Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([Li])CCC.[CH:18]1([CH:23]=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]1>CCCCCC.C1COCC1>[CH:18]1([CH:23]([OH:24])[C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:11]#[N:12])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: N#CC1(c2ccc(Br)cc2)CC1
Reactant: O=CC1CCCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#CC1(c2ccc(C(O)C3CCCC3)cc2)CC1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-bromophenyl)cyclopropanecarbonitrile (2.01 g, 0.00905 mol) in tetrahydrofuran (30 mL, 0.4 mol) was added 2.5 M of n-butyllithium in hexane (4.0 mL) at −78° C. and the mixture was stirred at −30° C. for 30 minutes. A solution of cyclopentanecarbaldehyde (0.972 g, 0.00990 mol) in THF (2 mL) was added to the above mixture and the resulting mixture was stirred at −78° C. for 2 hours. The reaction was then quenched with a small amount of saturated aqueous NH4Cl solution followed by extraction with ethyl acetate, drying with MgSO4, and concentrating under reduced pressure. The crude product was purified by flash chromatography, eluting with 30% AcOEt in hexanes.
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])(=O)C.[C:10]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)#[N:11].[H-].[Na+].CO>O1CCCC1.C(O)(=O)C>[C:10]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[C:6]2[CH2:7][CH2:8][NH:4][C:5]2=[O:9])=[CH:14][CH:13]=1)#[N:11]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC(=O)N1CCCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1ccc(C=C2CCNC2=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
A solution of 5.0 g of N-acetyl-2-pyrrolidone and 5.17 g of 4-cyanobenzaldehyde in 50 ml of tetrahydrofuran is added dropwise to a suspension of 5.36 g of sodium hydride (55% in oil) in 50 ml of tetrahydrofuran at 5°-10° C. and the mixture is then stirred at 0° C. for 1 hour. Excess sodium hydride is eliminated by the addition of some methanol, and the reaction mixture is poured onto ice and neutralized with glacial acetic acid. The precipitate is suction-filtered and dissolved in a methylene chloride/methanol mixture, and the solution is dried and evaporated down. The residue is triturated with ether and suction-filtered. 1.4 g of 3-(4-cyanobenzylidene)-2-pyrrolidone are obtained as a colourless powder of melting point 260° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:25])[C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[N:19]1[C:23]([CH3:24])=[CH:22][N:21]=[CH:20]1.[CH2:26]=[O:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:25])[C:9]1[CH:14]=[C:13]([C:15]([F:16])([F:18])[F:17])[CH:12]=[CH:11][C:10]=1[N:19]1[C:23]([CH3:24])=[CH:22][N:21]=[C:20]1[CH2:26][OH:27]
Reactant: C=O
Reactant: Cc1cncn1-c1ccc(C(F)(F)F)cc1C(=O)c1ccccc1Cl
Product: Cc1cnc(CO)n1-c1ccc(C(F)(F)F)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 1, 2'-chloro-5-(trifluoromethyl)-2-(5-methylimidazol-1-yl)benzophenone is heated in a bomb with 37% aqueous formaldehyde solution to give 2'-chloro-5-(trifluoromethyl)-2-[2-(hydroxymethyl)-5-methylimidazol-1-yl]benzophenone.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[C:19]4[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:36][O:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[ClH:31].[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([CH:20]2[C:19]3[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=3[C:17]3[N:16]=[C:15]([NH:14][C:11]4[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][N:43]5[CH2:44][CH2:45][N:40]([CH2:39][CH2:38][O:37][CH3:36])[CH2:41][CH2:42]5)=[CH:13][CH:12]=4)[N:24]=[CH:23][C:22]=3[CH2:21]2)=[CH:30][CH:29]=1
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccc(Cl)cc2)C3)cc1
Reactant: COCCN1CCNCC1
Product: COCCN1CCN(CCc2ccc(Nc3ncc4c(n3)-c3ccccc3C(c3ccc(Cl)cc3)C4)cc2)CC1
Product: Cl

Procedure:
This product was synthesized as described in general procedure 2 except 4-(6-(4-chlorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate was used instead of 4-(6-(3-bromophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate and 1-(2-methoxyethyl)piperazine was used instead of piperidine to afford 6-(4-chlorophenyl)-N-(4-(2-(4-(2-methoxyethyl)piperazin-1-yl)ethyl)phenyl)-5,6-dihydrobenzo[h]quinazolin-2-amine hydrochloride. M.p.=204-214° C. 1H NMR 400 MHz (DMSO) δ 12.03-11.35 (m, 2H), 9.64 (s, 1H), 8.34-8.29 (m, 2H), 7.82 (d, J=8.4 Hz, 2H), 7.54-7.46 (m, 2H), 7.35-7.31 (m, 2H), 7.25 (d, J=8.0 Hz, 2H), 7.16-7.10 (m, 3H), 4.47-4.41 (m, 1H), 3.90-3.30 (m, 16H), 3.30-3.00 (m, 5H). LCMS m/e 554 (M+H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[O:11][C:10]([CH:12]2[C:17]3=[C:18]4[N:31]([CH3:32])[C:30](=[O:33])[N:29]([CH3:34])[C:28](=[O:35])[C:19]4=[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=4)[N:16]3[CH2:15][C@H:14]([CH2:36][OH:37])[O:13]2)=[CH:9][CH:8]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][S:2]([O:37][CH2:36][C@@H:14]1[O:13][CH:12]([C:10]2[O:11][C:7]([Cl:6])=[CH:8][CH:9]=2)[C:17]2=[C:18]3[N:31]([CH3:32])[C:30](=[O:33])[N:29]([CH3:34])[C:28](=[O:35])[C:19]3=[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)[N:16]2[CH2:15]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)n3c(c2n(C)c1=O)C(c1ccc(Cl)o1)O[C@@H](CO)C3
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n3c(c2n(C)c1=O)C(c1ccc(Cl)o1)O[C@@H](COS(C)(=O)=O)C3
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (0.021 ml, 0.274 mmol) was added dropwise to a solution of (8R)-10-(5-chlorofuran-2-yl)-5-(3-fluorophenyl)-8-(hydroxymethyl)-1,3-dimethyl-7,8-dihydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]oxazine-2,4(3H,10H)-dione (Example 6, Step 3) (100 mg, 0.217 mmol), triethylamine (0.039 ml, 0.283 mmol) and DMAP (2.66 mg, 0.022 mmol) in DCM (2 mL). The mixture was stirred at 0° C. for 30 mins then diluted with DCM (20 ml) and quenched with water (20 mL). The phases were separated and the organic layer was dried over magnesium sulfate and evaporated under vacuum to afford the title compound.
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH2:7][CH2:8][OH:9])(=[O:5])[OH:4])[CH3:2].[CH2:10](O)[CH2:11][CH2:12][CH3:13].O>C1(C)C=CC=CC=1>[CH2:1]([P:3]([CH2:6][CH2:7][CH2:8][OH:9])(=[O:4])[O:5][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:2]
Reactant: CCP(=O)(O)CCCO
Reactant: CCCCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOP(=O)(CC)CCCO
Yield: 83.9 %

Procedure:
456 g (3 mol) of ethyl(3-hydroxypropyl)phosphinic acid (produced as in Example 5) are at 85° C. dissolved in 400 ml of toluene and admixed with 888 g (12 mol) of butanol. At a reaction temperature of about 100° C., the water formed is removed by azeotropic distillation to leave 524 g (84% of theory) of butyl ethyl(3-hydroxy-propyl)phosphinate purified by distillation at reduced pressure.
Reaction SMILES: [OH-:1].[K+].[F:3][C:4]([F:17])([F:16])[CH2:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.OO.Cl>CO>[F:3][C:4]([F:16])([F:17])[CH2:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]([OH:1])=[O:13])=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(OCCC(F)(F)F)cc1
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: CO
Product: O=C(O)c1ccc(OCCC(F)(F)F)cc1
Temperature: 65 °C
Yield: 83 %

Procedure:
To a stirred solution of 50% w/v KOH (0.8 ml) and 4-(3,3,3-trifluoropropoxy)benzaldehyde (0.4 g, 1.83 mmol) in MeOH (4 ml) at 65° C. was added dropwise over 20 min aqueous hydrogen peroxide (30 wt. % in water, 1.5 ml). On completion of the addition the reaction mixture was heated at 65° C. for a further 10 min. On cooling to room temperature, the reaction mixture was acidified with 1 M HCl and extracted with Et2O (3×25 ml). The combined organic extracts were washed with brine (25 ml), dried (Na2SO4) and the solvent removed under reduced pressure to give the title compound (0.36 g, 83%) as a colourless solid which was used without further purification.
