Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:18]=[C:17]([O:19][S:20]([C:23]2[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=2[CH3:31])(=[O:22])=[O:21])[C:16]([F:32])=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH:33]1[CH:37]=[CH:36][N:35]=[CH:34]1.Cl.C(OC(C)C)(C)C>C(Cl)Cl.O.C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:18]=[C:17]([O:19][S:20]([C:23]2[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=2[CH3:31])(=[O:22])=[O:21])[C:16]([F:32])=[CH:15][C:11]=1[C:12]([N:33]1[CH:37]=[CH:36][N:35]=[CH:34]1)=[O:13]
Reactant: c1c[nH]cn1
Reactant: Cc1cc(C)c(S(=O)(=O)Oc2nc(Nc3ccc(F)cc3F)c(C(=O)Cl)cc2F)c(C)c1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)Oc2nc(Nc3ccc(F)cc3F)c(C(=O)n3ccnc3)cc2F)c(C)c1
Yield: 91.1 %

Procedure:
In 10 ml of methylene chloride was dissolved 500 mg of 2-(2,4-difluorophenylamino)-5-fluoro-6-(mesitylenesulfonyloxy)nicotinoyl chloride, and 1 ml of a methylene chloride solution containing 77 mg of imidazole and 120 mg of triethylamine was dropped into the resulting solution at -20° C., after which the resulting mixture was subjected to reaction at room temperature for 30 minutes. Subsequently, 5 ml of water was added to the reaction mixture, and the pH thereof was adjusted to 2.0 with 2N hydrochloric acid. The organic layer was separated, washed successively with 5 ml of water and 5 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 2 ml of diisopropyl ether, after which crystals were collected by filtration to obtain 485 mg (yield 91.1%) of 1-[2-(2,4-difluorophenylamino)-5-fluoro-6-(mesitylenesulfonyloxy)nicotinoyl]imidazole having a melting point of 98°-101° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[NH:40]N>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:40][C:35]2[C:36]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]1)=[CH:37][CH:38]=[CH:39][C:34]=2[CH3:33]
Reactant: Cc1ccccc1NN
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3F)CC2)c1
Agent: Cl
Product: Cc1cccc2c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3ccccc3F)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 512.2 (M+H)+.
Reaction SMILES: [I-].[K+].C(=O)([O-])[O-].[Na+].[Na+].[CH:9]1([CH:15]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:16]([NH:18][C@@H:19]2[C@H:26]3[C@H:22]([CH2:23][NH:24][CH2:25]3)[CH2:21][CH2:20]2)=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.Br[CH:34]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(C(C)=O)C>[CH:34]([N:24]1[CH2:25][C@H:26]2[C@@H:19]([NH:18][C:16](=[O:17])[CH:15]([CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]3)[CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:20][CH2:21][C@H:22]2[CH2:23]1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(N[C@H]1CC[C@H]2CN(C(c3ccccc3)c3ccccc3)C[C@H]21)C(C1CCCCC1)C1CCCCC1
Temperature: 90 °C

Procedure:
Potassium iodide (12.48 mg, 0.075 mmol) and sodium carbonate (80 mg, 0.752 mmol) were combined with methyl ethyl ketone (5 mL) and then 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide (200 mg, 0.601 mmol) from Example 53 was added followed by the addition of (bromomethylene)dibenzene (124 mg, 0.501 mmol). The reaction was heated overnight at 90° C. The reaction mixture was concentrated with a stream of nitrogen and then purified by silica gel chromatography eluting with 2-10% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.74 (dd, J=6.7, 15.4, 1H), 7.61 (t, J=6.7, 3H), 7.35 (t, J=7.6, 4H), 7.28-7.23 (m, 3H), 4.42 (dt, J=7.4, 14.4, 1H), 4.16 (s, 1H), 2.96 (qd, J=4.2, 8.0, 1H), 2.63 (dd, J=4.1, 9.8, 1H), 2.57-2.48 (m, 1H), 2.42 (dt, J=9.4, 14.6, 2H), 2.33 (dd, J=3.7, 9.3, 1H), 2.09-1.90 (m, 3H), 1.90-1.80 (m, 3H), 1.79-1.70 (m, 4H), 1.69-1.55 (m, 6H), 1.46 (d, J=14.7, 1H), 1.39 (s, 1H), 1.33-1.00 (m, 8H), 1.00-0.89 (m, 1H); MS (ESI+) m/z 499 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]#[C:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:2]1>C(O)C.[Pd]>[S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:2]1
Reactant: OCCCCC#Cc1ccsc1
Agent: [Pd]
Solvent: CCO
Product: OCCCCCCc1ccsc1
Yield: 80.3 %

