Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:6]#[N:7])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][C:33]1([CH3:41])[O:38][CH2:37][CH:36]([CH2:39]O)[CH2:35][O:34]1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C1(C)C=CC=CC=1>[CH3:32][C:33]1([CH3:41])[O:38][CH2:37][CH:36]([CH2:39][O:11][C:10]2[C:9]([CH3:12])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[CH2:1][CH3:2])[CH2:35][O:34]1
Reactant: CC1(C)OCC(CO)CO1
Reactant: CCc1cc(C#N)cc(C)c1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCc1cc(C#N)cc(C)c1OCC1COC(C)(C)OC1
Reaction time: 0.25 h
Yield: 27.8 %

Procedure:
To a solution of 3-ethyl-4-hydroxy-5-methyl-benzonitrile (480 mg, 2.98 mmol) in THF (10 mL), triphenylphosphine (1.17 g, 4.47 mmol) and (2,2-dimethyl-[1,3]dioxan-5-yl)-methanol (478 mg, 3.28 mmol) is added. The mixture is cooled to 4° C. before DEAD (1.94 g, 4.47 mmol, 2.05 mL of a 40% solution in toluene) is added. Stirring is continued at 4° C. for 15 min, then at rt for 1 h. The solvent is removed in vacuo and the crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 4-(2,2-dimethyl-[1,3]dioxan-5-ylmethoxy)-3-ethyl-5-methyl-benzonitrile (240 mg) as a yellow oil; LC-MS: tR=1.04 min; [M+1+CH3CN]+=330.97. To a solution of this material (240 mg, 829 μmol) in methanol (5 mL), hydroxylamine hydrochloride (86 mg, 1.24 mmol) and NaHCO3 (104 mg, 1.24 mmol) is added. The mixture is stirred at 60° C. for 5 h before it is diluted with EA and washed with water. The org. extract is dried over MgSO4, filtered, concentrated and dried to give the title compound (280 mg) as a pale yellow oil; LC-MS: tR=0.72 min; [M+1+CH3CN]+=323.01.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[C:8](=[O:19])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH2:10][C:5]2=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]3[CH:39]=[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])[C:37](B4OC(C)(C)C(C)(C)O4)=[CH:36][C:30]=3[C:31]=2[C:32]([NH:34][CH3:35])=[O:33])=[CH:23][CH:22]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:9]2[CH2:10][C:5]3[C:6](=[N:7][C:2]([C:37]4[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])=[CH:39][C:29]5[O:28][C:27]([C:24]6[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=6)=[C:31]([C:32]([NH:34][CH3:35])=[O:33])[C:30]=5[CH:36]=4)=[CH:3][CH:4]=3)[C:8]2=[O:19])=[CH:13][CH:14]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: O=C1c2nc(Cl)ccc2CN1Cc1ccc(F)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)C(=O)N(Cc3ccc(F)cc3)C4)cc12
Yield: 27.2 %

Procedure:
A solution of 2-chloro-6-(4-fluorobenzyl)-5H-pyrrolo[3,4-b]pyridin-7(6H)-one (70 mg, 0.25 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (152 mg, 0.30 mmol), K3PO4.3H2O (200 mg, 0.76 mmol), Pd2(dba)3 (23 mg, 0.03 mmol) and X-Phos (23 mg, 0.06 mmol) in dioxane/H2O (2 mL/0.5 mL) was stirred at 110° C. for 1 hour. After the reaction, the mixture was filtered and the filtrate was diluted with water (20 mL) and extracted with EtOAc (20 mL*3). The organic layer was washed with brine (10 mL*3), dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to afford the product of 5-(6-(4-fluorobenzyl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (42 mg, yield: 27%). 1H-NMR (CDCl3, 400 MHz) δ 7.97˜8.02 (m, 3H), 7.82˜7.88 (m, 2H), 7.64 (s, 1H), 7.33˜7.36 (m, 2H), 7.22 (t, J=8.8 Hz, 2H) 7.18 (t, J=8.4 Hz, 2H), 6.08 (br s, 1H), 4.86 (s, 2H), 4.34 (s, 2H), 3.16 (s, 3H), 3.01 (d, J=4.8 Hz, 3H), 2.99 (s, 3H). MS (M+H)+: 617.
Reaction SMILES: [OH:1][CH:2]([CH2:30][OH:31])[CH2:3][O:4][C:5](=[O:29])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][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])=[CH:8][CH:7]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33].C(Cl)(Cl)Cl>O>[C:32]([N:12]([CH2:13][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])[C:9]1[CH:10]=[CH:11][C:6]([C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:30][OH:31])=[O:29])=[CH:7][CH:8]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCN(C(C)=O)c1ccc(C(=O)OCC(O)CO)cc1

