Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[N:25]1[C:34]2[C:29](=[CH:30][C:31]([OH:35])=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:35][C:31]3[CH:30]=[C:29]4[C:34](=[CH:33][CH:32]=3)[N:25]=[CH:26][CH:27]=[CH:28]4)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: Oc1ccc2ncccc2c1
Product: CC(NC(=O)c1coc(Oc2ccc3ncccc3c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 42.5 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with quinolin-6-ol (38 mg, 0.26 mmol) to give the title compound (27 mg, 42%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:10]=[CH:9][CH:8]=[C:6]([OH:7])[CH:5]=1)[OH:4].[I-].[Na+].[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CN(C)C=O.O1CCCC1>[CH2:28]([O:4][C:3]1[CH:5]=[C:6]([OH:7])[CH:8]=[CH:9][CH:10]=1)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: Oc1cccc(O)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCOc1cccc(O)c1
Temperature: 0 °C
Reaction time: 17 h

Procedure:
To a suspension of 29.6 g of sodium hydride in 215 ml of N,N-dimethylformamide was added dropwise over 1.5 hours a solution of 54.33 g of resorcinol in 145 ml of N,N-dimethylformamide and 72 ml of tetrahydrofuran. The resulting mixture was cooled to 0° C. and 7.4 g of sodium iodide added followed by the dropwise addition of 155.0 g of hexadecylbromide over 1 hour. The bath was removed and the mixture stirred at ambient temperature for 17 hours. The mixture was diluted with 500 ml of iced dilute hydrochloric acid, extracted with ether and filtered. The ether layer was dried over magnesium sulfate and evaporated to an oil which was purified by chromatography on silica gel using ethyl acetate-hexanes giving 37.2 g of the desired compound as a white solid, m.p. 58°-59° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][SH:12])=[CH:9][CH:8]=1)[CH2:4][CH3:5].Cl[C:16]1[N:21]=[C:20]([S:22][CH3:23])[N:19]([CH2:24][CH3:25])[C:18](=[O:26])[C:17]=1[CH3:27].O>CN(C)P(=O)(N(C)C)N(C)C>[CH3:27][C:17]1[C:18](=[O:26])[N:19]([CH2:24][CH3:25])[C:20]([S:22][CH3:23])=[N:21][C:16]=1[S:12][CH2:11][C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:3][CH2:4][CH3:5])=[CH:14][CH:13]=1
Reactant: CCn1c(SC)nc(Cl)c(C)c1=O
Reactant: CCCOc1ccc(CS)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCOc1ccc(CSc2nc(SC)n(CC)c(=O)c2C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
Sodium hydride (55% in mineral oil) (0.70 g) was suspended in 20 ml of hexamethyl phosphoric triamide, and then 3.0 g of 4-propyloxybenzyl mercaptan was added thereto. The mixture was stirred for one hour at room temperature and then incorporated with 3.0 g of 6-chloro-5-methyl-2-methylthio-3-ethyl-4(3H)-pyrimidinone. After stirring at room temperature, resulting mixture was heated to 80° C. under stirring for 3 hours. The resulting solution was poured into water and then extracted with benzene. The extract was washed with an aqueous sodium hydroxide solution and then with water, dried over anhydrous sodium sulfate and freed of solvent by distillation udner reduced pressure. The oil thus obtained was purified by means of column chromatography (on silica gel, eluting with chloroform) to give 2.6 g of the intended product.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]([CH3:13])([CH3:12])[NH:7][C:8](=[O:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:35])=[CH:19][N:18]=1>Cl.O1CCOCC1.CC(O)C>[NH2:7][C:8](=[O:11])[CH2:9][CH2:10][C:4]1[CH:3]=[C:2]([NH:1][C:17]2[N:22]=[C:21]([NH:23][C:24]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=3[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:35])=[CH:19][N:18]=2)[CH:15]=[CH:14][C:5]=1[C:6]([CH3:13])=[CH2:12]
Reactant: CC1(C)NC(=O)CCc2cc(N)ccc21
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: C=C(C)c1ccc(Nc2ncc(Cl)c(Nc3c(F)cccc3C(=O)NC)n2)cc1CCC(N)=O
Temperature: 120 °C