Procedure:
3-Thiophenehexanol was prepared by reduction of 8.4 g of 6-(3-thiophenyl)-5-hexyn-1-ol, in 100 ml of ethanol over 1.0 g of 10% palladium/carbon at atmospheric pressure. After 8 hours a second catalyst loading was added and the reduction continued over night. The residue obtained after filtration and evaporation of the solvent was evaporatively distilled to give 6.9 g (80%) of 3-thiophenehexanol, bp 135°-147° C./0.2 mm.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>O>[C:11]([NH:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)c1cc(N)no1
Solvent: O
Product: CC(=O)Nc1cc(C(C)(C)C)on1
Reaction time: 4 h

Procedure:
To 3-amino-5-t-butylisoxazole (2.80 g), acetic anhydride (6 ml) is added, and the resultant mixture is allowed to stand at room temperature for 4 hours. The reaction mixture is mixed with chilled water (50 ml), and the precipitated crystals are filtered. The crystals are washed with water and dried to give 3-acetylamino-5-t-butylisoxazole (3.39 g). This substance is recrystallized from hexane to give crystals melting at 120.5° to 121.0° C.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Ba+2].[OH-].COCCOC.[CH3:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[C:22]([Cl:27])[N:21]=1>O>[CH3:19][C:20]1[N:21]=[C:22]([Cl:27])[CH:23]=[C:24]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:25]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: OB(O)c1ccccc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: Cc1nc(Cl)cc(-c2ccccc2)n1
Temperature: 80 °C
Reaction time: 6 h
Yield: 51.3 %

Procedure:
A reaction vessel was charged with 2.19 g of tetrakistriphenylphosphine palladium, 847 mg of phenylboronic acid, and 2.99 g of barium hydroxide, to which 40 ml of 1,2-dimethoxyethane, 7 ml of water, and 1.01 g of 2-methyl-4,6-dichloropyrimidine were added, followed by stirring at 80° C. under an atmosphere of a nitrogen gas for 6 hours. The reaction mixture was then left for cooling to room temperature, and water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.65 g of 2-methyl-4-chloro-6-phenylpyrimidine.
Reaction SMILES: Cl[CH2:2][CH2:3][OH:4].[CH:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH2:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>O>[CH:11]([NH:18][CH2:2][CH2:3][OH:4])([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:8]1[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: OCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCCNC(c1ccccc1)c1ccccc1
Temperature: 90 °C
Yield: 59 %

