Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(CN1CCOCC1)CN1CCCC2NC(C=O)=C(C)C=2C1=O.[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=[O:35])/[C:29]/2=[CH:36]\[C:37]1[NH:46][C:45]2[CH2:44][CH2:43][CH2:42][N:41]([CH2:47][C@H:48]([OH:56])[CH2:49][N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)[C:40](=[O:57])[C:39]=2[C:38]=1[CH3:58].[F:59][C:60]1[C:65]([F:66])=[CH:64][CH:63]=[CH:62][C:61]=1C1C(F)=CC=C2C=1CC(=O)N2.N1CCCCC1>C(O)C>[F:59][C:60]1[C:65]([F:66])=[CH:64][CH:63]=[CH:62][C:61]=1[C:27]1[C:26]([F:25])=[CH:34][CH:33]=[C:32]2[C:28]=1/[C:29](=[CH:36]/[C:37]1[NH:46][C:45]3[CH2:44][CH2:43][CH2:42][N:41]([CH2:47][C@H:48]([OH:56])[CH2:49][N:50]4[CH2:51][CH2:52][O:53][CH2:54][CH2:55]4)[C:40](=[O:57])[C:39]=3[C:38]=1[CH3:58])/[C:30](=[O:35])[NH:31]2
Reactant: Cc1c(/C=C2\C(=O)Nc3ccc(F)cc32)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CCC2
Reactant: O=C1Cc2c(ccc(F)c2-c2cccc(F)c2F)N1
Agent: Cc1c(C=O)[nH]c2c1C(=O)N(CC(O)CN1CCOCC1)CCC2
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(/C=C2\C(=O)Nc3ccc(F)c(-c4cccc(F)c4F)c32)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CCC2
Temperature: 25 °C
Yield: 74.9 %

Procedure:
5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 53f (84 mg, 0.25 mmol) and 4-(2,3-difluoro-phenyl)-5-fluoro-1,3-dihydro-indol-2-one 74 g (60 mg, 0.23 mmol) were dissolved in 2 ml of ethanol, and added with 35 μl of piperidine to the solution at room temperature. Upon completion of the addition, the mixture was heated to reflux for 2 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature, and filtered. The filter cake was washed with anhydrous ethanol (3 ml×2) and dried to obtain the title compound 2-((Z)-(4-(2,3-difluorophenyl)-5-fluoro-2-oxoindolin-3-ylidene)methyl)-5-((R)-2-hydroxy-3-morpholinopropyl)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one 75 (100 mg, yield 78%) as an orange solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH2:11])=[O:10].CCN(CC)CC.[C:19]([Si:21]([CH3:24])([CH3:23])[CH3:22])#[CH:20]>CN(C=O)C.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.[Cu]I>[CH3:22][Si:21]([C:19]#[C:20][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH2:11])=[O:10])([CH3:24])[CH3:23]
Reactant: C#C[Si](C)(C)C
Reactant: NC(=O)Cc1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccccc1CC(N)=O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(2-iodophenyl)acetamide (I6) (12.91 g, 49.52 mmol), Et3N (26 mL), ethynyltrimethylsilane (9.08 mL, 64.3 mmol), PdCl2(PPh3)2 (0.347 g, 0.495 mmol) and CuI (0.188 g, 0.989 mmol) in DMF (44 mL) was stirred under a nitrogen atmosphere at 50° C. for 3 hours. The volatiles were removed in vacuo and the resulting residue partitioned between EtOAc (100 mL) and water. The aqueous phase was extracted with EtOAc (3×50 mL), then the combined organic extracts were washed with water (3×70 mL), brine, dried (MgSO4), filtered and evaporated in vacuo to give the title compound I7 as a brown solid (11.4 g, 99%); 1H NMR (300 MHz, d6-DMSO) δ 7.40 (d, J=7.5 Hz, 1H), 7.20-7.36 (m, 4H), 6.94 (brs, 1H), 3.58 (s, 2H), 0.24 (s, 9H). LCMS-B: rt 6.884 min; m/z 232 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](OS(C(F)(F)F)(=O)=O)=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[CH2:25]([N:27]([CH2:31][C:32]#[CH:33])[CH2:28][CH2:29][OH:30])[CH3:26]>>[CH2:25]([N:27]([CH2:31][C:32]#[C:33][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:9]=[CH:10]2)[CH2:28][CH2:29][OH:30])[CH3:26]
Reactant: O=S(=O)(Oc1ccc2c(ccn2-c2ccc(F)cc2)c1)C(F)(F)F
Reactant: C#CCN(CC)CCO
Product: CCN(CC#Cc1ccc2c(ccn2-c2ccc(F)cc2)c1)CCO

