Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:22])[C:6]([O:9][C:10](=[O:21])[C:11]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:12]=1[Cl:20])([CH3:8])[CH3:7])[CH:2]=[CH2:3].C1(C)C=CC=CC=1.[PH2](O)=O>[Pt].[C].[V].O>[CH2:1]([O:4][C:5](=[O:22])[C:6]([O:9][C:10](=[O:21])[C:11]1[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:12]=1[Cl:20])([CH3:8])[CH3:7])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C(C)(C)OC(=O)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Pt]
Agent: [V]
Agent: O=[PH2]O
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCOC(=O)C(C)(C)OC(=O)c1cc(N)ccc1Cl
Reaction time: 0.17 h
Yield: 94.8 %

Procedure:
0.9 g of vanadium-containing active carbon prepared according to Example A1 is added to a solution of 16.1 g of 2-(2-chloro-5-nitrobenzoyloxy)-2-methyl-propionic acid allyl ester and 100 mg of toluene in an autoclave having a stirrer. 82 mg of platinum-carbon catalyst together with 50 mg of hypophosphorous acid and 2 ml of deionised water are placed in a seperate glass vessel, and the mixture is stirred for 10 minutes. The catalyst suspension is then transferred to the autoclave, rinsing the glass vessel with 4 ml of deionised water, and hydrogenated for 2 hours at a temperature of 100° C. and a hydrogen pressure of 20 bar. After cooling and rendering the autoclave inert using nitrogen, the catalyst is filtered off and washed with 20 ml of toluene. After working up by distillation, 14 g of 2-(2-chloro-5-amino-benzoyloxy)-2-methyl-propionic acid allyl ester having a content of 98.9% according to HPLC are obtained (yield 94.8% of theory).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[N:3]=1.[CH3:20][N:21]([CH3:30])[CH2:22][CH2:23][N:24]([CH3:29])[S:25]([NH2:28])(=[O:27])=[O:26].C1(P(C2CCCCC2)C2(C(C)C)CC=CC=C2C2C(C(C)C)=CC(C(C)C)=CC=2)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:19][C:13]1[C:14]([F:18])=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][S:10][C:4]1[N:3]=[C:2]([NH:28][S:25]([N:24]([CH2:23][CH2:22][N:21]([CH3:30])[CH3:20])[CH3:29])(=[O:27])=[O:26])[CH:7]=[C:6]([O:8][CH3:9])[N:5]=1
Reactant: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: CN(C)CCN(C)S(N)(=O)=O
Agent: [Pd]
Agent: CC(C)c1ccc(C2=CC=CCC2(C(C)C)P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1cc(NS(=O)(=O)N(C)CCN(C)C)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of 4-Chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidine (the product of example 35 step i) (0.35 g), N-[2-(dimethylamino)ethyl]-N-methylsulfamide (prepared according to procedure outlined in Org. Letts 2004, 6 (16), 2705-2708) (0.18 g), tris(dibenzylideneacetone)dipalladium (0) (73 mg), 2-dicyclohexylphosphino-2,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (53 mg), cesium carbonate (0.39 g) and dioxane (20 mL). Purification was by reverse phase HPLC (symmetry as the stationary phase and TFA/acetonitrile as the mobile phase) then titurated with MeOH followed by Et2O to give the title compound as a white solid. Yield: 0.12 g
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[C:22]([C:23]([F:26])([F:25])[F:24])=[N:21][CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17].[BH4-].[Na+].Cl>C1COCC1.O>[F:13][C:14]1[C:22]([C:23]([F:25])([F:26])[F:24])=[N:21][CH:20]=[CH:19][C:15]=1[CH2:16][OH:17]
Reactant: O=C(O)c1ccnc(C(F)(F)F)c1F
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccnc(C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Carbonyldiimidazole (1.16 g, 7.17 mmol) was added to a solution of 3-fluoro-2-trifluoromethyl-isonicotinic acid (1.00 g, 4.78 mmol) in THF (13.7 mL). The reaction mixture was stirred at RT overnight and was then added to a cold (0° C.) solution of NaBH4 (0.905 g, 23.9 mmol) in water (34.2 mL). The mixture was stirred for 10 min at 0° C., and 1M HCl was then added carefully (caution: H2 evolving). Volatiles were removed under reduced pressure, and the residue was dissolved in saturated aqueous NaHCO3. The mixture was extracted repeatedly with CH2Cl2, the combined organics were dried (phase separator) and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluent gradient: c-hexane/EtOAc 1:1 to 0:1) afforded the title compound as a yellow oil. TLC, Rf (c-hexane/EtOAc 1:1)=0.27; MS (LC/MS): 196.0 [M+H]+; tR (HPLC conditions b): 2.62 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([CH:18]=O)=[C:11]3[N:10]=2)=[CH:4][CH:3]=1.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].N1CCCCC1>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([CH:18]=[C:24]4[S:20][C:21](=[O:26])[NH:22][C:23]4=[O:25])=[C:11]3[N:10]=2)=[CH:6][CH:7]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1cnn2ccc(Nc3ccc(Cl)cc3)nc12
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2cnn3ccc(Nc4ccc(Cl)cc4)nc23)S1
Temperature: 70 °C

