxaspiro[4.5]decane (1.82. g) obtained was purified by chromatography on 35 g of silica gel with hexane/ethyl acetate (vol. 9:1). Yield 1.30 g.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:3]=1[C:4]([N:6]([CH:13]([CH3:15])[CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[C:27]([C:29]1[CH:41]=[CH:40][C:32]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]Br)=[CH:31][CH:30]=1)#[N:28]>CN(C)C=O>[C:27]([C:29]1[CH:41]=[CH:40][C:32]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:20][C:18]2[CH:17]=[CH:16][C:3]([C:4]([N:6]([CH:13]([CH3:15])[CH3:14])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[O:5])=[C:2]([OH:1])[CH:19]=2)=[CH:31][CH:30]=1)#[N:28]
Reactant: N#Cc1ccc(OCCCCCBr)cc1
Reactant: CC(C)N(C(=O)c1ccc(O)cc1O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C#N)cc2)cc1O)c1ccccc1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
A stirred solution of 2,4-dihydroxy-N-(1-methylethyl)-N-phenylbenzamide (358 mg, 1.32 mmol) in 6 mL of N,N-dimethylformamide is treated with cesium carbonate (520 mg, 1.58 mmol), and 5-(4-cyanophenoxy)pentyl bromide (354 mg, 1.32 mmol) and stirred at 40° C. for 24 hours. The reaction is partitioned between ethyl acetate and water, dried over sodium sulfate and concentrated in vacuo to afford a yellow foam. This material is purified by chromatography on silica gel (30 g) with 30-70% ethyl acetate/hexane as the eluent to afford 4-[5-(4-cyanophenoxy)pentyloxy]-2-hydroxy-N-(1-methylethyl)-N-phenylbenzamide as colorless foam.
Reaction SMILES: [C:1]1([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[CH:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[N:25]=[C:24](Cl)[C:23]([C:27]#[N:28])=[C:22]([CH3:29])[N:21]=1.CCN(C(C)C)C(C)C>CC(O)C.CO>[NH2:19][C:20]1[N:21]=[C:22]([CH3:29])[C:23]([C:27]#[N:28])=[C:24]([NH:18][CH:16]([C:8]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH3:17])[N:25]=1
Reactant: CC(N)c1nc2cccnc2n1-c1ccccc1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Solvent: CC(C)O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N)nc(NC(C)c2nc3cccnc3n2-c2ccccc2)c1C#N
Temperature: 90 °C
Yield: 48.1 %

Procedure:
A mixture of 1-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)ethylamine (66 mg, 0.28 mmol), 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (38 mg, 0.23 mmol) and DIPEA (142 μL, 0.831 mmol) in IPA (1 mL) was heated at 90° C. in a sealed vial for 18 h. After cooling to RT, the reaction mixture was diluted with MeOH and loaded into an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 50-100% EtOAc in cyclohexane) followed by trituration from EtOAc to afford 366 as an off-white solid (41 mg, 40%). LCMS (Method K): RT 2.54 min [M+H]+ 371.10. 1H NMR (DMSO-d6, 400 MHz): δ 8.25 (1H, dd, J=4.77, 1.47 Hz), 8.14 (1H, dd, J=7.98, 1.47 Hz), 7.55-7.44 (6H, m), 7.33 (1H, m), 7.12-6.61 (2H, m), 5.52 (1H, m), 2.21 (3H, s), 1.47 (3H, d, J=6.81 Hz)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][C:32]5[CH:37]=[CH:36][C:35]([CH2:38][C:39]6[CH:44]=[CH:43][C:42]([N+:45]([O-])=O)=[CH:41][CH:40]=6)=[CH:34][CH:33]=5)=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-])=O.O.[H][H]>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][C:32]5[CH:37]=[CH:36][C:35]([CH2:38][C:39]6[CH:40]=[CH:41][C:42]([NH2:45])=[CH:43][CH:44]=6)=[CH:34][CH:33]=5)=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cc2ccc(Cc3ccc(Cc4ccc(Cc5ccc(Cc6ccc([N+](=O)[O-])cc6)cc5)cc4)cc3)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(Cc2ccc(Cc3ccc(Cc4ccc(Cc5ccc(Cc6ccc(N)cc6)cc5)cc4)cc3)cc2)cc1