Procedure:
A solution of 3.26 g. of 2,3-dihydroxypropyl-4-(n-hexadecylamino)benzoate and 0.85 ml. of acetic anhydride in 50 ml. of chloroform is heated to reflux for 1 hour and then cooled. The mixture is washed with 90 ml. of water and the solid at the interface filtered. The chloroform layer on concentration in vacuo gives a residue which on trituration with methylene chloride yields a white solid (starting material) after filtration. The filtrate on concentration in vacuo yields a pale yellow oil. The oil is stirred overnight with water, extracted with chloroform and azeotroped free of acetic acid with benzene. The pale yellow oil obtained by evaporation in high vacuum is then chromatographed to remove a trace of N,O-diacetylated material. The liquid product is characterized by elemental analyses, infrared spectrum and nuclear magnetic resonance.
Reaction SMILES: [CH2:1]([C@H:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C@H:9]([OH:18])[CH2:10][NH:11][O:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C)C1C=CN=CC=1>[CH2:1]([C@H:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[C@H:9]([OH:18])[CH2:10][N:11]([O:12][CH:13]([CH2:14][CH3:15])[CH2:16][CH3:17])[S:35]([C:32]1[CH:31]=[CH:30][C:29]([O:28][CH3:27])=[CH:34][CH:33]=1)(=[O:37])=[O:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC)ONC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)ON(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.3 %

Procedure:
A mixture of tert-butyl (1S,2R)-1-benzyl-3-[(1-ethylpropoxy)amino]-2-hydroxypropylcarbamate (100 mg, 0.273 mmol), 4-methoxyphenylsulphonyl chloride (57 mg, 0.273 mmol), and diisoproylethylamine (0.0476 mL, 0.273 mmol) in anhydrous tetrahydrofuran (2 mL) was stirred under Argon for 16 hours at ambient temperature. A catalytic quantity of 4-dimethylaminopyridine (˜1 mg) was added and the reaction was heated at reflux for approximately two hours. After cooling, the reaction was evaporated in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with aqueous potassium carbonate (5% w/v), aqueous hydrochloric acid (1N) and brine. The organic layer was then dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on a preparative TLC plate (20×20 cm, 500 NM) eluting with 95:5 methylene chloride:methanol. The product band was removed, eluted with 4:1 methylene chloride:methanol, filtered, and evaporated in vacuo. The residue was purified again on a preparative TLC plate (20×20 cm, 500 μM) eluting with 95:5 methylene chloride:ethyl acetate. The product band was removed, eluted with 4:1 methylene chloride:methanol, filtered, and evaporated in vacuo to provide tert-butyl (1S,2R)-1-benzyl-3-{(1-ethylpropoxy)[(4-methoxyphenyl)sulfonyl]amino}-2-hydroxypropylcarbamate (103 mg, 70%) as a foam. H1-NMR (chloroform-D3): 0.95 (m, 6H), 1.38 (s, 9H), 1.64 (m, 4H), 3.01 (m, 5H), 3.83 (m, 2H), 3.93 (s, 3H), 4.20 (m, 1H), 4.61 (m, 1H), 7.03 (d, 2H), 7.29 (m, 5H), 7.80 (d, 2H). MS(ESI): 559(M+Na).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[NH:27][C:13]4=[N:14][C:15]([N:18]5[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](O)=[O:25])[CH2:19]5)=[CH:16][CH:17]=[C:12]4[N:11]=3)[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1.C(N=C=NCCCN(C)C)C.[OH:39][C:40]1[C:48]2[N:47]=NN[C:44]=2[CH:43]=[CH:42]C=1.C(N(CC)CC)C.[C@@H]12O[C@@H](CC1)CNC2>CN(C)C=O.CN(C)C1C=CN=CC=1>[C@@H:43]12[CH2:44][C@@H:48]([N:47]([C:24]([C@@H:20]3[CH2:21][CH2:22][CH2:23][N:18]([C:15]4[N:14]=[C:13]5[NH:27][C:10]([C:8]6[CH:7]=[CH:6][N:5]=[C:4]([CH:1]7[CH2:3][CH2:2]7)[N:9]=6)=[N:11][C:12]5=[CH:17][CH:16]=4)[CH2:19]3)=[O:25])[CH2:42]1)[CH2:40][O:39]2
Reactant: O=C(O)[C@@H]1CCCN(c2ccc3nc(-c4ccnc(C5CC5)n4)[nH]c3n2)C1
Reactant: Oc1cccc2[nH]nnc12
Agent: C1C[C@H]2CNC[C@@H]1O2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C([C@@H]1CCCN(c2ccc3nc(-c4ccnc(C5CC5)n4)[nH]c3n2)C1)N1C[C@H]2C[C@@H]1CO2
Temperature: 0 °C
Reaction time: 18 h
Yield: 10.5 %

