Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]23[C:30]([CH3:32])([CH3:31])[C:27]([CH3:33])([CH2:28][CH2:29]2)[C:26](=[O:34])[CH2:25]3)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.C(O)C.[BH4-].[Na+]>>[Cl:1][C:2]1[C:3]([NH:23][C:24]23[C:30]([CH3:31])([CH3:32])[C:27]([CH3:33])([CH2:28][CH2:29]2)[CH:26]([OH:34])[CH2:25]3)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC12CCC(Nc3c(Cl)cnc4[nH]c(-c5ccc(N6CCOCC6)cc5)nc34)(CC1=O)C2(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC12CCC(Nc3c(Cl)cnc4[nH]c(-c5ccc(N6CCOCC6)cc5)nc34)(CC1O)C2(C)C
Temperature: 60 °C
Yield: 46.9 %

Procedure:
To a suspension of 4-(6-chloro-2-(4-morpholinophenyl)-3H-imidazo[4,5-b]pyridin-7-ylamino)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (Compound CXCVIII) (100 mg, 0.208 mmol) in ethanol NaBH4 (78 mg, 2.08 mmol) was added and the reaction mixture was heated at 60° C. for 16 h when LCMS confirmed consumption of staring material and formation of desired product. The reaction mixture was allowed to come to rt and acidified to pH 5. Solvent was then removed and the residue was suspended in water and filtered. The residue was triturated with ether to afford the desired product (47 mg, 47%) as a white solid. NMR: δ (1H, 400M Hz, DMSO-d6): 0.88 (3H, s), 0.91 (3H, s), 1.09 (3H, s), 1.00-1.60 (4H, m), 2.80-2.90 (1H, m), 3.15-3.25 (4H, m), 3.60-3.70 (1H, m), 3.70-3.80 (4H, m), 4.80 (1H, d, J=4.4 Hz), 5.26 (1H, s), 7.10 (2H, d, J=8.8 Hz), 8.02 (2H, d, J=8.8 Hz), 13.04 (s, 1H). LCMS (254 nm): [M+H]+ 482.15 (88.07%). HPLC: 86.94% (220 nm)
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[N:8][C:9]([C:14]([O:16]CC)=O)=[C:10]([OH:13])[C:11](=[O:12])[N:6]2[CH2:5][C:4](=[O:19])[N:3]1[CH3:20].[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:25][NH2:26]>>[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:25][NH:26][C:14]([C:9]1[N:8]=[C:7]2[N:6]([C:11](=[O:12])[C:10]=1[OH:13])[CH2:5][C:4](=[O:19])[N:3]([CH3:20])[N:2]2[CH3:1])=[O:16]
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC(=O)N(C)N2C
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: CN1C(=O)Cn2c(nc(C(=O)NCc3ccc(Cl)c(Cl)c3)c(O)c2=O)N1C
Yield: 74 %

Procedure:
Reaction of intermediate 22, ethyl 1,2-dimethyl-7-hydroxy-3,6-dioxo-2,3,4,6-tetrahydro-1H-pyrimido[2,1-c][1,2,4]triazine-8-carboxylate, (0.050 g, 0.177 mmol) with 3,4-dichlorobenzylamine (0.10 g, 0.57 mmol) as described in the preparation of example 1 gave 0.054 g (74% yield) of the title amide as a white solid. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.28 (3H, s, NCH3), 3.32 (3H, s, NCH3), 4.59 (2H, d, J=6.7 Hz, NCH2), 4.68 (2H, s, CH2), 7.21 (1H, dd, J=2.0 Hz and J=8.0 Hz, aromatic), 7.44 (1H, d, J=2.0 Hz, aromatic), 7.46 (1H, d, J=8.0 Hz, aromatic), 7.78 (1H, broad t, NH), 11.85 (1H, s, OH). MS (ESI+) m/z 413 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH:14]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].Cl.[NH2:23][OH:24]>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH:14]=[N:23][OH:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1C=NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
To the title compound of Example 2.1 (3.0 g, 14.1 mmol) in MeOH/H2O (30 mL/30 mL) in an ice-bath was added Na2CO3 (895 mg, 8.4 mmol) and hydroxylamine hydrochloride (1.2 g, 16.9 mmol). After stirring for 30 minutes, the reaction mixture was warmed to room temperature and stirred for an additional 4 hours. The reaction mixture was concentrated to half volume and then extracted with ethyl acetate (2 times), washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated to give the title product as a colorless oil (3.1 g, 97%).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Na+].[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1>S(=O)(=O)(O)O>[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][C:8]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])[O-]
Reactant: O=Cc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=Cc1ccc(Br)c([N+](=O)[O-])c1
Temperature: 10 °C
Yield: 94.8 %

