Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9](I)=[C:8]([CH3:12])[C:6]=2[N:7]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][N:21]=1.C([O-])([O-])=O.[Na+].[Na+]>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(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([C:23]3[CH:22]=[N:21][C:20]([F:19])=[CH:25][CH:24]=3)=[C:8]([CH3:12])[C:6]=2[N:7]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: Cc1c(I)sc2c(N3CCOCC3)nc(Cl)nc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1c(-c2ccc(F)nc2)sc2c(N3CCOCC3)nc(Cl)nc12

Procedure:
2-Chloro-6-iodo-7-methyl-4-morpholinothieno[3,2-d]pyrimidine (1 eg), 2-fluoro-5-pyridineboronic acid (1.1 eq) and bis(triphenylphosphine)palladium(II) dichloride (0.1 eq) in 1M Na2CO3 aqueous solution (3 eq) and an equal volume of acetonitrile was heated to 100° C. in a sealed microwave reactor for 30 min. Reaction mixture was concentrated, then crude product was purified by flash chromatography to give 4-(2-chloro-6-(6-fluoropyridin-3-yl)-7-methylthieno[3,2-d]pyrimidin-4-yl)morpholine. MS (Q1) 365 (M+)
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([C:32]([O:34]CC)=[O:33])=[N:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13](/[CH:17]=[CH:18]/[CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[C:22]=2[C:28]([O:30][CH3:31])=[O:29])[CH:12]=1)(=O)C.C([O-])([O-])=O.[K+].[K+].Cl.C(=O)=O>CCO.C1COCC1>[OH:27][C:23]1[C:22]([C:28]([O:30][CH3:31])=[O:29])=[C:21]([CH:26]=[CH:25][CH:24]=1)[O:20][CH2:19]/[CH:18]=[CH:17]/[C:13]1[CH:12]=[C:11]([C:10]2[O:9][N:8]=[C:7]([C:32]([OH:34])=[O:33])[C:6]=2[CH2:5][OH:4])[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1noc(-c2cccc(/C=C/COc3cccc(O)c3C(=O)OC)c2)c1COC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)c1c(O)cccc1OC/C=C/c1cccc(-c2onc(C(=O)O)c2CO)c1
Yield: 61.9 %

Procedure:
To a solution of ethyl 4-((acetyloxy)methyl)-5-(3-{(1E)-3-(3-hydroxy-2-(methoxycarbonyl)phenoxy)prop-1-enyl}phenyl)isoxazole-3-carboxylate (190 mg, 0.38 mmol) in EtOH (1.5 mL) was added 1 mL THF and 3 mL aqueous K2CO3 (sat'd). After 1.5 hour at ambient temperature 4 M HCl was added until CO2 evolution ceased. A precipitate formed which was filtered and dissolved in DMSO for purification by reverse phase HPLC (0–70% acetonitrile in 0.1% aqueous TFA) to provide the titled compound (100 mg, 61%). 1H NMR (300 MHz, DMSO-d6) δ 9.98 (s, 1H), 7.94 (broad s, 1H), 7.77 (broad d, J=7.8 Hz, 1H), 7.69 (broad d, J=7.8 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.19 (t, J=8.3 Hz, 1H), 6.81 (broad d, J=16 Hz, 1H), 6.60 (d, J=8.3 Hz, 1H), 6.57 (dt, J=16, 5.2 Hz, 1H), 6.51 (d, J=8.3 Hz, 1H), 4.75 (d, J=5.2 Hz, 2H), 4.65 (s, 2H), 3.78 (s, 3H). MS (ESI+) m/z 426 (M+H)+, 443 (M+NH4)+, 448 (M+Na)+: (ESI−) m/z 424 (M−H)−, 380 (M−CO2H)−.
Reaction SMILES: [F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]1[N:12]=[C:11](S(C)=O)[C:10]2[C:5](=[CH:6][C:7]([C:16]#[N:17])=[CH:8][CH:9]=2)[N:4]=1.BrC1C=C2C(C(SC)=[N:32][C:33]([C:37](F)(F)[C:38]3[CH:43]=CC(F)=C[N:39]=3)=[N:34]2)=CC=1>>[F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]1[N:12]=[C:11]([NH:32][C:33]2[CH:37]=[C:38]([CH3:43])[NH:39][N:34]=2)[C:10]2[C:5](=[CH:6][C:7]([C:16]#[N:17])=[CH:8][CH:9]=2)[N:4]=1
Reactant: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2cc(Br)ccc12
Reactant: CS(=O)c1nc(C(F)(F)c2ccc(F)cn2)nc2cc(C#N)ccc12
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3cc(C#N)ccc23)n[nH]1

