Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([Cl:26])=[C:20]([CH:25]=3)[C:21]([O:23][CH3:24])=[O:22])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[Cl:27][C:28]1[CH:37]=[CH:36][C:35]([NH:38][S:39]([C:42]2[CH:51]=[CH:50][C:49]3[C:44](=[CH:45][C:46]([N:52]=[C:53]=[S:54])=[CH:47][CH:48]=3)[CH:43]=2)(=[O:41])=[O:40])=[CH:34][C:29]=1[C:30]([O:32][CH3:33])=[O:31]>ClCCl>[Cl:26][C:19]1[CH:18]=[CH:17][C:16]([NH:15][S:12]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([NH:1][C:53]([NH:52][C:46]4[CH:47]=[CH:48][C:49]5[C:44](=[CH:43][C:42]([S:39]([NH:38][C:35]6[CH:36]=[CH:37][C:28]([Cl:27])=[C:29]([C:30]([O:32][CH3:33])=[O:31])[CH:34]=6)(=[O:40])=[O:41])=[CH:51][CH:50]=5)[CH:45]=4)=[S:54])=[CH:3][CH:4]=3)[CH:9]=2)(=[O:14])=[O:13])=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)c1cc(NS(=O)(=O)c2ccc3ccc(N)cc3c2)ccc1Cl
Reactant: COC(=O)c1cc(NS(=O)(=O)c2ccc3ccc(N=C=S)cc3c2)ccc1Cl
Solvent: ClCCl
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc3ccc(NC(=S)Nc4ccc5ccc(S(=O)(=O)Nc6ccc(Cl)c(C(=O)OC)c6)cc5c4)cc3c2)ccc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.2 %

Procedure:
To 3.0 g (7.68 mmol) of compound 134 was added a solution of 4.0 g (9.24 mmol) of compound 135 in 200 mL of dichloromethane. The reaction was allowed to stir at ambient temperature for 48 hours. The fine, white solid was collected to give 5.2 g of compound 157.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:34])[CH2:15][C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30](Br)[CH2:31][CH3:32])=[CH:24][CH:23]=1)[C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:41][C:42]([F:51])([F:50])[C:43]1[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=1>CN(C=O)C.O>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:34])[CH2:15][C@H:16]([C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]([O:49][C:46]2[CH:47]=[CH:48][C:43]([C:42]([F:41])([F:50])[F:51])=[CH:44][CH:45]=2)[CH2:31][CH3:32])=[CH:24][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CCC(Br)COc1ccc([C@H](CC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)c2ccon2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(COc1ccc([C@H](CC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)c2ccon2)cc1)Oc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.2 %

Procedure:
The bromide 49.1 (90 mg, 0.17 mmol) was dissolved in DMF (2.0 mL). Cesium carbonate (220 mg, 0.68 mmol) and 4-trifluoromethylphenol (110 mg, 0.68 mmol) were added to the solution and the mixture was then heated with stirring for three hours. The reaction mixture was then cooled to room temperature and diluted with water. The mixture was extracted with EtOAc (2×50 mL). The combined organic layers were washed with 1M lithium chloride solution (1×25 mL), water (1×25 mL) and brine (1×25 mL), and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure and the residue purified by medium pressure chromatography (silica, 0 to 60% EtOAc: hexanes) to obtain 49.2 (23 mg). MS ESI (pos.): m/e 609.1 (M+H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[O:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]([NH:33][NH2:34])=[O:32])[CH2:26][CH2:25]1>>[O:24]1[CH2:25][CH2:26][N:27]([CH2:30][C:31]([NH:33]/[N:34]=[C:21](/[C:18]2[N:17]=[C:16]3[N:12]([CH2:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)[N:13]=[N:14][C:15]3=[N:20][CH:19]=2)\[CH3:22])=[O:32])[CH2:28][CH2:29]1
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: NNC(=O)CN1CCOCC1
Product: C/C(=N\NC(=O)CN1CCOCC1)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1

