Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([C:23](=[O:25])[CH3:24])[C:5]([OH:22])=[C:6]([O:10][CH2:11][CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH3:14])[C:7]=1[O:8][CH3:9].Br[CH2:28][CH2:29][OH:30]>>[Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([C:23](=[O:25])[CH3:24])[C:5]([O:22][CH2:28][CH2:29][OH:30])=[C:6]([O:10][CH2:11][CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH3:14])[C:7]=1[O:8][CH3:9]
Reactant: OCCBr
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(O)c1OCCC(C)c1ccc(F)cc1
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCO)c1OCCC(C)c1ccc(F)cc1
Yield: 67 %

Procedure:
Example 7c (93 mg, 0.24 mmol) was reacted with 2-bromoethanol (1.5 eq.) as described under General Procedure F and the crude mixture was purified by flash chromatography (silica gel, Et2O/hexane 70:30) to afford the title compound (68 mg, 67%) as a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.19-7.15 (m, 2H), 7.01-6.95 (m, 2H), 4.13-4.11 (m, 2H), 3.95 (d, J=6.8 Hz, 2H), 3.84 (s, 3H), 3.76-3.70 (m, 2H), 3.00 (m, 1H), 2.80 (t, J=6.5 Hz, 1H), 2.50 (s, 3H), 2.20 (s, 3H), 2.06-1.98 (m, 2H), 1.29 (d, J=6.9 Hz, 3H). MS (ES+) m/z 425.2 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>CN(C)C=O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3](=[O:13])[CH2:2][N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[CH:7][CH:8]=1
Reactant: c1c[nH]cn1
Reactant: O=C(CCl)CCc1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: O=C(CCc1ccc(Cl)cc1)Cn1ccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
1-Chloro-4-(4-chlorophenyl)-2-butanone (110 g) was added portionwise over half an hour to a stirred suspension of imidazole (175 g) in dimethylformamide (150 ml) at 0° C. and the mixture stirred overnight at ambient temperature. The resulting solution was poured into wate (1500 ml) with seeding at the first sign of turbidity, and the precipitate filtered off and washed well with water and hexane. Chromatography of the product on silica gel (1 Kg), eluting with 7% methanol in methylene chloride gave 100 g of 1-[4-(4-chlorophenyl) butan-2-on-1-yl]imidazole. The hydrochloride salt from acetone/methanol had a m.p. of 172.5°-174° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:10]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])=[CH:9][C:8](=[O:20])[NH:7][C:6]1=[S:21].[NH2:22][C:23](=[N:29][C:30](=[O:33])[O:31][CH3:32])N1C=CC=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:32][O:31][C:30](=[O:33])[N:29]=[C:23]([NH2:22])[NH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:10]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])=[CH:9][C:8](=[O:20])[NH:7][C:6]1=[S:21]
Reactant: COC(=O)N=C(N)n1cccn1
Reactant: COc1ccc(Cl)cc1-c1cc(=O)[nH]c(=S)n1CCCN
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N=C(N)NCCCn1c(-c2cc(Cl)ccc2OC)cc(=O)[nH]c1=S
Reaction time: 72 h

Procedure:
To a solution of 1-(3-aminopropyl)-6-(5-chloro-2-methoxyphenyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (prepared in an analogous manner to Example 6; 50 mg, 0.14 mmol) and methyl [amino(1H-pyrazol-1-yl)methylidene]carbamate (28 mg, 0.16 mmol) in DMF (0.46 mL) was added N,N-diisopropylethylamine (0.024 mL, 0.14 mmol) at room temperature, and the mixture was stirred for 72 hours. The solvent was removed under reduced pressure, the residue was dissolved in DMSO (0.9 mL) and purified using mass-triggered automatic purification to give the title compound (4.9 mg) MS (ES+) 425.9 [M+H]+. Retention time: 1.54 min; Method: XBridge C18 5 um 4.6×50 mm, 95% H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0 min, HOLD at 5% H2O/95% MeCN to 5.0 min. (0.03% NH4OH). Flow rate: 2 mL/min.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:6][CH:5]([OH:7])[CH2:4]1.F[C:9]1[CH:10]=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[C:13]([CH3:15])[CH:14]=1>C1COCC1.O>[CH3:15][C:13]1[CH:14]=[C:9]([CH:10]=[CH:11][C:12]=1[N+:16]([O-:18])=[O:17])[O:7][CH:5]1[CH2:6][O:3][CH2:4]1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: OC1COC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OC2COC2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 53.1 %