Procedure:
In a 1-liter three-necked flask equipped with a stirring device and a nitrogen substituting device, 16.4 g of 1,1-bis(4-(4-(4-nitrophenylmethyl)phenylmethyl)phenyl)methane was dissolved in 500 milliliters of tetrahydrofuran, 1.7 g of a Pd-C catalyst (a 5% product, containing 54.8% of water) was added and contacted with hydrogen gas while cooled with water at a normal pressure and then stirred. After absorption of hydrogen was stopped, the catalyst was filtered off and the objective product adhered to a residual layer of the catalyst was washed with chloroform thoroughly and then the filtrate was concentrated. By recrystallizing the concentrate from a chloroform solvent, 11.0 g of a diamino compound according to the invention, that is, 1,1-bis(4-(4-(4-aminophenylmethyl)phenylmethyl)phenyl)methane was obtained as crystals. Melting point was from 192.0° to 193.0° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=O.C=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)C(C)C)C>C(#N)CC>[I:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1cccc(I)c1
Reactant: C=Cc1ccccc1
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: Ic1cccc(C=Cc2ccccc2)c1
Yield: 10 %

Procedure:
The procedure described in Example 1 is followed, except that 26.65 g (0.1 mol) of 3-iodobenzoyl chloride, 13 g (0.125 mol) of styrene, 12.93 g (0.1 mol) of ethyl-diisopropylamine and 0.575 g (0.001 mol) of bis-(dibenzylidene-acetone)-palladium(O) are used. After a reaction time of 3 hours at the reflux temperature in 150 ml of propionitrile, 3.05 g (0.01 mol) of 3-iodostilbene, corresponding to a yield of 10% of theory, are obtained; melting point 96° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][CH3:20])[C@H:14]1[C@H:9]([CH2:10][CH2:11][CH2:12][CH2:13]1)[N:8]=[C:7]2[C:21]1[CH:22]=[CH:23][C:24](Cl)=[N:25][CH:26]=1)[CH3:2].C(=O)([O-])[O-:29].[K+].[K+].[OH-].[K+].COCCOCCN(CCOCCOC)CCOCCOC>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][CH3:20])[C@H:14]1[C@H:9]([CH2:10][CH2:11][CH2:12][CH2:13]1)[N:8]=[C:7]2[C:21]1[CH:22]=[CH:23][C:24]([OH:29])=[N:25][CH:26]=1)[CH3:2]
Reactant: CCOc1cc2c(cc1OCC)[C@@H]1CCCC[C@@H]1N=C2c1ccc(Cl)nc1
Reactant: O=C([O-])[O-]
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCOc1cc2c(cc1OCC)[C@@H]1CCCC[C@@H]1N=C2c1ccc(O)nc1
Yield: 12.3 %

Procedure:
850 mg of (+/-)-cis-8,9-diethoxy-6-(2-chloropyrid-5-yl)-1,2,3,4,4a,10b-hexahydrophenanthridine are suspended in 60 ml of toluene, treated with 1.0 g of potassium carbonate, 2.0 g of potassium hydroxide and 0.26 mg of tris[2-(2-methoxyethoxy)ethyl]amine and refluxed overnight. The suspension is filtered, the solvent is removed in vacuo, the residue is taken up in water, and the mixture is neutralized with 0.1 M hydrochloric acid and extracted with ethyl acetate. The organic phase is dried using sodium sulfate, the solvent is removed in vacuo, and the precipitate which is deposited in the course of this is filtered off with suction and dried. M.p.: 211-213° C., yield 12.3% of theory.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[C:21]([O-:23])=O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[Pd]>[C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]3[NH:14][C:15]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:21](=[O:23])[C:10]=3[CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])C1=C(Nc2ccc(Nc3ccccc3)cc2)CCCC1
Agent: [Pd]
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1c2ccccc2[nH]c2ccc(Nc3ccccc3)cc12
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Dowtherm® A (100 ml) was brought to reflux in a mechanically stirred flask with a steam-heated condenser and nitrogen atmosphere. A solution of 30 g of a mixture of the methyl and ethyl esters of 2-{4'-[(phenyl)amino]phenyl}aminocyclohexenecarboxylate in 300 ml of Dowtherm® A was added dropwise over 2 hours. Reflux was continued for 1/2 hour after the addition was complete. The reaction was cooled slightly and 1.5 g of 10% palladium on carbon was added. The mixture was refluxed for an additional 6 hours. The mixture was cooled. The precipitate that formed was filtered. The precipitate was washed with petroleum ether. The precipitate was dissolved in 150 ml of warm dimethylformamide (DMF). The DMF solution was filtered and the solid remaining on the funnel was washed with an additional 75 ml of DMF. The combined DMF filtrates were diluted to 2 liters with water. The product precipitated and was collected on a funnel and was washed well with water. Vacuum oven drying at 80° C. for 2 days gave 25 g (96% yield) of 2-(phenyl)amino-9(10H)acridinone.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].[H-].[Na+].[CH3:13]I>O1CCCC1>[CH3:13][CH:5]([C:4](=[O:10])[CH2:3][O:2][CH3:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: CI
Reactant: COCC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC(=O)C(C)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 4-(methyloxy)-3-oxobutanoate (2.0 g, 13.69 mmol) was dissolved in tetrahydrofuran (THF) (14 mL), cooled in an ice bath and treated portionwise with 60% sodium hydride in mineral oil (0.547 g, 13.69 mmol). The resulting mixture was allowed to warm to room temperature over 25 minutes and then treated dropwise with a solution of methyl iodide (0.856 mL, 13.69 mmol) in tetrahydrofuran (THF) (2 mL). The resulting mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate and washed with water. The organic layer was separated, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (SP4, 40+M) eluting with a gradient of 0-50% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a colourless oil. (1.01 g);
Reaction SMILES: FC(F)(F)C(O)=O.CC([N:12]([C@H:16]([CH3:35])[C:17]([NH:19][C:20]1[CH:21]=[N:22][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:33][CH3:34])=[CH:24][CH:25]=1)=[O:18])C(=O)[O-])(C)C>ClCCl>[CH2:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[O:26][C:23]1[N:22]=[CH:21][C:20]([NH:19][C:17](=[O:18])[C@@H:16]([CH3:35])[NH2:12])=[CH:25][CH:24]=1)[CH3:34]
Reactant: CCc1ccccc1Oc1ccc(NC(=O)[C@@H](C)N(C(=O)[O-])C(C)(C)C)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccccc1Oc1ccc(NC(=O)[C@@H](C)N)cn1
Temperature: 25 °C