Procedure:
A suspension of sodium nitrate (1.37 g, 16.2 mmol) in concentrated sulfuric acid (15 mL) was stirred at 10° C. until a homogeneous solution was obtained. The solution was treated with 4-bromobenzaldehyde (2.50 g, 13.5 mmol) in portionwise fashion over a 20 minute period. The solution was poured onto ice (50 g) and the resulting pale yellow precipitate was collected by filteration. The precipitate was washed with copious amounts of water then dried at 30° C. under reduced pressure to provide the title compound as a pale yellow solid (2.95 g, 12.8 mmol, 95%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[N:31]3[CH2:34][C:33]([CH3:36])([CH3:35])[C:32]3=[O:37])[CH2:20][CH:19]2[OH:38])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[N:31]3[CH2:34][C:33]([CH3:35])([CH3:36])[C:32]3=[O:37])[CH2:20][C:19]2=[O:38])=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1)=[O:7]
Reactant: CC1(C)CN(c2cc(F)ccc2N2CCC(NC(=O)C3(NC(=O)c4ccco4)CCCCC3)C(O)C2)C1=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1(C)CN(c2cc(F)ccc2N2CCC(NC(=O)C3(NC(=O)c4ccco4)CCCCC3)C(=O)C2)C1=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 68.3 %