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.[Br:13]N1C(=O)CCC1=O.[CH3:21][O:22][C:23]([C:25]1[C:33]2[CH:32]=[C:31]([CH3:34])[O:30][C:29]=2[C:28]([O:35][CH:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:27][CH:26]=1)=[O:24]>C(Cl)(Cl)(Cl)Cl>[CH3:21][O:22][C:23]([C:25]1[C:33]2[CH:32]=[C:31]([CH2:34][Br:13])[O:30][C:29]=2[C:28]([O:35][CH:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:27][CH:26]=1)=[O:24]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(OC2CCCC2)c2oc(C)cc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(OC2CCCC2)c2oc(CBr)cc12
Temperature: 25 °C
Yield: 5.8 %

Procedure:
To a well stirred refluxing solution of AIBN (500 mg) and N-bromosuccinimide (30.5 g, 0.171 moles) in carbon tetrachloride (500 mL) was added a Methyl-7-cyclopentyloxy-2-methylbenzo[b]furan-4-carboxylate (43.0 g, 0.151 moles) and refluxed for 2-3 hours. Reaction mixture was cooled to room temperature and filtered thorough Celite bed. The filtrate was concentrated under vacuo to give product (3.1 g) as brown oil. The product obtained (50.0 g) was taken ahead for next step without further purification.
Reaction SMILES: [Na].Cl.[CH3:3][C:4]([CH3:11])([CH3:10])[CH2:5][CH2:6][C:7]([NH2:9])=[NH:8].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[S:21])=[CH:15][CH:14]=1>CC(C)=O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:8][C:7](=[NH:9])[CH2:6][CH2:5][C:4]([CH3:11])([CH3:10])[CH3:3])=[S:21])=[CH:15][CH:14]=1
Reactant: CC(C)(C)CCC(=N)N
Reactant: S=C=Nc1ccc(Cl)cc1
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CC(C)(C)CCC(=N)NC(=S)Nc1ccc(Cl)cc1

Procedure:
Following a procedure similar to that described in Example 1 but using 7.22 g. sodium in 705 ml. dry acetone, 51.7 g. 4,4-dimethylvaleramidine hydrochloride, and 53.2 g. 4-chlorophenyl isothiocyanate in 350 ml. dry acetone there was obtained 1-(4-chlorophenyl)-3-(4,4-dimethylpentanimidoyl)-2-thiourea; m.p. 135°-137° C. (from acetonitrile); hydrochloride (80.7 g.), m.p. 182°-186° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[S:6][C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH:17]C(=O)C(Cl)(Cl)Cl)[C:8]=2[N:24]=1)[CH3:2].C[O-].[Na+]>CO>[CH2:1]([O:3][CH2:4][C:5]1[S:6][C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:24]=1)[CH3:2]
Reactant: CCOCc1nc2c(NC(=O)C(Cl)(Cl)Cl)nc3ccccc3c2s1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOCc1nc2c(N)nc3ccccc3c2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trichloroacetyl isocyanate (0.7 mL) was added to a solution of 2-(ethoxymethyl)thiazolo[4,5-c]quinoline-5N-oxide (1.0 g) in dichloromethane (50 mL). The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated under vacuum to provide N-(2-(ethoxymethyl)thiazolo[4,5-c]quinolin-4-yl)trichloroacetamide. The amide was taken up in methanol and then combined with 1 equivalent of sodium methoxide. The reaction mixture was stirred at ambient temperature for 30 minutes and then concentrated under vacuum. The reaction was run a second time using 2 g of the N-oxide. The products were combined and recrystallized from isopropanol to provide 2.25 g of 2-(ethoxymethyl)thiazolo[4,5-c]quinoline-4-amine as light yellow needles, m.p. 149-151° C. Analysis: Calculated for C13H13N3OS: %C, 60.21; %H, 5.05; %N, 16.20; Found: %C, 59.86; %H, 4.97; %N, 16.16.