Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[N:7][NH:8][C:9]=2[CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:22]([CH3:24])[CH3:23]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[N:7][N:8]([CH:22]([CH3:24])[CH3:23])[C:9]=2[CH:10]=1
Reactant: CC(C)I
Reactant: COC(=O)c1cc(Br)cc2[nH]ncc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1cc(Br)cc2c1cnn2C(C)C
Temperature: 90 °C
Reaction time: 2 h
Yield: 33.8 %

Procedure:
To a stirred solution of methyl 6-bromo-1H-indazole-4-carboxylate (4 g, 14.92 mmol) in acetonitrile (30 mL), cesium carbonate (9.7 g, 29.8 mmol) was added followed by 2-iodopropane (3.8 g, 22.3 mmol) and the reaction mixture stirred at 90° C. for 2 h. On completion, the reaction mixture was concentrated under reduced pressure and the residue diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over sodium sulfate. Solvent was removed under reduced pressure to afford crude material which was purified by column chromatography to afford methyl 6-bromo-1-isopropyl-1H-indazole-4-carboxylate (1.5 g, 32.6%).
Reaction SMILES: N[C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][C:10]=3[O:20][CH3:21])[NH:8][C:4]=2[CH:3]=1.N([O-])=[O:25].[Na+].N>C(O)(=O)C.O>[OH:25][C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:11][C:10]=3[O:20][CH3:21])[NH:8][C:4]=2[CH:3]=1
Reactant: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ccc(N)cc2[nH]1
Reactant: O=N[O-]
Agent: N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ccc(O)cc2[nH]1
Reaction time: 1 h

Procedure:
An amount of 3.2 (9.6 mmol) of 5-amino-2-(2'-methoxy-4'-methanesulfonyloxy-phenyl)-benzimidazole was dissolved in 509 ml of glacial acetic acid, and then a solution of 1.38 gm (20 mmol) of sodium nitrite in 5.0 ml of water was added dropwise, under stirring. After one hour, the mixture was diluted with 100 ml of water, and the solution was refluxed for 1.5 hours. Subsequent to cooling, the solution was adjusted to a pH of 5 with concentrated ammonia and extracted three times, each time with 40 ml of methyl ethyl ketone, and the extracts are dried and concentrated by evaporation in vacuo. The oily residue was chromatographed over 500 gm of aluminium oxide (neutral) (eluant: methylene chloride with 8% ethanol).
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[CH3:8][C:9]1([CH3:21])[C:13]([CH3:14])=[CH:12][CH2:11][CH:10]1[CH:15]=[CH:16][CH2:17]C(O)C.O>CN(C)C1C=CN=CC=1.CC(OC)(C)C>[CH3:8][C:9]1([CH3:21])[C:13]([CH3:14])=[CH:12][CH2:11][CH:10]1[CH:15]=[CH:16][CH2:17][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CC1=CCC(C=CCC(C)O)C1(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: COC(C)(C)C
Product: CC(=O)OC(C)CC=CC1CC=C(C)C1(C)C
Temperature: 52.5 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
50 g (0.48 mol) of acetic anhydride was added dropwise to the solution of 78.6 g (0.40 mol) of 5-(2,2,3-trimethylcyclopent-3-enyl)pent-4-en-2-ol and 5.0 g of 4-dimethylaminopyridine in 150 ml of MTBE. The reaction mixture was stirred at 50-55° C. for 1 hour, treated with 0.5 l of water and extracted with 3×150 ml of hexane. The combined organic layers were neutralized with aqueous potassium hydrogen carbonate solution, washed with water, dried (MgSO4) and evaporated in vacuo. The residue (102 g) was distilled at 80-81° C./0.2 Torr to give 89.8 g (95% yield) of acetic acid 5-(2,2,3-trimethyl-cyclopent-3-enyl)pent-4-en-2-yl ester.
Reaction SMILES: CN(C=[N:5][C:6]1[N:7]([CH2:11][C:12]#[CH:13])[CH:8]=[CH:9][N:10]=1)C.[ClH:14]>>[ClH:14].[NH2:5][C:6]1[N:7]([CH2:11][C:12]#[CH:13])[CH:8]=[CH:9][N:10]=1
Reactant: C#CCn1ccnc1N=CN(C)C
Agent: Cl
Product: C#CCn1ccnc1N
Yield: 54 %