Procedure:
A mixture of 7-amino-1,1-dimethyl-1,2,4,5-tetrahydrobenzo[c]azepin-3-one (40 mg), 2-(2,5-dichloropyrimidin-4-ylamino)-3-fluoro-N-methylbenzamide (50 mg), and 2 drops of 4 N HCl/dioxane in IPA (3 mL) were microwave-heated at 120° C. for 1.5 hours. The mixture was concentrated to afford crude 2-(2-(3-(3-amino-3-oxopropyl)-4-(prop-1-en-2-yl)phenylamino)-5-chloropyrimidin-4-ylamino)-3-fluoro-N-methylbenzamide. The crude mixture was stirred for 4 hours in TFA and concentrated. Purification by semi-preparative HPLC provided 2-(5-chloro-2-(1,1-dimethyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-ylamino)pyrimidin-4-ylamino)-3-fluoro-N-methylbenzamide (45.7 mg) as a TFA salt: 1H NMR (300 MHz, CD3OD) δ 8.3 (s, 1H), 7.7-7.5 (m, 3H), 7.65 (s, 1H, slowly exchanging NH), 7.4 (d, 1H), 7.32 (d, 1H), 7.28 (dd, 1H), 3.0 (m, 2H), 3.0 (s, 3H), 2.7 (m, 2H), 1.8 (s, 6H).
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][C:8](O)=[O:9].[CH3:12][O:13][C:14](=[O:25])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:2][O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][C:8]([C:21]1[CH:20]=[CH:19][C:18]([O:23][CH3:24])=[C:17]([CH2:16][CH2:15][C:14]([O:13][CH3:12])=[O:25])[CH:22]=1)=[O:9]
Reactant: COC(=O)CCCC(=O)O
Reactant: COC(=O)CCc1ccccc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CCCC(=O)c1ccc(OC)c(CCC(=O)OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5.1g of glutaric acid monomethyl ester chloride and 5g of 3-(2-methoxyphenyl)-propionic acid methyl ester are added with ice cooling in succession to a suspension of 10g of aluminum chloride in 100 ml of dichloromethane and the mixture is stirred for 16 hours at room temperature. The reaction mixture is poured on ice/2n hydrochloric acid, shaken out with dichloromethane, the organic phase is dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with hexane/ethyl acetate (0-30% ethyl acetate). 4.45g of 5-[4-methoxy-3-(2-methoxycarbonylethyl)-phenyl]-5-oxo-pentanoic acid methyl ester is obtained as oil, that is heated together with 47.5g of pyridinehydrochloride for 5 hours to 180° C. for further reaction. After cooling to 90° C. the reaction mixture is mixed with water, acidified to pH 1 with concentrated hydrochloric acid, shaken out with ethyl acetate, the organic phase is dried on sodium sulfate and concentrated by evaporation. 3.9g of 5[3-(2-carboxyethyl)-4-hydroxyphenyl]-5-oxopentanoic acid of melting point of 169°-166° C. is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:22]=[CH:21][NH:20][N:19]=3)[CH:16]=2)[N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH:10]=1.CN(C)C=O.[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:22]=[CH:21][NH:20][N:19]=3)[CH:16]=2)[NH:11][CH:10]=1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc[nH]n3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cc[nH]n3)cc12
Reaction time: 4 h
Yield: 18.6 %