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH:22][CH2:23][C:24]3[C:25]([NH:37][CH:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[C:26]4[CH:34]=[N:33][N:32]([CH2:35][CH3:36])[C:27]4=[N:28][C:29]=3[CH2:30][CH3:31])=[O:21])[CH:15]=2)=[O:13])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[CH3:44][C:45]([O:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([CH2:57][C:58]2[CH:59]=[C:60](B(O)O)[CH:61]=[CH:62][CH:63]=2)[CH2:53][C@@H:52]1[CH3:67])=[O:50])([CH3:47])[CH3:46].C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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>[CH2:35]([N:32]1[C:27]2=[N:28][C:29]([CH2:30][CH3:31])=[C:24]([CH2:23][NH:22][C:20]([C:16]3[CH:15]=[C:14]([C:12]([NH:11][CH2:10][C:4]4[CH:3]=[C:2]([C:60]5[CH:61]=[CH:62][CH:63]=[C:58]([CH2:57][N:54]6[CH2:55][CH2:56][N:51]([C:49]([O:48][C:45]([CH3:47])([CH3:46])[CH3:44])=[O:50])[C@@H:52]([CH3:67])[CH2:53]6)[CH:59]=5)[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=4)=[O:13])[CH:19]=[CH:18][CH:17]=3)=[O:21])[C:25]([NH:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[C:26]2[CH:34]=[N:33]1)[CH3:36]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(Br)cc(OC)c2)c1
Reactant: C[C@H]1CN(Cc2cccc(B(O)O)c2)CCN1C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(OC)cc(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)[C@@H](C)C4)c3)c2)c1
Temperature: 150 °C
Yield: 65.8 %

Procedure:
237(a) A mixture of N-{[3-bromo-5-(methyloxy)phenyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (150 mg, 0.23 mmol), {3-[((3S)-4-{[(1,1-dimethylethyl)oxy]carbonyl}-3-methyl-1-piperazinyl)methyl]phenyl}boronic acid (100 mg, 0.30 mmol), Na2CO3 (74 mg, 0.69 mmol), Pd(PPh3)4 (13.3 mg, 0.01 mmol), water (0.75 mL) in dioxane (2.25 mL) was degassed for 5 min. and then heated in a microwave for 30 min at 150° C. The reaction was quenched with water and then extracted with ethyl acetate twice. The combined organic layers were washed with water and brine. The organic layer was filtered though a 0.45 μM filter and then concentrated to give a crude residue. It was then purified using Combi Flash chromatography, eluting with 0 to 10% MeOH in DCM. The product fractions were combined and concentrated under vacuum to give 1,1-dimethylethyl (2S)-4-{[3′-{[({3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]phenyl}carbonyl)amino]methyl}-5′-(methyloxy)-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate as a solid (130 mg, 65%): LC-MS m/z 859 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=3)[C:5]([CH2:18][CH3:19])([CH2:16][CH3:17])[C:4]=2[CH:3]=1.[CH2:20]([O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=2)=[CH:31][CH:30]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[Na+].[Na+].CO[CH2:52][CH2:53][O:54][CH3:55]>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.O>[CH2:16]([C:5]1([CH2:18][CH3:19])[C:4]2[CH:3]=[C:2]([C:38]3[CH:39]=[CH:40][C:35]([C:32]4[CH:33]=[CH:34][C:29]([O:28][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:30][CH:31]=4)=[CH:36][CH:37]=3)[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][C:8]([C:29]1[CH:30]=[CH:31][C:32]([C:35]3[CH:36]=[CH:37][C:53]([O:54][CH2:55][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])=[CH:52][CH:40]=3)=[CH:33][CH:34]=1)=[CH:9][CH:10]=2)[CH3:17]
Reactant: CCCCCCCCOc1ccc(-c2ccc(B(O)O)cc2)cc1
Reactant: CCC1(CC)c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: COCCOC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCOc1ccc(-c2ccc(-c3ccc4c(c3)C(CC)(CC)c3cc(-c5ccc(-c6ccc(OCCCCCCCC)cc6)cc5)ccc3-4)cc2)cc1
Yield: 65 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.70 g, 0.0006 mol) was added to a stirred solution of 2,7-dibromo-9,9-diethylfluorene (4) (2.33 g, 0.0061 mol), 4-octyloxybiphenyl-4′-yl boronic acid (5.00 g, 0.0153 mol), 20% sodium carbonate solution (100 cm3) and 1,2-dimethoxyethane (150 cm3). The reaction mixture was heated under reflux overnight. Water (300 cm3) was added to the cooled reaction mixture and the product extracted into DCM (3×300 cm3). The combined organic extracts were washed with brine (2×150 cm3), dried (MgSO4)), filtered and the filtrate evaporated down under partially reduced pressure. The residue was purified by column chromatography on silica gel using DCM and hexane (30:70) as eluent and recrystallisation from ethanol and DCM to yield a white crystalline solid (3.10 g, 65%, m.pt. 146° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2([CH2:20][CH2:19][N:18]([C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH2:17][CH2:16]2)[CH2:11]1.