Procedure:
The title compound was prepared in analogy to the synthesis of example 52 from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone and 2-morpholinoaceto-hydrazide. The title compound was obtained as light yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.45 (d, 1H), 8.90 (d, 1H), 8.36 (d, 1H), 8.01 (m, 2H), 7.83 (d, 1H), 7.53 (dd, 1H), 6.20 (s, 2H), 3.65 (d, 4H), 3.26 (s, 2H), 2.57 (d, 4H), 2.41 (s, 3H). LCMS (method B): [MH]+=446.2, tR=1.37 min.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:12][O:13][CH2:14][C:15](Cl)=[O:16]>N1C=CC=CC=1>[F:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:1][C:15](=[O:16])[CH2:14][O:13][CH3:12])[S:3][C:4]=2[CH:10]=1
Reactant: COCC(=O)Cl
Reactant: Nc1nc2ccc(F)cc2s1
Solvent: c1ccncc1
Product: COCC(=O)Nc1nc2ccc(F)cc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Amino-6-fluorobenzothiazole (3.3 g) is dissolved in pyridine (80 ml) and thereto is added dropwise methoxyacetyl chloride (2.0 ml) at room temperature. After the mixture is stirred at room temperature for 2 hours, the solvent is distilled off. The resulting solids are washed with water, then with diethyl ether, dried and recrystallized from ethanol to give the title compound (3.5 g) having the following physical properties.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[C:7]([NH:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[CH3:18])[N:8]=[C:9]([O:12][CH:13]3[CH2:15][CH2:14]3)[C:10]=2[N:11]=1.[C:29]([CH:31]1[CH2:33][CH2:32]1)#[CH:30].O>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>[CH:13]1([O:12][C:9]2[C:10]3[N:11]=[C:2]([C:30]#[C:29][CH:31]4[CH2:33][CH2:32]4)[CH:3]=[CH:4][C:5]=3[N:6]=[C:7]([NH:16][C@@H:17]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[CH3:18])[N:8]=2)[CH2:15][CH2:14]1
Reactant: CC(Nc1nc(OC2CC2)c2nc(Cl)ccc2n1)c1ccc(S(N)(=O)=O)cc1
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](Nc1nc(OC2CC2)c2nc(C#CC3CC3)ccc2n1)c1ccc(S(N)(=O)=O)cc1
Temperature: 80 °C
Yield: 77.7 %

Procedure:
A mixture of 4-[1-(6-Chloro-4-cyclopropoxy-pyrido[3,2-d]pyrimidin-2-ylamino)-ethyl]-benzenesulfonamide (300 mg, 0.71 mmol), PdCl2(PPh3)2 (25 mg, 0.035 mmol), CuI (13.5 mg, 0.07 mmol) in TEA (1 mL) and DMF (5 mL) was degassed for 10 min then purged with argon. Ethynyl-cyclopropane (0.3 mL, 3.5 mmol) was added and the reaction tube was sealed and heated at 80° C. for 3 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted twice with EtOAc. The combined organic layers were washed with 5% LiCl solution and brine. Solvent was removed by concentration in vacuo and the residue was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, to provide 248 mg (62%) of desired product. MS (m/z) 450.0 [M+H]+; HPLC Rt=2.16 min.
Reaction SMILES: [NH2:1][CH:2]([CH3:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[NH:6][CH:5]=1.C([O-])(O)=O.[Na+].O.ClC([O:24][CH2:25][CH:26]1C2C=CC=CC=2C2[C:27]1=CC=CC=2)=O>O1CCOCC1>[NH2:1][CH:2]([CH3:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:25](=[O:24])[CH2:26][CH3:27])[CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(N)Cc1c[nH]c2ccc(O)cc12
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCC(=O)Oc1ccc2[nH]cc(CC(C)N)c2c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 162.4 %

