Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)[CH3:2].[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][C:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:23])[CH3:22])=[CH:16][CH:15]=[C:14]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:13]=2.C(N(CC)CC)C>ClCCl>[CH2:33]([O:32][C:14]1[CH:15]=[CH:16][C:17]2[C:18]3[N:19]([CH2:20][C:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:23])[CH3:22])[C:5]([CH2:4][O:3][CH2:1][CH3:2])=[N:8][C:9]=3[CH:10]=[N:11][C:12]=2[CH:13]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CCOCC(=O)Cl
Reactant: CC(C)(CNc1c(N)cnc2cc(OCc3ccccc3)ccc12)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
Ethoxyacetyl chloride (1.82 mL, 16.60 mmol) was added to a chilled (0° C.) solution of tert-butyl [2-(3-amino-7-benzyloxyquinolin-4-ylamino)-1,1-dimethylethyl]carbamate (6.04 g, 13.8 mmol) and triethylamine (3.86 mL, 27.68 mmol) in 150 mL of anhydrous dichloromethane. After stirring for 30 minutes, the cooling bath was removed and the reaction was stirred for 24 hours at ambient temperature. The volatiles were removed under reduced pressure and the resulting residue was dissolved in ethanol, followed by the addition of 3.86 mL of trietylamine. The reaction was heated at reflux for 2.5 days and then cooled to ambient temperature. The solvent was removed under reduced pressure and dichloromethane was added. The solution was sequentially washed with aqueous sodium bicarbonate followed by brine; dried over sodium sulfate; filtered; and concentrated under reduced pressure. The residue was purified using flash column chromatography on silica gel, eluting with 5% methanol in dichloromethane. Clean fractions were concentrated; while fractions containing both the product and the starting material were resubmitted to the reaction conditions and repurified as described above. The combined lots provided a total of 5.07 g of tert-butyl [2-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]carbamate was obtained as an orange foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[Li]CCCC.CN([CH:20]=[O:21])C.Cl>O1CCCC1.O>[CH:20]([C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6])=[O:21]
Reactant: Cc1ccc(C(=O)O)cc1Br
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)O)cc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a stirred solution of 3-bromo-4-methylbenzoic acid (2.14 g, 10.00 mmol, 1.00 equiv) in tetrahydrofuran (30 mL) under nitrogen at −78° C. was added n-BuLi (10 mL, 2.5 M in THF, 2.50 equiv) dropwise. After stirring for 1 h below −70° C., DMF (5 mL) was slowly added. The resulting solution was warmed slowly to room temperature and stirred for 1 h. After carefully quenching the reaction by slowly adding 50 mL of water, the pH was adjusted to ˜3-4 using aqueous HCl (6 M). The resulting mixture was extracted with 2×50 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 1.6 g (98%) of the title compound as a yellow solid.
Reaction SMILES: [H-].[Na+].[F:3][CH2:4][CH2:5][CH2:6][OH:7].Cl[C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][N:10]=1.[OH-].[Na+]>CN(C)C=O.C(O)C>[F:3][CH2:4][CH2:5][CH2:6][O:7][C:9]1[CH:19]=[CH:18][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=1
Reactant: OCCCF
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(OCCCF)nc1
Reaction time: 0.42 h

Procedure:
Sodium hydride (0.220 g, 5.50 mmol) was added to a solution of 3-fluoropropan-1-ol (0.390 g, 5 mmol) in N,N-dimethylformamide (5 mL). The mixture was stirred under an atmosphere of nitrogen for 25 min and added a solution of ethyl 6-chloronicotinate (0.928 g, 5.00 mmol) in N,N-dimethylformamide (2.5 mL). The reaction mixture was stirred for 35 min and then quenched with water. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. Purification by column chromatography using a gradient of ethyl acetate in heptane yielded an oil. The crude was dissolved in 1M sodium hydroxide, (16.50 mL, 16.50 mmol) and ethanol (20 mL) and heated to 50° C. for 1.5 h. The organic solvent was removed in vacuo, and the residual aqueous solution was cooled on ice. 2 M hydrochloric acid was added until an acidic pH was reached. The obtained precipitate was filtered off, washed with ice-water, and dried in vacuo affording the title compound, 0.53 g (81%) as a white solid; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.71 (dd, 1 H), 8.14 (dd, 1 H), 6.90 (dd, 1 H), 4.65 (t, 1 H), 4.54 (t, 1 H), 4.43 (t, 2 H), 2.05-2.19 (m, 2 H); MS (APPI/APCI) m/z 228[M+H+].