Procedure:
According to the same manner as that in Example 1, 2-(dimethylaminomethylene)amino-1-(2-propynyl)imidazole (0.2 g) was treated with 6N hydrochloric acid to give 2-amino-1-(2-propynyl)imidazole hydrochloride (0.12 g, Yield: 54%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[C:3]=12.[Cl:31][C:32]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=1[S:39](Cl)(=[O:41])=[O:40].C(N(CC)CC)C>ClCCl>[Cl:31][C:32]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=1[S:39]([O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:12][CH:13]=1)(=[O:41])=[O:40]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(O)cc4)c4c(N)ncnc43)CC2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(OS(=O)(=O)c5cccc(Cl)c5Cl)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.4 %

Procedure:
A solution containing cis-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenol (100 mg, 0.245 mmol), 2,3-dichlorobenzenesulfonyl chloride (180 mg, 0.735 mmol) and triethylamine (0.34 mL, 2.45 mmol) in dichloromethane (8 mL) was stirred at ambient temperature for 17 h. Additional dichloromethane was added (20 mL) and the reaction was washed with brine (10 mL), saturated aqueous NaHCO3 (10 mL), dried (NaSO4) and concentrated under reduced pressure to afford cis-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl 2,3-dichloro-1-benzenesulfonate as a white solid (135 mg, 90%); RP-HPLC 11.787 min, 97% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z (MH+)=616.2.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[N:10]=[CH:11][NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C>[C:3]1([C:9]2[N:10]=[CH:11][N:12]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:13]=2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc(-c2nc[nH]c2-c2ccccc2)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cnc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
To a stirred suspension of 9.6 (0.24 mol) of 60% sodium hydride-mineral oil in 100 mL of DMF under nitrogen at 0° C. was added dropwise 50.0 g (0.226 mol) of 4,5-diphenylimidazole in 400 mL DMF. The mixture was allowed to warm, stirred at room temperature 1 hr, and 26.6 mL (0.24 mol) of ethyl bromoacetate was added. The reaction was stirred 18 hr at room temperature, heated on a steam bath 2 hr, cooled, and stripped. The residue was partitioned between water and methylene chloride, dried over MgSO4, and filtered through a silica gel column eluting with methylene chloride-ethyl acetate to provide 50.1 g of an oil that solidified on standing. It may be used in further reactions as is, or it may be recrystallized from ether to yield 35.1 g of product mp 89°-90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[C:7](=O)[N:6]([C:13]1[C:14]([CH3:35])=[C:15]([CH3:34])[C:16]3[O:20][C:19]([CH3:22])([CH3:21])[CH:18]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=4)[C:17]=3[C:32]=1[CH3:33])[C:5]2=O>CCCCCC>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][C:2]=1[Cl:1])[CH2:5][N:6]([C:13]1[C:14]([CH3:35])=[C:15]([CH3:34])[C:16]3[O:20][C:19]([CH3:21])([CH3:22])[CH:18]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=4)[C:17]=3[C:32]=1[CH3:33])[CH2:7]2
Reactant: Cc1c(C)c(N2C(=O)c3cc(Cl)c(Cl)cc3C2=O)c(C)c2c1OC(C)(C)C2c1ccc(C(C)C)cc1
Solvent: CCCCCC
Product: Cc1c(C)c(N2Cc3cc(Cl)c(Cl)cc3C2)c(C)c2c1OC(C)(C)C2c1ccc(C(C)C)cc1
Yield: 16 %

Procedure:
By using 5,6-dichloro-2-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-1H-isoindole-1,3(2H)-dione, the title compound was synthesized according to Example 2a. Yield: 16%. Melting point: 148-150° C. (Hexane).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:14][C:15]1(OCC)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH3:13]>>[CH2:12]([O:14][C:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1)[CH3:13]
Reactant: CCOC1(OCC)CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC1=CCCCC1

Procedure:
The synthesis was the same as in Example 1 except that about 50 mg of p-toluene sulfonic acid and 50 ml diethoxycyclohexane (from Lancaster) were employed. Under vacuum overnight at about 90° C., some small amount of distilled liquid was discarded, then the temperature was raised up to 120°-130° C. and the 1-ethoxycyclohexene was collected through distillation.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:3]1([CH3:8])[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[SH:15]
Reactant: Cc1ccccc1I
Reactant: Sc1ccccc1
Product: Cc1ccccc1-c1ccccc1S