Procedure:
In analogy to example 17.3, Trifluoro-methanesulfonic acid 1-(4-fluoro-phenyl)-1H-indol-5-yl ester and 2-(Ethyl-prop-2-ynyl-amino)-ethanol were converted to yield 2-(Ethyl-{3-[1-(4-fluoro-phenyl)-1H-indol-5-yl]-prop-2-ynyl}-amino)-ethanol as brown viscous oil, MS: 337 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[NH:14][C:15]1[CH:24]=[C:23]([C:25]#[N:26])[C:18]([C:19](OC)=[O:20])=[C:17]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:29]=2)[N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.CC(O)=O.[OH-].[OH-].[Pd+2]>[CH3:37][S:34]([C:30]1[CH:29]=[C:28]([NH:27][C:17]2[C:18]3[C:19](=[O:20])[NH:26][CH2:25][C:23]=3[CH:24]=[C:15]([NH:14][C@@H:10]3[CH2:11][CH2:12][CH2:13][C@@H:9]3[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[N:16]=2)[CH:33]=[CH:32][CH:31]=1)(=[O:35])=[O:36]
Reactant: COC(=O)c1c(C#N)cc(N[C@@H]2CCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc(S(C)(=O)=O)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1Nc1cc2c(c(Nc3cccc(S(C)(=O)=O)c3)n1)C(=O)NC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.9 %

Procedure:
A mixture of methyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclopentylamino)-4-cyano-2-(3-(methylsulfonyl)phenylamino)nicotinate (141.1 mg, 0.266 mmol) and palladium hydroxide on carbon (43.2 mg, 0.308 mmol) in MeOH (10 mL) and HOAc (10 mL) was stirred at RT for 12 h under a hydrogen atmosphere. The mixture was filtered to remove the catalyst and the filtrate was concentrated under reduced pressure. The residue was treated with saturated aq NaHCO3 (20 mL) and MeOH (20 mL). The mixture was stirred at RT for 6 h and then concentrated under reduced pressure. The residue was treated with saturated aq NaHCO3 (30 mL) and extracted with EtOAc (2×50 mL). The organic layers were washed with saturated aq NaHCO3 (20 mL), water (20 mL) and brine (20 mL), were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (DM1020, EtOAc) to give the desired product (46.5 mg). The product was washed with IPE/EtOAc to give the title compound as a pale brown solid (34.7 mg, 26%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.C[C:27]1([C:51]([NH2:53])=[O:52])[C:32]([CH3:34])([CH3:33])[S:31][CH2:30][CH2:29][N:28]1[S:35]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]#[C:47][CH2:48][CH2:49]O)=[CH:40][CH:39]=1)(=[O:37])=[O:36].C(Br)(Br)(Br)[Br:55]>C1COCC1>[Br:55][CH2:49][CH2:48][C:47]#[C:46][CH2:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([S:35]([N:28]2[CH2:29][CH2:30][S:31][C:32]([CH3:34])([CH3:33])[CH:27]2[C:51]([NH2:53])=[O:52])(=[O:36])=[O:37])=[CH:39][CH:40]=1
Reactant: CC1(C)SCCN(S(=O)(=O)c2ccc(OCC#CCCO)cc2)C1(C)C(N)=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC1(C)SCCN(S(=O)(=O)c2ccc(OCC#CCCBr)cc2)C1C(N)=O
Reaction time: 3 h