Procedure:
To the solution of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexane carbonyl]amino]-1-[4-fluoro-2-(3,3-dimethylazetidin-2-one-1-yl)phenyl]piperidin-3-ol (0.5 g) obtained in Step 2 in 10 ml of dimethylsulfoxide, was added 0.5 ml of triethylamine. The reaction mixture was cooled to 0° C. Pyridine-SO3 complex (0.45 g) was added to the reaction mixture, which was then stirred for about 4 hours at room temperature. The reaction mixture was diluted with 20 ml of ethyl acetate and washed with brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was filtered and dried to give 340 mg of the titled compound.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(Cl)Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[C:32][CH:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[OH:34])[CH:26]=1>C(OCC)C>[C:35]1([C:33](=[O:34])[C:32]#[C:31][C:27]2[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: OC(C#Cc1cccnc1)c1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(C#Cc1cccnc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Place pyridinium dichromate (1.75 g) and methylene chloride (20 mL) under argon atmosphere and cool to 0° C. Add α-[(3-pyridinyl)ethynyl]-benzenemethanol (663 mg, 3.2 mmol)). Stir overnight while slowly warming to room temperature. Dilute with ethyl ether and filter the chromium salts. Purify by silica gel chromatography (2:1 ethyl acetate/hexane) to yield the title compound.
Reaction SMILES: Cl.NO.[C:4]([C:8]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[C:11]([C:21]([N:23]([CH2:42][CH:43]([CH3:45])[CH3:44])[C@H:24]2[CH2:29][C@@H:28]([C:30]3[N:31]=NN[N:34]=3)[CH2:27][N:26]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:25]2)=[O:22])=[CH:10][N:9]=1)([CH3:7])([CH3:6])[CH3:5].C1C[O:49][CH2:48]C1>CO.C(N(CC)CC)C.O>[C:4]([C:8]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[C:11]([C:21]([N:23]([CH2:42][CH:43]([CH3:45])[CH3:44])[C@H:24]2[CH2:29][C@@H:28]([C:30]3[N:31]=[CH:48][O:49][N:34]=3)[CH2:27][N:26]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:25]2)=[O:22])=[CH:10][N:9]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@H]1C[C@@H](c2nn[nH]n2)CN(C(=O)OC(C)(C)C)C1
Reactant: C1CCOC1
Agent: Cl
Agent: NO
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@H]1C[C@@H](c2ncon2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydroxylamine hydrochloride (35 mg) was dissolved in THF (3 ml)-methanol (3 ml), triethylamine (0.07 ml) was added, and the mixture was stirred at room temperature for 1 hr. A solution of tert-butyl (3S*,5R*)-3-[({2-tert-butyl-4-[(furan-2-ylmethyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]-5-(2H-tetrazol-5-yl)piperidine-1-carboxylate (120 mg) in THF (3 ml) was further added, and the mixture was stirred at 60° C. for 3 hr. The reaction mixture was allowed to cool to room temperature, and diluted with water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in trimethyl orthoformate (5 ml), 4-methylbenzenesulfonic acid (20 mg) was added and the mixture was stirred at 100° C. for 10 hr. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography. The fraction eluted with ethyl acetate-hexane (5:95-50:50) was concentrated under reduced pressure to give the object compound (72.6 mg).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH2:11][CH2:12][C:13]3[N:14]=[C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[O:16][C:17]=3[CH3:18])[C:4]=2[CH:3]=[CH:2]1.[N+:25]([O-])([OH:27])=[O:26].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.O>[CH3:18][C:17]1[O:16][C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:14][C:13]=1[CH2:12][CH2:11][O:10][C:9]1[C:4]2[CH:3]=[CH:2][S:1][C:5]=2[C:6]([N+:25]([O-:27])=[O:26])=[CH:7][CH:8]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1cccc2sccc12
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc([N+](=O)[O-])c2sccc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
286 g (0.853 mol) of 4-[2-(benzothiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole were suspended in 6.3 l of glacial acetic acid. Temperature was raised to 60° C. The resulting clear solution was cooled to 25° C. 132 ml (3.18 mol) of 100% nitric acid were added within 3 minutes. The reaction mixture was cooled below 30° C. After crystallization the suspension was stirred at 18 to 20° C. for 1 hour. The precipitate was filtered with suction and washed with 2×600 ml of tert-butyl methyl ether. The residue was suspended in 4 l of acetic ester for 15 minutes. 200 g (1.9 mol) of sodium carbonate in 3 l water were added. The resulting suspension was stirred for 1 hour. Acetic ester was distilled off followed by addition of 2 l of water. The suspension was stirred for 30 minutes. The precipitate was filtered with suction, washed with water and dried (50° C., 24 hours).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24](OC)=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].[CH:30]([NH2:33])([CH3:32])[CH3:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24]([NH:33][CH:30]([CH3:32])[CH3:31])=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: CC(C)N
Reactant: COC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Product: CC(C)NC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2

Procedure:
Following Example 47 and General Procedure C, methyl 2-((2-chlorophenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylate 138 and isopropylamine gave 205. MS: (ESI+) 455.0
Reaction SMILES: Cl[CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[K+].CS(C)=O>O>[C:13]([C:7]1[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=1[CH:5]=[CH:2][C:3]#[N:4])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#CC(Cl)Cc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC=Cc1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 50.9 g (0.168 mole) of α,4-dichloro-2-(benzoyl)-benzenepropanenitrile, 17 g (0.14 mole) of potassium carbonate, 50.9 g (0.5 mole) of potassium bicarbonate and 510 ml of dimethyl sulfoxide was stirred at room temperature for 48 hr. The mixture was diluted with 1.5 l of water, and the resulting percipitate was collected by filtration. Recrystallization from a mixture of methylene chloride and ether gave off-white prisms, mp 89°-91°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].CCN(P1(N(C)CCCN1)=NC(C)(C)C)CC.[Cl:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33]Br>C(#N)C.C(Cl)Cl>[Cl:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[CH3:1])[C:7](=[O:12])[C:8]1=[O:11]
Reactant: Cc1cccc2c1NC(=O)C2=O
Reactant: Clc1ccccc1CBr
Agent: CCN(CC)P1(=NC(C)(C)C)NCCCN1C
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cccc2c1N(Cc1ccccc1Cl)C(=O)C2=O
Reaction time: 60 h
Yield: 88.2 %