Procedure:
To a solution of (R)-1-(2-(2-cyclopropylpyrimidin-4-yl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylic acid (70 mg, 0.192 mmol) in N,N-dimethylformamide (10 mL) were added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCl) (73.2 mg, 0.383 mmol), hydroxybenzotriazole (52 mg, 0.383 mmol), triethylamine (58.2 mg, 0.575 mmol), (1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane (186 mg, 1.64 mmol) and 4-dimethylaminopyridine (3 mg) at room temperature. The reaction mixture was stirred for 18 h, poured into ice water, extracted with ethyl acetate, washed with cold water and concentrated. The crude was purified via preparative TLC (3% methanol in dichloromethane) to afford the title compound (9 mg). MS (ES+) (M+H) 446.3; LCMS retention time 1.816 min (Method F)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=O)[C:7]2=[O:16])=[CH:2]1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1>CC(O)=O.CO>[CH3:24][C:21]1[CH:22]=[CH:23][C:18](/[N:17]=[C:8]2/[C:7](=[O:16])[N:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)[C:14]3[C:9]/2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:19][CH:20]=1
Reactant: O=C1C(=O)N(c2ccsc2)c2ccccc21
Reactant: Cc1ccc(N)cc1
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(/N=C2/C(=O)N(c3ccsc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 50.5 %

Procedure:
A solution of 1-(3-Thienyl)-1H-indole-2,3-dione (20 mg, 0.087 mmol) in 1% HOAc/MeOH (8 mL) was added to a solution of p-toluidine (19 mg, 0.18 mmol) in 1% HOAc/MeOH (8 mL). The reaction mixture was stirred for 12 h at room temperature, heated at 50° C. for 1 h, and concentrated in vacuo. The residue was purified by preparative TLC on silica using EtOAc/hexanes (3:7, 0.1% TEA) giving the desired product (14 mg, 50%).
Reaction SMILES: S(Cl)(Cl)=O.CC1C=CC(C(O)=O)=CN=1.CC1N=CC(C(Cl)=O)=CC=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][N:31]=[C:30]2[O:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1.[CH3:47][C:48]1[N:53]=[CH:52][C:51]([C:54]([N:56]=[C:57]=[S:58])=[O:55])=[CH:50][CH:49]=1>C1(C)C=CC=CC=1.C(O)C>[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][N:31]=[C:30]2[O:39][C:40]1[CH:46]=[CH:45][C:43]([NH:44][C:57]([NH:56][C:54]([C:51]2[CH:52]=[N:53][C:48]([CH3:47])=[CH:49][CH:50]=2)=[O:55])=[S:58])=[CH:42][CH:41]=1
Reactant: Cc1ccc(C(=O)N=C=S)cn1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: Cc1ccc(C(=O)Cl)cn1
Agent: Cc1ccc(C(=O)O)cn1
Solvent: O=S(Cl)Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4ccc(C)nc4)cc3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 6-methylnicotinic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 6-methyl-3-pyridinecarbonyl isothiocyanate was prepared using the resultant 6-methyl-3-pyridinecarbonyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 6-methyl-3-pyridinecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (71 mg, yield 89%).
Reaction SMILES: Cl.O1CCOCC1.C(OC([N:15]1[CH2:20][CH:19]=[C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[CH:23][N:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.O.[OH-].[Na+]>C(Cl)Cl>[N:28]1[CH:29]=[CH:30][CH:31]=[N:32][C:27]=1[C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH:17]=2)=[N:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(-c3ncccn3)cn2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: C1=C(c2ccc(-c3ncccn3)cn2)CCNC1
Reaction time: 4 h
Yield: 116.2 %

Procedure:
Added 4M HCl/dioxane (5 ml) to solution of 5-Pyrimidin-2-yl-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (2Q) (110 mg, 0.325 mmol) in MeCl2 (5 ml) at room temperature, then stirred 4 hours. Evaporated solvent. Added MeCl2 (100 ml), H2O (50 ml) and 10% NaOH (3 ml). The organic layer was separated, dried over MgSO4, filtered and solvent evaporated yielding 3Q as a white solid (90 mg, 100%) ESMS (MH, 239) LCMS (MH, 239) Retention time=1.53 minutes.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28](Cl)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:32]([CH:34]3[CH2:36][CH2:35]3)=[O:33])=[CH:16][N:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([F:54])[C:40]=1[OH:55]>>[C:1]([O:5][C:6](=[O:37])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:43]5[CH:42]=[C:41]([F:54])[C:40]([OH:55])=[C:39]([Cl:38])[CH:44]=5)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:32]([CH:34]3[CH2:35][CH2:36]3)=[O:33])=[CH:16][N:15]=2)[CH2:9]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Cl)nc34)cn2)C1
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)nc34)cn2)C1
Yield: 54.5 %