Procedure:
In a 500 mL round bottom flask equipped with a condenser and a thermometer, 2-choroethan-1-ol (23.3 grams, 0.39 mol, Kodak), α-aminodiphenylmethane (82.0 grams, 0.45 mol, Fluka), and water (17 mL) were placed. The mixture was heated on a steam bath (ca. 90° C.) for six hours. After cooling to ambient temperature, NaOH (15 grams, 0.37 mol) was added and the mixture heated on a steam bath for 45 minutes at ca. 90° C. Water (50 mL) was then added to the solution. The resulting two-layered mixture was extracted with two 50 mL portions of toluene. The combined toluene extracts were dried over sodium hydroxide pellets and the toluene then removed by rotary evaporation at reduced pressure. The residue was fractionally distilled using a 7.5 inch Vigreux column. The fraction boiling at 175-177° C./2 mm pressure was collected and then recrystallized from hexane. Yield 39.0 g (59% yield). 1H NMR (δ, 360 MHz, CDCl3) 2.32 (bs, 2H, --OH & --NH), 2.74 (m, 2H, --NCH2CH2O--), 3.64 (m, 2H, --NCH2CH2O--) 4.84 (s, 1H, CHPh2) and 7.30 (m, 10H, aromatic H); 13C NMR (δ, 90 MHz, {1H}, CDCl3); 49.5 (--NCH2CH2O--), 61.5 (--NCH2CH2O--) 67.0 (CHPh2), 127.2, 127.3, 128.3 and 147.5 (CHPh2) mp 69-70° C. uncorrected.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]1([O:16][C:17]2[CH:18]=[C:19]([CH:25]([C:29]#[C:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:26][CH2:27][OH:28])[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(N(CC)CC)C.[NH4+].[Cl-]>C(Cl)Cl>[CH:11]1([O:16][C:17]2[CH:18]=[C:19]([CH:25]([C:29]#[C:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:26][CH:27]=[O:28])[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: COc1ccc(C(C#Cc2ccccc2)CCO)cc1OC1CCCC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(C#Cc2ccccc2)CC=O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 61.8 %

Procedure:
To a solution of oxalyl chloride (0.265 mL, 3.0 mmol) in CH2Cl2 (11 mL) at -78° C. under an argon atmosphere was added DMSO (0.43 mL, 6.0 mmol). After 0.03 h, (+/-)-3-(3-cyclopentyloxy-4-methoxyphenyl)-5-phenylpent4ynol (0.96 g, 2.74 mmol) was added in CH2Cl2 (15 mL). After 0.25 h, triethylamine (2.0 mL, 13.7 mmol) was added. The mixture was allowed to warm to room temperature. Aqueous NH4Cl was added, the mixture was extracted three times with CH2Cl2, the organic extract was washed with 1N HCl, was dried (Na2SO4) and was evaporated. Purification by flash chromatography (silica gel, 25% EtOAc/Hex) provided the title compound as a yellow oil (0.59 g, 62%).MS(EI) m/e 349 [M+H]+.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[CH:7]([C:9]1[O:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[CH:13]=1)=[O:8].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>CCOCC.[I-].[Zn+2].[I-].O>[O:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[CH:13]=[C:9]1[CH:7]([OH:8])[CH2:5][NH2:6]
Reactant: O=Cc1cc2ccccc2o1
Reactant: C[Si](C)(C)C#N
Agent: [Al+3]
Agent: [H-]
Agent: [I-]
Solvent: CCOCC
Solvent: O
Product: NCC(O)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 10 h
Yield: 65.2 %