Procedure:
A 35 mL round bottom flask was charged with 3-(2-aminopropyl)-1H-indol-5-ol (0.20 g, 0.65 mmol) was added NaHCO3 (0.9 g, 11 mmol), water (2 mL) and 1,4-dioxane (8 mL). 9-Fluorenylmethyl chloroformate (0.20 g, 0.82 mmol) was added and the mixture stirred for 16 h at 23° C. TLC analysis indicated that the reaction was complete and the solution decanted into aqueous NaHCO3, then extracted with ether (2×30 mL). The combined organic extracts were washed with water (20 mL), dried over MgSO4 and concentrated. The crude product was purified by chromatography (silica, 65:35 hexanes:ethyl acetate) to furnish the title compound (0.26 g, 97%): 1H NMR (CDCl3) δ 7.88 (bs, 1H), 7.76 (d, J =6 Hz, 2H), 7.57 (d, J=6 Hz, 2H), 7.44-7.19 (m, 6H), 7.07 (s, 1H), 6.94 (s, 1H), 6.77 (dd, J=8, 2 Hz, 1H), 4.8 (m. 1H), 4.45 (m, J=8 Hz, 2H), 4.20 (m, J=8 Hz, 1H), 2.81 (bm, 2H), 1.15 (d, J=8 Hz); MS(ESI) m/z 430 (M+NH4)+, 413 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][C:6]([F:9])([F:8])[F:7])[CH3:3].C(N(CC)CC)C.[Cl:17][CH2:18][C:19](Cl)=[O:20]>C(Cl)Cl>[Cl:17][CH2:18][C:19]([N:4]([CH2:2][CH3:3])[CH2:5][C:6]([F:9])([F:8])[F:7])=[O:20]
Reactant: CCNCC(F)(F)F
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC(F)(F)F)C(=O)CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
To a cooled (0° C.) solution of N-ethyl-2,2,2-trifluoroethanamine hydrochloride, (0.45 g, 2.8 mmol) in DCM (10 mL) was added triethylamine (1.6 mL, 11.2 mmol) followed by 2-chloroacetyl chloride (0.22 mL, 2.8 mmol). The reaction was warmed to RT and stirred for 2 h. The reaction mixture was concentrated, redissolved in EtOAc (20 mL) and washed with brine (25 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to yield 0.6 g of crude product which was further purified by flash column chromatography using 1:1 EtOAc:hexanes as the eluent. 0.5 g of 2-chloro-N-ethyl-N-(2,2,2-trifluoroethyl)acetamide, (yield: 88%) was isolated.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:15][CH3:16])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([NH2:17])[N:3]=1.[C-:18]#[N:19].[K+]>CS(C)=O.CCOC(C)=O>[NH2:17][C:4]1[N:5]=[C:6]([N:8]([CH2:15][CH3:16])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:7]=[C:2]([C:18]#[N:19])[N:3]=1
Reactant: [C-]#N
Reactant: CCN(c1ccccc1)c1nc(N)nc(Cl)n1
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCN(c1ccccc1)c1nc(N)nc(C#N)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Chloro-N-ethyl-N-phenyl-[1,3,5]triazine-2,4-diamine (Intermediate 37, 400 mg, 1.60 mmol) was dissolved in anhydrous DMSO (5 mL) before the addition of potassium cyanide (200 mg, 3.07 mmol). The reaction mixture was stirred at 120 C in a pressure tube for 2 h before allowing to cool to room temperature. The product mixture was diluted with EtOAc (20 mL), extracted with water (2×10 mL), saturated sodium chloride (5 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The desired product was obtained and used directly without further purification (300 mg, 78%). Method C HPLC-MS: MH+ requires m/z=241. Found: m/z=241, Rt=1.27 min (89%).
Reaction SMILES: O/[CH:2]=[C:3](\[CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[N:13][CH:14]=1)/[C:4]([O:6]C)=O.[C:15](=[NH:37])([O:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[CH:22][CH:21]=1)[NH2:16].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[O:6]=[C:4]1[C:3]([CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[N:13][CH:14]=2)=[CH:2][NH:37][C:15]([O:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=3)=[CH:24][CH:25]=2)=[N:16]1
Reactant: N=C(N)OCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reactant: COC(=O)/C(=C/O)Cc1cncnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=c1nc(OCCc2ccc(Oc3cccc(C(F)(F)F)c3)cc2)[nH]cc1Cc1cncnc1
Temperature: 160 °C
Yield: 28.4 %