Procedure:
3-(2-Methoxy-phenyl)-5-(1H-pyrazol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (156 mg, 0.350 mmol) was dissolved in methanol (1.0 mL) and dimethylformamide (1.0 mL) and 50% w/v aqueous potassium hydroxide (1.0 mL) was added. After 4 hours, the reaction was quenched by addition of acetic acid (1.0 mL). The mixture was carefully poured into saturated sodium bicarbonate and extracted with ethyl acetate. The organic layers were dried over sodium sulfate, filtered and dried to a residue which was purified by preparative HPLC to afford 3-(2-methoxy-phenyl)-5-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine (18.9 mg, 18.6%). 1H-NMR (500 MHz, dimethylsulfoxide-d6) δ 3.78 (s, 3H), 6.69 (d, J=2.0 Hz, 1H), 6.99 (dt, J=7.0, J=0.5 Hz, 1H), 7.06 (d, J=7.5 Hz, 1H), 7.23 (dt, J=7.0, J=1.5 Hz, 1H), 7.50 (dd, J=7.5, J=1.5 Hz, 1H), 7.63 (d, J=2.5 Hz, 1H), 7.65 (br s, 1H), 8.29 (d, J=2.0 Hz, 1H), 8.63 (br s, 1H), 11.82 (s, 1H). MS: m/z 291 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([C:11]2[C:12](=[O:22])[O:13][C:14]3[C:19]([C:20]=2[OH:21])=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.Cl[CH2:30][CH2:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[OH:21][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:13][C:12](=[O:22])[C:11]=1[CH:8]([C:4]1[CH:3]=[C:2]([NH:1][S:32]([CH:31]=[CH2:30])(=[O:34])=[O:33])[CH:7]=[CH:6][CH:5]=1)[CH2:9][CH3:10]
Reactant: CCC(c1cccc(N)c1)c1c(O)c2ccccc2oc1=O
Reactant: O=S(=O)(Cl)CCCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CS(=O)(=O)Nc1cccc(C(CC)c2c(O)c3ccccc3oc2=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 14.7 mg of 3-[1-(3-aminophenyl)propyl]4 hydroxy-coumarin is added 1 ml of methylene chloride and 8.1 microliters of pyridine. 5.71 microliters of chloroethylsulfonyl chloride is added at room temperature and protection from moisture. The reaction mixture is allowed to stir at room temperature for 3 hours. 5 ml of methylene chloride is added and the solution is washed twice with 5 ml of water. The organic solution is dried over anhydrous sodium sulfate, filtered and dried to give crude title product. Chromatography over 15 g of silica gel using 5% methanol in chloroform and collecting material with Rf =0.3 gives 6.3 mg of the title product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1([CH3:19])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:53]1([S:58]([NH:61][C:62]([C@@:64]2([NH:69][C:70]([C@@H:72]3[CH2:83][C@:75]4([C:80]([CH3:82])([CH3:81])[C:76]54[CH2:79][CH2:78][CH2:77]5)[CH2:74][NH:73]3)=[O:71])[CH2:66][C@H:65]2[CH:67]=[CH2:68])=[O:63])(=[O:60])=[O:59])[CH2:57][CH2:56][CH2:55][CH2:54]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:13]1([CH3:19])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:10]([N:73]1[C@H:72]([C:70](=[O:71])[NH:69][C@:64]2([C:62]([NH:61][S:58]([N:53]3[CH2:54][CH2:55][CH2:56][CH2:57]3)(=[O:60])=[O:59])=[O:63])[CH2:66][C@H:65]2[CH:67]=[CH2:68])[CH2:83][C@:75]2([C:80]([CH3:81])([CH3:82])[C:76]32[CH2:77][CH2:78][CH2:79]3)[CH2:74]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1(C)CCOCC1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@]2(CN1)C(C)(C)C21CCC1)C(=O)NS(=O)(=O)N1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@]2(CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C1(C)CCOCC1)C(C)(C)C21CCC1)C(=O)NS(=O)(=O)N1CCCC1
Reaction time: 8 h