Procedure:
Following general procedure II, (R)-tert-butyl[1-(5-{[6-chloro-3-(cyclopropanecarbonyl)-1,5-naphthyridin-4-yl]amino}pyridin-2-yl)piperidin-3-yl]carbamate (150 mg, 0.29 mmol) was reacted with 2-chloro6-fluro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (120 mg, 0.43 mmol) to afford the product (100 mg, 54%) as an orange-red solid: ESI MS m/z 633 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([N+:12]#[C-:13])([CH3:11])([CH3:10])[CH3:9].[CH:14](=O)[CH3:15]>Cl(O)(=O)(=O)=O>[C:8]([NH:12][C:13]1[N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]2=[N:1][C:14]=1[CH3:15])([CH3:11])([CH3:10])[CH3:9]
Reactant: [C-]#[N+]C(C)(C)C
Reactant: Nc1ccccn1
Reactant: CC=O
Agent: [O-][Cl+3]([O-])([O-])O
Product: Cc1nc2ccccn2c1NC(C)(C)C

Procedure:
Compound (18) was prepared in accordance with general instructions 1 from 1.0 ml 2-aminopyridine solution (0.1 M, MC), 0.575 ml tert-butylisonitrile solution (0.2 M, MC), 0.500 ml acetaldehyde solution (0.3 M, MC), and 10 μl perchloric acid (w=20%).
Reaction SMILES: [SH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.Cl[CH2:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([CH3:22])=[CH:16][N:15]=1>>[CH3:21][O:20][C:18]1[C:17]([CH3:22])=[CH:16][N:15]=[C:14]([CH2:13][S:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:19]=1
Reactant: Sc1ncnc2ccccc12
Reactant: COc1cc(CCl)ncc1C
Product: COc1cc(CSc2ncnc3ccccc23)ncc1C
Yield: 3.7 %

Procedure:
The title compound(0.24 g) was prepared from 4-mercaptoquinazoline(3.5 g) and 2-chloromethyl-4-methoxy-5-methylpyridine(4.1 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]1[N:17]([CH3:18])[C:16]2[CH:19]=[CH:20][C:21]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31](=[O:40])[CH2:32][CH2:33][CH:34]4[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)[CH:25]=3)=[CH:22][C:15]=2[N:14]=1.C=O.[C:43](O)(=O)C.C([BH3-])#N.[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:4][C:3]=1[NH:12][C:13]1[N:17]([CH3:18])[C:16]2[CH:19]=[CH:20][C:21]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31](=[O:40])[CH2:32][CH2:33][CH:34]4[CH2:35][CH2:36][N:37]([CH3:43])[CH2:38][CH2:39]4)[CH:25]=3)=[CH:22][C:15]=2[N:14]=1
Reactant: CC(=O)O
Reactant: Cn1c(Nc2cc(C(F)(F)F)ccc2F)nc2cc(Oc3ccnc(NC(=O)CCC4CCNCC4)c3)ccc21
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CCC(CCC(=O)Nc2cc(Oc3ccc4c(c3)nc(Nc3cc(C(F)(F)F)ccc3F)n4C)ccn2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-3-piperidin-4-ylpropanamide (1 eq) in methanol was added formalin (2 eq) and acetic acid(5%) followed by sodium cyanoborohydride (2 eq) and the resulting mixture was stirred at ambient temperature for 3 h. LC/MS showed formation of the product. The crude mixture was then concentrated and to it was added sodium bicarbonate and the resulting mixture was partitioned between ethyl acetate and water. The organic layer was dried with sodium sulfate and purified by preparative chromatography to yield N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-3-(1-methylpiperidin-4-yl)propanamide. MS: MH+=571.6.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][NH:6][CH3:7].CCN(C(C)C)C(C)C.[C:20](Cl)(=[O:22])[CH3:21]>CN(C)C1C=CN=CC=1.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][N:6]([CH3:7])[C:20](=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: CNCc1cccc(Br)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N(C)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a DMF (0.1 M) solution of 3-bromo-N-methylbenzylamine (1 eq.), Hunig's base (3 eq) and 4-(dimethylamino)pyridine (5% loading) was added acetyl chloride (1.5 eq). The resulting reaction mixture was stirred at RT for 16 h. After quenching the reaction with sat. aq. NaHCO3, the mixture was extracted with EtOAc. The organic extract was washed with 10% aq. HCl, sat. aq. NaHCO3, and brine. Drying over Na2SO4, filtration and concentration of the filtrate in vacuo afforded the crude product as a yellow oil. Purification by way of flash chromatography (SiO2, 4:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17]2[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=[C:19]([NH:26][CH2:27][C:28]([OH:30])=O)[N:18]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17]2[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=[C:19]([NH:26][CH2:27][C:28](=[O:30])[N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[N:18]=2)[CH2:11][CH2:10]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)NC1CCC(CNc2nc(NCC(=O)O)ncc2[N+](=O)[O-])CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCC(CNc2nc(NCC(=O)N3CCCC3)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.2 %