Procedure:
2-(Difluoro(5-fluoropyridin-2-yl)methyl)-4-(5-methyl-1H-pyrazol-3-ylamino)quinazoline-7-carbonitrile was prepared as a white solid (12 mg, 10%) by following a procedure analogous to that described in Example 7 Step D, substituting 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylsulfinyl)quinazoline-7-carbonitrile for the 7-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline used in Example 7. 1H NMR (300 MHz, DMSO-d6) δ 12.23-12.30 (m, 1H), 11.06 (s, 1H), 8.86 (d, J=8.7 Hz, 1H), 8.67 (s, 1H), 8.42 (d, J=1.1 Hz, 1H), 7.97-8.05 (m, 3H), 5.99 (s, 1H), 2.18 (s, 3H); LC-MS (ESI) m/z 396 (M+H)+.
Reaction SMILES: NCC(N[C@H](C(NCC(N[C@H](C(N[C@H](C(O)=O)C(C)C)=O)CC(=O)O)=O)=O)CO)=O.[CH2:31](O)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][OH:41].OCCCCCCCCCC(O)=O.C1(N=C=NC2CCCCC2)CCCCC1.ON1C(=O)CCC1=O>>[CH2:40]([OH:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH3:31]
Reactant: OCCCCCCCCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)[C@H](NC(=O)[C@H](CC(=O)O)NC(=O)CNC(=O)[C@H](CO)NC(=O)CN)C(=O)O
Agent: O=C(O)CCCCCCCCCO
Product: CCCCCCCCCCO

Procedure:
Coupling of glycylserylglycylaspartylvaline with 1,10-decanediol. The protected peptide is reacted with 10-hydroxydecanoic acid (Aldrich) in the presence of dicyclohexylcarbodiimide (DCC) (Aldrich) and N-hydroxy-succinimide (Aldrich) according to Bergeron et al. (1981) J. Org. Chem. 46:4524, until the complete consumption of the peptide starting material is confirmed by thin layer chromatography. Flash column purification gives 10-(peptidyloxy) decanol as product, through formation of an amide linkage.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:9].[Cl-].[Al+3].[Cl-].[Cl-].[C:14]1([CH2:20][C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([C:21](=[O:22])[CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[CH:4][C:3]=1[S:8][CH3:9]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CSc1ccccc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CSc1ccc(C(=O)Cc2ccccc2)cc1Cl
Reaction time: 12 h
Yield: 68.8 %

Procedure:
To a stirred solution of 2-chlorothioanisole (3.0 g) in 120 ml dichloromethane, were added slowly first 2.8 g of aluminum chloride and 3.0 g of phenylacetyl chloride at 0° C. The reaction mixture was stirred at the temperature for 12 hours. Then the reaction solution was poured onto ice and aqueous hydrochloric acid. The quenched solution was stirred for 30 minutes and extracted with dichloromethane (80 ml×3). The organic layer was washed with brine and was dried over anhydrous magnesium sulfate. After the magnesium sulfate was removed by filtration, the filtrate was concentrated in vacuo. The resulting residue was recrystallized from hexane and dichloromethane to give 3.6 g of 1-{3-chloro-4-(methylthio)phenyl}-2-phenyl-ethanone. mp: 101-102° C. NMR: δ2.51 (s, 3H), 4.22 (s, 2H), 7.17 (d, J=8.4 Hz, 1H), 7.25 (m, 3H), 7.32 (m, 2H), 7.87 (J=8.4, 1.8 Hz, 1H), 7.97 (d, J 1.8 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[C:5]([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20]([C:22]3[NH:23][C:24]([CH3:29])=[C:25]([Cl:28])[C:26]=3[Cl:27])=[O:21])[CH2:15][CH2:14]2)[S:6][C:7]=1[C:8]([O:10]CC)=[O:9].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[Cl:27][C:26]1[C:25]([Cl:28])=[C:24]([CH3:29])[NH:23][C:22]=1[C:20]([NH:19][CH:16]1[CH2:15][CH2:14][N:13]([C:5]2[S:6][C:7]([C:8]([OH:10])=[O:9])=[C:3]([CH2:2][NH:1][S:31]([CH3:30])(=[O:33])=[O:32])[N:4]=2)[CH2:18][CH2:17]1)=[O:21]
Reactant: CCOC(=O)c1sc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc1CN
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: Cc1[nH]c(C(=O)NC2CCN(c3nc(CNS(C)(=O)=O)c(C(=O)O)s3)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.3 %

