Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C=CN=C1)(N1[CH:7]=[CH:6]N=C1)=O.[CH:13]1([CH:18]([CH3:24])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:17][CH2:16][CH2:15][CH2:14]1.CC[O-].[Na+].C(O)C>C1COCC1.[Na]>[CH:13]1([CH:18]([CH3:24])[CH2:19][CH2:20][C:21]([O:23][CH2:6][CH3:7])=[O:22])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(CCC(=O)O)C1CCCC1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCC(C)C1CCCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 48313.4 %

Procedure:
1,1′-Carbonyldiimidazole (101 g; 0.62 mmol) was added portionwise to 4-cyclopentylpentanoic acid (100 g; 0.58 mol) in THF (500 ml). After the gas evolution ceased, the reaction mixture was reacted with sodium ethylate solution prepared from sodium (0.3 g; 13 mmol) and ethanol (500 ml), stirred at room temperature for 2.5 hours, and the solvent evaporated in vacuo. The residue was dissolved in ether (300 ml), washed successively with water (300 ml), 1 N NaOH (300 ml), and 1 N HCl (300 ml), dried (MgSO4), concentrated in vacuo, and distilled over a 10 cm Vigreux column (66° C./0.08 torr) to give 59.4 g (52% yield) of ethyl 4-cyclopentylpentanoate.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.ClN1C(=O)CCC1=O.[CH:17]1([CH2:20][N:21]2[C:29]3[N:28]=[C:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([NH:37][CH3:38])=[CH:33][CH:32]=4)[NH:26][C:25]=3[C:24](=[O:39])[N:23]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[F:47])[C:22]2=[O:48])[CH2:19][CH2:18]1.C(N(CC)CC)C>ClCCl>[CH:17]1([CH2:20][N:21]2[C:29]3[N:28]=[C:27]([CH2:30][C:31]4[CH:32]=[CH:33][C:34]([N:37]([CH3:38])[C:6]([C:4]5[N:3]=[N:2][S:1][CH:5]=5)=[O:8])=[CH:35][CH:36]=4)[NH:26][C:25]=3[C:24](=[O:39])[N:23]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[F:47])[C:22]2=[O:48])[CH2:19][CH2:18]1
Reactant: O=C(O)c1csnn1
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)c1csnn1)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 26 %

Procedure:
A mixture of [1,2,3]thiadiazole-4-carboxylic acid (29 mg, 0.30 mmol) in dichloromethane (6 mL) at 25° C. was treated with triphenylphosphine-polystyrene 100–200 mesh (372 mg, 0.46 mmol). This mixture was cooled to 0° C. and then treated with N-chlorosuccinimide (49 mg, 0.37 mmol). This mixture was stirred at 0° C. for 15 min and at 25° C. for 15 min. At this time, the reaction was treated with 3-cyclopropylmethyl-1-(2-fluoro-benzyl)-8-(4-methylamino-benzyl)-3,7-dihydro-purine-2,6-dione (55 mg, 0.12mmol) and triethylamine (96 μL, 0.69 mmol). The reaction was then stirred at 25° C. for 3 days. At this time, the reaction was filtered to remove solids and rinsed with dichloromethane. The filtrate was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1:99 methanol/dichloromethane) afforded [1,2,3]thiadiazole-4-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (17 mg, 24.7%): LR-MS for C27H24FN7O3S (M+H)+ at m/z=546.