Procedure:
The general procedure was used to convert 2-iodotoluene and thiophenol to the title product. Purification by flash chromatography (hexane as the eluent) gave the analytically pure product as a clear oil (386 mg, 96% yield). 1H NMR (300 MHz, CDCl3) δ 7.20–7.00 (m, 9H; Ha, Hb, Hc, Hd, He, He′, Hf, Hf′, Hg), 2.26 (s, 3H; methyl protons). 13C NMR (75 MHz, CDCl3) δ 139.88 (C8), 136.08 (C6), 133.69 (C1), 132.93 (C2), 130.54 (C5), 129.55 (C9, C13), 129.07, (C10, C12), 127.84 (C3), 126.66 (C11), 126.27 (C4), 20.55 (C7). Anal. Calcd. for C13H12S: C, 77.95; H, 6.04; S, 16.01; Found C, 77.87; H, 6.06; S, 15.81.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH2:23]([O:30][C:31]([N:33]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]([CH2:40][OH:41])[CH2:34]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[CH2:23]([O:30][C:31]([N:33]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]([CH:40]=[O:41])[CH2:34]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(OCc1ccccc1)N1CCCCC(CO)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CC1CCCCN(C(=O)OCc2ccccc2)C1
Reaction time: 1 h
Yield: 23.5 %

Procedure:
Dess-Martin periodinane (2.78 g, 6.56 mmol) was slowly added to a stirring 0° C. solution of 3-hydroxymethyl-azepane-1-carboxylic acid benzyl ester (146) (1.2516 g, 5.02 mmol) in CH2Cl2 (18.2 mL). The reaction was stirred for 1 hour until the reaction was judged complete by HPLC. The reaction was concentrated in vacuo, and a minimal amount of CH2Cl2 was added. Et2O was added to precipitate the periodinane by-product, and the reaction was filtered, concentrated, and immediately purified through an automated silica gel column with 1:1 Hexanes:EtOAc to obtain pure 3-formyl-azepane-1-carboxylic acid benzyl ester (147) (0.3086 g) in 62% yield.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][CH2:13][CH:14]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:24]=1)[C:15]#[C:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH2:9][C:10]([NH:12][CH2:13][CH:14]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:24]=1)[C:15]#[C:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11]
Reactant: COc1ccc(C(C#Cc2ccccc2)CNC(=O)CNC(=O)OC(C)(C)C)cc1OC1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C(C#Cc2ccccc2)CNC(=O)CN)cc1OC1CCCC1
Reaction time: 1 h

Procedure:
A solution of 4-t-butoxycarbonylaminomethylcarbonylamino-3-(3-cyclopentyloxy-4methoxyphenyl)-1-phenyl-1-butyne (290 mg, 0.59 mmol) in CH2Cl2 (5 ml) at 0° was treated with trifluoroacetic acid (4 ml). After 1 hr, all the solvents were evaporated. The residue was partitioned between H2O and Et2O, basified with aqueous NaOH, and the Et2O layer seperated, dried, and the solvent evaporated, and gave 4-aminomethylcarbonylamino-3-(3-cyclopentyloxy-4-methoxyphenyl)-1-phenyl-1-butyne, 200 mg (86%). The salt was formed by treating this amine (180 mg) in Me2CO (2 ml) with sulfamic acid (82 mg). The solution was concentrated to almost dryness, and the resultant crystals were triturated with Me2CO, and gave the titled compound, mp 119-124°. 1H NMR (400 MHz, CDCl3) δ 8.22 (t, 1 H), 7.44 (m, 3 H), 7.28 (m, 3 H), 7.02 (d, 1 H), 6.94 (m, 1 H), 6.82 (d, 1 H), 4.80 (m, 1 H), 4.04 (t, 1 H), 3.80 (s, 3 H), 3.76 (m, 2 H), 3.62 (m, 1 H), 3.52 (m, 1 H), 3.18 (m, 1 H), 2.04 (m, 2 H), 1.80-1.98 (m, 6 H), 1.52-1.72 (m, 4 H), 1.08-1.32 (m, 6 H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:16]=[CH:15][C:8]([O:9]/[CH:10]=[CH:11]\[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1>CCO.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1
Reactant: COCCc1ccc(O/C=C\C(=O)O)cc1
Agent: [Pd]
Solvent: CCO
Product: COCCc1ccc(OCCC(=O)O)cc1
Reaction time: 2 h