Procedure:
To the suspension of methyl (2E)-3-hydroxy-2-(5-pyrimidinylmethyl)-2-propenoate (105 mg, 0.542 mmol) and 2-(4-{[3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl imidocarbamate (171 mg, 0.361 mmol) in NMP (4 mL) was added K2CO3 (150 mg, 1.084 mmol). The mixture was heated with a microwave reactor at 160° C. for 1 h. Purification via MDAP then afforded the title compound (48 mg, 28.4% yield). LCMS: rt=3.258 min, [M+H+]=469
Reaction SMILES: C(O[C:4]([C:6](C)([C:15](=[O:17])[CH3:16])[CH2:7][CH2:8][CH2:9][CH2:10][S:11]([O-:14])(=[O:13])=[O:12])=O)C.[Na]>Cl>[CH3:4][CH:6]([C:15](=[O:17])[CH3:16])[CH2:7][CH2:8][CH2:9][CH2:10][S:11]([OH:14])(=[O:12])=[O:13]
Reactant: CCOC(=O)C(C)(CCCCS(=O)(=O)[O-])C(C)=O
Agent: Cl
Agent: [Na]
Product: CC(=O)C(C)CCCCS(=O)(=O)O

Procedure:
5-(Ethoxycarbonyl)-5-methyl-6-oxoheptane-1-sulphonate, sodium salt (from 1.1) was heated at 90° C. in concentrated hydrochloric acid (200 ml), until TLC indicated complete reaction (˜3 hrs). The solvent was then evaporated under vacuum; the residue was purified by flash chromatography (Silica. Ethanol/dichloromethane mixtures) to give 49.6 g of 5-methyl-6-oxoheptane-1-sulphonic acid.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][C:15]2[N:18]=[C:19]([NH:21][C:22]([O:24]C3C=CC=CC=3)=O)[S:20][C:14]=2[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>CN(C=O)C.O>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][C:15]2[N:18]=[C:19]([NH:21][C:22]([NH:4][CH2:1][CH:2]=[CH2:3])=[O:24])[S:20][C:14]=2[CH2:13]1)=[O:11])([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(NC(=O)Oc3ccccc3)sc2C1
Reactant: C=CCN
Solvent: O
Solvent: CN(C)C=O
Product: C=CCNC(=O)Nc1nc2c(s1)CN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.3 %

Procedure:
45 mg allylamin was added to 200 mg 2-phenoxycarbonylamino-6,7-dihydro-4H-thiazolo (5,4-c) pyridine-5-carboxylic acid tert-butyl ester in 25 mL DMF. The reaction was stirred for 12 h at RT, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine solution and concentrated. The residue was purified by column chromatographie (silica gel, eluent: 40% ethylacetate in hexane) to give 179 mg of desired product. (M+H)+: 339
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.C1(OC2C=CC=CC=2)C=CC=CC=1.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Cc1cccc(C2CC2)c1O
Reactant: Oc1cc(Cl)nnc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 58.3 %