Procedure:
In a 50 mL round-bottomed flask 1,1-dimethylethyl[(1R)-2-({6-[(2-ethylphenyl)oxy]-3-pyridinyl}amino)-1-methyl-2-oxoethyl]carbamate (Intermediate 47, 251.1 mg) was dissolved in dichloromethane (2 mL) to give a pale orange solution. Trifluoroacetic acid (2 mL, 26.0 mmol) was added. The reaction mixture was stirred at room temperature. After 20 minutes the solvent was evaporated under vacuum affording a yellow oil which was charged on a 5 g SCX cartridge and flushed with 25 mL of MeOH followed by 25 mL of 2M solution of ammonia in MeOH. The ammonia eluate was evaporated under vacuum to afford the title compound as a yellow oil which solidified (170.0 mg).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>>[ClH:17].[Cl:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[S:18]([CH2:21][CH3:22])(=[O:19])=[O:20])[CH2:9][NH:8][CH2:16]2
Reactant: CCS(=O)(=O)c1cc2c(cc1Cl)CN(C(=O)OC(C)(C)C)C2
Agent: Cl
Product: CCS(=O)(=O)c1cc2c(cc1Cl)CNC2

Procedure:
Prepared in analogy to Example A3(e) from 5-chloro-6-ethanesulfonyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and HCl. Grey solid. MS (m/e): 248.1 ({37Cl}M+H+, 30%), 246.2 ({35Cl}M+H+, 100%).
Reaction SMILES: C1(O)[C:13]2[C:12]3[C:8](=[CH:9][NH:10][CH:11]=3)[CH:7]=[CH:6][C:5]=2NCN1.[ClH:15].[CH2:16]([OH:18])[CH3:17]>>[ClH:15].[Cl:15][C:5]1[CH:6]=[CH:7][C:17]([C:16]2([OH:18])[C:13]3[C:12](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:11]3=[N:10][CH2:9][CH2:8][CH2:9][N:10]23)=[CH:12][CH:13]=1
Reactant: OC1NCNc2ccc3c[nH]cc3c21
Reactant: CCO
Agent: Cl
Product: OC1(c2ccc(Cl)cc2)c2ccccc2C2=NCCCN21