Procedure:
A solution of (S)-tert-Butoxycarbonylamino-(4-methyl-tetrahydro-pyran-4-yl)-acetic acid (0.306 g; 1.12 mmol) (prepared according to Tetrahedron Let. 2007, 48, 6343-6347) and HATU (0.581 g; 1.53 mmol) in DCM (20 mL) was stirred for 10 min at ambient temperature. DIPEA (1.05 mL; 6.11 mmol) and (5R,8S)-10,10-Dimethyl-7-aza-dispiro[3.0.4.1]decane-8-carboxylic acid [(1R,2S)-1-(pyrrolidine-1-sulfonylaminocarbonyl)-2-vinyl-cyclopropyl]-amide (0.57 g; 1.02 mmol) were added, the reaction mixture was stirred overnight and purified without workup by preparative HPLC (method L) to yield the title compound. LC-MS (method E): Rt=2.55 min; M/z=706 [M+]; HPLC (method A3): Rt=6.16 min
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([CH:21]3[CH2:23][CH2:22]3)=[O:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1>CO.C(Cl)Cl>[NH2:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([CH:21]3[CH2:22][CH2:23]3)=[O:20])[CH:13]=2)=[N:4][CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Oc1ccnc(NC(=O)C2CC2)c1
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(N)cnc1Oc1ccnc(NC(=O)C2CC2)c1
Yield: 29.7 %

Procedure:
Dissolve N-[4-[(3-methyl-5-nitro-2-pyridyl)oxy]-2-pyridyl]cyclopropanecarboxamide (269 mg, 0.83 mmol) in MeOH (5 mL) and DCM (5 mL). Add Pd/C (10%, 104 mg), flush with H2. Stir the reaction under H2 at room temperature for 2 hrs. After the reaction, flush with N2, filter the reaction mixture; concentrate the filtrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:1) affords the title compound (70 mg, 30%). MS: (M+1): 285.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[C@H:12]([CH3:17])[CH2:13][CH2:14][CH2:15]O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:46].[Cl-].[NH4+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[C@H:12]([CH3:17])[CH2:13][CH2:14][CH2:15][Br:46])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: C[C@H](CCCO)N(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: C[C@H](CCCBr)N(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 12 h
Yield: 87.8 %

Procedure:
To a solution of 4-chloro-N-[5-fluoro-2-flurophenyl]-N-[(R)-1-methyl-4-hydroxybutyl]-benzenesulfonamide (317 mg, 0.813 mmol) in acetonitrile (4 mL) was added triphenylphosphine (425 mg, 1.62 mmol) and carbon tetrabromide (537 mg, 1.62 mmol) at 0° C. The resulting mixture was allowed to stir at 22° C. for 12 h followed by the addition of 25 mL of sat. ammonium chloride. The product was extracted with ether (2×25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:4 ethyl acetate:hexanes) of the concentrate afforded 323 mg of 4-chloro-N-[5-fluoro-2-flurophenyl]-N-[(R)-1-methyl-4-bromobutyl]benzenesulfonamide as a yellow oil in 86% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([O:13][CH3:14])[CH3:12].[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:15][C:16]1[CH:21]=[C:20]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[C:5]3([O:13][CH3:14])[CH3:12])[CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COC1(C)C(=O)Nc2ccc(Br)cc21
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
Solvent: COCCOC
Product: COC1(C)C(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Reaction time: 0.25 h
Yield: 29 %