Procedure:
To a solution of 2.123 g (8.093 mmol) of triphenylphosphine and 0.373 mL (4.61 mmol) of pyridine in 40 mL of dry THF under nitrogen was added 1.73 g (4.046 mmol) of methyl 4-({4-[(5-hydroxy-2-pentynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpholine carboxamide. The solution was cooled in a water bath and 1.34 g (4.046 mmol) of carbon tetrabromide was added and the resulting mixture was stirred for 3h. The resulting suspension was filtered and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate:hexanes (1:8) to provide 1.726 g (87%) of methyl 4-({4-[(5-bromo-2-pentynyl)oxy]phenyl}sulfonyl-2,2-dimethyl-3-thiomorpholine carboxamide as a pale yellow oil. Electrospray Mass Spec: 492.0 (M+H)+
Reaction SMILES: [CH2:1]([Sn:5]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[OH-].[K+].C(O)(=O)C.O>C(O)C>[CH2:20]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(=O)OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C(=O)O)cc1
Temperature: 0 °C
Yield: 90.3 %

Procedure:
To a solution of methyl 4-tri-n-butylstannylbenzoate (3.0 g, 7 mmol) in absolute ethanol (60 ml) was added 0.25 g KOH (9 mmol). The resulting solution was refluxed for 2 hours. The solution was cooled and poured into an ice-cold solution of acetic acid (0.64 g, 10.6 mmol) and water (100 ml). The solution was then extracted with diethyl ether (80 ml). The ether phase was washed with water (30 ml), dried over MgSO4 (5 g), filtered and evaporated under reduced pressure to afford 2.6 g (88%) of the title compound. This material was used without further purification.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)[CH2:2][CH3:3].Cl.[NH2:18][OH:19]>>[CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13](=[N:18][OH:19])[CH2:12][CH2:11]1)[CH2:2][CH3:3]
Reactant: NO
Reactant: CCCOCCCCCN1CCC(=O)CC1
Agent: Cl
Product: CCCOCCCCCN1CCC(=NO)CC1

Procedure:
1-(5-Propoxypentyl)-4-piperidone oxime is prepared from 1-(5-propoxypentyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[H-].[Na+].[CH2:30]([OH:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCOCC1>[CH2:30]([O:37][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Cl)c3)nc12
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(OCc4ccccc4)c3)nc12

Procedure:
From 2-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and benzyl alcohol in dioxane. ES-MS m/e (%): 499 (M+Na+, 40), 477 (M+H+, 100).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]3[CH:12]=[C:13]([I:16])[CH:14]=[N:15][C:8]=3[NH:7][C:6]2=[S:17])[CH2:3][CH2:2]1.[CH2:18](I)[CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]3[CH:12]=[C:13]([I:16])[CH:14]=[N:15][C:8]=3[N:7]=[C:6]2[S:17][CH2:18][CH2:19][CH3:20])[CH2:2][CH2:3]1
Reactant: CCCI
Reactant: O=c1c2cc(I)cnc2[nH]c(=S)n1CC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSc1nc2ncc(I)cc2c(=O)n1CC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
A mixture of the title compound of Step A (0.5 g, 1.39 mmol), n-propyl iodide (0.36 g, 2.09 mmol) and potassium carbonate (1.9 g, 13.9 mmol) in DMF (14 mL) were stirred at ambient temperature overnight. The reaction mixture was then concentrated to dryness in vacuo and the residue partitioned between 200 mL of ethyl acetate and 100 mL of H2O. The organic phase was separated, washed with saturated aqueous NaCl, dried over Na2SO4 and concentrated in vacuo to provide 0.5 g of crude product. Purification of this crude product was achieved via column chromatography (silica gel, 70:30 hexanes:ethyl acetate eluent) to deliver 0.19 g of the title compound of Step B, a compound of the invention, as a solid melting at 159-161° C. 1H NMR (300 MHz, CDCl3): δ 0.50-0.62 (m,4H), 1.10 (t,3H), 1.31-1.43 (m,1H), 1.79-1.94 (m,2H), 3.41 (t,2H), 4.10 (d,2H), 8.82 (s,1H), 9.02 (d,1H). Mass Spectrum: m/e 402 (protonated parent molecular ion measured by mass spectrometry using atmospheric pressure chemical ionization in the positive ion mode (APCI+); the ion shown corresponds to the M+H+ ion calculated from the integral values of the atomic weights of the most abundant isotope of each element present).
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13]O)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].C[N+](C)=C[Cl:20].[Cl-]>>[C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13][Cl:20])=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Cn2cncc2CO)cc1
Reactant: C[N+](C)=CCl
Agent: [Cl-]
Product: N#Cc1ccc(Cn2cncc2CCl)cc1