Procedure:
To a mixture of 308 mg (purity: 98.0%; 1.83 mmol) of 4-hydroxy-3,6-dichloropyridazine and 823 mg (5.50 mmol) of 2-cyclopropyl-6-methylphenol were added diphenyl ether (2.76 g) and 328 mg (5.56 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 295 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 58%) and 3.1 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.6%) were obtained.
Reaction SMILES: C(OC([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21](=[O:38])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH:28][CH2:29][C:30]3[CH:35]=[CH:34][N:33]=[C:32]([NH:36][CH3:37])[N:31]=3)=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:18][C:16]1([CH3:19])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21](=[O:38])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH:28][CH2:29][C:30]3[CH:35]=[CH:34][N:33]=[C:32]([NH:36][CH3:37])[N:31]=3)=[CH:13][CH:14]=2)[CH2:9][NH:8][CH2:17]1
Reactant: CNc1nccc(CNc2ccccc2C(=O)Nc2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1nccc(CNc2ccccc2C(=O)Nc2ccc3c(c2)CNCC3(C)C)n1

Procedure:
4,4-Dimethyl-7-{2-[(2-methylamino-pyrimidin-4-ylmethyl)-amino]-benzoylamino}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (Step D, 0.65 g, 1.26 mmol) in 10 mL of 50% of TFA in CH2Cl2 was stirred at RT for 1 h. The volatiles were removed under reduced pressure, the residue was purified by flash column chromatography, and the titled compound was obtained as a white solid. MS (ES+): 417.1 (M+H)+. Calc'd for C24H28N6O-416.52.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH2:9])[CH2:2]2.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][C:21](O)=[O:22])=[CH:14][CH:13]=1>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[CH:17][CH:16]=1)[CH2:2]2
Reactant: NC1CN2CCC1CC2
Reactant: COc1ccc(CCCC(=O)O)cc1
Product: COc1ccc(CCCC(=O)NC2CN3CCC2CC3)cc1
Yield: 28 %

Procedure:
Using general procedure I, 1-aza-bicyclo[2.2.2]oct-3-ylamine (200 mg, 1.00 mmol) and 4-(4-methoxy-phenyl)-butyric acid gave the title compound as a white solid (85 mg, 28%). 1H NMR (400 MHz, CD3OD) δ 7.08 (d, J=8.4 Hz, 2H), 6.81 (d, J=8.4 Hz, 2H), 4.18 (br s, 1H), 3.74 (s, 3H), 3.68 (d, J=11.6 Hz, 1H), 3.24-3.33 (m, 4H), 2.98-3.03 (m, 1H), 2.57 (t, J=7.6 Hz, 2H), 2.24 (t, J=7.6 Hz, 2H), 2.03-2.16 (m, 2H), 2.02 (br s, 2H), 1.85-1.91 (m, 3H) ppm. 13C NMR (400 MHz, CD3OD) δ 175.2, 158.3, 133.6, 129.2, 113.6, 54.5, 52.6, 47.2, 46.4, 44.5, 34.9, 34.2, 27.5, 24.4, 21.5, 17.1 ppm. Purity: 96.4% HPLCMS (210 nm); retention time 1.76 min; (M+1) 303.
Reaction SMILES: Cl.[S:2]([N:12]1[C:16]2=[N:17][CH:18]=[C:19]([NH2:21])[N:20]=[C:15]2[CH:14]=[CH:13]1)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[CH2:23][C:24]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=O.CCN(C(C)C)C(C)C>CCCCO>[CH:26]1([C:24]2[N:21]=[C:19]3[CH:18]=[N:17][C:16]4[N:12]([S:2]([C:5]5[CH:6]=[CH:7][C:8]([CH3:9])=[CH:10][CH:11]=5)(=[O:3])=[O:4])[CH:13]=[CH:14][C:15]=4[N:20]3[CH:23]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(CBr)C1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(N)cnc32)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nc(C4CCCCC4)cn23)cc1
Temperature: 170 °C

Procedure:
To a suspension of 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-amine hydrochloride (0.10 g, 0.35 mmol) and 2-bromo-1-cyclohexylethanone (0.078 g, 0.38 mmol, 3B Pharmachem) in n-BuOH (1.5 mL) was added DIEA (0.067 g, 0.52 mmol) and the resulting solution was heated at about 170° C. in the CEM™ microwave for about 30 min. The solvent was removed under reduced pressure to afford 7-cyclohexyl-3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine as a crude solid that was used in Step D without further purification: LC/MS (Table 2, Method a) Rt=2.71 min; MS m/z: 395 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[N:11]1([CH2:16][CH2:17][OH:18])[CH2:15][CH2:14][CH2:13][CH2:12]1.C1(C)C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:18][CH2:17][CH2:16][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1
Reactant: OCCN1CCCC1
Reactant: N#Cc1ccc(Cl)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(Cl)cc1OCCN1CCCC1