Reaction SMILES: [CH2:1](/[C:3](/[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=[CH:4]/[CH3:5])[CH3:2].[OH2:16]>>[CH3:15][O:14][C:8]1[CH:7]=[C:6]([CH:3]([CH2:1][CH3:2])[CH:4]([OH:16])[CH3:5])[CH:11]=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: O
Reactant: C/C=C(/CC)c1ccc(OC)c(OC)c1
Product: CCC(c1ccc(OC)c(OC)c1)C(C)O

Procedure:
Addition of H2O to 4-((1Z)-1-ethylprop-1-enyl)-1,2-dimethoxybenzene to yield 3-(3,4-dimethoxyphenyl)pentan-2-ol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:25][CH2:24][C:12]3([CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[C:5]([CH3:26])=[CH:4][N:3]=1.Cl.[CH3:28][N:29]1[CH:33]=[C:32]([NH2:34])[CH:31]=[N:30]1.CCN(C(C)C)C(C)C>CCCCO>[CH3:26][C:5]1[C:6]([NH:8][CH:9]2[CH2:25][CH2:24][C:12]3([CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)=[N:7][C:2]([NH:34][C:32]2[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=2)=[N:3][CH:4]=1
Reactant: Cc1cnc(Cl)nc1NC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Reactant: Cn1cc(N)cn1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(Nc2cnn(C)c2)nc1NC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 150 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
To a suspension of tert-butyl 8-((2-chloro-5-methylpyrimidin-4-yl)amino)-2-azaspiro[4.5]decane-2-carboxylate (1.04 g, 2.73 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride (365.4 mg, 2.73 mmol) in n-BuOH (8 mL) was added DIPEA (1.06 g, 8.20 mmol) and the reaction mixture was stirred in a sealed tube at 150° C. overnight then concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/100) to give the title compound as yellow oil (1.21 g, 100%).
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9]2[N:13]3[CH:14]=[C:15]([O:18][C@H:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[C@@H:22]([NH:29][C:30](=[O:55])[NH:31][C:32]5[N:36]([C:37]6[CH:38]=[C:39]([CH:48]=[CH:49][CH:50]=6)[O:40][CH2:41][CH2:42]OS(C)(=O)=O)[N:35]=[C:34]([C:51]([CH3:54])([CH3:53])[CH3:52])[CH:33]=5)[CH2:21][CH2:20]4)[CH:16]=[CH:17][C:12]3=[N:11][N:10]=2)[CH2:2]1.[CH3:56][NH:57][CH3:58].C1C[O:62]CC1>>[CH:30]([OH:55])=[O:62].[CH2:2]1[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9]2[N:13]3[CH:14]=[C:15]([O:18][C@H:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[C@@H:22]([NH:29][C:30]([NH:31][C:32]5[N:36]([C:37]6[CH:50]=[CH:49][CH:48]=[C:39]([O:40][CH2:41][CH2:42][N:57]([CH3:58])[CH3:56])[CH:38]=6)[N:35]=[C:34]([C:51]([CH3:53])([CH3:54])[CH3:52])[CH:33]=5)=[O:55])[CH2:21][CH2:20]4)[CH:16]=[CH:17][C:12]3=[N:11][N:10]=2)[CH2:1]1
Reactant: CNC
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC56CC6)n4c3)c3ccccc32)n(-c2cccc(OCCOS(C)(=O)=O)c2)n1
Reactant: C1CCOC1
Product: CN(C)CCOc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC56CC6)n4c3)c3ccccc32)c1
Product: O=CO
Yield: 65 %

Procedure:
A brown solution of Intermediate 148g (0.099 mmol) and dimethylamine (2M in THF, 0.99 mL, 1.98 mmol) in THF (1 mL) was stirred in a sealed vial at 60° C. for 16 h. The solution was decanted and concentrated. MDAP (Method 7) gave the title compound as a pale yellow solid (50 mg, 65%). LCMS (Method 5): Rt 3.62 min, m/z 718.6 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.42-0.53 (4H, m), 1.27 (9H, s), 1.53-1.61 (2H, m), 1.74-1.96 (6H, m), 1.99-2.15 (2H, m), 2.20 (6H, s), 2.63 (2H, t, J=5.8 Hz), 3.22-3.29 (2H, m), 4.09 (2H, t, J=5.8 Hz), 4.81 (1H, td, J=8.6, 5.5 Hz), 5.48 (1H, t, J=4.3 Hz), 6.33 (1H, s), 6.95-6.98 (1H, m), 7.06-7.12 (3H, m), 7.14 (1H, dd, J=9.9, 2.2 Hz), 7.25-7.42 (5H, m), 7.56 (1H, d, J=2.1 Hz), 7.61 (1H, dd, J=9.8, 0.8 Hz), 8.12 (1H, s), 8.17 (1.4H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23])=[O:5])[CH3:2].[CH2:24](Br)[C:25]#[CH:26].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[N:14]([CH2:26][C:25]#[CH:24])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23])=[O:5])[CH3:2]