Procedure:
Ethyl 4-(aminomethyl)-2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-thiazole-5-carboxylate (Example 246; 312 mg, 0.677 mmol) was dissolved in DCM and methanesulfonyl chloride (65 μl; 0.844 mmol) was added slowly. The reaction was stirred at room temperature for 16 h, diluted with DCM, washed well with water dried over Na2SO4 and concentrated in vacuo to give the title compound as a light brown thick oil (350 mg)-(LCMS (ES) MH+: 538). The ethyl ester product was hydrolysed with lithium hydroxide/THF in a manner analogous to Example 31 to give the title compound (30 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([C:16]3[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=3[C:18]([OH:20])=O)=[O:15])[CH:5]=[CH:4][C:3]1=2.P(Cl)(Cl)Cl.[CH2:30]([NH:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH3:33]>ClCCl>[CH2:30]([N:34]([CH2:35][CH2:36][CH2:37][CH3:38])[C:18](=[O:20])[C:17]1[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=1[C:14]([C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:25])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=2[CH:7]=1)=[O:15])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCNCCCC
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)c3ccccc3C(=O)O)ccc21
Solvent: ClP(Cl)Cl
Solvent: ClCCl
Product: CCCCN(CCCC)C(=O)c1ccccc1C(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 26.8 %

Procedure:
To a solution of 1.68 g (5 mmoles) of 2-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl]benzoic acid in 20 cm3 of anhydrous dichloromethane, there is added 0.22cm3 (2.5 mmoles) of phosphorus trichloride. The mixture is heated for 3 hours at reflux. After cooling to +5° C., 2.6 cm3 (15 mmoles) of dibutylamine are added. Stirring is maintained for 30 minutes at +5° C., and then for 1 additional hour so as to permit the reaction mixture to return to ambient temperature. The reaction mixture is then diluted to about 80 cm3 by the addition of dichloromethane. It is then transferred to a decanting ampoule and washed first with diluted HCl and then with water. The dichloromethane phase is dried on sodium sulfate and then concentrated under reduced pressure. The resulting crude product is purified by chromatography on silica 60 gel in a 5/3/2 toluene/dichloromethane/ethyl acetate eluant mixture. After evaporation and drying under a vacuum a 80° C., 0.6 g of N,N-di-n-butyl 2-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl) carbonyl]benzamide in the form of a colorless thick oil is obtained. The NMR1H 80 MHz and IR spectra correspond to the expected structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[S:17][CH3:18])[N:10]3[CH2:19][CH2:20][CH2:21][CH:22]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:9]=23)=[CH:4][CH:3]=1.C1C=C(C([O-])=[O:36])C(C(O[O-])=O)=CC=1.[Mg+2]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[S:17]([CH3:18])=[O:36])[N:10]3[CH2:19][CH2:20][CH2:21][CH:22]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:9]=23)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC1CCCn2c1c(-c1ccc(Cl)cc1)c1c(SC)cccc12
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CC1CCCn2c1c(-c1ccc(Cl)cc1)c1c(S(C)=O)cccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the sulfide of Step 12 (110 mg, 0.1 mmol) in 8 ml of CH2Cl2/MeOH (10:1) at 0° C. was added MMPP (79 mg, 0.1 mmol). The reaction mixture was stirred at 0° C. for 1 hour and then quenched with a saturated aqueous solution of NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 70% EtOAc in Hexanes to provide 40 mg of the less polar diastereomer and 38 mg of the more polar diastereomer as a white solid.
Reaction SMILES: [CH2:1]([O:3][Si:4]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2].[O-:14]CC.[Ge+2:17].[O-]CC.CN1CCCN(C)CCN(C)CCCN(C)CC1>O>[CH3:7][CH2:6][O:5][Si:4]([O:3][CH2:1][CH3:2])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13].[Ge:17]=[O:14]
Reactant: [Ge+2]
Reactant: CC[O-]
Agent: CCO[Si](OCC)(OCC)OCC
Agent: CN1CCCN(C)CCN(C)CCCN(C)CC1
Solvent: O
Product: O=[Ge]
Reaction time: 48 h