Procedure:
(E)/(Z)-3-(4-(2-methoxyethyl)phenoxy)acrylic acid (0.3 g) was dissolved in EtOH (10 mL) and Pd/C (5%, degussa type E101, 40 mg) was added. The mixture was hydrogenated at atmospheric pressure for 2 hours and then filtered and the solvent removed to dryness. After purification by column chromatography using a mixture of hexane/ethyl acetate, 3-(4-(2-methoxyethyl)phenoxy)propanoic acid was obtained as a white solid (0.236 g). NMR (CDCl3, 400 mHz, ppm); 2.85 (t, 4H), 3.35 (s, 3H), 3.55 (t, 2H), 4.25 (t, 2H), 6.85 (d, 2H), 7.1 (d, 2H).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[O:22][N:21]=[C:20]([C:23]([NH2:25])=[O:24])[N:19]=1)C1C=CC=CC=1>CO.C1COCC1.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[O:22][N:21]=[C:20]([C:23]([NH2:25])=[O:24])[N:19]=1
Reactant: NC(=O)c1noc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)c1noc([C@@H]2CC[C@@H]3CN2C(=O)N3O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
To a solution of 5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)-1,2,4-oxadiazole-3-carboxamide (220 mg, 0.641 mmol) in MeOH (4.0 mL) and THF (12.0 mL) was added 10% Pd/C (13.6 mg, 0.013 mmol). The reaction mixture was stirred under hydrogen balloon for 1 h at rt, then filtered and concentrated to afford 5-((2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)-1,2,4-oxadiazole-3-carboxamide (˜150 mg, 93%), which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[CH3:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: Cc1ccc(-c2nc(N3CCCCC3)nc(C)c2CO)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1ccc(-c2nc(N3CCCCC3)nc(C)c2C=O)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 61.3 %

Procedure:
To a solution of (4-methyl-2-(piperidin-1-yl)-6-p-tolylpyrimidin-5-yl)methanol (0.800 g; 2,69 mmol) in dichloromethane (27 mL) was added molecular sieves (4 Å) and pyridinium dichromate (1,52 g; 4,04 mmol). The reaction was stirred at room temperature for 21 h. An excess of celite was added to the reaction and the suspension was stirred for 30 min, filtered on a plug of celite and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane furnished 0.487 g (61%) of the desired compound as a white solid.
Reaction SMILES: C(OC(=O)[N:7]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH:14](O)[C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[C:10]([Cl:25])[N:9]=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[NH:17]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:23]2[C:15]([CH2:14][C:11]2[CH:12]=[CH:13][C:8]([NH:7][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=3)=[N:9][C:10]=2[Cl:25])=[CH:16]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)cc1)c1ccc(C(O)c2c[nH]c3ncccc23)c(Cl)n1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(CNc2ccc(Cc3c[nH]c4ncccc34)c(Cl)n2)cc1

Procedure:
To (4-chloro-benzyl)-6-chloro-5-[hydroxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl-carbamic acid tert-butyl ester (542, 1.00 g, 2.00 mmol) in acetonitrile (130.0 mL) were added triethylsilane (11.5 mL, 0.0720 mol) and trifluoroacetic acid (5.5 mL, 0.071 mol). The reaction was heated to reflux for 2 hours, then concentrated, poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and washed with ethyl acetate and hexane to give a light yellow solid (P-0161, 480 mg, 62%). MS (ESI) [M+H+]+=383.1, 385.1.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][C:7]1[C:12]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:11][N:10]=[C:9]([NH:19][C@@H:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[N:28]=3)[NH:23][C@H:22]([CH2:32][CH3:33])[CH2:21]2)[N:8]=1.[H-].[Na+].I[CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48]>CN(C)C=O>[F:40][C:37]([F:38])([F:39])[C:35]1[CH:34]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:41])[F:42])[CH:36]=1)[CH2:6][C:7]1[C:12]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:11][N:10]=[C:9]([NH:19][C@@H:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[N:28]=3)[N:23]([CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[C@H:22]([CH2:32][CH3:33])[CH2:21]2)[N:8]=1
Reactant: CCOC(=O)CI
Reactant: CC[C@@H]1C[C@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)c2nc(OC)ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1c2ccc(OC)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-1,2,3,4-tetrahydro-[1,5]naphthyridine (300 mg) is dissolved in N,N-dimethylformamide (3 ml), and thereto is added sodium hydride (62.7%, 21 mg) under ice-cooling, then after 1 hour added ethyl iodoacetate (71 μl). The mixture is stirred at room temperature for 24 hours. The reaction solution is partitioned by adding water and ethyl acetate. The organic layer is washed with saturated brine, then dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by NH-column chromatography (silica gel; hexane:ethyl acetate=9:1→4:1) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-1-ethoxycarbonylmethyl-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine (107 mg). MS (m/z): 683 [M+H]+.
Reaction SMILES: [C:1]([O-:6])(=O)[C:2]([NH2:4])=[O:3].[NH2:7][C:8]1[CH:13]=[CH:12][C:11](C(C2C=CC(O)=CC=2)(C)C)=[CH:10][CH:9]=1>ClC1C=CC=CC=1Cl>[CH:11]1[CH:12]=[CH:13][C:8]([NH:7][C:1]([C:2]([NH:4][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:3])=[O:6])=[CH:9][CH:10]=1
Reactant: NC(=O)C(=O)[O-]
Reactant: CC(C)(c1ccc(N)cc1)c1ccc(O)cc1
Solvent: Clc1ccccc1Cl
Product: O=C(Nc1ccccc1)C(=O)Nc1ccccc1