Procedure:
reacting 1-(4-Cyanobenzyl)-5-Hydroxymethyl-imidazole of formula IA ##STR97## with Vilsmeier reagent to obtain 1-(4-Cyanobenzyl)-5-Chloromethyl-imidazole of formula IF: ##STR98##
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[S:14][C:13]([C:15]2[N:20]=[N:19][C:18](N)=[N:17][CH:16]=2)=[N:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:22]C(Cl)C.N(OC(C)(C)C)=O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Si:1]([O:8][CH2:9][C:10]1[S:14][C:13]([C:15]2[N:20]=[N:19][C:18]([Cl:22])=[N:17][CH:16]=2)=[N:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(Cl)Cl
Reactant: CC(C)(C)[Si](C)(C)OCc1cnc(-c2cnc(N)nn2)s1
Agent: CC(C)(C)ON=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: CC(C)(C)[Si](C)(C)OCc1cnc(-c2cnc(Cl)nn2)s1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
To a vial was added 6-(5-((tert-butyldimethylsilyloxy)methyl)thiazol-2-yl)-1,2,4-triazin-3-amine (2.5 g, 10.7 mmol), tetrabutylammonium chloride (6.3 g, 27.7 mmol) and dichloroethane (25 mL). The mixture was heated to 75° C., followed by the addition of t-butyl nitrite (3.3 mL, 27.7 mmol). The reaction was stirred at 75° C. for 3 h, followed by cooling to rt, quenching with brine (200 mL). The reaction was extracted four times with CH2Cl2. The combined organic layers were dried over Na2SO4, concentrated, and purified using silica gel chromatography to afford the 1.1 g of the title compound as an off-white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH2:5][OH:6].F[C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:19])[NH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1>CN(C)C=O>[OH:6][CH2:5][CH2:4][CH2:3][O:7][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:19])[NH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1
Reactant: O=c1[nH]cnc2cc(F)ccc12
Reactant: OCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1[nH]cnc2cc(OCCCO)ccc12
Temperature: 60 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
Sodium hydride (14.6 g, 365 mmol) was added at 0° C. to a solution of 1,3-propanediol (27.8 g, 365 mmol) in dimethylformamide (70 ml). 7-Fluoroquinazolin-4(3H)-one (10 g, 60.9 mmol) was added portionwise and the reaction mixture heated at 60° C., then at 110° C. for 3 hours. The reaction was cooled to 0° C., quenched with water (280 ml) and adjusted to pH 5.9. The resulting suspension was filtered, washed with water then ether and dried over phosphorus pentoxide to afford 7-(3-hydroxypropoxy)quinazolin-4(3H)-one as a white powder (12.41 g, 92% yield):
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[OH:7])[CH3:3].F[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]>CN1CCN(C)C1=O>[CH3:1][N:2]([CH2:4][CH2:5][CH:6]([O:7][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:3]
Reactant: CN(C)CCC(O)c1ccccc1
Reactant: Cc1ccccc1F
Solvent: CN1CCN(C)C1=O
Product: Cc1ccccc1OC(CCN(C)C)c1ccccc1