Procedure:
Sodium hydride (0.084 g, 2.11 mmol) was added to a solution of oxetan-3-ol (0.12 g, 1.62 mmol) in THF (10 mL) at 0° C. The mixture was stirred at 0° C. for 20 minutes, after which time a solution of 5-fluoro-2-nitrotoluene (0.26 g, 1.62 mmol) in THF (10 mL) was added. The mixture was allowed to warm to room temperature, and stirring was continued for 16 h. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with brine. The organic layer was concentrated under vacuum and the resulting crude material was purified by column chromatography (silica gel: 100-200 mesh, 8-30% EtOAc/hexane) to give the title compound (0.18 g, 54%) as a yellow gum. LCMS (ES+) no mass ion observed, RT 1.71 minutes (method 2).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[C:4]=1[C:11]#[N:12])[CH3:2].N>[Ni].CO>[NH2:12][CH2:11][C:4]1[C:5](=[O:10])[NH:6][C:7]([CH3:9])=[CH:8][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cc(C)[nH]c(=O)c1C#N
Agent: [Ni]
Agent: N
Solvent: CO
Product: CCc1cc(C)[nH]c(=O)c1CN
Temperature: 25 °C
Reaction time: 48 h
Yield: 54.6 %

Procedure:
To a suspension of Raney Nickel (6 g) in methanol (200 mL) was added 4-ethyl-1,2-dihydro-6-methyl-2-oxopyridine-3-carbonitrile (10 g, 61.7 mmol) and methanolic ammonia (750 mL). The reaction mixture was stirred at room temperature under hydrogen pressure (80 psi) for 48 hrs. The reaction mixture was filtered through Celite and washed with methanol (250 mL). The filtrate was concentrated under reduced pressure and the residue purified by filter column using silica gel (60-120 mesh), eluted with 10% MeOH in CHCl3, to afford 3-(amino methyl)-4-ethyl-6-methylpyridin-2(1H)-one (5.6 g, 54%) as an off white solid. 1H NMR (DMSO-D6, 400 MHz) (free amine): δ ppm 1.063-1.101 (t, 3H, J=7.6 Hz), 2.101 (s, 3H), 2.412-2.449 (m, 2H), 3.448 (s, 2H), 5.835 (s, 1H). MS(ES) [M+H]+ 167.06.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1Cl.O.[CH2:13]([NH2:16])[CH2:14][NH2:15]>>[N+:9]([C:4]1[CH:5]=[CH:6][C:7]([NH:15][CH2:14][CH2:13][NH2:16])=[C:2]([Cl:1])[CH:3]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: NCCN
Solvent: O
Product: NCCNc1ccc([N+](=O)[O-])cc1Cl
Temperature: 0 °C
Yield: 95.1 %

Procedure:
192 g (1mole) of 3,4-dichloro-nitrobenzene is added to 810 cm3 (10 moles) ethylene diamine hydrate. The reaction mixture is heated at reflux for 4 hours and then poured into 2.5 liters of ice water. Drying yields 205 g of 4-nitro-2-chloro-N-(β-aminoethyl) aniline which, after recrystallization in absolute ethanol, melts at 116° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:24]1[S:28][C:27]([C:29]2[CH:30]=[CH:31][C:32]3[CH2:39][CH:38]4[C:40]5([CH2:44][N:43]([CH2:45][C:46]([F:49])([F:48])[F:47])[S:42](=[O:51])(=[O:50])[NH:41]5)[CH:35]([CH2:36][CH2:37]4)[CH2:34][C:33]=3[CH:52]=2)=[N:26][CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:24]2[S:28][C:27]([C:29]3[CH:30]=[CH:31][C:32]4[CH2:39][CH:38]5[C:40]6([CH2:44][N:43]([CH2:45][C:46]([F:47])([F:48])[F:49])[S:42](=[O:51])(=[O:50])[NH:41]6)[CH:35]([CH2:36][CH2:37]5)[CH2:34][C:33]=4[CH:52]=3)=[N:26][CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S1(=O)NC2(CN1CC(F)(F)F)C1CCC2Cc2cc(-c3ncc(Br)s3)ccc2C1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: CC(C)(C)OC(=O)N1CC=C(c2cnc(-c3ccc4c(c3)CC3CCC(C4)C34CN(CC(F)(F)F)S(=O)(=O)N4)s2)CC1