Procedure:
To 5-(4-chlorophenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (117 mg, 0.430 mmol) in EtOH was added thiazolidine-2,4-dione (50 mg, 0.430 mmol) and piperidine (43 μl, 0.430 mmol). The mixture was heated at 70° C. and the product formed quickly. The solid formed was isolated by filtration and air dried to yield 5-((5-(4-chlorophenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)thiazolidine-2,4-dione. LCMS (M+1=372)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][C:26]([F:35])([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])=[C:4]([CH3:36])[CH:3]=1.[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][C:26]([F:35])([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:22])=[C:4]([CH3:36])[CH:3]=1
Reactant: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC(F)(c3ccccc3)CC2)cnc2c(C(=O)O)cnn12
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)N3CCC(F)(c4ccccc4)CC3)cnc12
Yield: 28.9 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(4-fluoro-2-methylphenylamino)-6-(4-fluoro-4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (95 mg, 0.19 mmol) obtained in step 4 and ethanesulfonamide (100 mg, 0.95 mmol), the title compound (32 mg, 29%) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:26][CH2:25][C:14]2[NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:22](O)=[O:23])=[CH:20][C:21]=3[C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:53][CH:54]1[CH2:59][CH2:58][N:57]([CH2:60][C:61]2[CH:66]=[CH:65][C:64]([C:67]#[N:68])=[CH:63][CH:62]=2)[CH2:56][CH2:55]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)C.CO.C(Cl)Cl.C(Cl)Cl>[C:67]([C:64]1[CH:65]=[CH:66][C:61]([CH2:60][N:57]2[CH2:58][CH2:59][CH:54]([NH:53][C:22]([C:19]3[CH:18]=[CH:17][C:16]4[NH:15][C:14]5[CH2:25][CH2:26][N:11]([C:9]([O:8][CH2:1][C:2]6[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=6)=[O:10])[CH2:12][C:13]=5[C:21]=4[CH:20]=3)=[O:23])[CH2:55][CH2:56]2)=[CH:62][CH:63]=1)#[N:68]
Reactant: O=C(O)c1ccc2[nH]c3c(c2c1)CN(C(=O)OCc1ccccc1)CC3
Reactant: N#Cc1ccc(CN2CCC(N)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: N#Cc1ccc(CN2CCC(NC(=O)c3ccc4[nH]c5c(c4c3)CN(C(=O)OCc3ccccc3)CC5)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(benzyloxycarbonyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylic acid (3, 0.5 g, 1.4 mmol) in DMF (10 mL), HATU (0.65 g, 1.7 mmol), 4-amino-1-(4-cyanobenzyl)piperidine dihydrochloride (0.41 g, 1.4 mmol) and triethylamine (1.05 mL, 0.76 g, 7.5 mmol) were added. The resulting reaction mixture was allowed to stir at room temperature overnight, poured into saturated sodium bicarbonate solution (75 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (2×30 mL), brine (1×30 mL), dried (MgSO4), filtered and concentrated to give a tan solid. Column chromatography (neat DCM→5% MeOH/DCM) provided benzyl 8-(1-(4-cyanobenzyl)piperidin-4-ylcarbamoyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (4a in Scheme 1(b)) as a white solid upon trituration with ethyl ether (0.55 g, 70%). 1H NMR (DMSO-d6, 300 MHZ) 11.14 (br s, 1H), 8.04 (d, J=8.0 Hz, 1H), 8.00 (s, 1H), 7.79 (d, J=8.0 Hz, 2H), 7.59 (d, J=8.5 Hz, 1H), 7.51 (d, J=7.7 Hz, 2H), 7.39-7.27 (m, 6H), 5.14 (s, 2H), 4.67 (br s, 2H), 3.80 (br s, 3H), 3.57 (s, 2H), 2.82 (br s, 4H), 2.08 (t, J=11.0 Hz, 2H), 1.80 (d, J=11.3 Hz, 2H), 1.61 (q, J=10.7 Hz, 2H) ppm; MS (ES) 548 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=[O:24])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[OH-].[Na+].Cl>CO.C1COCC1>[CH:23]([C:14]1[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:25])=[O:2])[CH:6]=1)=[O:24]
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.301 g, 0.85 mmol) in MeOH (2.4 mL) and THF (3 mL) was added aqueous 1N NaOH (1.9 mL), and the solution was stirred overnight at room temperature. Once no starting material was seen by analytical LCMS, the reaction was neutralized with aqueous 1N HCl and extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography (50-100% EtOAc in hexanes, followed by 5% MeOH in CH2Cl2) to give the title compound.
Reaction SMILES: CN(C=O)C.[C:6]([Cl:11])(=O)[C:7](Cl)=O.[N:12]1[C:17]2[S:18][CH:19]=[CH:20]C=2C(=O)[NH:14][CH:13]=1.O>ClCCl>[Cl:11][C:6]1[C:7]2[CH:20]=[CH:19][S:18][C:17]=2[N:12]=[CH:13][N:14]=1
Reactant: O=c1[nH]cnc2sccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ncnc2sccc12
Temperature: 25 °C
Yield: 95.7 %