Procedure:
reacting an alkoxide of N,N-dimethyl-3-phenyl-3-hydroxypropylamine) with 2-fluorotoluene in 1,3-dimethyl-2-imidazolidinone to give N,N-dimethyl-3-(2-methylphenoxy)-3-phenylpropylamine;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[C:11]([CH:13]([CH2:18][CH:19](OC)OC)[C:14]([O:16][CH3:17])=[O:15])#[N:12].Cl>O1CCCC1>[C:11]([CH:13]([C:18]1[C:7]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:8]=2)[NH:9][CH:19]=1)[C:14]([O:16][CH3:17])=[O:15])#[N:12]
Reactant: COc1ccc(NN)cc1
Reactant: COC(=O)C(C#N)CC(OC)OC
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)C(C#N)c1c[nH]c2ccc(OC)cc12
Temperature: 67 °C
Yield: 40.3 %

Procedure:
A vigorously stirred suspension of para-methoxyphenylhydrazine chlorhidrate (6.47 g, 0.037 mole) in 260 ml of tetrahydrofuran was heated to 67° C. under an argon atmosphere. Compound IV, prepared above (10 g, 0.054 mole)was added at once and a solution of 12 ml of 10N hydrochloric acid in 70 ml of tetrahydrofuran was added over a period of 10 minutes. The reaction mixture was heated at reflux temperature for 35 minutes and further treated as described in Example 3. After chromatography on Silica gel 62 with hexane-ethyl acetate (3:1 v:v) solvent and evaporation of the solvent in vacuo, the viscous oily residue was crystallized from chloroform-hexane to yield 3.65 g (40.3%) of product mp 98°-100° C.
Reaction SMILES: [CH:1]([C:3]1[C:4](=[O:10])[NH:5][C:6](=[O:9])[NH:7][CH:8]=1)=[O:2].[H-].[Na+].I[CH2:14][CH3:15].CO>CN(C)C=O>[CH2:14]([N:7]1[CH:8]=[C:3]([CH:1]=[O:2])[C:4](=[O:10])[NH:5][C:6]1=[O:9])[CH3:15]
Reactant: O=Cc1c[nH]c(=O)[nH]c1=O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCn1cc(C=O)c(=O)[nH]c1=O
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 24.8 %

Procedure:
A suspension of 5-formyluracil (0.84 g, 6.0 mmol) in anhydrous dimethylformamide (12 mL) under a nitrogen atmosphere was cooled to −40° C. The reaction mixture was treated with sodium hydride (60% mineral oil dispersion, 0.26 g, 6.6 mmol), stirred 30 min., then treated with iodoethane (0.53 mL, 6.6 mmol). The mixture warmed to 20° C. over 3 h., then was brought to 40° C. for 48 h. At this time the reaction mixture was cooled to room temperature, treated with methanol (5 mL) and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel eluted with a gradient of ethyl acetate in hexanes (1:3 to 1:2 to 1:1) to leave the product (0.25 g) as a white powder. MS (ESI-POS): [M+H]+=169.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([NH2:21])=[CH:19][N:18]=[C:17]3[N:22]([S:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:27])=[O:26])[CH:23]=[CH:24][C:16]=23)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34]([NH:37][CH2:38][C:39](O)=[O:40])(=[O:36])[CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[C:20]([NH:21][C:39](=[O:40])[CH2:38][NH:37][C:34](=[O:36])[CH3:35])=[CH:19][N:18]=[C:17]3[N:22]([S:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:26])=[O:27])[CH:23]=[CH:24][C:16]=23)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Reactant: CC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NCC(=O)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.2 %