Reactant: C#CCBr
Reactant: CCOC(=O)c1[nH]c2ccncc2c1Nc1ccc(I)cc1F
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: C#CCn1c(C(=O)OCC)c(Nc2ccc(I)cc2F)c2cnccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
A mixture of 3-(2-fluoro-4-iodo-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (70.0 mg, 0.164 mmol), propargyl bromide (80% in xylene, 45.5 μL, 0.41 mmol, 2.5 eq), DBU (3.2 mL), and anhydrous THF (3.2 mL) was stirred at 50° C. under N2 for 1 h, and then at ambient temperature for 17 h. The solvent was evaporated and the resultant residue was diluted with ethyl acetate (75 mL). The organic layer was washed with water (20 mL), followed by brine (20 mL), dried (Na2SO4), filtered and evaporated to give a brown oil. The oil was purified by flash column chromatography (silica, ISCO, 45 mL/min, Hexane:EtOAc, gradient 100:1 to 1:100). Crystallization from EtOAc-hexane gave the desired compound as a yellow solid (34.5 mg, 45.3%). 1H NMR (400 MHz, CDCl3) δ ppm 8.74 (s, 1H), 8.44 (d, J=5.87 Hz, 1H), 7.60 (s, 1H), 7.45 (dd, J=10.26 Hz, 2.0 Hz, 1H), 7.37-7.27 (m, 2H), 6.87 (t, J=9.20 Hz, 1H), 5.29 (s, 2H), 4.46 (q, J=7.14 Hz, 2H), 2.29 (t, J=2.47 Hz, 1H), 1.49-1.40 (t, J=7.20 Hz, 3H); LC-MS (method D): [M+H]+=464.0, RT=2.40 min.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7](C(=O)C)=[CH:6][CH:5]=1.[C:15]([O-])(=O)[CH3:16].[NH4+].C([BH3-])#[N:21].[Na+]>CO>[F:14][C:2]([F:1])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:15]([NH2:21])[CH3:16])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: CC(=O)[O-]
Reactant: [BH3-]C#N
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)c1cccc(OC(F)(F)F)c1
Temperature: 120 °C

Procedure:
An Emrys Process Vial (2-5 ml) was charged with 420 mg (2 mmol) of 1-(4-trifluoromethoxy-phenyl)-ethanone, ammonium acetate in MeOH (4.0 ml of a 5 M solution, 20 mmol) and sodium cyanoborohydride in MeOH (0.440 ml of a 5 M solution, 2.2 mmol). The reaction vessel was sealed and heated to 120° C. for 5 min in an Emrys Optimizer. After cooling and manual release of remaining pressure the vessel was uncapped and the reaction mixture concentrated at reduced pressure. The residue was dissolved in Et2O (10 ml) and extracted with 2 M aqueous HCl (3×5 ml). The combined aqueous phases were adjusted to pH 9 with a 10 M aqueous KOH and extracted with CH2Cl2 (4×10 ml). The combined organic phases were dried over MgSO4 and the solvent evaporated at reduced pressure to afford 1-(3-trifluoromethoxy-phenyl) -ethyl amine which is used as crude product for step 2.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[N+:14]([O-])=O)[CH:2]=[CH2:3].[CH3:17]N>C(O)(C)C>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[NH:14][CH3:17])[CH:2]=[CH2:3]
Reactant: CN
Reactant: C=CCOc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Solvent: CC(C)O
Product: C=CCOc1cccc([N+](=O)[O-])c1NC

Procedure:
A mixture of 9.0 g of 1-allyloxy-2,3-dinitrobenzene, 400 ml of isopropanol and 12.4 g of gaseous methylamine is heated, in a pressure vessel, to 90° for 3 hours, whilst stirring. After cooling and letting-down, the reaction solution is evaporated under reduced pressure. The resulting oil is dried at 50°/0.01 mm Hg for 2 hours, whereupon 1-allyloxy-2-methylamino-3-nitrobenzene is obtained; this can be used further without purification.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:7]=[C:6]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[NH:5][N:4]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([F:26])[CH:25]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:19][C:20]1[CH:21]=[C:22]([N:5]2[C:6]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[CH:7][C:3]([C:2]([F:1])([F:17])[F:18])=[N:4]2)[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CC(C)(C)OC(=O)NCc1cc(C(F)(F)F)n[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCc1cc(C(F)(F)F)nn1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
To a mixture tert-butyl (3-(trifluoromethyl)-1H-pyrazol-5-yl)methylcarbamate (251 mg, 0.946 mmol, 1 equiv.), 3,5-difluorophenylboronic acid (299 mg, 1.89 mmol, 2 equiv.) and copper acetate (258 mg, 1.49 mmol, 1.5 equiv.) in dichloromethane (14 mL) was added pyridine (151 mg, 0.151 mL, 1.89 mmol, 2 equiv) and the mixture was stirred in the presence of air for 2 d at room temperature. The reaction mixture was filtered over silica gel, the filter cake was washed with dichloromethane (250 mL) and the solvent of the filtrate was evaporated to give tert-butyl (1-(3,5-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylcarbamate (214 mg, 60%).
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][NH:8]2)=[CH:4][C:3]=1[O:23][CH3:24].Br[CH2:26][C:27](Br)=[O:28].[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[OH:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:26][C:27]([NH:37][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])=[CH:4][C:3]=1[O:23][CH3:24]
Reactant: COc1cc(CC2NCCc3cc(OC)c(OC)cc32)ccc1O
Reactant: O=C(Br)CBr
Reactant: NCc1ccccc1
Product: COc1cc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)ccc1O

Procedure:
prepared by reaction of 1-(4-Hydroxy-3-methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with benzylamine
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])=[CH:11][C:10]=2[F:26])[CH:5]=[CH:4][N:3]=1.[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31][NH2:32].C([O-])([O-])=O.[Cs+].[Cs+].CC(C)(C(=O)CC(=O)C(C)(C)C)C>CN1C(=O)CCC1>[ClH:1].[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31][NH:32][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])=[CH:11][C:10]=2[F:26])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Nc1ccc(Oc2ccnc(Cl)c2)c(F)c1)c1c(F)cccc1F
Reactant: CN(C)CCCN
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CN(C)CCCNc1cc(Oc2ccc(NC(=O)c3c(F)cccc3F)cc2F)ccn1
Product: Cl
Temperature: 120 °C
Yield: 7.7 %

Procedure:
A mixture of N-(4-(2-chloropyridin-4-yloxy)-3-fluorophenyl)-2,6-difluorobenzamide (70 mg, 0.19 mmol), 3-(dimethylamino)propylamine (44 mL, 0.35 mmol), Cs2CO3 (85 mg, 0.26 mmol) and CuCi (17 mg, 0.17 mmol) in a screw capped vial was purged with N2. NMP and 2,2,6,6,-tetramethyl-3,5-heptanedione (31 mg, 0.17 mmol) were added to the mixture which was then heated at 120° C. for 4 h. The mixture was cooled, partitioned between EtOAc and saturated aq. NaHCO3 solution and the EtOAc phase was separated, dried (MgSO4) and concentrated in vacuo to give the crude product. Purification of the residue by preparative HPLC (Column C) and conversion to the hydrochloride salt was carried out in a similar manner as Step D of Example 33 to give the title compound (7 mg, 7%) as an off-white solid. MS(ESI+): m/z 517.37 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:4]([O:6][CH3:7])=[O:5].CCN(CC)CC.[C:24](Cl)(=[O:34])[O:25][CH2:26][C:27]([CH3:33])([CH3:32])[CH2:28][CH2:29][CH:30]=[CH2:31]>C1COCC1>[CH3:14][C:13]([CH3:16])([O:12][C:10](=[O:11])[NH:9][CH2:8][CH:3]([C:4]([O:6][CH3:7])=[O:5])[NH:2][C:24](=[O:34])[O:25][CH2:26][C:27]([CH3:33])([CH3:32])[CH2:28][CH2:29][CH:30]=[CH2:31])[CH3:15]
