Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[CH2:11]([O:13][C:14](=[O:17])[CH2:15][OH:16])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[OH-].[Na+]>[CH2:11]([O:13][C:14]([C:15]1[O:16][C:2]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=2[C:4]=1[NH2:5])=[O:17])[CH3:12]
Reactant: CCOC(=O)CO
Reactant: N#Cc1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1oc2ccc(F)cc2c1N
Reaction time: 24 h
Yield: 20.8 %

Procedure:
To a solution of 2,5-difluoro-benzonitrile (10 g, 72.0 mmol) in DMF (200 mL) was added hydroxy-acetic acid ethyl ester (8.6 mL, 86.4 mmol) followed by K2CO3 (43.7 g, 316 mmol). After 24 h at 100° C., the reaction mixture was diluted with 1 N NaOH (200 mL) and extracted with CH2Cl2 (3×150 mL). The combined organic layers were washed with 1 N NaOH (100 mL), dried, and concentrated to afford the desired product (3.35 g, 21%). 1H NMR (CDCl3): 7.39 (dd, J=9.0, 4.0 Hz, 1H), 7.21-7.15 (m, 2H), 4.90 (s, 2H), 4.45 (q, J=7.1 Hz, 2H), 1.47 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH:8]([CH3:19])[N:9]3[C:14]=2[C:13]=1[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]3.[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH:8]([CH3:19])[N:9]3[C:14]=2[C:13]=1[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]3)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CC1CCc2ccc(N)c3c(=O)c(C(=O)O)cn1c23
Product: CC(=O)Nc1ccc2c3c1c(=O)c(C(=O)O)cn3C(C)CC2

Procedure:
10-Amino-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]-quinolizine-2-carboxylic acid (5.0 g., 0.018 mole) and acetic anhydride (50 ml.) are stirred and heated on a steam bath for three hours. After cooling, the solid precipitate is separated by filtration, washed with water, dried, then recrystallized from N,N-dimethyl formamide to provide 10-acetamido-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, m.p. 277°-279° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][N:13]1[CH2:18][CH2:17][C:16]([CH2:25][NH2:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:14]1>>[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:26][CH2:25][C:16]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]1)=[O:6]
Reactant: CN1CCC(CN)(c2ccccc2)CC1
Reactant: Cc1cccc(C(=O)O)c1C
Product: Cc1cccc(C(=O)NCC2(c3ccccc3)CCN(C)CC2)c1C

Procedure:
From 2,3-dimethylbenzoic acid and C-(1-methyl-4-phenyl-piperidin-4-yl)-methylamine. LCMS (MH30 ) m/z=337.0, tR (minutes, Method A)=0.65
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:39][C:40]1[CH:41]=[CH:42][C:43]([N:67]2[N:71]=[CH:70][CH:69]=[N:68]2)=[C:44]([C@H:46]([O:48][C:49]2[C:50]([NH2:66])=[N:51][CH:52]=[C:53]([C:55]3[CH:56]=[N:57][N:58]([CH:60]4[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]4)[CH:59]=3)[CH:54]=2)[CH3:47])[CH:45]=1>CS(C)=O.CO>[NH2:66][C:50]1[N:51]=[CH:52][C:53]([C:55]2[CH:56]=[N:57][N:58]([CH:60]3[CH2:61][CH2:62][N:63]([C:4](=[O:5])[CH2:3][N:2]([CH3:7])[CH3:1])[CH2:64][CH2:65]3)[CH:59]=2)=[CH:54][C:49]=1[O:48][C@@H:46]([C:44]1[CH:45]=[C:40]([F:39])[CH:41]=[CH:42][C:43]=1[N:67]1[N:71]=[CH:70][CH:69]=[N:68]1)[CH3:47]
Reactant: CN(C)CC(=O)O
Reactant: C[C@@H](Oc1cc(-c2cnn(C3CCNCC3)c2)cnc1N)c1cc(F)ccc1-n1nccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@@H](Oc1cc(-c2cnn(C3CCN(C(=O)CN(C)C)CC3)c2)cnc1N)c1cc(F)ccc1-n1nccn1
Reaction time: 0.25 h