Procedure:
1.01 g tetraethylorthosilicate, 2.0 g deionized water, and 0.41 g germanium ethoxide were mixed together in a tared 23 mL Teflon liner. Then 0.42 g of 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane (Strem Chemicals) was dissolved in the mixture. The Teflon container was then capped, sealed, and placed within an 23-mL steel Parr autoclave. The autoclave was allowed to remain at room temperature for 2 days during which time the TEOS and germanium ethoxide were allowed to hydrolyze. The Teflon cup was then removed from the autoclave and 0.13 g 50% HF was added and mixed to create a white viscous gel. The ethanol (formed from the hydrolysis of the TEOS and germanium oxide) and water were allowed to evaporate within a vented hood with flowing air over the course of 3-4 days. Sufficient water was added and mixed into the gel to bring the molar ratio H2O/(Si+Ge) to 7. The liner was then capped and placed within a Parr Steel autoclave reactor. The autoclave was then fixed in a rotating spit within an oven heated at 160° C. for 10 days. The solid products were recovered from the cooled reactor by vacuum filtration and washed with copious quantities of water.
Reaction SMILES: N[C:2]1(CO)[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[O:4][CH2:3]1.[OH:12]P([O-])(O)=O.[K+]>O>[CH3:9][C:5]1([CH3:8])[O:4][CH2:3][C:2](=[O:12])[CH2:7][O:6]1
Reactant: O=P([O-])(O)O
Reactant: CC1(C)OCC(N)(CO)CO1
Agent: [K+]
Solvent: O
Product: CC1(C)OCC(=O)CO1
Temperature: 0 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To a water (1.5 L) solution of (5-amino-2,2-dimethyl-1,3-dioxan-5-yl)methanol (251 g, 1.57 mol) and KH2PO4 (213 g, 1.57 mol) at 0° C., a water solution (1.8 L) of NaIO4 (336 g, 1.57 mol) was added dropwise. The reaction mixture was stirred at 0° C. for 2 hours and room temperature overnight. The product was extracted by CH2Cl2 (5×300 mL), dried over MgSO4 and distilled, yielding 2,2-Dimethyl-1,3-dioxan-5-one (153 g, 75%) as a colorless liquid, by 102° C./40 torr. 1H NMR (300 MHz, CDCl3) δ1.26 (s, 6H), 3.96 (s, 4H).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([O:21][CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[C:15]3[CH:14]=[N:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].CCN(CC)CC.[CH2:35]([C:37]([CH2:39]Br)=[O:38])[CH3:36].C(O)(C(F)(F)F)=O>O1CCOCC1.CC#N.O>[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([O:21][CH:22]4[CH2:27][CH2:26][N:25]([CH2:39][C:37](=[O:38])[CH2:35][CH3:36])[CH2:24][CH2:23]4)=[C:15]3[CH:14]=[N:13]2)=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: CCC(=O)CBr
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(=O)CN1CCC(Oc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2)CC1
Temperature: 100 °C
Yield: 19 %