Procedure:
DMF (1.53 ml, 19.7 mmol) in dichloromethane (50 ml) was cooled to 0° C. and oxalyl chloride (2.5 ml, 29.6 mmol) was added slowly forming a white gel. Thieno[2,3-d]pyrimidin-4(3H)-one (1.5 g, 9.86 mmol) was added and the reaction mixture was refluxed for 3 hours. The mixture was cooled down to room temperature and poured into water. The mixture was extracted with dichloromethane, dried over sodium sulfate and concentrated in vacuo. The crude residue was purified by silica gel chromatography (EtOAc/hexane 15:1) to yield the title compound as a white solid (1.61 g, 96%).
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[N:10]=[C:9]2[S:11][C:12]([SH:14])=[N:13][C:8]2=[CH:7][CH:6]=1.Br[CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17]([OH:19])=[O:18]>C(N(CC)CC)C>[Cl:4][C:5]1[N:10]=[C:9]2[S:11][C:12]([S:14][CH:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]([OH:19])=[O:18])=[N:13][C:8]2=[CH:7][CH:6]=1
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: Sc1nc2ccc(Cl)nc2s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)C(Sc1nc2ccc(Cl)nc2s1)c1ccccc1
Yield: 74.3 %

Procedure:
A methylene chloride solution of 4.05 g (0.02 m) 5-chloro-2-mercaptothiazolo[5,4-b]pyridine, 4.30 g (0.02 m) α-bromophenylacetic acid and 4.0 g (0.04 m) triethylamine is heated to gentle reflux overnight. The methylene chloride solution is extracted twice with a dilute hydrochloric acid solution and once with water and then dried over anhydrous MgSO4. After the solvent is removed, the residual solid is recrystallized from acetonitrile. 5.0 g (74% yield) of title compound, melting at 175°-7° C., is obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[N:5]=[C:4]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[CH2:67]([OH:73])[CH:68]1[O:72][CH2:71][CH2:70][CH2:69]1>O1CCOCC1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[N:5]=[C:4]([NH:18][C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)[CH:3]=[C:2]([O:73][CH2:67][CH:68]3[CH2:69][CH2:70][CH2:71][O:72]3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: OCC1CCCO1
Reactant: C[C@H](Nc1nc(Cl)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(OCC2CCCO2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To 200 mg of (S)-6-chloro-N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine, 246 mg of tripotassium phosphate, 111 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl and 60 mg of tris(dibenzylideneacetone)(chloroform)dipalladium, 4 ml of tetrahydrofurfurylalcohol and 2 ml of 1,4-dioxane were added, and the mixture was subjected to degassing, and substituted by argon gas, and then was stirred at 100° C. for 1 hour. The reaction solution was diluted with ethyl acetate and was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 77 mg of the objective compound as pale yellow powder.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[CH:4][N:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])O.[Na+]>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.C(OCC)(=O)C.O.C(O)C.C1(C)C=CC=CC=1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:7]=[C:6]([CH2:8][NH:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[CH:4][N:3]=2)=[CH:16][CH:15]=1
Reactant: CC(C)NCc1ccnc(Br)c1
Reactant: OB(O)c1ccc(F)cc1
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: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)NCc1ccnc(-c2ccc(F)cc2)c1
Temperature: 150 °C
Yield: 53 %