Procedure:
To a solution of 2-(dimethylamino)acetic acid (54 mg, 0.55 mmol) and HATU (105 mg, 0.27 mmol) in DMSO (1 mL) was added triethylamine (0.063 ml, 0.46 mmol). After stirring for ˜15 min, the mixture was added to a flask containing 3-{(1R)-1-[5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]ethoxy}-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine (example 80) (43 mg, 0.09 mmol. The mixture was stirred at room temperature for 18 hr. Additional portion of 2-(dimethylamino)acetic acid (28 mg), HATU (105 mg) and TEA (63 μL) were added and the mixture was stirred at RT for 2 hr. LCMS indicated the reaction complete. The mixture was diluted with MeOH and purified by reverse phase prep-HPLC. The desired fractions were lyophilized to give the title compound as an acetic acid salt (17 mg).
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.C[Al](C)C.[NH:18]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:19]1[C:20](OCC)=[O:21].Cl>C(Cl)Cl.O>[Cl:1][C:2]1[C:8]([O:9][CH:10]([CH3:11])[CH3:12])=[CH:7][C:5]([NH:6][C:20]([CH:19]2[CH2:25][CH2:26][CH2:27][CH2:28][NH:18]2)=[O:21])=[C:4]([F:13])[CH:3]=1
Reactant: CCOC(=O)C1CCCCN1
Reactant: CC(C)Oc1cc(N)c(F)cc1Cl
Agent: C[Al](C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)Oc1cc(NC(=O)C2CCCCN2)c(F)cc1Cl
Reaction time: 48 h

Procedure:
The product of Example 1, Step A (4.25 g, 26.37 mmol) was dissolved in CH2Cl2 (200 mL). A solution of 2.0M trimethylaluminum (52.75 mmol) was added dropwise under nitrogen at 0° C. The resultant mixture was stirred at room temperature overnight. Ethyl pipecolinate (4.15 g) was added dropwise to the mixture and the mixture was stirred for 2 days. To the reaction mixture 6N HCl (100 mL) was added dropwise at 0° C. 200 mL of H2O was added, followed by the addition of 150 mL of methylene chloride. The aqueous layer was separated and basicified to pH 10 with 50% aqueous NaOH. 500 mL of CH2Cl2 was added. The organic layer was separated, dried over MgSO4, filtered and evaporated to dryness under vacuum to give the title compound of Step A as a white solid, 4.7 g. m.p. 96°-98° C. 1H NMR (CDCl3): δ9.25 (br s,1H), 8.17 (d,1H), 7.13 (d,1H) 4.58 (m,1H), 3.20 (M,1H), 3.10 (m,1H), 2.79 (m,1H), 2.00 (m,1H), 1.89 (m,2H), 1.60-1.40 (m,4H), 1.36 (d,6H).
Reaction SMILES: [C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](O)=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].S(Cl)([Cl:15])=O>>[C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8]([Cl:15])=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Reactant: O=S(Cl)Cl
Product: CC(=O)N1CCC(C(=O)Cl)CC1

Procedure:
A sample of 65.4 g of 1-acetylisonipecotic acid is dissolved in 400 ml of thionyl chloride. The acid chloride precipitates from solution and one liter of petroleum ether is added. The mixture is filtered, the solid residue is washed several times with petroleum ether and dried, giving 1-acetylisonipecotoyl chloride as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:25])[C:6]=1[N:7]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14]C(=O)OCC2C=CC=CC=2)[CH2:9][CH2:8]1.C(OC([NH:33][C:34]1[S:38][C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:40]=2[F:46])=[N:36][C:35]=1[C:47](O)=[O:48])=O)(C)(C)C>>[NH2:33][C:34]1[S:38][C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:40]=2[F:46])=[N:36][C:35]=1[C:47]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:25])[C:6]=1[N:7]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH2:14])[CH2:9][CH2:8]1)=[O:48]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2cccc(F)c2F)nc1C(=O)O
Reactant: Cn1ncc(N)c1N1CCC[C@@H](NC(=O)OCc2ccccc2)CC1
Product: Cn1ncc(NC(=O)c2nc(-c3cccc(F)c3F)sc2N)c1N1CCC[C@@H](N)CC1