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])([CH3:9])[CH3:8].[S:21](Cl)(=[O:24])(=[O:23])[NH2:22]>>[S:21]([NH:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])([CH3:8])[CH3:9])(=[O:24])(=[O:23])[NH2:22]
Reactant: NS(=O)(=O)Cl
Reactant: CCNC(=O)NC(C)(C)COc1cccc(N)c1C#N
Product: CCNC(=O)NC(C)(C)COc1cccc(NS(N)(=O)=O)c1C#N
Yield: 100 %

Procedure:
Prepared as in Example 215a from 1-(1-(3-amino-2-cyanophenoxy)-2-methylpropan-2-yl)-3-ethylurea (Example 230b) and sulfamoyl chloride in 100% yield. MS 356 (MB).
Reaction SMILES: CC1C=CC([C:8]2CC[CH2:11][C:10](=[O:14])[CH:9]=2)=CN=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][N:17]=1.C[O-].[Na+].C(C(C)=O)=C>C1C=CC=CC=1.CO>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH:23]([CH2:8][CH2:9][C:10](=[O:14])[CH3:11])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:29])=[CH:18][N:17]=1
Reactant: Cc1ccc(C2=CC(=O)CCC2)cn1
Reactant: CCOC(=O)CC(=O)c1ccc(C)nc1
Agent: C=CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: CCOC(=O)C(CCC(C)=O)C(=O)c1ccc(C)nc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
B-2. 3-(2-Methyl-5-pyridinyl)-2-cyclohexen-1-one--To a stirred solution containing 48 g. of ethyl 3-(2-methyl-5-pyridinyl)-3-oxopropanoate in a mixture of 300 ml. of dry benzene and 100 ml. of dry methanol, said solution kept under nitrogen, was added 0.1 g. of sodium methoxide followed by the dropwise addition over a period of about 1 hour of the solution containing 16g. of freshly distilled methyl vinyl ketone in a mixture of 60 ml. of benzene and 10 ml. of methanol. After the reaction had proceeded slowly at room temperature overnight, an additional 0.1 g. of sodium methoxide plus 4 ml. of additional methyl vinyl ketone were added and the reaction mixture was heated with stirring at 40° C for 8 hours. The solvent was distilled-off in vacuo; 300 ml of benzene was added; the benzene solution was washed once with brine, dried over anhydrous sodium sulfate and heated in vacuo to remove the benzene thereby yielding a quantative yield (63.5 g.) of ethyl 2-(2-methyl-5-pyridinylcarbonyl)-5-oxohexanoate which was added to a mixture containing 95 ml. of concentrated sulfuric acid and 185 ml. of water. The acidic reaction mixture was slowly heated. After about 30 minutes, the temperature reached 55° C. and the evolution of carbon dioxide became noticeable. The temperature of the reaction mixture was maintained at 65° C. for about 1 hour and then heated to 80° C. and held there for several minutes. By this time the evolution of carbon dioxide appeared to be over. The reaction mixture was cooled and poured into a solution of 305 g. of potassium carbonate in 1 liter of ice water. Chloroform was added; the mixture was shaken well and filtered to remove the precipitated potassium sulfate; and, the layers were separated. The aqueous layer was extracted further with chloroform; the combined chloroform extracts were dried over anhydrous sodium sulfate and filtered; the dried filtrate