Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.[C:15](OC(=O)C)(=[O:17])[CH3:16]>S(=O)(=O)(O)O.O>[C:15]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1cccc2cc(O)ccc12
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1ccc2c(C(=O)O)cccc2c1
Temperature: 25 °C

Procedure:
6-Hydroxy-1-naphthoic acid (1 g) was mixed with acetic anhydride (5 ml) and sulfuric acid (5 drops). The mixture was refluxed for 3 hours and cooled at RT for 10 hours then mixed with water (15 ml). The solid was filtered and washed with water and cold MeOH to give the product as 6-acetoxy-1-naphthoic acid (900 mg) that was mixed with EDC (1.5 eq), HOBt (1 eq), MeNH2—HCl (2.5 eq, methylamine hydrochloride) and DIPEA (2.5 eq) in DCM (25 ml). The reaction was stirred at RT overnight and washed with NaHCO3 solution, dried. The solution was evaporated and mixed with 15% KOH (2 ml) in MeOH (10 ml) further stirred at RT for 30 minutes. The solvent was evaporated and the residue was adjusted to weak acidic with 2N HCl, the solid was filtered and washed with water twice and cold MeOH to give 6-Hydroxy-N-methyl-1-naphthamide (720 mg).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][CH:8]([CH3:31])[CH2:9][NH:10][C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]2[NH:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Br:30])[CH:25]=3)[N:23]=2)[CH2:15][CH2:14]1)=[O:12]>C(Cl)Cl.CS(C)=O.O>[O:7]=[C:8]([CH3:31])[CH2:9][NH:10][C:11]([C@H:13]1[CH2:14][CH2:15][C@H:16]([C:19]2[NH:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Br:30])[CH:25]=3)[N:23]=2)[CH2:17][CH2:18]1)=[O:12]
Reactant: CC(O)CNC(=O)[C@H]1CC[C@H](c2nc(-c3cccc(Br)c3)c[nH]2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)CNC(=O)[C@H]1CC[C@H](c2nc(-c3cccc(Br)c3)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a cooled solution (−78° C. to −60° C.) of oxalyl chloride (0.12 mmol) in CH2Cl2 (5 mL), DMSO (0.25 mmoL) was added dropwise. The mixture was stirred for 2 minutes, and then trans-4-[4-(3-bromo-phenyl)-1H-imidazol-2-yl]-cyclohexane-carboxylic acid (2-hydroxy-propyl) amide (0.12 mmol) in 2 ml of CH2Cl2 was added. The mixture was stirred for 15 minutes at the same temperature following the addition of TEA (0.60 mmol). The mixture was stirred for another 5 minutes, warmed to room temperature and diluted with water. The organic layer was isolated, dried over Na2SO4, concentrated under vacuum, and purified with flash chromatography (90:10:1 CH2Cl2/MeOH/NH4OH) to give trans-4-[4-(3-bromo-phenyl)-1H-imidazol-2-yl]-cyclohexane-carboxylic acid (2-oxo-propyl) amide.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:35][N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[C:21]2[C:25]=1[N:24]([S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH:23]=[CH:22]2.[NH:42]1CCNC[CH2:43]1.C[Si](C#N)(C)C>CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH:35]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[C:43]#[N:42])=[C:21]2[C:25]=1[N:24]([S:26]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27])[CH:23]=[CH:22]2
Reactant: C1CNCCN1
Reactant: COc1ccc(CN2CCNCC2)c2ccn(S(=O)(=O)c3ccccc3)c12
Agent: C[Si](C)(C)C#N
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1ccc(C(C#N)N2CCNCC2)c2ccn(S(=O)(=O)c3ccccc3)c12

Procedure:
1-Benzenesulfonyl-7-methoxy-1H-indole-4-carbaldehyde (50 mg, 0.2 mmol, prepared as in Example 79), piperazine (28 mg, 0.3 mmol) and methanol (0.5 mL) was charged into a tube suitable for microwave irradiation. The mixture was heated at 100° for 1 min in the microwave oven. Trimethylsilyl cyanide (21 μl, 0.2 mmol) was added and the heat treatment, 100° 1 min, was repeated. LCMS indicated the formation of expected product. The crude product was purified using prep LC on a YMC column (24-52% MeCN over 16 min). Obtained 26.2 mg (40%). MS ESI+ for C16H13NO4S, m/z 325 (M-piperazine)+, m/z 384 (M-nitrile)+, m/z 411 (M+H)+.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]([CH3:14])[CH:12]([CH2:15][CH2:16][CH3:17])[C:11](=[O:18])[NH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[NH:19][C:20]([C:22]1[N:23]([CH3:27])[CH:24]=[CH:25][CH:26]=1)=[O:21].C(O)(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[CH3:14][C@@H:13]1[C:8]([C:6]2[CH:5]=[CH:4][C:3]3[N:19]=[C:20]([C:22]4[N:23]([CH3:27])[CH:24]=[CH:25][CH:26]=4)[O:21][C:2]=3[CH:7]=2)=[N:9][NH:10][C:11](=[O:18])[C@H:12]1[CH2:15][CH2:16][CH3:17]
Reactant: CCCC1C(=O)NN=C(c2ccc(NC(=O)c3cccn3C)c(O)c2)C1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: O
Product: CCC[C@@H]1C(=O)NN=C(c2ccc3nc(-c4cccn4C)oc3c2)[C@H]1C
Temperature: 200 °C
Reaction time: 1 h

Procedure:
150 mg (407 mmol) 1-methyl-1H-pyrrole-2-carboxylic acid[2-hydroxy-4-(4-methyl-6-oxo-5-propyl-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenyl]-amide are placed in 5 mL dioxane. 300 μL (5.19 mmol) acetic acid and 140 mg (814 μmol) p-toluenesulphonic acid monohydrate are added and the mixture is stirred for 60 min in the microwave at 200° C. The reaction mixture is extracted successively with 10% sodium carbonate solution, 1% acetic acid, 10% sodium carbonate solution and saline solution. Then the solv. of the organic phase is eliminated i.V. and the residue is purified through silica gel. (Cyclohexane/EA) The solv. of the corresponding fractions is eliminated i.V. and the residue is crystallised with diethyl ether/petroleum ether.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@:12]([CH3:16])([C:13]([OH:15])=O)[CH2:11][O:10][C:9]1([CH3:18])[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:52]([S:60][C:61]1[CH:70]=[CH:69][C:64]([C:65]([NH:67][NH2:68])=[O:66])=[CH:63][C:62]=1[C:71]([F:74])([F:73])[F:72])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59].C([O-])(O)=O.[Na+]>CN(C=O)C.C1COCC1>[CH3:17][C:9]1([CH3:18])[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@@:12]([CH3:16])([C:13]([NH:68][NH:67][C:65](=[O:66])[C:64]2[CH:69]=[CH:70][C:61]([S:60][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])=[C:62]([C:71]([F:72])([F:73])[F:74])[CH:63]=2)=[O:15])[CH2:11][O:10]1
Reactant: CCCCCCCCSc1ccc(C(=O)NN)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCCCCCSc1ccc(C(=O)NNC(=O)[C@@]2(C)COC(C)(C)N2C(=O)OC(C)(C)C)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.8 %

Procedure:
To a solution of (R)-3-(tert-butoxycarbonyl)-2,2,4-trimethyloxazolidine-4-carboxylic acid 4 (129.6 mg, 0.5 mmol) in DMF (1 mL) was added HATU (209 mg, 0.55 mol) and DIPEA (0.436 mL, 2.5 mmol). After being stirred at rt for 10 min, the reaction mixture was treated with 4-(octylthio)-3-(trifluoromethyl)benzohydrazide 3a (174 mg, 0.5 mmol) in THF (2 mL) and was left stirred overnight. Aqueous NaHCO3 solution was added and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure to give a residue, which was purified by SiO2 column chromatograph (n-hexane/EtOAc=3:7) to give (R)-tert-butyl 2,2,4-trimethyl-4-(2-(4-(octylthio)-3-(trifluoromethyl)benzoyl)hydrazinecarbonyl)oxazolidine-3-carboxylate 5a (247 mg, 84%). HPLC retention time on a C18 column (30×4.6 mm, 3.5μ) was 3.08 min with gradient 10-95% acetonitrile-H2O (0.1% TFA) in 3.5 min as mobile phase. MS (ESI, M+H+)=590.5
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[O:8])[C:3]=1[N+:16]([O-])=O.Cl[Sn]Cl.[OH-].[Na+]>O1CCCC1.Cl>[NH2:16][C:3]1[C:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[O:8])=[N:5][O:6][C:2]=1[CH3:1]
Reactant: Cc1onc(C(=O)c2ccccc2Cl)c1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1onc(C(=O)c2ccccc2Cl)c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
A solution of (5-methyl-4-nitroisoxazol-3-yl)-2-chlorophenylmethanone of Example IIIa (5.3 g, 20 mmoles) in tetrahydrofuran (THF) (25 ml) was added to a mixture of SnCl2. 2H2O (18 g, 80 mmoles) in concentrated hydrochloric acid (35 ml) and THF (20 ml) over 1 hour. After stirring overnight at room temperature (about 16 hours), the reaction mixture was poured into cold 10% sodium hydroxide (500 ml) with stirring and extracted with ethyl acetate. The extracts were washed with dilute sodium chloride and dried (sodium sulfate). Concentration gave an oil which was flash chromatographed (20% ethyl acetate:hexane) to yield 3.0 g (64%) of an oil that solidified. The resultant amine was triturated with cyclohexane (40 ml) to yield 2.4 g (51%) of a powder, melting point 75°-78° C.
Reaction SMILES: CCN=C=NCCCN(C)C.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]([OH:24])=O.[NH2:25][C@H:26]([C:30]([NH:32][CH:33]([CH:42]([OH:45])[CH2:43][F:44])[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:31])[CH:27]([CH3:29])[CH3:28]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]([NH:25][C@H:26]([C:30]([NH:32][CH:33]([CH:42]([OH:45])[CH2:43][F:44])[CH2:34][C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[O:31])[CH:27]([CH3:28])[CH3:29])=[O:24]
Reactant: Cn1c(C(=O)O)cc2ccccc21
Reactant: CC(C)[C@H](N)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1cc2ccccc2n1C)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF

Procedure:
DMAP (95 mg, 0.78 mmol) and EDAC (200 mg, 1.04 mmol) were added as solid to a solution of 1-methylindole-2-carboxylic acid (130 mg, 0.74 mmol) and N-(valinyl)-3-amino-4-hydroxy-5-fluoropentanoic acid, t-butyl ester (227 mg, 0.74 mmol) in methylene chloride (5 mL), and the resultant solution was stirred for 1 hour under a nitrogen atmosphere at 0° C. and then 4 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution and the aqueous solution was back-extracted with ethyl acetate. The combined ethyl acetate solutions were washed with 5% KHSO4 solution, saturated sodium bicarbonate solution (2×) and brine, dried over sodium sulfate, and concentrated to give a foam. The foam was triturated with ether to yield the title product as a slightly brown solid (224 mg, 65%). TLC: (methanol/methylene chloride, 1:9): Rf =0.46.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[CH2:13](Cl)Cl.C1CCN2C(=NCCC2)CC1.CI>C1(C)C=CC=CC=1.O>[CH3:13][O:11][C:1](=[O:12])[CH:2]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH2:3][OH:4]
Reactant: ClCCl
Reactant: O=C(O)C(CO)c1ccccc1
Solvent: O
Solvent: CI
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C(CO)c1ccccc1
Reaction time: 8 h
Yield: 18 %

Procedure:
To a solution of tropic acid (5.0 g, 30 mmol) in toluene:CH2Cl2 (150 mL; 2:1) was added DBU (4.6 g; 30 mmol), followed by MeI (4.3 g; 30 mmol). The mixture was stirred overnight, water was added and the phases were allowed to separate. The water phase was extracted with ether, and the combined organic phase was washed with NaHCO3/aq, HCl/aq and water, dried (Na2SO4) and concentrated to yield 0.95 g (18%) of the sub-title compound.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)[CH:5]=[CH:4][N:3]=[CH:2]1.O.NN.[ClH:24]>C(O)C>[ClH:24].[ClH:24].[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH2:10])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCn1ccnc1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCCn1ccnc1

Procedure:
A mixture of 10.0 g. of N-[4-(1H-imidazol-1-yl)-butyl]isoindole-1,3(2H)-dione, 1.97 ml. of hydrazine hydrate and 100 ml. of ethanol was heated at reflux for 3 hours and then cooled. A 160 ml. of portion of 3N hydrochloric acid was added, the mixture was heated at reflux for one hour and then concentrated. The residue was stirred with 150 ml. of 3N hydrochloric acid and then filtered. The mother liquor was concentrated to dryness, diluted with 10 ml. of ethanol and cooled, giving 1H-imidazole-1-butanamine dihydrochloride (m.p. 132°-146° C.) which was recovered by filtration.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.C([Li])(C)(C)C.I[C:23]1[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=1.Cl>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[CH3:1][N:2]1[C:3]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:9][CH:8]=2)=[CH:4][CH:5]=[C:6]1[C:23]1[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: Cn1cccc1-c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2ccc(-c3ccc(C(F)(F)F)cc3)n2C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
To a solution (5 ml) of 1-methyl-2-(4-trifluoromethylphenyl)pyrrole (1.13 g) in tetrahydrofuran was added dropwise t-butyl lithium (1.7 M solution in pentane, 3.00 ml) under an argon atmosphere at −78° C. This mixed solution was heated to room temperature, and a solution (10 ml) of zinc chloride (0.756 g) in tetrahydrofuran was added. This mixture was stirred for 1 hr., and ethyl 4-iodobenzoate (0.381 ml) and tetrakis (triphenylphosphine)palladium (0.144 g) were added. This mixture was stirred overnight under an argon atmosphere and poured into 0.5 M hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1, volume ratio) and recrystallized from hexane-ethyl acetate to give ethyl 4-[1-methyl-5-(4-trifluoromethylphenyl)-2-pyrrolyl]benzoate (0.573 g, yield 31%) as colorless needle crystals. melting point: 150–151° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]([C:17]2[N:18](COCC[Si](C)(C)C)[CH:19]=[C:20]([C:22]#[N:23])[N:21]=2)=[O:16])[CH2:4][CH2:3]1.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl.CCO>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]([C:17]2[NH:18][CH:19]=[C:20]([C:22]#[N:23])[N:21]=2)=[O:16])[CH2:4][CH2:3]1
Reactant: CC1CCN(c2ccccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CCN(c2ccccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 40 °C
Reaction time: 48 h
Yield: 10 %

Procedure:
A solution of 153 mg (0.348 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-(4-methyl-piperidin-1-yl)-phenyl]-amide (as prepared in the previous step) in CH2Cl2 (5 mL) was treated with EtOH (1 drop) and TFA (1 mL), and the mixture was warmed to 40° C. for 2 h and left at RT for 2 days. The mixture was concentrated to dryness, taken up in CH2Cl2 (5 mL), and treated with EtOH (1 drop) and TFA (1.00 mL) at RT for 7 h. The mixture was concentrated in vacuo. The residue was taken up in MeOH (2.5 mL) and a 10% solution of acetonitrile in water (7.5 mL) to form a suspension. The solid was filtered and triturated with a minimum amount of acetone to afford 50.7 mg (34%) of the title compound as a white solid: 1H-NMR (CD3OD; 400 MHz): δ 8.35-8.32 (m, 1H), 8.03 (s, 1H), 7.29-7.26 (m, 1H), 7.15-7.12 (m, 2H), 3.09-2.99 (m, 2H), 2.81-2.74 (m, 2H), 1.85-1.80 (m, 2H), 1.72-1.56 (m, 3H), 1.09 (d, 3H, J=6.0 Hz). Mass spectrum (ESI, m/z): Calcd. for C17H19N5O, 310.2 (M+H), found 310.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].Cl.[NH2:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([OH:40])[CH2:36][CH2:35]1.C(N(CC)CC)C>C1COCC1>[OH:40][C@H:37]1[CH2:38][CH2:39][C@H:34]([NH:33][C:16]2[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]3[CH:12]=[CH:11][C:10](=[O:31])[N:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[C:14]=3[N:15]=2)[CH2:35][CH2:36]1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(N[C@H]2CC[C@H](O)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 48 h

Procedure:
The product of Example 48 (300 mg, 0.67 mmol), trans-4-aminocyclohexanol hydrochloride (226 mg, 1.5 mmol), and triethylamine (0.42 mL, 3 mmol) were combined in THF (15mL) and stirred under Ar at 50° for 2 days. The solvents were removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography with 0-20% EtOAc/CH2Cl2 followed by recrystallization from CH2Cl2/hexane gave the product as a white-crystalline solid. mp 158-160°, LC MS m/z=481 (MH+) Retention time=2.08 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([NH2:12])=[O:11])[CH:5]=[N:4][C:3]=1[C:15]#[N:16].[C:17]1([C:23]2[CH:27]=[C:26]([NH2:28])[S:25][N:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:15]([C:3]1[N:4]=[CH:5][C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([NH2:12])=[O:11])=[N:7][C:2]=1[NH:28][C:26]1[S:25][N:24]=[C:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:27]=1)#[N:16]
Reactant: CC[C@@H](Nc1cnc(C#N)c(Cl)n1)C(N)=O
Reactant: Nc1cc(-c2ccccc2)ns1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC[C@@H](Nc1cnc(C#N)c(Nc2cc(-c3ccccc3)ns2)n1)C(N)=O
Reaction time: 4 h
Yield: 16.9 %

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)butanamide (50 mg, 0.208 mmol), 3-phenylisothiazol-5-amine (22 mg, 0.125 mmol), K2CO3 (100 mg, 0.724 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (15 mg, 0.066 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 4 h. HOAc (0.2 mL) was added. The mixture was concentrated in vacuo. The residue was purified by HPLC to give (R)-2-(5-cyano-6-(3-phenylisothiazol-5-ylamino)pyrazin-2-ylamino)butanamide (8 mg)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:12])[CH2:10][CH3:11])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([OH:12])[CH2:10][CH3:11])=[CH:6][CH:7]=1
Reactant: CCC(=O)Cc1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC(O)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
To a solution of 70B (478 mg, 2.1 mmol) in 5 mL MeOH at 0° C., was added NaBH4 (110 mg, 2.98 mmol). The solution was stirred at rt for 30 min, then was diluted with EtOAc and washed with H2O and brine, dried (Na2SO4) and concentrated. Purification via flash chromatography (0-30% EtOAc/hexanes) afforded 70C (460 mg, 96%). MS (ESI) m/z 221.2 (M-OH)+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]#[N:21])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N)(=[S:24])C.Cl.O1CCOCC1>C(Cl)(Cl)Cl>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][C:20](=[S:24])[NH2:21])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(N)=S
Reactant: CC(C)(C)c1csc(-c2cc3cc(CC#N)ccc3o2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1csc(-c2cc3cc(CC(N)=S)ccc3o2)n1

Procedure:
A mixture of 4-tert-butyl-2-[5-(cyanomethyl)benzofuran-2-yl]thiazole (1.31 g) and thioacetamide in a mixture of 4N-hydrogen chloride of 1,4-dioxane (4 ml) and chloroform was stirred under reflux for 30 minutes and removed the solvent at the same temperature. The residue was washed with water to give crude 4-tert-butyl-2-[5-(thiocarbamoylmethyl)-benzofuran-2-yl]thiazole (1.23 g).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=C(C=O)C=1.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:34]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=[C:26]([NH2:35])[C:25]=2[N:24]=[C:23]1[CH2:36][O:37][CH2:38][CH3:39].NCCCCN1C2C3C=CC=CC=3N=C(N)C=2N=C1COC.FC(F)(F)C([O-])=O>>[CH2:1]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:34]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=[C:26]([NH2:35])[C:25]=2[N:24]=[C:23]1[CH2:36][O:37][CH2:38][CH3:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCCCN
Agent: COCc1nc2c(N)nc3ccccc3c2n1CCCCN
Agent: O=C([O-])C(F)(F)F
Agent: O=Cc1cccnc1
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCCNCc1ccccc1

Procedure:
The compounds in the table below were prepared and purified according to the methods of Parts B and C of Examples 246-257 using 1-(4-benzylaminobutyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine in lieu of 2-methoxymethyl-1-{4-[(pyridin-3-ylmethyl)amino]butyl}-1H-imidazo[4,5-c]quinolin-4-amine. 1-(4-Benzylaminobutyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine was prepared according to the general method of Part A of Examples 246-257 using benzaldehyde in lieu of pyridine 3-carboxaldehyde and 1-(4-aminobutyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine in lieu of 1-(4-aminobutyl)-2-methoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine. The table below shows the reagent used for each example, the structure of the resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[NH:32][C:33]([NH:35][C:36]1[CH:41]=[C:40]([CH3:42])[CH:39]=[CH:38][C:37]=1[F:43])=[O:34])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)=[O:16])[S:14][C:7]=12.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:15]([C:13]1[S:14][C:7]2[C:8](=[N:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]2[CH:29]=[CH:30][C:31]([NH:32][C:33]([NH:35][C:36]3[CH:41]=[C:40]([CH3:42])[CH:39]=[CH:38][C:37]=3[F:43])=[O:34])=[C:2]([F:1])[CH:3]=2)[CH:12]=1)=[O:16]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCCNC(=O)OC(C)(C)C)sc34)cc2F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCCN)sc34)cc2F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred suspension of tert-butyl {3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}carbamate (300 mg, 0.49 mmol) in 10 ml of methylene chloride was added 3 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 10 minutes and evaporated to dryness under reduced pressure. The residue was re-dissolved in MeOH (5 ml) and poured into 100 ml of water with vigorous stirring. Saturated NaHCO3 solution was added until pH=8˜9. The precipitates were filtered, washed with water and dried in vacuo to give N-(3-aminopropyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide as yellow solid. Yield: 250 mg, 100%.