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[C:32]1[S:33][CH:34]=[C:35]([C:37](O)=[O:38])[N:36]=1.C(N(CC)C(C)C)(C)C.CN(C=[O:53])C>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:37]([C:35]2[N:36]=[C:32]([C:28]3[S:27][CH:31]=[CH:30][CH:29]=3)[S:33][CH:34]=2)=[O:38])=[C:3]([N:10]2[CH2:15][CH2:14][CH2:13][C:12]3([CH2:16][CH2:17][N:18]([C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH2:19][CH2:20]3)[CH2:11]2)[CH:4]=1)(=[O:53])[NH2:7]
Reactant: O=C(O)c1csc(-c2cccs2)n1
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(N)c(N2CCCC3(CCN(C(=O)C(F)(F)F)CC3)C2)c1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc(NC(=O)c2csc(-c3cccs3)n2)c(N2CCCC3(CCN(C(=O)C(F)(F)F)CC3)C2)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To Intermediate 4-Amino-3-[9-(2,2,2-trifluoro-acetyl)-2,9-diaza-spiro[5.5]undec-2-yl]-benzonitrile was added 2-thiophen-2-yl-thiazole-4-carboxylic acid (098 eq) in DMF (1 mL). Then, a solution of N,N-diisopropylethylamine (1.5 eq) HATU (1.5 eq) was added. The resulting reaction was stirred at room temperature for 15 hours and then concentrated and treated with 3 mL of (4:1) TFA:H2SO4. The reaction mixture was concentrated and purified using reverse phase HPLC to provide 2-Thiophen-2-yl-thiazole-4-carboxylic acid {4-carbamoyl-2-[9-(2,2,2-trifluoro-acetyl)-2,9-diaza-spiro[5.5]undec-2-yl]-phenyl}-amide. HPLC-MS RT=4.46 min, mass calculated for formula C26H26F3N5O3S2 577.14, observed LCMS m/z 578.21 (M+H).
Reaction SMILES: [Mg].II.C(Br)C.[C:7]([C:11]#[CH:12])([CH3:10])([CH3:9])[CH3:8].CC.[CH:15]([CH:17]=[CH2:18])=[O:16]>C1(C)C=CC=CC=1.O1CCCC1>[CH3:8][C:7]([CH3:10])([CH3:9])[C:11]#[C:12][CH:15]([OH:16])[CH:17]=[CH2:18]
Reactant: C#CC(C)(C)C
Reactant: C=CC=O
Agent: CC
Agent: II
Agent: [Mg]
Solvent: CCBr
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CC(O)C#CC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 48.5 %

Procedure:
At dry and inert atmosphere, magnesium (6.4 gr., 0.26 mole) was heated with a trace of iodine until brown vapors evolved (−60° C). It was cooled down to room temperature and toluene (300 ml) and tetrahydrofuran (30 ml) were added. The mixture was heated to 450-50° C. and a mixture of ethyl bromide (30 gr., 0.26 mole) and toluene (30 ml) was added dropwise. The mixture was stirred at 50° C. until all the magnesium had practically been consumed. The mixture was cooled and a mixture of t-butylacetylene (20 gr., 0.24 mole) mixed with toluene (20 ml) was added gradually. The mixture was stirred at 30°-40° C. for 4-6 hours. Progress of the reaction could be monitored by the evolution of ethane. The reaction mixture was cooled to 0° C.-5° C. and a mixture of acrolein (stabilized by hydroquinone) (14 gr., 0.25 mole) diluted with toluene (20 ml) was added gradually during 1 hour. The mixture was heated to room temperature and stirred for 4 hours. The reaction mixture was quenched with ammonium chloride solution. The phases were separated. The organic phase was extracted with toluene (3×50 ml). The combined organic phases were washed with water to neutrality. The solution was dried and the solvent stripped. The crude product was obtained (20.2 gr., 65% yield). The crude product was distilled (boiling point 68° C.-69.5° C. at 12 mbar) to give pure 6,6-dimethylhept-1-en-4-yn-3-ol (16.1 gr., 48%).