Procedure:
A solution of 5-bromo-3-methoxy-3-methyl-1,3-dihydro-indol-2-one (0.52 g, 2.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.12 g, 0.1 mmol) was dissolved in dimethoxyethane (22 cm3). After 15 min., 3-chlorophenylboronic acid (0.63 g, 4.1 mmol) and sodium carbonate (1.0 g) in water (10 cm3) was added and the reaction was heated under reflux. After 2 h the mixture was cooled, poured into water and extracted with EtOAc (×2), the combined organic extracts were washed with sodium hydroxide solution (1N, ×2) water, brine, dried (MgSO4) and evaporated. The residue was then purified by column chromatography (SiO2, EtOAc:hexane, 5:1) to afford 5-(3-chloro-phenyl)-3-methoxy-3-methyl-1,3-dihydro-indol-2-one (0.17 g, 0.58 mmol, 29%): 1H NMR (CDCl3) δ 1.65 (s, 3H), 2.91 (s, 1H), 3.24 (s, 3H), 6.92 (d, 1H, J=8.1 Hz), 7.26-7.38 (m, 2H), 7.43-7.46 (m, 1H), 7.52-7.55 (m, 1H), 7.62 (d, 1H, J=1.8 Hz); MS ((+) APCI) m/z 288 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH2:26]Cl)[CH:25]=1)[CH2:13][CH2:12]2.O>CN(C=O)C>[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH2:26][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH:25]=1)[CH2:13][CH2:12]2
Reactant: O=C1c2ccc(Cl)cc2CCN1c1cncc(CCl)c1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccc(Cl)cc2CCN1c1cncc(Cn2ccnc2)c1
Temperature: 3.5 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
To a solution of 1H-imidazole (50 mg, 0.73 mmol) dissolved in DMF (5.0 mL) was added NaH (60% dispersion in mineral oil, 25 mg, 0.63 mmol) at 0° C. The reaction mixture was stirred at 2-5° C. for 0.5 h before 6-chloro-2-(5-chloromethyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one (example 140 [A]) (85 mg, 0.28 mmol) was added. The mixture was then stirred at 2-5° C. for additional 2 hours before it was warmed up to room temperature and poured into water (5.0 mL). After extraction with EtOAc (2×50 mL), the organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by prep-HPLC to give the title compound (30 mg, 31%) as a white foam. MS: 339.2 (M+H+).
Reaction SMILES: [Cl:1][B:2]([Cl:4])Cl.[CH:5]([NH:8][CH:9]([CH3:11])[CH3:10])([CH3:7])[CH3:6].C(N(CC)CC)C>C(Cl)Cl>[CH:5]([N:8]([B:2]([Cl:4])[Cl:1])[CH:9]([CH3:11])[CH3:10])([CH3:7])[CH3:6]
Reactant: ClB(Cl)Cl
Reactant: CC(C)NC(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N(B(Cl)Cl)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
To a methylene chloride solution of trichloroborane (1.0 M, 100 ml, 0.10 mole) was added dropwise at −78° C. diisopropylamine (13.108 ml, 0.100 mole) over a 30 minute period. The solution was allowed to stir for 1 hour, during which a white precipitate formed. The mixture was allowed to warm to room temperature, and solvent was removed under reduced pressure. The residue was dissolved in 100 ml of dry toluene, triethylamine (13.94 ml, 0.10 mole) was added and the solution was stirred overnight at room temperature. The mixture was filtered, the residue was washed with 20 ml of toluene. Solvent was removed under reduced pressure from the combined filtrates, and the resulting oil was purified by vacuum distillation (25-28° C., 13 Pa, 0.1 mm) to give 9.2 g (51 percent) of product as a colorless liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:18][C:19]([F:23])([F:22])[CH2:20][OH:21]>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:21][CH2:20][C:19]([F:23])([F:22])[F:18])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCC(F)(F)F
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Product: CC(C)(C)OC(=O)N1Cc2ccc(OCC(F)(F)F)cc2C1

Procedure:
Prepared in analogy to Example A6(a) from 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and 2,2,2-trifluoroethanol. Yellow solid. MS (m/e): 262.0 ([M+H−Me2C═CH2]+, 100%)
Reaction SMILES: [C:1]([C:3]1[C:4](=O)[NH:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:8]=1)#[N:2].C1(P(Cl)([Cl:25])=O)C=CC=CC=1.[NH4+].[OH-]>>[Cl:25][C:4]1[C:3]([C:1]#[N:2])=[CH:8][C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][N:5]=1
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c[nH]c1=O
Reactant: O=P(Cl)(Cl)c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Product: N#Cc1cc(-c2ccc(Cl)cc2)cnc1Cl
Temperature: 175 °C