was heated in vacuo to remove the chloroform to yield, after air-drying, 27.4 g. (80% of 1-(2-methyl-5-pyridinyl)hexan-1,5-dione, a tan solid melting at 85°-87° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][N:5]([CH3:38])[C:6]=1[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([C@@H:17]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1)[CH2:18][N:19]1C(=O)C3C(=CC=CC=3)C1=O)[CH2:10]2.NN>CO.O1CCCC1>[NH2:19][CH2:18][C@@H:17]([N:11]1[CH2:10][C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:6]3[N:5]([CH3:38])[N:4]=[CH:3][C:2]=3[F:1])[CH:8]=2)[C:12]1=[O:16])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1
Reactant: Cn1ncc(F)c1-c1ccc2c(c1)CN([C@@H](Cc1cccc(F)c1)CN1C(=O)c3ccccc3C1=O)C2=O
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: Cn1ncc(F)c1-c1ccc2c(c1)CN([C@H](CN)Cc1cccc(F)c1)C2=O
Yield: 36.5 %

Procedure:
A solution of 2-[(2S)-2-[5-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (30.0 mg, 0.058 mmol) and hydrazine (0.2 mL, 6 mmol) in methanol (1.0 mL) and tetrahydrofuran (1.0 mL) was stirred at room temperature overnight. Direct purification on prep.—HPLC (pH=10) gave 8.1 mg of the desired product as white solid. LC/MS found: 383.0 (M+1)+; 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.73 (d, J=7.8 Hz, 1H), 7.71 (s, 1H), 7.61 (d, J=4.9 Hz, 1H), 7.57 (d, J=7.9 Hz, 1H), 7.23 (ddd, J1=8.2 Hz, J2=7.8 Hz, J3=6.4 Hz, 1H), 7.03 (m, 2H), 6.93 (dddd, J1=8.6 Hz, J2=8.4 Hz, J3=2.6 Hz, J4=0.8 Hz, 1H), 4.48 (s, 2H), 4.42 (m, 1H), 3.79 (s, 3H), 3.05 (dd, J1=14.40 Hz, J2=5.20 Hz, 1H), 2.88 (dd, J1=14.40 Hz, J2=10.00 Hz, 1H), 2.81 (d, J=6.70 Hz, 2H).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([NH:41][CH:42]3[CH2:44][CH2:43]3)=[C:20]([N:25]3[CH2:30][CH2:29][CH:28]([O:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=4[F:40])[CH2:27][CH2:26]3)[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[CH:42]1([NH:41][C:19]2[N:18]=[C:17]3[CH2:16][NH:15][CH2:24][CH2:23][C:22]3=[N:21][C:20]=2[N:25]2[CH2:30][CH2:29][CH:28]([O:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=3[F:40])[CH2:27][CH2:26]2)[CH2:43][CH2:44]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: COc1ccc(OC2CCN(c3nc4c(nc3NC3CC3)CN(Cc3ccccc3)CC4)CC2)c(F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc(OC2CCN(c3nc4c(nc3NC3CC3)CNCC4)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-benzyl-N-cyclopropyl-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (46.8 mg, 0.076 mmol) and Pd(OH)2 on carbon (20 wt %, 5 mg, 0.036 mmol) in THF (760 μL) was stirred under an atmosphere of hydrogen gas (balloon) at rt. After 2 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (39.6 mg, 99%) as a yellow oil. 1H NMR (400 MHz, methanol-d4) δ ppm 0.52-0.59 (m, 2H), 0.75-0.83 (m, 2H), 1.84-1.97 (m, 2H), 2.02-2.12 (m, 2H), 2.64-2.71 (m, 1H), 2.93-3.16 (m, 4H), 3.35 (s, 2H), 3.52-3.63 (m, 2H), 3.75 (s, 3H), 4.20-4.31 (m, 2H), 4.32-4.40 (m, 1H), 6.63-6.69 (m, 1H), 6.73 (dd, J=12.9, 3.0 Hz, 1H), 7.03-7.10 (m, 1H); ESI-MS m/z [M+H]+ 414.3.