Procedure:
The above prepared tetrahydropyrimidoisoindolol is dissolved in ethanol and admixed with an aqueous solution containing an equivalent amount of hydrochloric acid. The mixture is stirred for ten minutes and the solvent removed by evaporation. In this manner, is obtained 6-(4-chlorophenyl)-2,3,4,6-tetrahydropyrimido[2,1-a]isoindol-6-ol hydrochloride, m.p. 232°-4°C., as a white crystalline solid, which is soluble in hot water.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].CC([O-])(C)C.[K+].O>CS(C)=O.CC(O)(C)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([O:28][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:13]=[N:12][NH:11][C:10](=[O:14])[CH:9]=3)=[CH:6][N:7]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: O=c1cc(-c2ccc(Cl)nc2)cn[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-c3cn[nH]c(=O)c3)cn2)CC1
Temperature: 110 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
A solution of 5-(6-chloropyridin-3-yl)-2H-pyridazin-3-one (73 mg, 0.35 mmol) and 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (140 mg, 0.70 mmol) in 2.7 mL of DMSO was stirred as KOtBu in 2-methyl-2-propanol (1.0 M, 14.4 mL) was added dropwise. After stirring at 110° C. overnight, the reaction was cooled to rt, and 2 mL of water was added. The mixture was extracted with CH2Cl2 (3×10 mL), the extracts combined and dried over Na2SO4. The crude product was purified by prep. TLC with 10% MeOH in CH2Cl2 to give 71 mg (54%) of 4-[5-(6-oxo-1,6-dihydropyridazin-4-yl)-pyridin-2-yloxy]piperidine-1-carboxylic acid tert-butyl ester; MS m/z 273 (M-Boc-H).
Reaction SMILES: C([O:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]3[N:23]=[CH:22][N:21]([C:24]4[CH:25]=[C:26]([NH:38][S:39]([CH2:42][CH3:43])(=[O:41])=[O:40])[CH:27]=[C:28]([C:30]5[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=5[F:37])[CH:29]=4)[C:18]3=[N:19][CH:20]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[F:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[C:28]1[CH:29]=[C:24]([N:21]2[C:18]3=[N:19][CH:20]=[C:15]([C:12]4[CH:11]=[CH:10][C:9](=[O:8])[NH:14][CH:13]=4)[CH:16]=[C:17]3[N:23]=[CH:22]2)[CH:25]=[C:26]([NH:38][S:39]([CH2:42][CH3:43])(=[O:41])=[O:40])[CH:27]=1
Reactant: CCS(=O)(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4ccc(OCc5ccccc5)nc4)cnc32)c1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4ccc(=O)[nH]c4)cnc32)c1
Yield: 23.7 %

Procedure:
A solution of N-(5-(6-(6-(benzyloxy)pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)ethanesulfonamide (0.140 g, 0.234 mmol) in TFA (5 ml) was stirred at RT for 16 h. The mixture was concentrated on vacuo, quenched with sodium bicarbonate and extracted as in Example 1(d). The solvent was distilled off to give the product in 23.7% yield (0.028 g). 1H NMR (400 MHz, DMSO-d6): δ 10.35 (s, 1H), 9.07 (s, 1H), 8.70 (s, 1H), 8.44 (s, 1H), 8.01 (d, 1H), 7.93 (s, 2H), 7.78-7.72 (m, 2H), 7.48-7.45 (d, 2H), 7.30-7.26 (t, 1H), 6.52-6.50 (d, 1H), 3.30-3.28 (q, 2H), 1.28-1.25 (t, 3H); LC-MS (ESI): Calculated mass: 507.51; Observed mass: 508.1 [M+H]+ (rt: 0.1 min).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].Cl[C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][C:39]=2[Cl:43])[N:34]=1>>[F:31][C:2]([F:30])([F:1])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][N:27]([C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][C:39]=4[Cl:43])[N:34]=3)[CH2:28][CH2:29]2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]2[C:19]1=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:6]
Reactant: Clc1ccc2c(Cl)cccc2n1
Reactant: O=C(NCC(F)(F)F)C1(CCCCN2CCNCC2)c2ccccc2-c2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc4c(Cl)cccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 21 from 9-(4-piperazin-1-yl-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2,5-dichloro-quinoline.
Reaction SMILES: O=[CH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])[C:11]([O:13][CH3:14])=[O:12])=[CH:6][C:5]=1[O:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26].[N:33]1C=CC=CC=1.FC(F)(F)C(ONC(=O)C(F)(F)F)=O>C1(C)C=CC=CC=1>[C:2]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])[C:11]([O:13][CH3:14])=[O:12])=[CH:6][C:5]=1[O:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26])#[N:33]
Reactant: c1ccncc1
Reactant: COC(=O)C(NC(=O)c1ccccc1)c1ccc(CC=O)c(OC(=O)c2ccccc2)c1
Agent: O=C(NOC(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)C(NC(=O)c1ccccc1)c1ccc(CC#N)c(OC(=O)c2ccccc2)c1

Procedure:
A solution of methyl 4-(2-oxoethyl)-α-[(phenylcarbonyl)amino]-3-[(phenylcarbonyl)oxy]benzeneacetate from Preparation 9 above in toluene containing pyridine (2.3 eq) is treated with O,N-bistrifluoroacetyl hydroxyl amine (1.0 eq). The resulting solution is allowed to stir until no starting material remains. The reaction mixture is washed with saturated eq NaHCO3 solution, dried (MgSO4), and concentrated. The product of the formula 15 above is purified by silica gel chromatography.