Procedure:
A mixture of 4-chloro-2-fluoro-benzonitrile (869 mg, 5.58 mmol) and 2-pyrrolidin-1-yl-ethanol (0.80 mL, 6.70 mmol) in THF (30 mL) is treated with a 0.5 M toluene solution of KHMDS (13.4 mL, 6.7 mmol) at 0° C. After completion of the reaction at RT, the reaction mixture is quenched by H2O. EtOAc is added and the organic layer is washed with brine, dried over MgSO4. Concentration in vacuo affords the corresponding 4-chloro-2-(2-pyrrolidin-1-ylethoxy)-benzonitrile. A THF (7 mL) solution of 4-chloro-2-(2-pyrrolidin-1-yl-ethoxy)-benzonitrile is added to a suspension of LAH (293 mg, 7.71 mmol) in THF (50 mL) at 0° C. The reaction is allowed to stir for 2 h at ambient temperature and then quenched by Na2SO4.10H2O, and the product is isolated by filtration with Celite and washed with THF and dried under reduced pressure to give the title compound as oil; ES-MS: M+=255.2; HPLC: AtRet=1.22 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].ClCCl.[CH3:17][NH2:18]>O1CCCC1>[CH3:17][NH:18][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CN
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 2-nitrobenzenesulfonyl chloride (25 g, 0.113 mol) and dichloromethane (450 mL) at 4° C. was added dropwise 2M methylamine in tetrahydrofuran (68 mL). The mixture was stirred overnight allowing the ice bath to melt. More 2M methylamine in tetrahydrofuran (97 mL) was added and the reaction was stirred for 1 hour. The reaction mixture was concentrated in vacuo. The residue was dissolved in chloroform (500 mL) and was washed with saturated sodium bicarbonate (250 mL). The aqueous layer was extracted with chloroform (250 mL) and all the chloroform layers combined, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue purified by silica gel chromatography using 0-4% methanol in dichloromethane. 22.63 g of N-methyl-2-nitrobenzenesulfonamide was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[S:24]([CH3:23])(=[O:26])=[O:25])=[CH:7][CH:8]=1)#[N:2]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(NCc2cccnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1cccnc1)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A 4.2 g. portion of 3-(4-cyanophenylaminomethyl)pyridine was dissolved in 25 ml. of dichloromethane, and 4.1 g. of potassium carbonate and 2.4 ml. of methanesulfonyl chloride were added. The mixture was stirred at ambient temperature for 4 days, and was then diluted with 30 ml. of dichloromethane. It was then extracted with 20 ml. of water, dried over magnesium sulfate, and evaporated to an oily residue. The residue was applied to a silica gel column and eluted with dichloromethane. The product-containing fractions were combined and evaporated, and the residue was triturated with diethyl ether to obtain 1 g. of the desired product, m.p. 73°-75°.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[CH3:15][O:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:15][O:16][CH2:17][CH2:18][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: COCCBr
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1

Procedure:
A mixture of [A] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg, 0.5 mmol), 2-bromoethyl methyl ether (58 uL, 0.62 mmol, Aldrich, Cat. No. 238155), and cesium carbonate (500.0 mg, 1.5 mmol) in acetonitrile (1 mL) was stirred at 90° C. overnight. After cooling it was quenched with water, extracted with ethyl acetate. The extract was washed with water twice, brine once; dried over Na2SO4. After filtration the filtrate was concentrated to yield 90 mg of the product. LCMS (M+H)+: m/z=253.1