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]([NH:11][C:12](=[O:14])[CH3:13])[C:3]=1[C:4]#[N:5].Cl.[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>O.C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[C:9]([CH2:10][Br:16])=[CH:8][CH:7]=[C:6]([NH:11][C:12](=[O:14])[CH3:13])[C:3]=1[C:4]#[N:5]
Reactant: CC(=O)Nc1ccc(C)c(C)c1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC(=O)Nc1ccc(CBr)c(C)c1C#N
Reaction time: 1 h
Yield: 42.3 %

Procedure:
In a carefully dried Pyrex reaction vessel were combined 10 g of 2,3-dimethyl-6-acetamidobenzonitrile, 300 ml of CCl4, and 200 ml of HCl-free CHCl3 under argon. To this solution was added 10.8 g of N-bromosuccinimide (recrystallized from H2O) and 0.5 g of azo bisisobutyronitrile (AIBN). The reaction was heated to reflux and irradiated with an external General Electric sunlamp. The initially yellow reaction turned red-brown after 1 h when an additional 0.5 g of AIBN was added. After another 2 h, the reaction mixture was poured into H2O, separated, and the aqueous layer reextracted with CHCl3. The combined CHCl3 layers were washed with H2O, saturated NaHCO3 solution, and brine. The dried organic solution was evaporated at reduced pressure and the residue was crystallized from ethyl acetate to yield 6 g (42%) of the title compound, m.p. 152°-153° C. NMR (CDCl3) 2.30 (3H, s, CH3CON), 2.60 (3H, s, CH3), 4.50 (2H, s, --CH2Br), 7.40 (1H, d, ArH), 8.10 (1H, d, ArH), Anal. Calc'd for C11H11BrN2O: C, 49.5; H, 4.15; N, 10.5. Found: C, 50.3, H, 4.31; N, 10.6.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].CN(C=O)C.[CH3:10][C:11]1[C:16]2[NH:17][C:18](=[O:20])[O:19][C:15]=2[CH:14]=[CH:13][CH:12]=1.[CH3:21][C:22](OC(C)=O)=[O:23]>O>[C:22]([C:13]1[CH:12]=[C:11]([CH3:10])[C:16]2[NH:17][C:18](=[O:20])[O:19][C:15]=2[CH:14]=1)(=[O:23])[CH3:21]
Reactant: Cc1cccc2oc(=O)[nH]c12
Reactant: CC(=O)OC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cc(C)c2[nH]c(=O)oc2c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
20.0 g (149.99 mmol) aluminium(III) chloride were combined with 5.0 mL DMF, with cooling. After 15 min stirring, first of all 5.0 g (33.52 mmol) 4-methylbenzo[d]oxazol-2(3H)-one and then 5.0 mL (52.90 mmol) acetanhydride were added and the mixture was stirred for 1 h at 80° C. The cooled reaction mixture was mixed with water. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[N:6][CH:7]=1.[C:12]1([C:18]#[CH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:11][S:8]([C:5]1[N:4]=[CH:3][C:2]([C:19]#[C:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][N:6]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ncc(Br)cn1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Temperature: 65 °C
Reaction time: 4 h
Yield: 56.9 %

Procedure:
Bis-(triphenylphosphine)-palladium(II)dichloride (1.48 g, 2.11 mmol, 0.05 equiv.) was dissolved in 200 ml THF. (10 g, 42.2 mmol) 5-Bromo-2-(methylsulfonyl)pyrimidine and phenylacetylene (9.26 ml, 84.4 mmol, 2 equiv.) were added at room temperature. Triethylamine (17.6 ml, 127 mmol, 3 equiv.), triphenylphosphine (330 mg, 1.3 mmol, 0.03 equiv.) and copper(I)iodide (80 mg, 420 μmol, 0.01 equiv.) were added and the mixture was stirred for 4 hours at 65° C. The reaction mixture was cooled and extracted with saturated NaHCO3 solution and two times with EtOAc. The organic layers were extracted with water, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography on a silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 100:0. The desired 2-methanesulfonyl-5-phenylethynyl-pyrimidine (6.2 g, 57% yield) was obtained as a yellow solid, MS: m/e=259.1 (M+H+).