Procedure:
Trimethylsilylcyanide (1.63 g, 2 ml) was added to a solution of 2-formylbenzofuran (2.0 g), (prepared as described in French Pat. No. 1.537.206) and a trace of zinc iodide in dry ether (50 ml) at 0° under nitrogen. The reaction mixture was stirred under nitrogen at ambient temperature for 10 h. This solution was then added dropwise to a suspension of lithium aluminium hydride (0.63 g) in dry ether under nitrogen. The mixture was heated under reflux for 1 h at the end of the addition. The reaction mixture was cooled; water (0.63 ml), 2 M sodium hydroxide (0.63 ml) and more water (1.89 ml) added, the reaction mixture filtered, the residue washed with chloroform and the combined solvents evaporated to give 2-(2-benzofuranyl)-2-hydroxyethanamine, (1.58 g).
Reaction SMILES: C(N(C(=O)C1C=CC(O)=CC=1)C1C=C(OC)[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.Cl[CH2:39][C:40]([N:42]([CH2:44][CH2:45][CH2:46][O:47][CH3:48])[CH3:43])=O>>[CH2:40]([N:42]([CH2:43][C:14]1[CH:19]=[CH:18][C:17]([O:22][CH2:39][CH2:40][N:42]([CH2:44][CH2:45][CH2:46][O:47][CH3:48])[CH3:43])=[CH:16][CH:15]=1)[C:44]1[CH:45]=[C:46]([O:47][CH3:48])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:39]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: COCCCN(C)C(=O)CCl
Product: CCN(Cc1ccc(OCCN(C)CCCOC)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 110.5 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-N-(3-methoxypropyl)-N-methylacetamide (10 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.8 mg) was obtained.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH:5]([O:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[Cl:14])C.[O:18]([C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][CH2:31][CH2:32]O)=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(C)C=CC=CC=1.[OH-].[Na+]>>[Cl:14][C:8]1[CH:9]=[C:10]([O:13][CH2:32][CH2:31][CH2:30][O:29][C:28]2[CH:34]=[CH:35][C:25]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:26][CH:27]=2)[CH:11]=[CH:12][C:7]=1[CH2:6][CH:5]([O:15][CH3:16])[C:4]([OH:3])=[O:17]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1Cl)OC
Reactant: OCCCOc1ccc(Oc2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COC(Cc1ccc(OCCCOc2ccc(Oc3ccccc3)cc2)cc1Cl)C(=O)O

Procedure:
A mixture solution of 3-(2-Chloro-4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester from Example 191, Step F and 3-(4-phenoxy-phenoxy)-propan-1-ol were allowed to react under the Standard Mitsounobu coupling conditions B (DIAD/toluene) to give the corresponding coupled product which by the Standard hydrolysis procedure C (NaOH) yield the title compound. MS (ES) for C25H25ClO6 [M+NH4]+: 474.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[CH:10]3)=[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:4][C:3]=1[C:22]([O:24]C)=O.C([O-])=O.[NH4+].[CH:30]([NH2:32])=O>>[NH:12]1[C:13]2[C:9](=[CH:8][C:7]([C:6]3[C:2]4[N:1]=[CH:30][NH:32][C:22](=[O:24])[C:3]=4[S:4][C:5]=3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:15][CH:14]=2)[CH:10]=[CH:11]1
Reactant: NC=O
Reactant: COC(=O)c1sc(-c2ccccc2)c(-c2ccc3[nH]ccc3c2)c1N
Agent: O=C[O-]
Agent: [NH4+]
Product: O=c1[nH]cnc2c(-c3ccc4[nH]ccc4c3)c(-c3ccccc3)sc12

Procedure:
A mixture of EXAMPLE 8B (95 mg, 0.27 mmol) and ammonium formate (68 mg, 1.08 mmol) in formamide (5 mL) was heated at 170° C. for 4 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by reverse phase HPLC on a C18 column using 0-70% acetonitrile/0.1% trifluoroacetic acid in water to give 40 mg of the title compound. 1H NMR (DMSO-d6) δ 12.57 (br, 1H), 11.14 (s, 1H), 8.15 (s, 1H), 7.53 (s, 1H), 7.30-7.36 (m, 7H), 6.93 (dd, J=8.2, 1.5, 1H), 6.41 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].N1C=CC=CC=1.Cl[C:22]([O:24][CH2:25][Cl:26])=[O:23]>C(OCC)C>[C:22](=[O:23])([O:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:6])[O:24][CH2:25][Cl:26]
Reactant: O=C(Cl)OCCl
Reactant: O=C(CCCO)OCc1ccccc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(CCCOC(=O)OCCl)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of benzyl 4-hydroxybutanoate (synthesized by the procedure described in Weber et al., J. Med. Chem, 1991, 34, 2692-2701, 5.0 g) in diethyl ether (100 ml), pyridine (2.3 ml) was added under a nitrogen atmosphere, and chloromethyl chloroformate (3.7 g) was added dropwise at −10° C. The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was filtered with glass filter and then the filtrate was washed with water and a saturated sodium chloride aqueous solution successively. The organic layer was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure, and thus the residue was subjected to silica gel column chromatography and eluted with acetone/hexane (1:1 v/v) to obtain chloromethyl (3-benzyloxycarbonylpropyl) carbonate (7.25 g) as a colorless oily product.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9](/[CH:16]=[CH:17]/[CH3:18])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([CH3:19])[CH:4]=1.C(Cl)Cl.B(Br)(Br)Br>>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9](/[CH:16]=[CH:17]/[CH3:18])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([CH3:19])[CH:4]=1
Reactant: C/C=C/[C@H](CC(=O)OCC)c1ccc(OC)cc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C/C=C/[C@H](CC(=O)OCC)c1ccc(O)cc1C
Reaction time: 1 h
Yield: 24.2 %

