Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:13])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.C([Li])(C)(C)C.CCCCC.[B:24](OC)([O:27]C)[O:25]C>O1CCCC1>[CH3:10][C:7]1([CH3:11])[C:6]2[CH:12]=[C:2]([B:24]([OH:27])[OH:25])[CH:3]=[C:4]([CH3:13])[C:5]=2[O:9][CH2:8]1
Reactant: COB(OC)OC
Reactant: Cc1cc(Br)cc2c1OCC2(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: Cc1cc(B(O)O)cc2c1OCC2(C)C

Procedure:
Following General Procedure A and using 5-bromo-3,3,7-trimethyl-2,3-dihydro-benzofuran (1.2 g, 5 mmol), 12 mL of anhydrous tetrahydrofuran, 1.7M solution of t-butyllithium in n-pentane (6.17 mL, 10.5 mmol) and trimethyl borate (1.2 mL, 10.5 mmol) the title compound was obtained as a foam that was used as such for the next step without purification and characterization. 5-Bromo-3,3,7-trimethyl-2,3-dihydro-benzofuran can be prepared as described in U.S. Pat. No. 6,093,838, incorporated herein by reference.
Reaction SMILES: CS(C)=O.[OH-].[K+].[C:7]1([C:13]2[NH:17][CH:16]=[N:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:18]I>O>[CH3:18][N:15]1[CH:14]=[C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:17]=[CH:16]1
Reactant: CI
Reactant: c1ccc(-c2cnc[nH]2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cn1cnc(-c2ccccc2)c1
Reaction time: 0.08 h
Yield: 77.9 %

Procedure:
Add 20 mL dimethyl sulfoxide (35 mL; 492.74 mmoles) to powdered potassium hydroxide (20.81 mmoles; 1.17 g). Add 5-phenyl-1H-imidazole (13.87 mmoles; 2.00 g) at room temperature and solid quickly dissolves giving an orange solution. After stirring 5 min add methyl iodide (15.26 mmoles; 950.36 μL) in one portion. Stir 4h at room temp. Dilute with water and extract with ethyl acetate (2×), then wash the organics with saturated aq. sodium chloride/water (2×) solution, dry over MgSO4, filter, evaporate to give 1.71 g yellow solid. Purify the crude by using ISCO chromatography over a biotage 40M column eluting with a gradient of 0.5% MeOH/DCM to 5% MeOH/DCM at a flow rate of 40 mL/min. Dry product fractions to give 1.43 g (65% yield) off-white solid. (7% of undesired regioisomer) MS (ES): (m/z)=159.0 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15](=[S:24])[NH:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].C([O-])([O-])=O.[K+].[K+].[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:33]=1[CH2:34]Cl>CC(C)=O>[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:33]=1[CH2:34][S:24][C:15]1[N:16]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[C:12]([C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)([CH3:11])[CH3:10])=[CH:13][N:14]=1
Reactant: CC(C)(c1ccc(Cl)c(Cl)c1)c1c[nH]c(=S)n1-c1ccc(F)cc1
Reactant: Fc1cccc(Cl)c1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(SCc2c(F)cccc2Cl)n1-c1ccc(F)cc1
Reaction time: 2 h
Yield: 40.6 %

Procedure:
To a mixture of 5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2(3H)-thione (138 mg, 0.362 mmol) and K2CO3 (76 mg, 0.543 mmol) in acetone (6 mL) was added 2-chloro-6-fluorobenzyl chloride (79 mg, 0.434 mmol). After stirring 2 h, the reaction mixture was filtered, concentrated and purified by flash chromatography to provide the title product (77 mg, 33%). 1H NMR (400 MHz, CDCl3) δ 7.25 (m, 1H), 7.22 (s, 1H), 7.16-7.11 (m, 2H), 7.03 (d, 1H), 6.91 (m, 1H), 6.83 (dd, 1H), 6.78 (t, 2H), 6.34 (m, 2H), 4.25 (s, 2H), 1.49 (s, 6H); MS (EI) m/z 523, 525 (MH+).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([OH:14])=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]#[N:24]>CN(C=O)C>[CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([O:14][CH2:22][C:23]#[N:24])=[CH:3][CH:2]=1
Reactant: N#CCBr
Reactant: Oc1cccc2[nH]c3ccccc3c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCOc1cccc2[nH]c3ccccc3c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 22.6 %

Procedure:
A mixture of 9H-carbazol-4-ol (2.543 g, 0.014 mol), potassium carbonate (0.2.386 g, 0.017 mol), bromoacetonitrile (2.5 mL, 0.036 mol) and DMF (42 mL) is stirred at room temperature for 4 h. The mixture is then partitioned between water and ethyl acetate. The combined organic layers are dried over sodium sulfate and concentrated to a residue. The resulting residue is chromatographed on silica gel (200 mL) using ethyl acetate/hexane (20/80) to give 0.703 g (23%) of the title compound; mp 120-120.5° C.; MS (ESI−) for C14H10N2O m/z 221.0 (M−H)−; IR (drift) 3399, 1605, 1585, 1508, 1452, 1346, 1336, 1269, 1242, 1212, 1106, 785, 757, 750, 723 cm−1; 1H NMR (CDCl3) δ5.07, 6.76, 7.21, 7.29, 7.38-7.47, 8.18, 8.28. Anal. Calcd for C14H10N2O: C, 75.66; H, 4.53; N, 12.60. Found: C, 75.41; H, 4.52; N, 12.48.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]#[C:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=O.[NH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]#[C:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([NH:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:20]
Reactant: Cc1onc(-c2ccccc2)c1C#Cc1cccc(C(=O)O)c1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccccc2)c1C#Cc1cccc(C(=O)NC2CCOCC2)c1
Yield: 87 %

Procedure:
As described for example 7b, 3-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-benzoic acid (250 mg; 0.82 mmol) was converted (using 4-amino-tetrahydropyrane instead of aminomethylcyclopropane) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 276 mg, 87%) which was obtained as a white solid. MS: m/e=387.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][C:6]2[NH:7][C:8](=[O:35])[N:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[C:22]([O:24][C:25]5[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[C:27]([CH3:34])[CH:26]=5)[N:21]=[CH:20][N:19]=4)[CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.CO.[H][H]>C1COCC1.[Pd]>[NH2:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][C:22]2[N:21]=[CH:20][N:19]=[C:18]([N:15]3[CH2:14][CH2:13][CH:12]([N:9]4[CH2:10][CH2:11][C:5]5[CH:4]=[C:3]([O:2][CH3:1])[CH:37]=[CH:36][C:6]=5[NH:7][C:8]4=[O:35])[CH2:17][CH2:16]3)[CH:23]=2)=[CH:26][C:27]=1[CH3:34]
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4ccc([N+](=O)[O-])c(C)c4)ncn3)CC1)C(=O)N2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4ccc(N)c(C)c4)ncn3)CC1)C(=O)N2

Procedure:
930 mg (1.84 mmol) 7-methoxy-3-(1-(6-(3-methyl-4-nitrophenoxy)pyrimidin-4-yl)piperidin-4-yl)-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one were placed in 20 mL THF and 20 mL MeOH and hydrogenated under a hydrogen atmosphere with the addition of 150 mg Pd/C (10%) at RT and a hydrogen pressure of 3 bar until all the hydrogen had been taken up. The catalyst was filtered off. Everything was distilled off from the filtrate to leave a residual volume of 15 mL. DIPE was added. The precipitate was suction filtered, washed and dried.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[C:7]([NH:13]C(=O)C(C)(C)C)=[CH:6][N:5]=1)[CH3:3].Cl>>[NH2:13][C:7]1[C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]([N:2]([CH3:1])[CH3:3])=[N:5][CH:6]=1
Reactant: CN(C)c1cc(C(=O)O)c(NC(=O)C(C)(C)C)cn1
Agent: Cl
Product: CN(C)c1cc(C(=O)O)c(N)cn1
Yield: 98.8 %

Procedure:
2-(N,N-Dimethylamino)-5-(2,2-dimethylpropionamido)-pyridine-4-carboxylic acid (0.8 g) was treated with 5N HCl at reflux for 5 hours. The mixture was allowed to cool and evaporated to dryness to give the title compound (0.54 g);δH [2H6]DMSO 8.15(1H,s), 7.35(2H,bs), 6.70(1H,s), 3.10(6H,s); m/z (M+1+)182.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.Cl[CH2:14][CH:15]1[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:15]1([CH2:14][O:1][C:2]2[CH:3]=[C:4]([CH3:12])[C:5]([C:9](=[O:11])[CH3:10])=[C:6]([CH3:8])[CH:7]=2)[CH2:17][CH2:16]1
Reactant: CC(=O)c1c(C)cc(O)cc1C
Reactant: ClCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1c(C)cc(OCC2CC2)cc1C
Temperature: 80 °C
Yield: 99.7 %

Procedure:
A vigorously stirred mixture of 1-(4-hydroxy-2,6-dimethylphenyl)ethanone (4-2, 1.00 g, 10.9 mmol), chloromethylcyclopropane (4-1, 1.22 g, 7.4 mmol), and powdered potassium carbonate (1.54 g, 11.1 mmol) in DMF (10.0 mL) was heated at 80° C. for 16 h under N2. The mixture was allowed to cool and was filtered through Diatomaceous earth. The filtrate was concentrated under reduced pressure and the residue was extracted with EtOAc. The organic layer was washed with saturated aqueous sodium carbonate and dried over Na2SO4. The solution was concentrated under reduced pressure to provide 1-(4-(cyclopropylmethoxy)-2,6-dimethylphenyl)ethanone (4-3, 1.61 g) as off-white solids in 99% yield: 1H NMR (500 MHz, CDCl3) δ 6.55 (s, 2 H), 3.77 (d, J=6.9 Hz, 2 H), 2.45 (s, 3 H), 2.27 (s, 6 H), 1.19 (s, 1 H), 0.64 (m, 2 H), 0.33 (m, 2 H).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][CH:7]=[CH:6][N:5]=1.[H][H]>CO.[Pd]>[NH2:10][C:9]1[C:4]([C:3]([NH:2][CH3:1])=[O:13])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: CNC(=O)c1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1ncccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-methyl-3-nitropicolinamide (3.0 g, 16.6 mmol) in methanol (150 mL) was added Pd/C (10% Pd in carbon, 0.45 g, 15 wt %) under argon. Hydrogen balloon was used as the hydrogen source. The reaction was stirred at room temperature overnight. The mixture was filtered through celite and the celite pad was washed several times. The solvent was removed to obtain the desired product (quantitative yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:21]=[C:22]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[CH:23]=[CH:24][CH:25]=2)=[CH:14][CH:13]=1)[C:9](O)=[O:10])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.C(Cl)CCl.[CH3:51][NH:52][CH3:53]>ClCCl>[C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:21]=[C:22]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[CH:23]=[CH:24][CH:25]=2)=[CH:14][CH:13]=1)[C:9]([N:52]([CH3:53])[CH3:51])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)CC(C(=O)O)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CN(C)C(=O)C(CC(=O)OC(C)(C)C)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Yield: 91 %

Procedure:
A solution of compound 50.3 (50 mg, 0.1 mmol) in dichloromethane (2 mL) was treated with 1-hydroxybenzotriazole (15 mg, 0.11 mmol) and EDC (21 mg, 0.11 mmol) sequentially. The resulting mixture was stirred for 1 h. before dimethylamine (9 mg, 0.2 mmol) was added dropwise. The reaction was quenched 30 min. later with water (5 mL). The reaction mixture was extracted with dichloromethane (2 mL×3). The organic extracts were combined, dried over MgSO4 and concentrated under reduced pressure to yield amide 50.4 (48 mg). The product was used in the next step without further purification. MS ESI (pos.) m/e: 527 (M+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)(=[O:15])=[O:14].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[O:14]=[S:13]1(=[O:15])[C:16]2=[CH:17][N:18]=[CH:19][CH:20]=[C:21]2[C:22](=[O:24])[N:12]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1
Reactant: O=C(O)c1ccncc1S(=O)(=O)NCCCCOC1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1c2ccncc2S(=O)(=O)N1CCCCOC1CCCCO1
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a stirred solution of 19 g of N-(4-(2-tetrahydropyranyloxy)butyl) 4-carboxypyridine-3-sulfonamide and 16 mL of triethylamine in 300 mL of dichloromethane at 0° C. was added 6.5 mL of methyl chloroformnate dropwise. After 30 min, the mixture was shaken with 100 mL of saturated sodium bicarbonate, dried over MgSO4 and concentrated under reduced pressure. Chromatography of the dark brown oil over silica gel, eluting with 1:1 ethyl acetate:hexane gave 16 g of homogeneous 1,1-dioxido-2-(4-(2-tetrahydropyranyloxy) butyl)-isothiazolo[5,4-c]pyridin-3(2H)-one as an amber oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[CH3:20][NH:21][CH2:22][C@H:23]([OH:31])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=1>>[C:8]1([C:5]2[N:6]=[CH:7][C:2]([N:21]([CH2:22][C@@H:23]([C:24]3[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=3)[OH:31])[CH3:20])=[N:3][C:4]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: CNC[C@H](O)c1cccc(O)c1
Product: CN(C[C@H](O)c1cccc(O)c1)c1cnc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
In the same manner as in the step 1 of Example 9, except that 2-chloro-5,6-diphenylpyrazine was used in place of 2-chloro-5,6-di-p-tolylpyrazine and L-phenylephrine was used in place of 4-(methylamino)-1-butanol, the desired compound was prepared as a pale brown amorphous.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH:5]([NH:23][CH:24]1[C:33]2[C:28](=[C:29]([O:34][CH3:35])[CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1)[C:6]1[O:7][C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1.O=S(Cl)Cl>C(Cl)Cl>[C:11]1([C:9]2[N:10]=[C:6]([CH:5]3[CH2:4][CH2:3][CH2:2][N:23]3[CH:24]3[C:33]4[C:28](=[C:29]([O:34][CH3:35])[CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][CH2:25]3)[O:7][C:8]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1cccc2c1CCCC2NC(CCCO)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cccc2c1CCCC2N1CCCC1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Reaction time: 4 h
Yield: 65.9 %

Procedure:
To a solution of 1-[[4-hydroxy-1-(4,5-diphenyloxazol-2-yl)butyl]amino]-5-methoxy-1,2,3,4-tetrahydronaphthalene (0.9 g) in CH2Cl2(20 ml) was added SOCl2(3 ml). After being stirred for 4 hours, the solvent was removed. The residue was dissolved in CH3CN (20 ml) and K2CO3 (5 g) was added to the solution. After being stirred for 4 hours under reflux, the solution was poured into the mixture of ethyl acetate and water. The organic layer was washed with water and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 1-[2-(4,5-diphenyloxazol-2-yl)pyrrolidin-1-yl]-5-methoxy-1,2,3,4-tetrahydronaphthalene (0.57 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C(=O)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:31][C:32]1[C:40]2[C:35](=[CH:36][C:37]([S:41](Cl)(=[O:43])=[O:42])=[CH:38][CH:39]=2)[N:34]([CH3:45])[CH:33]=1>C1COCC1.CC(C)=O>[Br:31][C:32]1[C:40]2[C:35](=[CH:36][C:37]([S:41]([N:6]([CH2:5][C:4]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=3[O:2][CH3:1])[C:7]3[S:11][N:10]=[CH:9][N:8]=3)(=[O:42])=[O:43])=[CH:38][CH:39]=2)[N:34]([CH3:45])[CH:33]=1
Reactant: Cn1cc(Br)c2ccc(S(=O)(=O)Cl)cc21
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cn(C)c3c2)c(OC)c1
Reaction time: 0.08 h

Procedure:
A 1 L round bottom flask was charged with N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (10.36 g, 41.2 mmol) and THF (190 ml) to give a clear, pale-yellow solution. The flask was cooled to −78° C. in a dry ice and acetone bath, then lithium bis(trimethylsilyl)amide (1M in THF) (43.1 ml, 43.1 mmol) was added dropwise. The cooling bath was removed for 10 min, which led to the formation of a clear, orange-colored solution. The flask was placed back in the cooling bath for 5 min, then a solution of 3-bromo-1-methyl-1H-indole-6-sulfonyl chloride (11.56 g, 37.5 mmol) in minimal THF was added dropwise via cannula. Following the addition, the cooling bath was removed and the reaction was stirred for two hours. The reaction mixture was diluted with a saturated aq. ammonium chloride solution and water, and extracted with EtOAc (2×). The aq. layer was filtered to give some desired product as a pink solid. The filtrate was again extracted with EtOAc, and the organic extracts were combined. The combined solution was dried over sodium sulfate, filtered, and concentrated. The residue was triturated with EtOAc, and the resulting solid was collected via filtration to give a second crop of desired product. The filtrate was absorbed onto silica gel, and the impregnated silica gel was eluted onto a silica gel column (0 to 100% EtOAc/Heptane). The material thus obtained was still impure, so it was further purified by chromatography on silica gel (0 to 10% EtOAc/DCM) to give a third crop of desired product. The three crops were combined to afford 3-bromo-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (16.47 g, 31.5 mmol, 84% yield) as a light pink solid. 1H NMR (400 MHz, DMSO-d6) δ=8.34 (s, 1 H), 8.05 (dd, J=0.6, 1.6 Hz, 1 H), 7.95 (s, 1 H), 7.66-7.52 (m, 2 H), 6.95 (d, J=8.4 Hz, 1 H), 6.47-6.26 (m, 2 H), 5.12 (s, 2 H), 3.88 (s, 3 H), 3.69 (s, 3 H), 3.66 (s, 3 H). m/z (ESI) 545.0 (M+H)+.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:10][C@@H:11]1[O:15]C(C)(C)[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[N:36]=2)=[CH:31][CH:30]=1)=O)(C)(C)C.Cl>C1COCC1.O1CCOCC1>[NH2:8][C@@H:9]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:10][C@H:11]([OH:15])[C@@H:12]([NH:13][C:18](=[O:19])[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[N:36]=2)=[CH:31][CH:30]=1
Reactant: COc1cccc(-c2ccc(C[C@H]3[C@H](C[C@H](Cc4ccccc4)NC(=O)OC(C)(C)C)OC(C)(C)N3C(=O)OCc3ccccc3)cc2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COc1cccc(-c2ccc(C[C@H](NC(=O)OCc3ccccc3)[C@@H](O)C[C@@H](N)Cc3ccccc3)cc2)n1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A solution containing the product from Example 119A (0.095 g, 0.14 mmol) in THF (1 mL) was treated with a solution of HCl in dioxane (0.25 mL, 4 N), stirred at 50° C. for 16 hours, cooled and concentrated under reduced pressure. The residue was dissolved in ethanol and concentrated several times to give the title compound as hydrochloride salt, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]([CH:17]([O:23][CH2:24][CH2:25][N:26]3[CH:30]=[CH:29][N:28]=[CH:27]3)[C:18]3[S:19][CH:20]=[CH:21][N:22]=3)[CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[CH:4][CH:3]=1.[C:31]([O:35][C:36](=[O:43])[C@H:37]([CH2:39][CH2:40][S:41][CH3:42])[NH2:38])([CH3:34])([CH3:33])[CH3:32]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]([CH:17]([O:23][CH2:24][CH2:25][N:26]3[CH:30]=[CH:29][N:28]=[CH:27]3)[C:18]3[S:19][CH:20]=[CH:21][N:22]=3)[CH:14]=[CH:13][C:9]=2[C:10]([NH:38][C@@H:37]([CH2:39][CH2:40][S:41][CH3:42])[C:36]([O:35][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:43])=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(C(OCCn2ccnc2)c2nccs2)cc1-c1ccc(F)cc1
Reactant: CSCC[C@H](N)C(=O)OC(C)(C)C
Product: CSCC[C@H](NC(=O)c1ccc(C(OCCn2ccnc2)c2nccs2)cc1-c1ccc(F)cc1)C(=O)OC(C)(C)C
Yield: 63 %

Procedure:
The title compound was prepared from 2-(4-fluorophenyl)4-[1-(thiazol-2-yl)-2-(imidazol-1-yl)ethoxymethyl]benzoic acid by a similar method to that used for Example 1 but using L-methionine tert-butyl ester in place of L-methionine methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[CH3:11].C[Si](C)(C)[O:14][K].O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:10])=[O:14])=[CH:4][C:3]=1[CH3:11]
Reactant: C[Si](C)(C)O[K]
Reactant: Cc1cc(CC#N)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(CC(N)=O)ccc1F
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 70 %

Procedure:
4-Fluoro-3-methylphenylacetonitrile (1.1 g) was dissolved in toluene (35 ml), and trimethylsiloxypotassium (3.7 g) was added. After stirring at 110° C. for 2.5 hours, saturated sodium bicarbonate water was added, followed by separation with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to obtain 863 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:29][O:30][CH2:31][CH3:32])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:5][C:4]=2[N:3]=1.[OH-].[NH4+]>O>[CH2:31]([O:30][CH2:29][C:13]1[N:14]([CH2:15][CH:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)[C:10]2[C:9]3[CH:8]=[CH:7][C:6]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1)[CH3:32]
Reactant: CCOCc1nc2c(N)nc3cc(-c4ccccc4)ccc3c2n1CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CCOCc1nc2c(N)nc3cc(-c4ccccc4)ccc3c2n1CC1CCNCC1
Yield: 54.3 %

Procedure:
tert-Butyl 4-[(4-amino-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate (0.64 g) was deprotected according to the method described in Example 177. The crude solid was dissolved in water (10 mL), and ammonium hydroxide was added until the solution was basic. The mixture was then extracted with chloroform (2×10 mL), and the combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from acetonitrile and dried for 16 hours in a vacuum oven at 60° C. to provide 0.28 g of 2-ethoxymethyl-7-phenyl-1-(piperidin-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white, crystalline solid, mp 142-143° C.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:14]([O-])([OH:16])=[O:15]>FC(F)(F)C(O)=O.O>[N+:14]([C:3]1[CH:2]=[CH:1][C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=1)([O-:16])=[O:15]
Reactant: c1ccc2c(c1)oc1ccccc12
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc2c(c1)oc1ccccc12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Dibenzofuran (30 g, 178 mmol) was dissolved in 276 ml, trifluoroacetic acid (TFA) and cooled in ice water bath. Fuming nitric acid 15 g (˜17 mL) was diluted with 3 mL water and then dissolved in 25 mL TFA and added to dibenzofuran solution drop wise. Reaction takes place almost instantly and a thick light green color precipitate forms. At the end of addition, flask was stirred for 20 minutes more and then poured over ice. Light green precipitate was then filtered off, washed with 2 M NaOH, dried and recrystallized from boiling ethanol 30 g (76%) of product was obtained.