Procedure:
Prepared from the boronate from Step 2 and the bromide from Example 36, Step 2 by the method described for Example 36, Step 3. Contains ˜10% unsubstituted thiazole.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:18][CH:17]=3)[C:12]2=[O:28])=[CH:7][CH:6]=1.[CH:29]1([CH2:32][NH:33][CH3:34])[CH2:31][CH2:30]1>>[CH:23]1([O:22][C:19]2[CH:18]=[CH:17][C:16]([N:13]3[CH:14]=[CH:15][N:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:33]([CH2:32][CH:29]5[CH2:31][CH2:30]5)[CH3:34])=[CH:6][CH:7]=4)[C:12]3=[O:28])=[CH:21][CH:20]=2)[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: O=c1n(-c2ccc(OCCBr)cc2)ccn1-c1ccc(OC2CCCC2)cc1
Reactant: CNCC1CC1
Product: CN(CCOc1ccc(-n2ccn(-c3ccc(OC4CCCC4)cc3)c2=O)cc1)CC1CC1

Procedure:
1-[4-(2-Bromoethoxy)phenyl]-3-(4-cyclopentyloxyphenyl)-1,3-dihydroimidazol-2-one was reacted with cyclopropylmethyl(methyl)amine as described in example 5. The product with the molecular weight of 447.58 (C27H33N3O3); MS (ESI): 448 ([M+H]+) was obtained in this way.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C@@H:7]2[CH2:11][CH2:10][C@H:9]([C@H:12]([OH:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:4][CH:3]=1.C1C(=O)N([Br:36])C(=O)C1>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]2[CH2:11][CH2:10][C@H:9]([C@H:12]([OH:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]2[C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])=[CH:27][C:28]=1[Br:36]
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(N)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(N)c(Br)c2)CC[C@@H]1[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
To a solution of tert-butyl (2S,5R)-2-(4-aminobenzyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidine-1-carboxylate (intermediate i-13a, 214 mg, 0.559 mmol) in DMF (2 mL) cooled to 0° C. via ice/water bath was added NBS (100 mg, 0.559 mmol) and the resulting solution stirred for 1.5 h allowing to warm to rt. The mixture was evaporated under vacuum and the residue purified via Biotage Horizon MPLC using a gradient of 0-40% ethyl acetate in hexane to afford the product (232 mg, 90%) as a white foam. LC-MS: m/z (ES) 483 (MNa)+ and 485 (MNa+2)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[NH:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]=[CH:7][C:6]=1[N+:22]([O-:24])=[O:23].I[CH3:27].[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:25])[N:4]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:8]=[CH:7][C:6]=1[N+:22]([O-:24])=[O:23])[CH3:27]
Reactant: CI
Reactant: COC(=O)Nc1cc(OCCOCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)N(C)c1cc(OCCOCc2ccccc2)ccc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 44 %

Procedure:
To a solution of [5-(2-benzyloxy-ethoxy)-2-nitro-phenyl]-carbamic acid methyl ester (2.03 g, 5.86 mmol) in anhydrous dimethylformamide (20 ml) was added iodomethane (1.82 ml, 29.3 mmol), followed by portion wise addition of NaH (0.35 g, 60%, 8.79 mmol). The reaction was stirred under nitrogen for 2 h. The reaction was quenched with NH4Cl (sat) (10 ml) and brine (10 ml), and the aqueous layer was extracted with ether (3×30 ml). The combined organics were dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel eluting with hexanes, then 30% ethyl acetate/hexanes to give [5-(2-benzyloxy-ethoxy)-2-nitro-phenyl]-methyl-carbamic acid methyl ester (0.93 g, 89%) as an oil. Analysis calculated for C18H20N2O6 : C, 59.99; H, 5.59; N, 7.77. Found: C, 59.30; H, 5.34; N, 7.62.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5].[CH3:13][C:14]1([CH3:28])[O:19][CH2:18][C:17]([CH3:27])([C:20](=[O:26])[CH2:21][C:22](OC)=[O:23])[CH2:16][O:15]1.CO>CCCCCCCC.C1(C)C=CC=C(C)C=1.C(OCC)C>[N+:10]([C:7]1[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[C:4]([NH:5][C:22](=[O:23])[CH2:21][C:20](=[O:26])[C:17]2([CH3:27])[CH2:16][O:15][C:14]([CH3:13])([CH3:28])[O:19][CH2:18]2)[CH:6]=1)([O-:12])=[O:11]
Reactant: COc1ccc([N+](=O)[O-])cc1N
Reactant: COC(=O)CC(=O)C1(C)COC(C)(C)OC1
Solvent: CCOCC
Solvent: CCCCCCCC
Solvent: CO
Product: COc1ccc([N+](=O)[O-])cc1NC(=O)CC(=O)C1(C)COC(C)(C)OC1