Procedure:
Following the procedures from Example 140, (R)-benzyl 1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate from Example 16 and 5-(tert-butoxycarbonylamino)-2-(2,3-difluorophenyl)thiazole-4-carboxylic acid from Example 42 were converted to 377. 1H NMR (400 MHz, DMSO) δ 8.92 (br, 1H), 8.06 (t, J=7.2 Hz, 1H), 7.62-7.39 (m, 4H), 7.34 (dd, J=13.1, 7.8 Hz, 1H), 3.66 (s, 4H), 3.20-3.01 (m, 5H), 1.92-1.76 (m, 3H), 1.71-1.47 (m, 3H). MS (ESI) m/z: 448.2 [M+H+].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[N+:16]([O-])([O-:18])=[O:17].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:16]([C:15]1[CH:14]=[CH:13][C:4]([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:6])=[CH:3][C:2]=1[OH:1])([O-:18])=[O:17]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(c1ccccc1)c1cccc(O)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccc([N+](=O)[O-])c(O)c1
Reaction time: 24 h
Yield: 30 %

Procedure:
3-Hydroxybenzophenone (3.00 g, 15.1 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (1.42 g, 16.7 mmol). The addition of sulfuric acid (25 mL/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(1.10 g, 30%). 1H NMR (CD3COCD3): d 8.25 (d,1H), 7.86 (d, 1H), 7.71 (m, 1H), 7.59 (d, 1H), 7.48 (s, 1H), 7.39 (dd, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([OH:9])=O.C(Cl)(=O)C([Cl:13])=O>CN(C)C=O.O1CCCC1.C(OCC)C>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([Cl:13])=[O:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1[nH]cnc1C(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1[nH]cnc1C(=O)Cl
Temperature: 25 °C

Procedure:
Under a dry nitrogen atmosphere, a stirred suspension of 5-methyl-1H-imidazole-4-carboxylic acid (12.6 g, 0.10 mole) and several drops of dimethylformamide in 125 ml of dry tetrahydrofuran was cooled in an ice bath. Oxalyl chloride, 20 ml, in 50 ml of tetrahydrofuran was carefully added dropwise. Upon complete addition the reaction mixture was heated under reflux for two hours, cooled to ambient temperature and diluted with 100 ml of diethyl ether. A solid precipitated and was collected by filtration, washed with diethyl ether, and dried to give 5-methyl-1H-imidazole-4-carboxylic acid chloride.
Reaction SMILES: [CH2:1]([C:3]1(C2C=CC(OC)=CC=2)[C:12](=O)[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][CH:10]=2)[S:5][CH2:4]1)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.[CH2:31]([Si](C)(C)C)[CH:32]=[CH2:33]>O1CCCC1.[I-].[Zn+2].[I-].O.CO.C(OCC)(=O)C>[CH2:32]([C:31]1([C:11]2[CH:10]=[CH:9][C:8]([O:14][CH3:15])=[CH:7][CH:6]=2)[CH:12]([CH2:3][CH:1]=[CH2:2])[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][CH:10]=2)[S:5][CH2:4]1)[CH3:33]
Reactant: CCC1(c2ccc(OC)cc2)CSc2cc(OC)ccc2C1=O
Reactant: C=CC[Si](C)(C)C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C=CCC1c2ccc(OC)cc2SCC1(CC)c1ccc(OC)cc1
Temperature: -20 °C
Reaction time: 4 h
Yield: 117.8 %