Procedure:
To a solution of 1-(4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride (30.0 mg, 0.073 m mmol) and Et3N (35 μL) in dioxane (1.5 mL) was added bromomethyl ethyl ketone (22 μL, 0.219 mmol). The mixture was heated by microwave irradiation at 100° C. for 10 min. The mixture was diluted with CH3CN (3 mL) and purified by reverse-phase HPLC: Phenomenex® Luna C18 column (10μ, 250×21.2 mm), 5% (v/v) CH3CN (containing 1% v/v TFA) in H2O (containing 1% v/v TFA) gradient to 95% H2O, 20 mL/min, λ=214 nm to give Compound A168 (7.8 mg, 0.014 mmol, 19% yield) isolated as a white solid. HPLC/MS: Alltech® Prevail C18 column (5μ, 50×4.6 mm), 5% v/v CH3CN (containing 1% v/v TFA) in H2O (containing 1% v/v TFA) gradient to 99% v/v CH3CN in H2O, 3.5 mL/min, tr=1.69 min, ESI+=444.3 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:8]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[N:19]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Br:1][C:2]1[C:3]([CH2:8][N:22]2[CH2:21][CH2:20][N:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ncccc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(Cc2ncccc2Br)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.6 %

Procedure:
To a stirred suspension of 0.10 g (0.54 mmol) of 3-bromopyridine-2-carbaldehyde in 10 mL of dichloromethane was added activated powdered 4 Å molecular sieves, 0.20 mL (1.1 mmol) of N,N-diisopropylethylamine and 0.10 g (0.54 mmol) of tert-butyl piperazine-1-carboxylate. The resulting solution was stirred at ambient temperature for 1 h, then 0.34 g (1.6 mmol) of solid sodium triacetoxyborohydride was added in one portion. The heterogeneous reaction was allowed to stir at ambient temperature overnight and was then filtered through a pad of Celite®. The pad was washed with dichloromethane and the combined filtrates were washed with brine, dried over magnesium sulfate, filtered, and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography eluting with a 0-100% ethyl acetate in hexanes gradient to afford the title compound as a colorless gum (0.055 g, 29%). LC-MS: m/z (ES) 356.2, 358.2 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16]([S:21][CH3:22])=[N:17][CH:18]=3)[N:13]([CH2:23][CH3:24])[C:12]2=[O:25])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C1(C2[O:34]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16]([S:21]([CH3:22])=[O:34])=[N:17][CH:18]=3)[N:13]([CH2:23][CH3:24])[C:12]2=[O:25])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CCN1C(=O)N(c2cc(OC)cc(OC)c2)Cc2cnc(SC)nc21
Solvent: ClCCl
Product: CCN1C(=O)N(c2cc(OC)cc(OC)c2)Cc2cnc(S(C)=O)nc21
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a solution of 3-(3,5-dimethoxy-phenyl)-1-ethyl-7-methylsulfanyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one (5.61 g, 15.57 mmol) in dichloromethane (100 mL) at ambient temperature was added 3-phenyl-2-(phenylsulfonyl)oxaziridine (4.88 g, 18.69 mmol, PD 0191006, Org. Synth., 1987; 66:203-210) in portions. The reaction mixture was stirred overnight, then washed with brine and water. The organic layer was dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography eluting with a solvent mixture of 3% methanol in dichloromethane to yield 4.6 g (78%) of the titled compound: mp 167-169° C. Mass Spectrum (APCI, 80/20 CH3CN/H2O, Probe=450° C.) (m+1)/z 377.1
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:20][CH2:19][CH2:18]1)=[O:15].[CH3:21][O:22][C:23]1[N:28]=[C:27]([O:29][CH3:30])[C:26](B(O)O)=[CH:25][N:24]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:26]3[C:27]([O:29][CH3:30])=[N:28][C:23]([O:22][CH3:21])=[N:24][CH:25]=3)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:20][CH2:19][CH2:18]1)=[O:15]
Reactant: Nc1c(C(=O)NC2CCC2)nnc2c(Br)c(F)ccc12
Reactant: COc1ncc(B(O)O)c(OC)n1
Product: COc1ncc(-c2c(F)ccc3c(N)c(C(=O)NC4CCC4)nnc23)c(OC)n1
Yield: 42.8 %