Procedure:
2-Methoxy-5-nitroaniline (63 parts) and methyl 2,2,5-trimethyl-β-oxo-1,3-dioxane-5-propanoate (90 parts) are dispersed in n-octane (500 parts) and m-xylene (100 parts). The mixture is stirred vigorously while methanol is removed by a slow distillation under an inert atmosphere. Additional m-xylene is added as needed to replenish the reaction solvent as it co-distills with methanol of reaction. After the solution is allowed to cool slowly with vigorous stirring, a yellow-orange solid resulted, ca. 2 hr. The precipitate is dissolved in ethyl ether and the ethereal solution extracted with dilute hydrochloric acid, washed once with dilute sodium bicarbonate, once with water, the organic layer separated from the aqueous layer, dried and the excess solvent removed in vacuo. The residue is recrystallized from ethyl alcohol, m.p. 113-115° C. Proton NMR and combustion analysis were consistent with those values predicted for the desired product. Combustion Analysis for C17H22N2O7 --Calculated: C, 55.7%; H, 6.1%; N, 7.7%. Found: C, 55.6%; H, 6.1%; N, 7.5%.
Reaction SMILES: [N+:1]([C:4]1[C:8]([N:9]=[N:10][C:11]2[C:12]([N+:16]([O-:18])=[O:17])=[N:13][O:14][N:15]=2)=[N:7][O:6][N:5]=1)([O-:3])=[O:2].C(O)(=O)C>CO.[Zn]>[N+:1]([C:4]1[C:8]([NH:9][NH:10][C:11]2[C:12]([N+:16]([O-:18])=[O:17])=[N:13][O:14][N:15]=2)=[N:7][O:6][N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1nonc1N=Nc1nonc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1nonc1NNc1nonc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
To a suspension of 3,3′-dinitro-4,4′-azofurazan (1.42 g, 6.0 mmol) and Zn (0.78 g, 12 mmol) in 10 ml of methanol at room temperature, was added dropwise glacial acetic acid (0.8 ml, 12 mmol). A vigorous reaction took place, and after the greenish reaction mixture was stirred at room temperature for 2 hours. The slurry was filtered through a bed of celite and the filtrate was concentrated on a rotary evaporator and passed through a bed of silica gel using CH2Cl2/EtOAc. Removal of solvent gave 1.46 g (100% yield, one spot by TLC) of 3,3′-dinitro-4,4′-hydrazofurazan, a pale yellow solid, 1H NMR(DMSO-d6); δ9.98 (s) ppm. Recrystallization from chloroform/acetone gave 1.26 g of 3,3′-dinitro-4,4′-hydrazofurazan, mp 171-173° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH2:14][C:15]#[CH:16])=[O:12])=[CH:4][CH:3]=1.[N:21]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:26]=1)=[N+:22]=[N-:23].O.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>S([O-])([O-])(=O)=O.[Cu+2].C(O)(C)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH2:14][C:15]2[N:23]=[N:22][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:26]=3)[CH:16]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NCc1cccc(Oc2ccccc2)c1
Reactant: C#CCNC(=O)c1cccnc1Nc1ccc(Cl)cc1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(NCc1cn(Cc2cccc(Oc3ccccc3)c2)nn1)c1cccnc1Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 76.8 %