Procedure:
To a stirred solution of (S,E)-ethyl 3-(4-methoxy-2-methylphenyl)hex-4-enoate 28.6 (0.500 g, 2 mmol) in DCM (19 mL, 2 mmol) at 0° C. was added boron tribromide (9 mL, 9 mmol). The resulting mixture was stirred for 1 hour. The reaction wasquenched by the addition of pH 7 buffer. The resulting mixture was extracted with DCM. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The resulting product was purified by silica gel flash chromatography (0-10% EtOAc/hexane) to afford (S,E)-ethyl 3-(4-hydroxy-2-methylphenyl)hex-4-enoate (28.7) (0.12 g, 25% yield) as a colorless oil. MS ESI (pos.) m/e: 266.2 (M+H2O), 249.1 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Br[C:11]1[CH:12]=[N:13][C:14]2[C:15]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:23]([CH2:29][O:30][CH2:31][CH3:32])=[N:22][C:16]=3[C:17]([NH2:21])=[N:18][C:19]=2[CH:20]=1.C(O)CC.C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH2:31]([O:30][CH2:29][C:23]1[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:15]2[C:14]3[N:13]=[CH:12][C:11]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:20][C:19]=3[N:18]=[C:17]([NH2:21])[C:16]=2[N:22]=1)[CH3:32]
Reactant: OB(O)c1cccnc1
Reactant: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Solvent: O
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)cnc3c2n1CC(C)C
Temperature: 25 °C
Yield: 67.4 %

Procedure:
Pyridine-3-boronic acid (0.39 g, 3.2 mmol) was added to 7-bromo-2-(ethoxymethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (1.0 g, 2.6 mmol) and 1-propanol (17 mL). The mixture was degassed and backfilled with nitrogen. Aqueous 2M sodium carbonate (1.6 mL), water (2 mL), triphenylphosphine (0.021 g, 0.079 mmol), and palladium (II) acetate (0.0058 g, 0.026 mmol) were added to the reaction mixture followed by subsequent degassing. The mixture became homogenous upon heating at reflux for 1 hour. After an additional 1 hour of heating, the reaction was cooled to ambient temperature and extracted into chloroform. The resulting solution was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by automated flash chromatography (using a silica gel cartridge, eluting with CMA:chloroform ranging in ratios from 0:100 to 30:70) and concentrated under reduced pressure. The product was recrystallized from acetonitrile, filtered, and dried at 60° C. under vacuum to provide 0.66 g of 2-(ethoxymethyl)-1-(2-methylpropyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine as a white solid, mp 177-179° C.
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[CH:6]=[C:7]2[C:11]=1[NH:10][N:9]=[CH:8]2.BrC1C=C2C(=CC=1)NN=C2[C:27]([F:30])([F:29])[F:28]>>[F:28][C:27]([F:30])([F:29])[C:8]1[C:7]2[C:11](=[CH:3][CH:4]=[C:5]([C:12]([OH:14])=[O:13])[CH:6]=2)[NH:10][N:9]=1
Reactant: FC(F)(F)c1n[nH]c2ccc(Br)cc12
Reactant: O=C(O)c1cc(C(F)(F)F)c2[nH]ncc2c1
Product: O=C(O)c1ccc2[nH]nc(C(F)(F)F)c2c1