Procedure:
Combine 7-methylisatin (80 mg, 0.5 mmol), 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polystyrene beads(630-720 mg, 1.4-1.6 mmol, 2.2 mmol/g, Fluka) and 2-chlorobenzyl bromide (0.065 mL, 0.5 mmol) in acetonitrile (5 mL) in a 20 dram scintillation vial and shake on a rotator for 2.5 days at room temperature. Dilute with CH2Cl2 or acetonitrile and filter off beads. Concentrate in vacuo to obtain 126 mg (88%) of the title compound as crude product as a red-orange solid. MS (ES): m/z=286 (M+1).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]([CH3:22])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Sn](Cl)(Cl)(Cl)Cl.[CH3:28][O:29]C(Cl)Cl>ClCCCl.ClCCl>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([O:11][C:12]2[CH:21]=[C:20]3[C:15](=[C:14]([CH3:22])[CH:13]=2)[CH:16]=[C:17]([CH:28]=[O:29])[CH:18]=[CH:19]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(Cl)Cl
Reactant: Cc1cc(OC2CCC(C(C)(C)C)CC2)cc2ccccc12
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1cc(OC2CCC(C(C)(C)C)CC2)cc2ccc(C=O)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
To a mixture of 3-(4-tert-butyl-cyclohexyloxy)-1-methyl-naphthalene (450 mg, 1.5 mmol) in 1,2-dichloroethane (9 mL) was added tin tetrachloride (236 uL, 2 mmol) at 0° C. After stirred at 0° C. for 1 hr, dichloromethyl methyl ether (183 uL, 2 mmol) was added. The solution was stirred at 0° C. for 1 hr and then warmed to room temperature. The mixture was added ice water and stirred for 1 hr, then the dark solution was diluted with dichloromethane and washed with water. The organic phase was washed with sodium bicarbonate aqueous, and dried over MgSO4. The drying agent was filtered off and the solvent was concentrated to dryness to give dark solid product (0.48 g, yield: 97%). ESI-MS: 325.20 (M+H)+.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[C:8]([CH3:10])[O:7][C:6](=[O:11])[CH:5]=1)=[N+]=[N-].[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[C:8]([CH3:10])[O:7][C:6](=[O:11])[CH:5]=1
Reactant: Cc1cc(N=[N+]=[N-])cc(=O)o1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)cc(=O)o1
Yield: 101.4 %

Procedure:
To a 0.310 g (2.05 mmol) of 38 and 0.031 g of 10% Pd/C in 10 mL of ethanol was maintained under 1 atm (a ballonn) of hydrogen gas for 1 hour. The reaction mixture was then filtered through Celite, and ethanol of the filtrate was removed through rotary evaporation to give 0.260 g of 39 (100% yield). 1H NMR δ 5.56 (s, 1H, C3H), 5.12 (s, 1H, C5H), 4.45 (s, 2H, NH2), 2.20 (s, Me); 13C NMR δ 163.6 (s, C2), 161.3 (s), 98.6 (d, C5), 80.4 (d, C3), 19.5 (q, Me).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13].[CH2:18](Br)[C:19]#[CH:20].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])[C:19]#[CH:18]
Reactant: Cc1ccccc1C(=O)Nc1cccc(O)c1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C#CCOc1cccc(NC(=O)c2ccccc2C)c1
Yield: 87.4 %