Procedure:
A mixture of 4-(5-amino-1-benzene sulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 2.12 mmol), N-acetylglycine (0.30 g, 2.5 mmol), HBTU (1.0 g, 2.8 mmol) and DIEA (1.1 mL, 6.4 mmol) in DMF (5 mL) was stirred at ambient temperature for 20 h. Diluted with water and the solid was collected by filtration, washed with water and dried in vacuum oven at 50° C. for 20 h to afford 4-[5-(2-Acetylamino-acetylamino)-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (1.20 g, 99%). This intermediate was suspended in acetic acid (6 mL) and heated at 100° C. for 7 h. Cooled, diluted with DCM and stirred over aqueous sodium bicarbonate solution. Organic layer separated, washed with water, brine dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0-10% MeOH/DCM) to afford 4-[2-(acetylamino-methyl)-6-benzenesulfonyl-6H-1,2,3,5,6-tetraaza-as-indacen-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.26 g, 24%): LCMS (Method E, ESI): RT=1.53 min, m+1=553.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl>>[O:24]1[CH2:23][CH:22]1[CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: ClCC1CO1
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(-c2ccc(OCC3CO3)cc2)cc1

Procedure:
A suspension of 10 g of 4-hydroxybiphenyl and 10 g of pulverised potassium carbonate in 75 ml of epichlorohydrin is stirred under reflux from 4 hours. The reaction mixture is concentrated by evaporation, water is added to the residue and the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulphate and concentrated by evaporation. The residue is recrystallised from isopropanol, yielding 4-(2,3-epoxypropoxy)-biphenyl having a melting point of 86°-88°.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=4)=[N:15][N:14]4[CH2:24][CH2:25][CH2:26][C:13]=34)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(N(CCCC)CCCC)CCC.[C:40]([O:44][CH3:45])(=[O:43])[CH:41]=[CH2:42].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].CN(C)C=O>[CH3:45][O:44][C:40](=[O:43])[CH:41]=[CH:42][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=4)=[N:15][N:14]4[CH2:24][CH2:25][CH2:26][C:13]=34)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: Cc1cccc(-c2nn3c(c2-c2ccnc4cc(Br)ccc24)CCC3)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)C=Cc1ccc2c(-c3c(-c4cccc(C)n4)nn4c3CCC4)ccnc2c1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Nitrogen is bubbled through a solution of 7-bromo-4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline (0.050 g, 0.12 mmol), tributylamine (0.032 mL, 0.17 mmol), methyl acrylate (0.027 mL, 0.24 mmol), and N,N-dimethylformamide (0.5 mL) in toluene (1.0 mL) for 20 min. Pd(OAc)2 (0.002 g, 0.006 mmol) and tri(o-tolyl)phosphine (0.007 g, 0.021 mmol) are added and nitrogen bubbled through the reaction mixture for 10 min. The mixture is heated to 80° C. for 24 h. An additional portion of Pd(OAc)2 (0.002 g, 0.006 mmol) and tri(o-tolyl)phosphine (0.007 g, 0.021 mmol) is added and heating continues for another 24 h. The reaction is cooled and concentrated in vacuo and the residue chromatographed on SiO2 (2% methanol in methylene choloride) to yield the title compound, 0.49 g (97%), as a yellowish solid.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[N:6]=[C:7]([NH:10][CH:11]3[C:19]4[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=4)[CH2:13][CH2:12]3)[O:8][CH2:9][C:4]=2[CH:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]=1>>[F:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[CH:11]([NH:10][C:7]1[O:8][CH2:9][C:4]3[CH:3]=[C:2]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:31])[F:33])[N:25]=4)[CH:22]=[CH:21][C:5]=3[N:6]=1)[CH2:12][CH2:13]2
Reactant: Nc1cccc(C(F)(F)F)n1
Reactant: Fc1ccc2c(c1)CCC2NC1=Nc2ccc(Br)cc2CO1
Product: Fc1ccc2c(c1)CCC2NC1=Nc2ccc(Nc3cccc(C(F)(F)F)n3)cc2CO1
Yield: 41.1 %

Procedure:
The title compound (91 mg, 41%), light brown foam, MS (ISP): m/e=443.3 (M+H+), was prepared in accordance with the general method of Example 35 from rac-(6-bromo-4H-benzo[d][1,3]oxazin-2-yl)-(5-fluoro-indan-1-yl)-amine (Example 53) (181 mg, 0.5 mmol) and commercially available 2-amino-6-trifluoromethyl-pyridine (162 mg, 1.0 mmol).