Procedure:
The title compound was prepared by a method analogous to that described in Steps 3-4 of Intermediate 21, using 5-bromo-3-(trifluoromethyl)-1H-indazole. +ESI (M+H) 231.1.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:25]4[C:21](=[N:22][O:23][N:24]=4)[CH:20]=[CH:19][C:18]=3[OH:26])[C:9]2=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:34]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4[C:25]5=[N:24][O:23][N:22]=[C:21]5[CH:20]=[CH:19][C:18]=4[O:26][CH2:34]3)[C:9]2=[O:27])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: O=C1C(c2c(O)ccc3nonc23)c2ccccc2N1C(c1ccccc1)c1ccccc1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1ccc3nonc3c12

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-3-(5-hydroxy-2,1,3-benzoxadiazol-4-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one was obtained (50%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.82 (d, J=9.6 Hz, 1H), 7.58-6.92 (m, 15H), 6.55 (d, J=7.8 Hz, 1H), 5.25 (d, J=9.3 Hz, 1H), 4.99 (d, J=9.3 Hz, 1H); MS (ES+) m/z 446 (M+1).
Reaction SMILES: CS[C:3]1[NH:4][C:5]2[C:6]([N:19]=1)=[N:7][C:8]1[CH:9]=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:11]=[CH:12][C:13]=1[CH:14]=2.C(O)(=[O:22])C.Cl>O>[F:16][C:15]([F:18])([F:17])[C:10]1[CH:11]=[CH:12][C:13]2[CH:14]=[C:5]3[NH:4][C:3](=[O:22])[NH:19][C:6]3=[N:7][C:8]=2[CH:9]=1
Reactant: CC(=O)O
Reactant: CSc1nc2nc3cc(C(F)(F)F)ccc3cc2[nH]1
Agent: Cl
Solvent: O
Product: O=c1[nH]c2cc3ccc(C(F)(F)F)cc3nc2[nH]1

Procedure:
A mixture of 2-(methylthio)-6-(trifluoromethyl)-1H-imidazo[4,5-b]quinoline (1.77 g, 6 mmol), acetic acid (25 mL) and 3N hydrochloric acid solution (25 mL) was heated on a steam bath for 4 hours. The solution was diluted with hot water (250 mL), cooled and filtered. The filtrate was concentrated to afford a second crop. Solids were combined with acetic acid (25 mL) and 3N hydrochloric acid solution (25 mL) and the mixture heated on a steam bath overnight. The mixture was diluted with hot water (250 mL), cooled, the solid collected and dried in vacuo to accord 1,3-dihydro-6-(trifluoromethyl)-2H-imidazo[4,5-b]quinolin-2-one (1.38 g, 83%), m.p. >250° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[H-].[Na+].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21]([C:30]#[N:31])([CH2:24]OS(C)(=O)=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].O>CN(C)C=O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21]([C:30]#[N:31])([CH2:24][O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Cc1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(COS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1OCC1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 117.4 %

Procedure:
After dissolving 230 mg of 2-methylphenol in 20 ml of N,N-dimethylformamide, 43 mg of sodium hydride (70% suspension in oil) was added and the mixture was stirred at 80° C. for 30 minutes. Next, 224 mg of 1-(tert-butoxycarbonyl)-4-cyano-4-(methanesulfonyloxymethyl)piperidine was added and the mixture was stirred at 100° C. for 8 hours. After cooling it to room temperature, water was added and extraction was performed with ethyl acetate. The organic layer was washed with a 1N sodium hydroxide solution and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (273 mg, 100% yield).