Reactant: C=CCCC(C)(C)COC(=O)Cl
Reactant: COC(=O)C(N)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCCC(C)(C)COC(=O)NC(CNC(=O)OC(C)(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
To a stirring solution of 381 mg of methyl 2-amino-3-(tert-butoxycarbonylamino)propanoate hydrochloride, and 1 mL of Et3N in 10 mL of anhydrous THF, was added 1.5 mmol of 2,2-dimethylhex-5-enyl carbonochloridate. The resulting mixture was stirred at rt overnight, then concentrated. The residue was subject to column chromatography on silica gel with heptanes/EtOAc (v/v 7/1) as eluent, giving 500 mg colorless oil (90%). 1HNMR (400 MHz, CDCl3) d 5.82 (m, 1H), 5.64 (br s, 1H), 5.02 (dd, 1H, J=13.2, 1.8 Hz), 4.95 (d, 1H, J=8.2 Hz), 4.83 (br s, 1H), 4.39 (br d, 1H, J=6.0 Hz), 3.83 (br s, 2H), 3.80 (s, 3H), 2.55 (m, 2H), 2.02 (m, 2H), 1.43 (s, 9H), 1.35 (m, 2H), 0.91 (s, 6H).
Reaction SMILES: C[O:2][C:3]([CH:5]1[C:9]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:8][N:7]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:6]1)=[O:4].[OH-].[Na+]>O1CCOCC1.O>[CH2:18]([O:17][C:15]([N:7]1[CH2:6][CH:5]([C:3]([OH:4])=[O:2])[C:9]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:8]1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)C1CN(C(=O)OCc2ccccc2)CC12CCCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)CC12CCCCC2
Temperature: 35 °C
Reaction time: 6 h

Procedure:
To a solution of (6) (300 mg; 0.9 mmol) in a mixture dioxane/water (6 mL; 9:1) was added a 2 M solution of NaOH (0.90 mL; 1.8 mmol). The reaction mixture was stirred at 35° C. for 6 hours. Solvents were removed in vacuo. The residue was diluted in water (15 mL) and was washed with diethyl ether (3×10 mL). The aqueous phase was acidified with 2N HCl and was extracted with ethyl acetate (3×15 mL). The ethyl acetate extracts were combined, dried over MgSO4, and concentrated to give 254 mg (0.8 mmol; 89%) of (7) as a colorless gum.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:14])(=[O:13])[NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=2)[CH:7]=1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Reactant: COc1cccc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C=Cc1cccc(S(=O)(=O)Nc2cccc(OC)c2)c1
Yield: 82.8 %

Procedure:
A solution of 3-(3-chlorosulfonylphenyl)-acrylic acid methyl ester (3) (0.4 g, 1.53 mmol) in dioxane (5 ml) was added to a mixture of 3-methoxyphenylamine (0.189 g, 1.53 mmol) in dioxane (1 ml) and NaHCO3 (0.25 g, 3.06 mmol) in water (3 ml), and the resultant solution was stirred at room temperature until the completion of the reaction (control by TLC). The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with petroleum ether-ethyl acetate (2:1, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.44 g, 82%) as a white solid. 1H NMR (DMSO-d6, HMDSO), δ: 3.60 (3H, s), 3.71 (3H, s); 6.52–6.74 (3H, m); 6.63 (1H, d, J=16.0 Hz); 7.07 (1H, m); 7.43–8.05 (5H, m); 10.27 ppm (1H, br s).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[Si]([O:20][CH2:21][CH2:22][N:23]1[C:28](=[O:29])[C:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=3)=[CH:33][CH:32]=2)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]2[N:48]=[CH:49][N:50]=[C:24]12)(C(C)(C)C)(C)C>O.C(OCC)(=O)C>[OH:20][CH2:21][CH2:22][N:23]1[C:28](=[O:29])[C:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[C:43]3[NH:44][C:4](=[O:7])[O:5][N:3]=3)=[CH:33][CH:32]=2)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]2[N:48]=[CH:49][N:50]=[C:24]12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CCO[Si](C)(C)C(C)(C)C)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CCO)c2ncnn12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