Procedure:
Compound 8 (194 mg, 1 mmol) and 4-chloroaniline (9c, 127 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(4-chlorophenylamino)-N-(prop-2-ynyl)nicotinamide 10c as pure product. To a solution of 2-(4-chlorophenylamino)-N-(prop-2-ynyl)nicotinamide (10c 150 mg, 0.52 mmol) and 1-(azidomethyl)-3-phenoxybenzene (12c, 130 mg, 0.57 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 10 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 1c (204 mg 76%); mp: 127-129° C.; 1H NMR (300 MHz, CDCl3) δ 10.51 (s, 1H), 8.25 (dd, J=2.2, 1.5 Hz, 1H), 7.84 (dd, J=2.2, 1.5 Hz, 1H), 7.80 (brs, 1H), 7.61-7.58 (m, 3H), 7.35-7.23 (m, 4H), 7.08 (t, J=7.5 Hz, 1H), 6.98-6.91 (m, 7H), 6.67-6.63 (m, 1H), 5.45 (s, 2H), 4.62 (d, J=5.2 Hz, 2H); MS (ESI m/z): 511 [M+H]+. Yield: 76%
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N:35](C(C2C=NC(Cl)=CC=2)=O)[S:36]([CH3:39])(=[O:38])=[O:37])[C:8]([O:33][CH3:34])=[C:9]([NH:11][C:12]([C:14]2[S:18][C:17]3[C:19]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][C:28](Cl)=[N:27][CH:26]=4)=[CH:20][CH:21]=[CH:22][C:16]=3[CH:15]=2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH:49]1([NH2:52])[CH2:51][CH2:50]1>>[C:1]([C:5]1[CH:6]=[C:7]([NH:35][S:36]([CH3:39])(=[O:37])=[O:38])[C:8]([O:33][CH3:34])=[C:9]([NH:11][C:12]([C:14]2[S:18][C:17]3[C:19]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][C:28]([NH:52][CH:49]5[CH2:51][CH2:50]5)=[N:27][CH:26]=4)=[CH:20][CH:21]=[CH:22][C:16]=3[CH:15]=2)=[O:13])[CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1c(NC(=O)c2cc3cccc(NC(=O)c4ccc(Cl)nc4)c3s2)cc(C(C)(C)C)cc1N(C(=O)c1ccc(Cl)nc1)S(C)(=O)=O
Reactant: NC1CC1
Product: COc1c(NC(=O)c2cc3cccc(NC(=O)c4ccc(NC5CC5)nc4)c3s2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 100 °C
Yield: 71 %

Procedure:
To N-(2-{5-tert-butyl-3-[(6-chloro-pyridine-3-carbonyl)-methanesulfonyl-amino]-2-methoxy-phenylcarbamoyl}-benzo[b]thiophen-7-yl)-6-chloro-nicotinamide (see Example 1) (33 mg) in a sealed tube was added 200 μL of cyclopropylamine. The reaction was purged with Ar and heated to 100° C. in the sealed tube 12 h. The reaction mixture was cooled to room temperature and diluted with EtOAc, washed by NH4Cl solution, water, and brine. The organics were dried over MgSO4, filtered, concentrated down to give a residue which was purified by flash chromatography on silica gel (CH2Cl2-2% MeOH/CH2Cl2) to provide the title compound (21 mg, 71%), m.p. >264° C. dec.
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:17]#[N:18])#[N:2].[ClH:19]>O=[Pt]=O.C(O)(=O)C>[ClH:19].[ClH:19].[ClH:19].[ClH:19].[NH2:18][CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3][CH2:1][NH2:2]
Reactant: N#CCCNCCCCCCCCNCCC#N
Agent: O=[Pt]=O
Agent: Cl
Solvent: CC(=O)O
Product: NCCCNCCCCCCCCNCCCN