Reaction SMILES: FC(F)(F)C(O)=O.[N+:8]([O-:11])([O-])=[O:9].[K+].[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]2[CH:35]=[N:34][CH:33]=[CH:32][N:31]=2)=[O:29])=[CH:23][C:22]=1[F:36])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)(Cl)Cl>[CH2:13]([O:20][C:21]1[C:22]([F:36])=[CH:23][C:24]([NH:27][C:28]([C:30]2[CH:35]=[N:34][CH:33]=[CH:32][N:31]=2)=[O:29])=[C:25]([N+:8]([O-:11])=[O:9])[CH:26]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(Nc1ccc(OCc2ccccc2)c(F)c1)c1cnccn1
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C(Nc1cc(F)c(OCc2ccccc2)cc1[N+](=O)[O-])c1cnccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40 ml of trifluoroacetic acid and 1.99 g of potassium nitrate were added to a chloroform (40 ml) suspension of 5.80 g of N-(4-benzyloxy-3-fluorophenyl)pyrazinecarboxamide, with cooling with ice, and the reaction liquid was stirred overnight at room temperature. The solvent was evaporated away under reduced pressure, and aqueous saturated sodium bicarbonate was added to it. The resulting solid was washed with a mixed solvent of ethyl acetate and hexane to obtain the entitled compound as a yellow solid.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[Br:9][C:10]1[C:24]([F:25])=[CH:23][C:13]2[O:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[CH:17]=[N:18][C:12]=2[CH:11]=1.CCOCC>C1(C)C(C)=CC=CC=1>[Br:9][C:10]1[C:24]([F:25])=[CH:23][C:13]2[O:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C@H:17]3[C@H:2]([C:1]([OH:7])=[O:8])[CH2:3][CH2:4][C:5](=[O:6])[N:18]3[C:12]=2[CH:11]=1
Reactant: O=C1CCCC(=O)O1
Reactant: Fc1cc2c(cc1Br)N=Cc1ccccc1O2
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: O=C(O)[C@@H]1CCC(=O)N2c3cc(Br)c(F)cc3Oc3ccccc3[C@@H]12
Temperature: 140 °C
Yield: 74.6 %

Procedure:
Glutaric anhydride (7.2 g, 63 mmol) was added to a stirred solution of 8-bromo-7-fluoro-dibenz[b,f][1,4]oxazepine (46.5 mmol) in xylene (26 mL) and the mixture was heated to 140° C. for 120 h. The reaction mixture was allowed to cool to ambient temperature, ether was added and the solution extracted (3×) with 2M NaOH. The pH of the combined extracts was adjusted to pH 4 by adding 3M hydrochloric acid. The product was collected by filtration and dried to yield the title compound (14.1 g, 81%) which was used without further purification. 1H-NMR (400 MHz, CDCl3) 2.03-2.14 (m, 1H), 2.31-2.4 (m, 1H), 2.53-2.62 (m, 1H), 2.67-2.81 (m, 1H), 3.55-3.60 (m, 1H), 5.46-5.49 (m, 1H), 7.05-7.09 (d, J=8.6, 1H), 7.11-7.32 (m, 4H), 7.56-7.59 (d, J=7.8, 1H). (m/z)=406+408 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([O:9]C)=O.O.[NH2:12][NH2:13]>CC(O)C>[OH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([NH:12][NH2:13])=[O:9]
Reactant: NN
Reactant: COC(=O)[C@@H]1CCC[C@H]1O
Solvent: O
Solvent: CC(C)O
Product: NNC(=O)[C@@H]1CCC[C@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
To a 200-mL four-necked flask were added 18.47 g (128.1 mmol) of methyl (R,R)-2-hydroxycyclopentanecarboxylate and 75 mL of 2-propanol and stirring was started. Hydrazine monohydrate (12.83 g; 256.2 mmol) was dropped thereinto at 20° C. taking 1 hour and 30 minutes. After the dropping, the mixture was stirred at 85° C. for 15 hours. After the reaction, heating was stopped and the mixture was cooled to room temperature to precipitate the crystals. The crystals were filtered and washed with small amount of 2-propanol. The resulting crystals were dried to give 10.89 g of the title compound. The yield was 59%. Ratio of anti-form to syn-form of the compound was measured by a high-performance liquid chromatography (column: Inertsil ODS-3V) and found that the anti/syn ratio was more than 99/1.