Procedure:
A mixture of N-[(2-bromopyridin-4-yl)methyl]propan-2-amine (2.00 g), 4-fluorophenylboronic acid (1.34 g), cesium carbonate (4.26 g), tetrakis(triphenylphosphine)palladium (1.01 g), toluene (4.5 mL), ethanol (4.5 mL) and water (3.0 mL) was stirred under irradiation with microwave while heating at 150° C. for 30 min. Saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction mixture, and the resulting mixture was then filtered through Celite and extracted with ethyl acetate. The whole organic phase was collected and dried over magnesium sulfate. After the desiccant was filtered off, the solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel cartridge, chloroform:methanol=96:4-92:8) and (NH silica gel cartridge, hexane:ethyl acetate=90:10-60:40) to afford the title compound (1.13 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][SH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:21]1[C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:28])=[CH:25][CH:24]=[C:23]([Cl:36])[N:22]=1>CN(C=O)C>[Cl:36][C:23]1[N:22]=[C:21]([S:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:26]([C:27]([NH:29][CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(NC1CCCCC1)c1ccc(Cl)nc1Cl
Reactant: SCCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)c1ccc(Cl)nc1SCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 84.9 %

Procedure:
To a solution of 2-phenylethanethiol (295 μl, 2.2 mmol) in DMF (3 ml) was added NaHMDS (2.2 ml, 2.2 mmol). The reaction was stirred at ambient temperature for 2 minutes then added to a solution of 2,6-dichloro-N-cyclohexyl-pyridine-3-carboxamide (Intermediate 1, 600 mg, 2.2 mmol) in DMF (2 ml). The reaction was stirred at ambient temperature for one hour. The solvent was evaporated under reduced pressure and the resulting residue was partitioned between citric acid (20 ml) and EtOAc (40 ml). The layers were separated and the organic layer was washed with sat NaHCO3 (20 ml), water (20 ml) and brine (10 ml), then dried (MgSO4), filtered and evaporated to a solid. This solid was triturated with EtOAc/IH (1:9) to yield the product as a white solid (700 mg, 85%).
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([C:20]([F:23])([F:22])[F:21])([O:15]CC(O)=O)[C:6]=2[CH:5]=[C:4]([CH3:24])[CH:3]=1.C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.Cl>CN(C)C=O.O.C(O)(C)(C)C>[Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([C:20]([F:21])([F:22])[F:23])([OH:15])[C:6]=2[CH:5]=[C:4]([CH3:24])[CH:3]=1
Reactant: Cc1cc(Cl)c2c(c1)C(OCC(=O)O)(C(F)(F)F)c1ccccc1-2
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1cc(Cl)c2c(c1)C(O)(C(F)(F)F)c1ccccc1-2
Temperature: 0 °C
Yield: 113.8 %

Procedure:
To a mixture of dimethylformamide (90 ml) and an optically active form (30 g) of (4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid was added triethylamine (14.1 ml), and the mixture was stirred at 0° C. A solution of diphenylphosphoryl azide (20.0 ml) in dimethylformamide (60 ml) was added dropwise over 20 min, and the mixture was further stirred at 0° C. for 2 hr. To the reaction mixture was added t-butyl alcohol (75 ml), and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was ice-cooled, 2N hydrochloric acid (300 ml) was added and the mixture was stirred at room temperature overnight. To this mixture was added water (100 ml) and the mixture was placed in a separatory funnel. The aqueous layer was extracted twice with toluene (300 ml, 200 ml). The combined organic layer was successively washed twice with water (200 ml), twice with 1N aqueous sodium hydroxide solution (150 ml) and once with saturated brine (150 ml), and dried over anhydrous sodium sulfate. Thereto was added silica gel (6 g) and the mixture was stirred at room temperature. The insoluble material was filtered off, and washed with toluene (500 ml). The filtrate was concentrated under reduced pressure to give the title compound (28.58 g).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C:8](=[CH2:10])[CH2:7][C@H:6]1[C:11](=[O:20])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=[O:4]>CO.[OH-].[Na+]>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:11]([C@@H:6]2[CH2:7][C:8](=[CH2:10])[CH2:9][C@H:5]2[C:3]([OH:4])=[O:2])=[O:20])=[CH:18][CH:17]=1
Reactant: C=C1C[C@@H](C(=O)Nc2ccc(Cl)cc2)[C@H](C(=O)OC)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=C1C[C@@H](C(=O)O)[C@H](C(=O)Nc2ccc(Cl)cc2)C1