Procedure:
A mixture of 22.7 g (0.1 mol) of 3'-hydroxy-2-methylbenzanilide, 11.9 g (0.1 mol) of propargylbromide, 10.6 g (0.1 mol) of sodium carbonate and 250 ml of acetone was prepared and the mixture was refluxed for 4 hours with stirring. After cooling, the reaction mixture was filtered and the acetone was removed by distillation. The residual material was dissolved in benzene, washed with water and dehydrated over anhydrous sodium sulfate. The benzene was removed and the product was recrystallized from aqueous ethanol to obtain a 23.2 g (87.7%) of fine white needles having a melting point of 93°-95°C.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][OH:18])[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>C1COCC1>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][S:27]([CH3:26])(=[O:29])=[O:28])[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CC(c1cccc(CO)c1)C1CC1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(c1cccc(COS(C)(=O)=O)c1)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(hydroxymethyl)phenyl)propanoate (690 mg) in THF (14 mL) were added triethylamine (775 μL) and methanesulfonyl chloride (258 μL) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was cooled to 0° C., water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (934 mg) as a colorless oil.
Reaction SMILES: [H-].[Na+].[OH:3]/[N:4]=[C:5](/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)\[CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].[Cl:18][C:19]1[N:24]2[CH:25]=[C:26]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([CH2:36]Cl)=[CH:32][CH:31]=3)[N:27]=[C:23]2[CH:22]=[CH:21][CH:20]=1.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CCCCCC>[Cl:18][C:19]1[N:24]2[CH:25]=[C:26]([CH2:28][O:29][C:30]3[CH:31]=[CH:32][C:33]([CH2:36][O:3]/[N:4]=[C:5](/[C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)\[CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:34][CH:35]=3)[N:27]=[C:23]2[CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)CC/C(=N\O)c1ccccc1
Reactant: ClCc1ccc(OCc2cn3c(Cl)cccc3n2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)CC/C(=N\OCc1ccc(OCc2cn3c(Cl)cccc3n2)cc1)c1ccccc1
Reaction time: 1 h
Yield: 66.8 %

Procedure:
Sodium hydride (60%, in oil, 143 mg) was added to a solution of methyl E-4-(hydroxyimino)-4-phenylbutyrate (676 mg) and 5-chloro-2-(4-chloromethylphenoxymethyl)imidazo[1,2-a]pyridine (1.00 g) in N,N-dimethylormamide (10 ml) at room temperature and stirred for 1 hour. 1N hydrochloric acid (7 ml) was added, an aqueous saturated solution of sodium bicarbonate was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain methyl E-4-[4-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)benzyloxyimino]-4-phenylbutyrate (1.04 g, yield 67%) as a colorless oil from an ethyl acetate-hexane (2:1, v/v)-eluted fraction.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:13](O)(=[O:15])[CH3:14]>>[C:13]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 150 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
Phenylalanine (1 g, 6.05 mmol) and acetic acid (20 mL) were mixed together and heated at 150° C. in a microwave for one hour. The excess acetic acid was removed using a rotary evaporator. The residue was taken up in toluene and the solvent was removed using a rotary evaporator. The residue was stirred in methyl t-butyl ether (MTBE) at ambient temperature for one hour. The mixture was filtered and the solid was washed with MTBE. The solid was dried in a vacuum oven at 60° C. The product was obtained as a white solid (983 mg, 78.4%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.79 (s, 3H), 2.84 (dd, 1H), 3.05 (dd, 1H), 4.41 (td, 1H), 7.09-7.33 (m, 6H), 8.20 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=O)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C([O-])(=O)C.[NH4+:30].C(=O)(O)[O-].[Na+]>O>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21]([NH2:30])=[O:23])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCCC(=O)OCC
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOCc1nc2cnc3ccccc3c2n1CCCC(N)=O
Temperature: 130 °C
Reaction time: 72 h

Procedure:
Ethyl 4-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butanoate (15.9 g, 46.6 mmol, prepared as described in Parts A through C of Example 5) and ammonium acetate (35.0 g, 455 mmol) were sealed and heated in a high-pressure vessel at 130° C. for two days. An analysis by LC/NS indicated the presence of starting material, and additional ammonium acetate (15 g, 190 mmol) was added. The reaction was heated to 130° C. for several hours, allowed to cool to ambient temperature, stirred for three days, and poured into water (200 mL). Solid sodium bicarbonate was added until the solution was basic. The solution was extracted with dichloromethane (3×100 mL, 5×75 mL, and then in a continuous extractor for about 20 hours). The extracts were dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 10.3 g of 4-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butanamide as a light yellow solid.