Reaction SMILES: [NH2:1][C@H:2]1[C:5](=[O:6])[N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[O:16][CH3:17])[C@H:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]1[O:28][CH2:27][CH2:26][O:25]1.C(N(CC)CC)C.[O:36]([CH2:43][C:44](Cl)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(OCC)(=O)C>[CH3:17][O:16][C:9]1[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=1[CH2:7][N:4]1[C:5](=[O:6])[C@H:2]([NH:1][C:44](=[O:45])[CH2:43][O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@@H:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]1[O:28][CH2:27][CH2:26][O:25]1
Reactant: COc1ccc(CN2C(=O)[C@H](N)[C@@H]2c2ccccc2C2OCCO2)c(OC)c1
Reactant: O=C(Cl)COc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(CN2C(=O)[C@H](NC(=O)COc3ccccc3)[C@@H]2c2ccccc2C2OCCO2)c(OC)c1
Reaction time: 0.75 h

Procedure:
The amino compound from Example 3 (4.22 g, 11 mmol) was dissolved in ethyl acetate (60 ml) and cooled in an ice-alcohol bath. Triethylamine (1.67 g, 16.5 mmol) was added, followed by the dropwise addition of phenoxyacetyl chloride (2.06 g, 12.1 mmol) over a period of 5 minutes. The reaction was stirred for 45 minutes with cooling and then filtered. The filtrate was washed with 5% NaHCO3 and brine. The dried filtrate was evaporated to give the title product; 2.0 g. The product was recrystallized from ethyl acetate-ether; 1.02 g, mp 137-138°. The solid which was filtered from the reaction solution was stirred with hot ethyl acetate (100 ml) and filtered. The filtrate was treated with ether (200 ml) and cooled to give additional product; 3.91 g, mp 138-139°.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:15]1([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([O:20][C:2]2[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: OC1CCCC1
Product: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1

Procedure:
Prepared in analogy to example 2.2 (b) from 2-chloro-5-methanesulfonyl-benzoic acid and cyclopentanol.
Reaction SMILES: Cl.Cl.Cl.[CH2:4]([O:6][CH2:7][C:8]1[N:9]([CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]2)[C:10]2[C:19]3[CH:18]=[CH:17][C:16]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:15][C:14]=3[N:13]=[C:12]([NH2:26])[C:11]=2[N:27]=1)[CH3:5].C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)(Cl)Cl>[CH2:4]([O:6][CH2:7][C:8]1[N:9]([CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][N:30]2[S:43]([CH3:42])(=[O:45])=[O:44])[C:10]2[C:19]3[CH:18]=[CH:17][C:16]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:15][C:14]=3[N:13]=[C:12]([NH2:26])[C:11]=2[N:27]=1)[CH3:5]
Reactant: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CC1CCCCN1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CC1CCCCN1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.9 %

Procedure:
A solution of 2-ethoxymethyl-1-(piperidin-2-ylmethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine trihydrochloride (0.60 g, 1.1 mmol) and triethylamine (0.79 mL, 5.7 mmol) in chloroform (50 mL) was cooled to 4° C. Methanesulfonyl chloride (0.12 mL, 1.5 mmol) was added, and the reaction was allowed to warm to ambient temperature and stirred overnight. Additional methanesulfonyl chloride (2.5 equivalents) was added at 4° C. over the course of several days. The work-up procedure described in Examples 178 to 181 was carried out. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from about 100:0 to 70:30) followed by recrystallization from acetonitrile to provide 0.19 g of 2-ethoxymethyl-1-{[1-(methanesulfonyl)piperidin-2-yl]methyl}-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 152-154° C.
Reaction SMILES: [C:1](OCC)(OCC)([O:3][CH2:4][CH3:5])[CH3:2].[C:12](#[N:16])[CH2:13][C:14]#[N:15]>C(O)(=O)C.C(O)C>[CH2:1]([O:3][C:4](=[C:13]([C:12]#[N:16])[C:14]#[N:15])[CH3:5])[CH3:2]
Reactant: N#CCC#N
Reactant: CCOC(C)(OCC)OCC
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(C)=C(C#N)C#N
Reaction time: 0.67 h
Yield: 91.4 %

Procedure:
Triethyl orthoacetate (97 g, 0.6 mol), malononitrile (33 g, 0.5 mol) and glacial acetic acid (1.5 g) were placed in a 1 L flask equipped with a stirrer, thermometer and a Vigreux column (20×1 in.) on top of which a distillation condenser was placed. The reaction mixture was heated and ethyl alcohol began to distill when the temperature of the reaction mixture was about 85-90° C. After about 40 min., the temperature of the reaction mixture reached 140° C. Then the reaction was concentrated in a rotary evaporator to remove the low-boiling materials and the residue was crystallized from absolute alcohol to yield the pure product (62.2 g, 91%) as a light yellow solid mp 91.6° C.