A mixture of hydroxylammonium chloride (1.6 g), sodium hydrogen carbonate (2.6 g) and dimethyl sulfoxide (15 mL) was stirred at 50° C. for 30 min, 4′-{[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.82 g) was added, and the mixture was stirred at 90° C. for 20 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, and dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.3 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). Tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 2.7 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was extracted with ethyl acetate and 1 N hydrochloric acid, and the organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.31 g, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[C:10]([C:11]#[N:12])[C:3]=12.[H-].[Na+].Cl[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21]>O1CCCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:9]=[C:10]([C:11]#[N:12])[C:3]=12
Reactant: N#Cc1c[nH]c2nccc(Cl)c12
Reactant: C[Si](C)(C)CCOCCl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(C#N)c2c(Cl)ccnc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (2.5 g, 14.08 mmol) in tetrahydrofuran (200 mL) was cooled to 0° C. and treated with sodium hydride (0.5 g, 21.1 mmol). The mixture was stirred at 0° C. for 30 minutes and (2-(chloromethoxy)ethyl)trimethylsilane (2.8 g, 16.9 mmol) was added. After stirring at room temperature for 2 hours, the mixture was treated with brine and extracted with ethyl acetate (three times) and the organic layers were dried over sodium sulfate. Filtration, concentration and purification by flash chromatography (Combi Flash Rf) (silica gel, 40% ethyl acetate in hexane) afforded the title compound. MS (ESI+) m/z 308 (M+H)+.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].Br[CH2:13][C:14]1[C:23]2[C:18](=[C:19]([NH:24][C:25](=[O:34])[C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:33])[CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][CH:15]=1.O>CN(C)C=O>[N:1]1([CH2:13][C:14]2[C:23]3[C:18](=[C:19]([NH:24][C:25](=[O:34])[C:26]4[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=4[Cl:33])[CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(Nc1cccc2c(CBr)ccnc12)c1c(Cl)cccc1Cl
Reactant: c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cccc2c(Cn3cnc4ccccc43)ccnc12)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a stirred solution of benzimidazole (26.5 mg) in N,N-dimethylformamide (1 ml) was added sodium hydride (60% in oil, 8.6 mg) in an ice bath, and the mixture was stirred at the same temperature for half an hour. To this mixture was added 4-bromomethyl-8-(2,6-dichlorobenzoylamino)quinoline (80 mg) one portion, and the reaction mixture was stirred at the same temperature for half an hour and then at ambient temperature for one hour. Water was added thereto, and the resulting precipitate was collected by filtration. The solid was washed with hot 95% aqueous ethanol (1 ml) and allowed to cool to ambient temperature. The solid was collected by filtration and air-dried to give 4-(1H-benzimidazol-1-ylmethyl)-8-(2,6-dichlorobenzoylamino)quinoline (65 mg) as an off-white solid.