Procedure:
The crude material 1b (13.7 g) was dissolved in 200 ml of MeOH and 20 ml of 7 N NaOH, the solution was stirred at 22° C. for 2 h and evaporated. The residue was partitioned between 0.1 N NaOH and CH2Cl2, the aqueous layer was washed with CH2Cl2 and the aqueous layer was acidified with 25% HCl, the suspension was filtered and the residue dried to give 11.0 g (45% overall) of the pure title compound 1c as a pale brown solid. MS: 278.3 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:9]=1[NH:10][CH:11]1[CH2:13][CH2:12]1)=[O:4].N#N.[Cl:22][C:23]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>ClC(Cl)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:9]=1[N:10]([CH:11]1[CH2:13][CH2:12]1)[C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:23]=1[Cl:22])=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC1CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: N#N
Solvent: CC(Cl)Cl
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)c1ccc(Cl)cc1Cl)C1CC1
Reaction time: 16 h
Yield: 100.2 %

Procedure:
To a solution of 3-Cyclopropylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester (52 mg, 0.19 mmol) in dichloroethane (10 ml) in an atmosphere of N2 was added 2,4-dichlorobenzoyl chloride (45 mg, 0.21 mmol). The reaction mixture was stirred for 16 h at reflux. Then, the solvent was removed and the residue was purified by flash chromatography (8:2 Hexane/EtOAc) to obtain 85 mg (99%) of 3-[Cyclopropyl-(2,4-dichloro-benzoyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester. NMR 1H (CDCl3, 400 MHz): 7.64 ppm (d, 2H, Haro); 7.47 ppm (m, 2H, Haro); 7.44-7.33 ppm (m, 3H, Haro); 7.21-7.12 ppm (m, 2H, Haro); 3.89 ppm (s, 3H); 3.33 ppm (m, minor rotamer); 3.13 ppm (m, 1H, major rotamer) 1.01-0.49 ppm (m, 4H).
Reaction SMILES: [CH:1]1[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.C1C(=O)N([Br:24])C(=O)C1>C(Cl)(Cl)Cl>[Br:24][C:8]1[C:7]2[C:16]3=[C:15]4[C:4](=[CH:5][CH:6]=2)[CH:3]=[CH:2][CH:1]=[C:14]4[CH:13]=[CH:12][C:11]3=[CH:10][CH:9]=1
Reactant: c1cc2ccc3cccc4ccc(c1)c2c34
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Brc1ccc2ccc3cccc4ccc1c2c34
Temperature: 65 °C
Yield: 71.9 %

Procedure:
Pyrene (2 g, 9.9 mmol), NBS (1.78 g, 10 mmol) were dissolved in 20 mL of CHCl3 under dry nitrogen topped with a reflux condenser. The reaction was stirred at 65° C. and monitored by GC-MS until complete. After evaporation of the solvent the crude product was further purified by chromatography on silica gel using 20:1 petroleum ether 60-80: EtOAc as eluent to afford a yellow solid (2 gr, 72%). 1H-NMR (500 MHz, CD2Cl2): δ 8.02-8.11 (m, 4H), 8.17-8.24 (m, 4H), 8.41 (d, J=9.2 Hz, 1H). 13C-NMR (125 MHz, CD2Cl2): δ 120.2, 124.4, 125.4, 126.1, 126.2, 126.3, 127.1, 127.6, 128.2, 129.5, 130.0, 130.5, 131.1, 131.2, 131.4, 131.7. EI-MS: m/z M+ Calculated 280.0, found 280.0.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:21][C:22]3[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=3)=[N:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[O:13])=[N:9]2)=[CH:4][CH:3]=1.FC1C=C2C(=CC=1)N=C(C(C1C=CC(F)=CC=1)=O)N=C2NC1C=C(C)NN=1>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:21][C:22]3[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=3)=[N:7][C:8]([CH:12]([C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[OH:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3cc(Br)ccc23)n[nH]1
Agent: Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3ccc(F)cc23)n[nH]1
Product: Cc1cc(Nc2nc(C(O)c3ccc(F)cc3)nc3cc(Br)ccc23)n[nH]1

Procedure:
(7-Bromo-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)(4-fluorophenyl)methanol was prepared using a procedure analogous to that described in Example 54 substituting (7-bromo-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)(4-fluorophenyl)methanone from Example 56 (240 mg, 0.56 mmol) for the (6-fluoro-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)(4-fluorophenyl)methanone used in Example 54 (31 mg, 13%). 1H NMR (300 MHz, DMSO-d6) δ 12.17 (s, 1H), 10.55 (s, 1H), 8.54 (br s, 1H), 7.97 (br s, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.52-7.56 (m, 2H), 7.12-7.17 (m, 2H), 6.44 (s, 1H), 5.84 (s, 1H), 5.66 (s, 1H), 2.25 (s, 3H); LC-MS (ESI) m/z 428 (M+H)+.