Procedure:
Combine 14.4 g (0.057 mol) of the product of Step A, 200 ml of acetic acid, 30 ml of conc. HCl, and 1.2 g PtO2 and treat the mixture with H2 at 45 lbs/in2 in a shaker flask until H2 is no longer being reacted. Filter the mixture and remove the solvent at reduced pressure. 22.5 g of the title compound is obtained after purification. (Rf is 0.17 for TLC on silica gel developed with 40% conc. ammonia/methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]3[CH:19]=[CH:20][N:21]=[C:9]23)=[C:4]([F:22])[CH:3]=1.[Cl:23]N1C(=O)CCC1=O>C(#N)C>[Cl:23][C:20]1[N:21]=[C:9]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[F:22])[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[N:10]2[CH:19]=1
Reactant: O=c1cc(C(F)(F)F)n2ccnc2n1-c1ccc(Cl)cc1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: O=c1cc(C(F)(F)F)n2cc(Cl)nc2n1-c1ccc(Cl)cc1F

Procedure:
A mixture of 8-(4-chloro-2-fluorophenyl)-7,8-dihydro-5-trifluoromethylimidazo[1,2-a]pyrimidin-7-one (1.0 g), N-chlorosuccinimide (0.4 g) and acetonitrile (30 ml) was heated to reflux for 3 hours. The solvent was distilled off under reduced pressure and the residue was purified by a preparative thin-layer plate of silica gel (developing solvent: ethyl acetate/hexane=2/8) to give the compound of interest (0.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:26])([F:25])[C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[NH2:17]>>[F:12][C:13]([F:25])([F:26])[C:14]1[CH:15]=[C:16]([NH:17][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[OH:11])[CH:18]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:20]=1
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Br)ccc1O
Yield: 88.5 %

Procedure:
Using 5-bromosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH:1]1([C:6]2[O:7][C:8]3[C:9](=[C:11]([CH:17]=O)[CH:12]=[CH:13][C:14]=3[O:15][CH3:16])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19]O.C([O-])=O.[Na+].C(OCC)(=O)C>C(O)=O>[CH:1]1([C:6]2[O:7][C:8]3[C:9](=[C:11]([C:17]#[N:19])[CH:12]=[CH:13][C:14]=3[O:15][CH3:16])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C=O)c2cc(C3CCCC3)oc12
Reactant: NO
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: CCOC(C)=O
Product: COc1ccc(C#N)c2cc(C3CCCC3)oc12
Temperature: 0 °C

Procedure:
27.6 g of 2-cyclopentyl-7-methoxybenzofuran-4-carbaldehyde are heated to reflux for 1.5 h with 11.6 g of hydroxylamine and 19.7 g of sodium formate in 250 ml of formic acid. The cooled solution is stirred in about 1.5 l of a 1:1 mixture of ice water and ethyl acetate, and the organic phase is separated off, dried over ignited potassium carbonate and evaporated in vacuo. The residual oil is sufficiently pure for further processing.
Reaction SMILES: [CH2:1]([NH:8][CH:9]([CH3:41])[CH2:10][C:11]1[C:16]2[C:17](I)=[N:18][N:19](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:15]=2[CH:14]=[C:13]([Cl:40])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[C:43]([O-:46])(C)C.[Na+].C1COCC1>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.CCOC(C)=O>[Cl:40][C:13]1[CH:14]=[C:15]2[NH:19][N:18]=[C:17]3[C:16]2=[C:11]([CH2:10][CH:9]([CH3:41])[N:8]3[CH2:1][C:2]2[CH:7]=[CH:6][C:5]([O:46][CH3:43])=[CH:4][CH:3]=2)[N:12]=1
Reactant: CC(Cc1nc(Cl)cc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)NCc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CN2c3n[nH]c4cc(Cl)nc(c34)CC2C)cc1
Temperature: 55 °C

Procedure:
N-benzyl-1-(6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)propan-2-amine (670 mg, 0.958 mmol) and RuPhos pre-catalyst (70 mg, 0.096 mmol) were charged in a 2 dram vial, evacuated and backfilled with nitrogen and taken in toluene (4.8 mL). A solution of 2M NaOtBu in THF (1.2 ml, 2.4 mmol) was added and the reaction mixture was heated to 55° C. for 12 hours. The reaction mixture was cooled and diluted with EtOAc and washed with water, brine, dried with sodium sulfate and concentrated. Purification of the residue by flash column (0-50% EtOAc-hexanes) gave 7-chloro-3-(4-methoxybenzyl)-4-methyl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridine. MS ESI calc'd. for C35H30ClIN4 [M+H]+ 572. found 572.