Procedure:
Ar=2,2-(4,4′-phenylene)propyl (also known as compound (VIII)): A mixture of oxamate, compound (XII), (2.415 g, 10.18 mmol) and 2-(4-aminophenyl)-2-(4′-hydroxyphenyl)propane (2.545 g, 11.2 mmol) were suspended in o-dichlorobenzene (10 ml), degassed, and heated to reflux for 20 hrs. TLC indicated complete conversion of the oxamate. The crude reaction mixture was concentrated under reduced pressure, taken up in dichloromethane, and filtered through a plug of silica gel. The product was recrystallized from hexanes/dichloromethane and again filtered through silica gel, yielding the desired oxanilide as white fine crystals.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]([OH:15])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].I[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:34]=[CH:33][C:24]2[CH2:25][CH2:26][CH:27]([C:29]([O:31][CH3:32])=[O:30])[O:28][C:23]=2[C:22]=1[CH2:35][CH2:36][CH3:37].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[OH:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]([CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5])[O:15][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:34]=[CH:33][C:24]2[CH2:25][CH2:26][CH:27]([C:29]([O:31][CH3:32])=[O:30])[O:28][C:23]=2[C:22]=1[CH2:35][CH2:36][CH3:37]
Reactant: CCCc1c(OCCCI)ccc2c1OC(C(=O)OC)CC2
Reactant: CCCc1c(O)ccc(C(=O)NC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2ccc3c(c2CCC)OC(C(=O)OC)CC3)ccc(C(=O)NC)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 10 (200 mg, 0 96 mmol), the compound of Example 23 (400 mg, 0.96 mmol) and potassium carbonate (264 mg, 1.92 mmol) were added to about 20 ml of DMF. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate and concentrated under vacuum. Chromatography of the crude material on silica gel with 30% ethyl acetate/hexane as eluant followed by rechromatography using the same solvent system gave the product.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].Cl>[OH-].[Na+]>[CH2:14]([O:13][C:11]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the solution of L-leucine (0.400 g, 3.049*10−3 mol) in 2M NaOH aq. (3.75 ml) cooled to 0° C., benzyl chloroformate (3.5374*10−3 mol, 0.52 ml) was added dropwise over 15 min. The mixture was stirred at RT for another 2 h, and then acidified with HCl conc. The aqueous layer was extracted with AcOEt (3×10 ml) and the combined organic layers were dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo to give crude N-benzoxycarbonyl-L-leucine. (colourless oil) (76%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.[H-].[Na+].[CH2:11](Cl)[C:12]#[CH:13]>CN(C)C=O>[CH2:13]([O:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:12]#[CH:11]
Reactant: OCc1cccnc1
Reactant: C#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCOCc1cccnc1
Yield: 45.3 %

Procedure:
While maintaining the reaction mixture at 5°-10° C., 3-pyridylcarbinol (50.0 g., 0.45 mol) was slowly added to a mixture of sodium hydride (24.0 g of a 50% suspension in mineral oil, 0.5 mol) in 250 ml dry N,N-dimethylformamide. Propargyl chloride (37.0 g, 0.5 mole) was then slowly added to this mixture at 15° C. Following the addition, the reaction mixture was warmed to 35° and maintained for 15 mins at this temperature. The reaction was then cooled to 15°-20°, carefully quenched by dropwise addition of water and extracted with ether. The combined ether extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 45 g crude product. Distillation gave 30.0 g of 3-(2-propynyloxymethyl)pyridine. Yield 44% theory; b.p. 95° C. (0.9 mm).