Reaction SMILES: [N:1](Cl)=[O:2].[Cl-].[Na+].[N:6]([O:8]S(=O)(=O)O)=O.C1CO[C:15]2([CH2:33][CH2:32][C@@:31]3([CH3:34])[C:17](=[CH:18][CH2:19][C@@H:20]4[C@:30]3([OH:35])[CH2:29][CH2:28][C@@:27]3([CH3:36])[C@H:21]4[CH2:22][CH2:23][C:24]3=[CH:25][CH3:26])[CH2:16]2)O1>C(Cl)Cl>[OH:8][N:6]=[C:15]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C:17]([CH2:18][CH2:19][C@@H:20]3[C@:30]2([OH:35])[CH2:29][CH2:28][C@@:27]2([CH3:36])[C@H:21]3[CH2:22][CH:23]=[C:24]2[C:25](=[N:1][OH:2])[CH3:26])=[CH:16]1
Reactant: O=NOS(=O)(=O)O
Reactant: CC=C1CC[C@H]2[C@@H]3CC=C4CC5(CC[C@]4(C)[C@@]3(O)CC[C@]12C)OCCO5
Reactant: O=NCl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=NO)C1=CC[C@H]2[C@@H]3CCC4=CC(=NO)CC[C@]4(C)[C@@]3(O)CC[C@]12C
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
Nitrosyl chloride, prepared from sodium chloride and nitrosyl sulfuric acid, was passed into methylene chloride (7 ml) at 0° C., until a burgundy colour had developed. The solution was added in one action to 3,3-ethylenedioxypregna-5,17(20)-dien-9α-ol (301 mg). The reaction mixture was stirred for 3 minutes after which the solvents were evaporated under reduced pressure. The residue was taken up in a mixture of tetrahydrofuran (15 ml) and water (1.5 ml). Triethylamine (1.6 ml) was added dropwise, then the mixture was refluxed for 2 hours. After cooling to room temperature, methylene chloride (100 ml) was added and the mixture was washed twice with a 5% aqueous potassium carbonate solution, dried (MgSO4) and concentrated under reduced pressure. The crude product (251 mg) was chromatographed (silica gel, toluene/acetone 3/1) to afford the title compound as a isomeric mixture of syn and anti 20-oximes, both containing a 3-hydroxyimino group in the syn configuration.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:17]([C:19]3[O:20][C:21](=[O:35])[C:22]4[C:27]([C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH3:18])[N:9]=[C:10](C3C=NC=CN=3)[C:3]=12.[F:36][C:37]1[CH:42]=[CH:41][C:40]([S:43]([NH:46][C:47]2[CH:48]=[N:49][CH:50]=[C:51]([Sn](C)(C)C)[CH:52]=2)(=[O:45])=[O:44])=[CH:39][CH:38]=1.NC1N=CN=C2N(C(C3OC(=O)C4C(C=3C3C=CC=CC=3)=CC=CC=4)C)N=C(I)C=12>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:17]([C:19]3[O:20][C:21](=[O:35])[C:22]4[C:27]([C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH3:18])[N:9]=[C:10]([C:51]3[CH:52]=[C:47]([NH:46][S:43]([C:40]4[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=4)(=[O:45])=[O:44])[CH:48]=[N:49][CH:50]=3)[C:3]=12
Reactant: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cnccn2)c2c(N)ncnc21
Reactant: C[Sn](C)(C)c1cncc(NS(=O)(=O)c2ccc(F)cc2)c1
Agent: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(I)c2c(N)ncnc21
Product: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cncc(NS(=O)(=O)c3ccc(F)cc3)c2)c2c(N)ncnc21
Yield: 17.4 %

Procedure:
The title compound was made in a similar way as that of the compound of example 52 from 4-fluoro-N-(5-(trimethylstannyl)pyridin-3-yl)benzenesulfonamide (Intermediate G9, 98 mg, 0.236 mmol) and 3-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-phenyl-1H-isochromen-1-one (intermediate D2a, 60 mg, 0.118 mmol) affording the title compound (13 mg, 0.021 mmol, 17.4% yield) as white solid