Procedure:
Using Method A, 4-amino-8-bromo-7-fluoro-N-cyclobutyl-cinnoline-3-carboxamide (175 mg) and 2,4-dimethoxypyrimidin-5-yl boronic acid (207 mg) were reacted to afford the title compound (88 mg) as white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.24 (d, 1H), 8.57 (m, 1H), 8.38 (s, 1H), 7.77 (m, 1H), 4.49 (m, 1H), 4.00 (s, 3H), 3.84 (s, 3H), 2.26-2.10(m, 4H), 1.72-1.62 (m, 2H). MS APCI, m/z=399 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[K+].[NH2:19]OS(O)(=O)=O>C1(C)C=CC=CC=1.O.CN(C)C=O>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([NH2:19])[CH:3]=1
Reactant: NOS(=O)(=O)O
Reactant: Clc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Nn1cc(Cl)c2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 92.9 %

Procedure:
To a 12 L round bottom flask equipped with a mechanical stirrer, thermometer and a Gooch tube was added sieve-dried dimethylformamide (2.8 L), 3-chloroindole (240 g, 91.6% pure), milled potassium carbonate (200.4 g), milled potassium hydroxide (574.3 g, 85% pure) and dimethylformamide (900 mL) at -2° to 5° C. The reaction mixture was cooled to about 0° C. and hydroxylamine-O-sulfonic acid (338.2 g, 97% pure) was added portionwise via the Gooch tube over a period of about 4 hrs, maintaining the reaction temperature at about 0° C. When the reaction was >95% complete (by high performance liquid chromatography), the reaction mixture was poured into a well-stirred, cold mixture of water (18 L and 3.6 kg ice) and toluene (2.4 L). After about 5 mins, the phases were separated and the aqueous phase was extracted with toluene (1×2.4 L and 1×1 L). The organic fractions were combined and filtered through Celite. The filtrate was concentrated under reduced pressure (about 50 mm Hg) at about 60° C. to yield 245 g (86%) of product.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[CH3:16][C@H:17]1[CH2:22][NH:21][CH2:20][CH2:19][N:18]1C(OC(C)(C)C)=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:16][C@@H:17]1[NH:18][CH2:19][CH2:20][N:21]([S:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:15])([F:14])[F:1])=[CH:5][CH:6]=2)(=[O:12])=[O:11])[CH2:22]1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CCN1
Reaction time: 8 h
Yield: 63.2 %

Procedure:
A solution of 4-[(trifluoromethyl)oxy]benzenesulfonyl chloride (3.25 g, 12.48 mmol), 1,1-dimethylethyl(2S)-2-methyl-1-piperazinecarboxylate (2.5 g, 12.48 mmol) and DIPEA (4.58 ml, 26.2 mmol) in DCM (200 ml) was stirred at room temperature overnight. The mixture was washed with saturated aqueous NaHCO3 then brine. The organics were concentrated under vacuum, then re-dissolved in dioxane (200 ml). A 4M solution of HCl in dioxane (20 ml) and water (0.5 ml) were added and the mixture stirred overnight. The mixture was concentrated under vacuum, applied to an SCX-2 cartridge (20 g) washing with MeOH and eluting with 0.5M NH3 in MeOH; concentration under vacuum gave the title compound as a white solid (2.56 g).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[N:23]O)[C:14]=2[CH:13]=[CH:12][CH:11]=1>[Ni].C(O)C.O1CCCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]([NH2:23])[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1nc2ccccc2[nH]1
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: NC1c2ccccc2-c2c(-c3nc4ccccc4[nH]3)cccc21
Yield: 87.4 %

Procedure:
Carry out the procedure as in Example 6, starting from 1.57 g of 4-(1H-benzimidazol-2-yl)-fluoren-9-one oxime (Z,E), obtained in Example 68, and 5.6 mg of Raney Nickel in 80 ml of ethanol and 80 ml of tetrahydrofuran for 4 hours at 60° C. under a hydrogen pressure of 1 bar. After purification by making a paste in diisopropyl ether, we obtain 1.31 g of 4-(1H-benzimidazol-2-yl)-9H-fluoren-9(R,S)-ylamine, in the form of a white powder, with the following characteristics: