Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][CH:14]1[C:21](=[O:22])[N:20]2[CH:23]([C:27](O)=[O:28])[CH2:24][CH2:25][CH2:26][CH:19]2[CH2:18][CH:17]=[CH:16][CH2:15]1)=[O:12].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.ON1C2C=CC=CC=2N=N1.[CH2:59]([O:66][C:67](=[O:80])[CH2:68][CH:69]([NH2:79])[CH2:70][O:71][Si:72]([C:75]([CH3:78])([CH3:77])[CH3:76])([CH3:74])[CH3:73])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>C1COCC1.O>[CH2:59]([O:66][C:67](=[O:80])[CH2:68][CH:69]([NH:79][C:27]([CH:23]1[N:20]2[C:21](=[O:22])[CH:14]([NH:13][C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[O:12])[CH2:15][CH:16]=[CH:17][CH2:18][CH:19]2[CH2:26][CH2:25][CH2:24]1)=[O:28])[CH2:70][O:71][Si:72]([C:75]([CH3:76])([CH3:77])[CH3:78])([CH3:74])[CH3:73])[C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(N)CC(=O)OCc1ccccc1
Reactant: O=C(NC1CC=CCC2CCCC(C(=O)O)N2C1=O)c1ccc2ccccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC(CC(=O)OCc1ccccc1)NC(=O)C1CCCC2CC=CCC(NC(=O)c3ccc4ccccc4c3)C(=O)N21
Reaction time: 0.33 h

Procedure:
7-[(Naphthalene-2-carbonyl)-amino]-6-oxo-1,3,4,6,7,8,11,11a-octahydro-2H-pyrido[1,2-a]azocine-4-carboxylic acid (0.44 gm) is dissolved in 15 mL THF to which 0.24 gm of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC), 0.15 mL of N-methylmorpholine, and 0.17 gm of 1-hydroxybenzotriazole (HOBt) is added. The reaction mixture is stirred for 20 min then added to a solution of 3-amino-4-(tert-butyl-dimethyl-silanyloxy)-butyric acid benzyl ester (0.52 gm, prepared by methods described in Chem. Pharm. Bull. 1999, 47, 11–21) in 5 mL THF. The resulting mixture is striired at RT for ˜18 h, then poured into water, and extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, then dried over sodium sulfate powder. Filtration and evaporation produces a crude product which is then purified over silica (1:1 ethylacetate:hexanes) to afford the desired product.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[CH:14][N:15]([CH3:23])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[S:10][C:9]1=[S:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:31][O:32][CH2:33][CH2:34]Br>CN(C=O)C.C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[CH:14][N:15]([CH3:23])[C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:34][CH2:33][O:32][CH3:31])=[CH:20][CH:21]=2)[S:10][C:9]1=[S:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCBr
Reactant: CN(C=C1SC(=S)N(Cc2ccccc2)C1=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COCCOc1ccc(N(C)C=C2SC(=S)N(Cc3ccccc3)C2=O)cc1
Temperature: 50 °C
Yield: 72.4 %

Procedure:
To a solution of 3-benzyl-5-{[N-(4-hydroxyphenyl)-methylamino]-methylene}-2-thioxothiazolidin-4-one (71 mg, 0.20 mmol) in DMF (1.0 mL, anhyd) was added anhyd K2CO3 (29 mg, 0.21 mmol) and 2-bromoethyl methyl ether (20 μL, 0.21 mmol). The reaction mixture was heated at 50° C. After 20 h the reaction mixture was cooled, diluted with CHCl3 (50 mL), washed with H2O (3×25 mL) and brine, dried over anhyd Na2SO4, concentrated and then chromatographed (silica gel, 0:100 to 20:80 EtOAc-DCM) to give the title product (60 mg, 73%) as a yellow solid. 1H-NMR (CDCl3): δ 7.73 (1H, s), 7.44 (2H, d), 7.21-7.30 (3H, m), 7.11 (2H, d), 6.97 (2H, d), 5.23 (2H, s), 4.15 (2H, m), 3.79 (2H, m), 3.48 (3H, s), 3.47 (3H, s).
Reaction SMILES: C1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([O:37][CH3:38])[CH:28]=2)=[O:25])[C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)CCCCC1.[CH:39]1[CH:40]=[CH:41][C:42]2N(O)N=N[C:43]=2[CH:44]=1.CCN=C=NCCCN(C)C.[CH2:60]([O:62][C:63](=[O:68])[C@H:64]([OH:67])[CH2:65][NH2:66])[CH3:61]>CN(C=O)C.C(OCC)(=O)C.O>[CH2:60]([O:62][C:63](=[O:68])[C@H:64]([OH:67])[CH2:65][NH:66][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([CH:13]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[C:29]([O:37][CH3:38])[CH:28]=2)=[O:25])[C:8]2[CH:9]=[CH:10][C:11]([CH:39]3[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]3)=[CH:12][CH:7]=2)=[CH:15][CH:16]=1)[CH3:61]
Reactant: CCOC(=O)[C@H](O)CN
Reactant: COc1cc(NC(=O)NC(c2ccc(C(=O)O)cc2)c2ccccc2C2CCCCC2)cc(C(F)(F)F)c1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](O)CNC(=O)c1ccc(C(NC(=O)Nc2cc(OC)cc(C(F)(F)F)c2)c2ccc(C3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
4-[1-(Cyclohexylphenyl)-3-(3-methoxy-5-trifluormethylphenyl)ureidomethyl]benzoic acid (420 mg, 0.8 mmol) was dissolved in DMF (10 mL), and then HOBt (160 mg, 1.2 mmol) and EDAC (230 mg, 1.2 mmol) were added. The reaction mixture was allowed to stand for 30 min, then (R)-isoserine ethyl ester (260 mg, 1.2 mmol) and dissopropylethylamine (210 mL, 1.2 mmol) dissolved in DMF (5 mL) were added and the reaction mixture was stirred at room temperature for 16 hours. Water (50 mL) and ethyl acetate (100 mL) were added and the organic phase was washed with water (5×50 mL), dried (magnesium sulphate), filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a mixture of heptane and ethyl acetate (1:3) to afford 510 mg of (R)-3-{4-[1-(4-cyclohexylphenyl)-3-(3-methoxy-5-trifluoromethylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid ethyl ester as an amorphous solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[NH:28]1[CH2:31][CH:30]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:29]1>>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([N:28]3[CH2:31][CH:30]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH2:29]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CC(NC(=O)OC(C)(C)C)C2)n1
Yield: 90 %

Procedure:
Reaction of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole and tert-butyl 3-azetidinylcarbamate gave tert-butyl 1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinylcarbamate in 90% yield: mp (CH2Cl2/hexanes) 217-220° C.; 1H NMR (DMSO-d6) δ7.98 (d, J=8.0 Hz, 1H), 7.73 (t, JHF=53.0 Hz, 1H), 8.24 (t, J=8.2 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 4.42 and 4.36-4.32 (2m, 3H), 4.01-3.98 (m, 2H), 3.79-3.77 (m, 4H), 3.68 (m, 4H), 1.40 (s, 9H). Anal. Calcd. for C24H30F2N8O4: C, 54.1; H, 5.7; N, 21.0. Found: C, 54.4; H, 5.8; N, 21.2%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)[N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][C:3]=12.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][OH:25])=[CH:19][CH:18]=1>>[O:9]1[CH:10]=[CH:11][N:12]=[C:8]1[C:6]1[N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][C:3]2=[C:2]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][OH:25])=[CH:19][CH:18]=2)[CH:7]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: Clc1cc(-c2ncco2)nc2c1CCC2
Product: OCCc1ccc(Nc2cc(-c3ncco3)nc3c2CCC3)cc1
Yield: 56.5 %

Procedure:
Following general procedure B1, 2-(4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)oxazole (0.059 g, 0.27 mmol) was reacted with 2-(4-aminophenyl)ethanol (0.044 g, 0.32 mmol) to afford the title compound (0.049 g, 57%) as a light yellow solid. MW=321.37. 1H NMR (DMSO-d6, 500 MHz) δ 8.19-8.14 (m, 2H), 7.45 (s, 1H), 7.30-7.28 (m, 1H), 7.24 (d, J=8.5 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 4.64 (s, 1H), 3.66-3.59 (m, 2H), 2.90 (t, J=7.5 Hz, 2H), 2.84 (t, J=7.0 Hz, 2H), 2.72 (t, J=7.0 Hz, 2H), 2.09 (quin, J=7.5 Hz, 2H); APCI MS m/z 322 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Cl:11])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].Cl[Sn]Cl>C(O)C>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:11])=[CH:4][C:3]=1[C:12]([F:15])([F:13])[F:14]
Reactant: Nc1c([N+](=O)[O-])cc(Cl)cc1C(F)(F)F
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cc(Cl)cc(C(F)(F)F)c1N
Temperature: 90 °C
Yield: 82.4 %

Procedure:
To a stirred mixture of 2-amino-5-chloro-3-nitrobenzotrifluoride (250 mg, 1.043 mmol) in ethanol (4 mL) was added SnCl2 ·2 H2O (1.174 g, 5.217 mmol) in one portion. The mixture was refluxed at 80° C. (oil bath 90° C.) for 1 h. The solution was cooled to room temperature and ice water (20 g) was added. It was adjusted to pH=7 and extracted with ethyl acetate. The extract was dried (Mg2SO4) and evaporated to give 181 mg (83%) of 2,3-diamino-5-chlorobenzotrifluoride as a brown solid. 1H NMR (CDCl3): δ3.515 (s, 2H); 3.878 (s, 2H); 6.845 (s, 1H); 6.988 (s, 1H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:19]1C(=O)C2C(=CC=CC=2)C1=O)[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1COCC1.CO.O.NN>C1COCC1>[Si:1]([O:8][CH2:9][C@H:10]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=1)[NH2:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(F)c1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC[C@@H](N)c1ccc(Cl)c(F)c1
Temperature: 60 °C
Yield: 88.1 %

Procedure:
To a solution of 66 (14.35 g, 33.07 mmol) and THF/MeOH (1:1, 400 mL) was added hydrazine monohydrate (4.138 g, 82.67 mmol) and the reaction was heated to 60° C. for 3 h. The reaction was diluted with THF and filtered. The solid was discarded and the filtrate was concentrated and the residue dissolved in ether (200 mL). The organic layer was washed twice with water (100 mL). The organic layer was then dried, filtered and concentrated. The crude product was purified by SiO2 (Biotage 65) eluting with an EtOAc/hexane gradient (30 to 40% EtOAc) to afford 8.85 g (88.1%) of (S)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanamine (68).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-])=O.C(=O)([O-])[O-].[K+].[K+].[CH:26]1([NH2:29])[CH2:28][CH2:27]1.[H][H]>C(O)C.[C].[Pd].O>[CH:26]1([NH:29][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:4][C:3]=2[NH2:17])[CH2:28][CH2:27]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: NC1CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 45.8 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (300 mg, 1.16 mmol) in ethanol (5 mL) was added potassium carbonate (176 mg, 1.28 mmol) and cyclopropylamine (99.3 mg, 1.74 mmol), and this was heated to reflux for 7 hours. After the reaction was complete, this was cooled to room temperature, water was added, and the precipitated crystals were filtered, washed with water and then dried. To a tetrahydrofuran solution (5 mL) of the crystals obtained was added 10% palladium-carbon (50 mg). A hydrogen atmosphere was substituted in the flask, and this was stirred at room temperature for 14 hours. After the reaction was complete, this was filtered through Celite and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (141 mg, 46% yield).
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].Br[CH2:7][CH2:8][CH:9]1[O:13][CH2:12][CH2:11][O:10]1.O1CCCC1.C([N-]C(C)C)(C)C.[Li+]>CCOCC.C1CCCCC1>[CH3:3][C:2]([CH3:4])([CH2:7][CH2:8][CH:9]1[O:13][CH2:12][CH2:11][O:10]1)[C:1]#[N:5]
Reactant: CC(C)C#N
Reactant: BrCCC1OCCO1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC(C)(C#N)CCC1OCCO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
To a stirring solution of 25.1 g of isobutyronitrile and 61.0 g of 2-(2-bromoethyl)-1,3-dioxolane in 300 ml of anhydrous ether was slowly added 310 ml of a 1.5M solution of lithiumdiisopropylamide mono(tetrahydrofuran) in cyclohexane at 0°-5° C. After removal of the cooling bath, the reaction mixture was stirred for 4 hours at room temperature, treated with a saturated solution of ammonium chloride and worked up with ether. The organic phase was washed with water, dried over anhydrous magnesium sulfate and concentrated to give 61 g of a crude oil. Purification of this material on a silica gel column (eluting system:ether-hexane 4:1) afforded 47.9 g (77.9%) of α, α-dimethyl-1,3-dioxolane -2-butanenitrile. A solution of 47.9 g of α,α-dimethyl-1,3dioxolane-2-butanenitrile in 500 ml of anhydrous ethyl ether was treated with 200 ml of 1.4M methyllithium solution in ether at 0°-5° C. The reaction mixture was stirred for 2 hours at room temperature, treated with a saturated ammonium chloride solution and worked up with ether. The ethereal solution was washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to give 39.2 g of a crude yellow oil. This material was treated with 70 ml of 4N-sulfuric acid and refluxed for 13 hours. After being cooled, the mixture was extracted with ether. The organic phase was washed with water, a saturated solution of sodium bicarbonate, water, dried over anhydrous magnesium sulfate and concentrated to give 23.1 g (65.8%) of 6,6-dimethyl-2-cyclohexen-1-one as an orange oil. This material was used without further purification.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:27][CH2:28][N:29]([C:12]([C:11]2[CH:10]=[CH:9][C:8]([CH2:7][N:3]3[CH2:4][CH2:5][CH2:6][S:2]3(=[O:1])=[O:17])=[CH:16][CH:15]=2)=[O:14])[CH2:30][CH2:31]1
Reactant: O=C(O)c1ccc(CN2CCCS2(=O)=O)cc1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCN(C(=O)c3ccc(CN4CCCS4(=O)=O)cc3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
4-(1,1-Dioxo-1λ6-isothiazolidin-2-ylmethyl)benzoic acid (268 mg) described in Preparation Example 18, 1-(2,4-dimethylphenyl)piperazine (199 mg), 1-hydroxybenzotriazole 1 hydrate (142 mg) were dissolved in N,N-dimethylformamide (5 mL), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (202 mg) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (256 mg).
Reaction SMILES: O[CH2:2][C:3]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[S:5][C:4]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.CCN(S(F)(F)[F:27])CC>C(Cl)Cl>[N:18]1[CH:19]=[CH:20][C:15]([C:4]2[S:5][C:6]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)=[C:7]([CH3:8])[C:3]=2[CH2:2][F:27])=[CH:16][CH:17]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1c(-c2ccncc2)sc(-c2ccncc2)c1CO
Solvent: ClCCl
Product: Cc1c(-c2ccncc2)sc(-c2ccncc2)c1CF
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of diethylaminosuifer trifluoride (DAST, 0.06 mL) in CH2Cl2 (5 mL) was added 3-hydroxymethyl-2,5-di(4-pyridyl)-4-methylthiophene (0.144 g) at 0° C. under nitrogen. The resulting mixture was stirred at room temperature for 1 hour. DAST (0.06 mL) was additionally added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice-water and the whole was extracted with CH2Cl2 (50 mL). The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatographyeiuting with ethyl acetate-CH2Cl2 (1:1). The resulting solid was recrystallized from diisoplopanol-diisopropyl ether to give the title compound (0.056 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+]>>[OH2:8].[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cccc(CN)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NCc1cccc(C(=O)O)c1
Product: O
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.5 %

Procedure:
A mixture of methyl 3-aminomethylbenzoate hydrochloride (2.014 g, 0.0098 mol) in 1N sodium hydroxide (25 mL, 0.025 mol) was stirred at room temperature for 4 h. The mixture was neutralized with Dowex-H+ resin. The mixture was filtered and acetone (400 mL) was added to the filtrate. The white precipitate was collected by filtration and recrystallized from water-acetone to give 0.80 g of the title compound as a white powder, mp 278°-280° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:30][O:31][CH2:32][CH3:33])[N:18]([CH2:19][C:20]([NH:23][C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:25])([CH3:22])[CH3:21])[C:14]=2[C:13]2[CH:12]=[CH:11][C:10]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])=[CH:9][C:8]=2[N:7]=1.C(N(CC)CC)C>ClCCl>[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:30][O:31][CH2:32][CH3:33])[N:18]([CH2:19][C:20]([NH:23][C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:25])([CH3:21])[CH3:22])[C:14]=2[C:13]2[CH:12]=[CH:11][C:10]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:1](=[O:3])[CH3:2])=[CH:9][C:8]=2[N:7]=1
Reactant: CCOCc1nc2c(N)nc3cc(OCCCCCCN)ccc3c2n1CC(C)(C)NC(=O)NC(C)C
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3cc(OCCCCCCNC(C)=O)ccc3c2n1CC(C)(C)NC(=O)NC(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 26.6 %

Procedure:
Acetyl chloride (180 μL, 2.53 mmol) was added to a stirred solution of N-{2-[4-amino-7-[(6-aminohexyl)oxy]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-N′-isopropylurea (prepared as described in Parts A-H of Example 369, 1.18 g, 2.30 mmol) and triethylamine (0.64 mL, 4.60 mmol) in dichloromethane (100 mL) at 0° C. After approximately 20 minutes, the solution was allowed to warm to room temperature and was stirred overnight. The solution was transferred to a separatory funnel and washed with water (2×). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, elution with 10% methanol in dichloromethane) to yield 0.34 g of N-(6-{[4-amino-2-(ethoxymethyl)-1-(2-{[(isopropylamino)carbonyl]amino}-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}hexyl)acetamide as a tan solid, mp 90-110° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([C:39]2[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[CH:41][CH:40]=2)[CH:10]([C:25](N2C(C3C=CC=CC=3)COC2=O)=[O:26])[CH2:11][CH2:12][CH:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:14][Si](C)(C)C)=[CH:4][CH:3]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>COC(C)(C)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:25](=[O:26])[CH:10]([CH2:11][CH2:12][CH:13]([OH:14])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:9]2[C:39]2[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[CH:41][CH:40]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)OC(CCC(C(=O)N1C(=O)OCC1c1ccccc1)C(Nc1ccc(F)cc1)c1ccc(C#N)cc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: [F-]
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(F)cc2)cc1
Reaction time: 8 h

Procedure:
2.7 g of 4-[1-(4-fluorophenylamino)-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)-5-phenyl-5-trimethylsilanyloxypentyl]benzonitrile in 30 ml of tert-butyl methyl ether, 1.6 ml of bistrimethylsilylacetamide and 0.2 g of tetrabutylammonium fluoride trihydrate are heated at reflux for 3 hours. The mixture is allowed to stand overnight, 0.2 ml of glacial acetic acid are added, and the mixture is stirred for 15 min and then substantially concentrated. 15 ml of a mixture of isopropanol/2N sulfuric acid=10:1 are added, and the mixture is stirred at room temperature for 1 hour. The mixture is then treated with a little solid sodium bicarbonate and again substantially concentrated and the residue is taken up in ethyl acetate and washed with water. The residue of the dried organic phase is purified by column filtration (SiO2, ethyl acetate/n-heptane=1:1). This gives the product of molecular weight 400.5 (C25H21FN2O2); MS (DCl+): 401 (M+H+), 383 (M+H+−H2O).
Reaction SMILES: [CH2:1]([C:4]1[CH2:5][C@@H:6]2[C@H:9]([CH:10]=1)[C@@:8]([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])([CH2:11][N+:12]([O-])=O)[CH2:7]2)[CH:2]=[CH2:3].[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH2:1]([C:4]1[CH2:5][C@@H:6]2[C@H:9]([CH:10]=1)[C@@:8]([CH2:15][C:16]([OH:18])=[O:17])([CH2:11][NH2:12])[CH2:7]2)[CH:2]=[CH2:3]
Reactant: C=CCC1=C[C@H]2[C@@H](C1)C[C@]2(CC(=O)OC(C)(C)C)C[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: C=CCC1=C[C@H]2[C@@H](C1)C[C@@]2(CN)CC(=O)O
Reaction time: 2 h
Yield: 28.4 %

Procedure:
Tert-butyl(±)-[(1S,5R,6R)-3-allyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate (335.2 mg, 1.09 mmol) was dissolved in ethanol (10 mL) and water (5 mL). To the solution, iron powder (611.0 mg, 10.9 mmol) and ammonium chloride (57.8 mg, 1.09 mmol) were added, and the mixture was stirred for 2 hours under heating to reflux. The mixture was allowed to cool, then diluted with saturated saline, a saturated aqueous solution of sodium bicarbonate, and ethyl acetate, and filtered through Celite to remove insoluble matter. The filtrate was separated into organic and aqueous layers. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. To the residue, a 4 N hydrochloric acid-ethyl acetate solution (10 mL) was added, and the mixture was stirred at room temperature for 1 hour. Then, the solvent was distilled off under reduced pressure. The residue was suspended in dichloromethane. To the suspension, triethylamine was added dropwise, and the resulting powder was collected by filtration, then washed with dichloromethane, and then dried to obtain the compound of interest as a white powder (68.5 mg, 28%).