Procedure:
A mixture of 3-cyano-5-(4-chlorophenyl)-2-(1H)-pyridone (2.0 grams) and phenylphosphonic dichloride (3.8 grams) was heated for 4 hours at 175° C. in an oil bath. The mixture was poured into ice water and was made alkaline by stirring with NH4OH. The resulting brownish solid product was used without further purification, yield 2.0 g., m.p. 185°-187° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[CH:8][C:9]=1[F:10].[F:12][C:13]1[CH:18]=[C:17]([CH2:19][CH2:20][CH3:21])[CH:16]=[CH:15][C:14]=1[C:22]1[CH:27]=[CH:26][C:25]([CH2:28]Br)=[C:24]([F:30])[CH:23]=1.Cl>CN(C)C=O>[F:3][C:4]1[CH:5]=[C:6]([O:11][CH2:28][C:25]2[CH:26]=[CH:27][C:22]([C:14]3[CH:15]=[CH:16][C:17]([CH2:19][CH2:20][CH3:21])=[CH:18][C:13]=3[F:12])=[CH:23][C:24]=2[F:30])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: CCCc1ccc(-c2ccc(CBr)c(F)c2)c(F)c1
Reactant: Oc1ccc(F)c(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1ccc(-c2ccc(COc3ccc(F)c(F)c3)c(F)c2)c(F)c1
Reaction time: 1 h

Procedure:
Into the mixture of 0.6 g (13.8 mmol) of NaH and 3 ml of dimethyl formamide (DMF), a solution of 1.8 g (13.8 mmol) of 3,4-difluorophenol dissolved in 20 ml of DMF was added dropwise, and the mixture was stirred for 1 hour. Into this mixture, 3.0 g (9.2 mmol) of 2′-fluoro-4′-propyl-3-fluoro-4-bromomethylbiphenyl was added, and the mixture was heated and refluxed for 4 hours. The reaction mixture was poured into 50 ml of 1N-HCl and extracted by 100 ml of ethyl acetate, and the obtained organic layer was washed twice with a diluted NaHCO3 solution and three times with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to a silica gel column chromatograph (eluent: heptane) to obtain crude (2′-fluoro-4′-propyl-3-fluorobiphenyl-4-yl)methyl 3,4-difluorophenyl ether.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.ClC1N=C([NH:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)C=C(Cl)N=1.C1(N)CCCC1>>[CH:18]1([NH:17][C:2]2[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: Clc1cc(NC2CCCC2)nc(Cl)n1
Agent: NC1CCCC1
Product: Clc1cc(Cl)nc(NC2CCCC2)n1
Yield: 35.2 %

Procedure:
Preparation of 2-cyclopentylamino-4,6-dichloroplrrimidine and 2,6-dichloro-4-cyclopentylaminopyrimidine 2,4,6-Trichloropyrimidine is reacted with cyclopentylamine as described in Example 2 to obtain the less polar 2-cyclopentylamino-4,6-dichloropyrimidine in a yield of 35.2%, m.p.: 48°-52° C.
Reaction SMILES: [ClH:1].CO[C:4](=O)[CH:5]([NH2:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[CH:12].[N:15]#[C:16][NH2:17]>>[ClH:1].[CH2:6]([C:5]1[N:13]=[C:16]([NH2:17])[NH:15][CH:4]=1)[CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[CH:12]
Reactant: N#CN
Reactant: C#CCCCCCC(N)C(=O)OC
Agent: Cl
Product: C#CCCCCCc1c[nH]c(N)n1
Yield: 53 %

Procedure:
2-Amino-non-8-ynoic acid methyl ester hydrochloride (2.02 g, 9.20 mmol) was treated to an Akabori reduction followed by a cyanamide condensation employing conditions previously reported to produce 4-Hept-6-ynyl-1H-imidazol-2-ylamine hydrochloride (1.04 g, 53%) as a pale yellow solid (Olofson et al., Journal of Organic Chemistry 1997, 62, (23), 7918-7919). 1H NMR (300 MHz, CD3OD) δ 6.17 (s, 1H), δ 2.19 (t, 2H), δ 1.90 (t, 1H), δ 1.86 (m, 2H), δ 1.24-1.13 (m, 6H) ppm; 13C NMR (75 MHz, CD3OD) δ 147.5, 128.3, 108.8, 83.8, 65.5, 28.4, 28.3, 28.2, 24.5, 17.8 ppm; HRMS (ESI) calcd for C10H16N3(M+) 178.1338, found 178.1337.