Procedure:
To {4-[(4-tert-butoxycarbonylamino-cyclohexylmethyl)-amino]-5-nitro-pyrimidin-2-ylamino}-acetic acid (120 mg, 0.28 mmol) in DMF (1.5 mL) were added pyrrolidine (48 μL, 0.57 mmol), TBTU (141 mg, 0.43 mmol), and diisopropylethylamine (99 μL, 0.57 mmol). The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with ethyl acetate and washed with water (×2) and brine. The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 95:5 CH2Cl2:MeOH as an eluant to afford 19 mg of (4-{[5-nitro-2-(2-oxo-2-pyrrolidin-1-yl-ethylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexyl)-carbamic acid tert-butyl ester as a light brown solid.
Reaction SMILES: C(=O)(O)[O-].[Na+].C(O[CH2:10][C:11]1[CH2:12][S:13][C@@H:14]2[CH:21]([NH2:22])[C:20](=[O:23])[N:15]2[C:16]=1[C:17]([OH:19])=[O:18])(=O)C.[CH3:24][C:25]1[CH:30]=[C:29]([CH3:31])[N:28]=[C:27]([SH:32])[N:26]=1>O.CC(C)=O>[NH2:22][CH:21]1[C:20](=[O:23])[N:15]2[C:16]([C:17]([OH:19])=[O:18])=[C:11]([CH2:10][S:32][C:27]3[N:28]=[C:29]([CH3:31])[CH:30]=[C:25]([CH3:24])[N:26]=3)[CH2:12][S:13][C@H:14]12
Reactant: Cc1cc(C)nc(S)n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(C)nc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)n1
Reaction time: 23 h

Procedure:
A solution of sodium bicarbonate (9.45 g.) in water (100 ml.) was added in portions to a stirred suspension of 3-acetoxymethyl-7-aminoceph-3-em-4-carboxylic acid (13.5 g.) in water (100 ml.) and acetone (50 ml.). The solid dissolved with effervescence. To this solution under nitrogen at 55° was added rapidly, drop by drop, a solution of 4,6-dimethyl-2-mercaptopyrimidine (10.5 g.) in water (100 ml.) and acetone (100 ml.), the pH being maintained between 7.4 and 7.8 by addition of 6 NHCl or 5% w/v aqueous NaHCO3. After 23 hours at 55°, the reaction mixture was cooled to 0° and acidified to pH 4.0. The resulting precipitate was filtered, washed with water and acetone, and dried over P2O5 to give 7-amino-3-(4,6-dimethylpyrimid-2-yl)thiomethylceph-3-em-4-carboxylic acid. A mixture of this acid (3.52 g.) and O-t-butyl-1,3-diisopropylisourea (6.0 g.) in dry CH2Cl2 (60 ml.) was stirred under nitrogen for 20 hours. The reaction mixture was filtered, the filtrate evaporated and the residue purified by chromatography on silica gel (200 g.) at -40° using CH2Cl2 /ether 6:4 v/v as eluant to give the t-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[C:13]#[C:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH:37]=O)=[N:29]1>CO.N1CCCCC1>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30](/[CH:37]=[C:8]2\[O:9][C:5]3[C:4]([C:13]#[C:14][CH:15]4[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:29]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COc1ccc2c(c1C#CC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1C#CC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
A solution of tert-butyl 4-[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)ethynyl]piperidine-1-carboxylate (0.103 g, 0.277 mmol) in methanol (5 mL) was added with 1H-indazole-3-carboxaldehyde (0.0386 g, 0.264 mmol) and piperidine (7 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}ethynyl)piperidine-1-carboxylate (0.105 g, 80%).