Procedure:
A solution of 3-ethyl-7-methoxy-3-(4-methoxyphenyl)-thiochroman-4-one (13.7 g, 41.8 mmol) in anhydrous tetrahydrofuran (100 ml) was added dropwise to a solution of lithium aluminum hydride (950 mg, 25 mmol) in anhydrous tetrahydrofuran (100 ml) at −78° C. under argon atmosphere, and the resulting mixture was warmed to −20° C. over 1 hour. Ethyl acetate, methanol and 2N aqueous hydrochloric acid were added sequentially to the reaction mixture, which was then filtered through cellite. After extraction with ethyl acetate, the organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the resulting residue (13.10 g) was dissolved in 1,2-dichloroethane (360 ml) and then mixed with allyltrimethylsilane (12.47 ml, 78.75 mmol). Zinc iodide (15.08 g, 47.27 mmol) was added to this solution at 0° C. under argon atmosphere, and the resulting mixture was stirred for 4 hours at 40° C. Water and dilute hydrochloric acid were added sequentially to this mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel flash column chromatography (eluent: hexane/ethyl acetate=20/1) to give (3RS,4RS)-3-ethyl-7-methoxy-3-(4-methoxyphenyl)-4-(2-propenyl)thiochroman (8.73 g, Yield 62% for 2 steps).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)(=[O:23])=[O:22])[CH:16]=[CH:15]3)[CH2:9]1)=O)(C)(C)C.[ClH:34]>C(O)=O.CCOCC>[ClH:34].[NH:8]1[CH2:11][CH:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=2)(=[O:22])=[O:23])[CH:16]=[CH:15]3)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc3c(ccn3S(=O)(=O)c3cccc(C(F)(F)F)c3)c2)C1
Agent: Cl
Solvent: O=CO
Solvent: CCOCC
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)n1ccc2cc(C3CNC3)ccc21
Reaction time: 2 h
Yield: 44 %

Procedure:
3-[1-(3-Trifluoromethyl-benzenesulfonyl)-1H-indol-5-yl]-azetidine-1-carboxylic acid tert-butyl ester (compound 13) (400 mg, 0.83 mmol) was dissolved in formic acid (4.7 ml) at 0° C. and stirred for 2 hours. The reaction mixture was evaporated to dryness at 30° C. The residue was dissolved in ethyl acetate (50 ml), and washed with a 1 molar aqueous solution of NaOH (10 ml). The organic layer was dried over magnesium sulphate, filtered, and evaporated to dryness to yield the crude product (231 mg, 82%). The crude product was dissolved in ether (50 ml), treated with a solution of hydrochloric acid in ether, and the precipitate was collected to give the product (151 mg, 44%).
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:16]3=[O:17])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH2:28]([OH:30])[CH3:29].Cl>C(Cl)(Cl)Cl>[CH2:28]([O:30][C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[CH2:10][CH2:11][CH:12]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:16]3=[O:17])[CH2:13][CH2:14]2)=[O:8])=[CH:26][CH:27]=1)=[NH:2])[CH3:29]
Reactant: N#Cc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Reactant: CCO
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=N)c1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Reaction time: 96 h

Procedure:
1-[1-(4-Cyanobenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (1 g) is dissolved in chloroform (10 ml) and thereto is added ethanol (0.18 ml). Under ice cooling, hydrochloric acid gas is passed through the mixture to saturate and further the mixture is stirred at 5°-7° C. for 4 days. After the reaction, the solvent is concentrated to give 1-{1-[4-(1-ethoxy-1-iminomethyl)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (1 g). This product is used for the subsequent reaction.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=[C:4]([Cl:15])[N:3]=1.[N:16]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26][NH2:27])=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.CCN(CC)CC>CC#N>[Cl:15][C:4]1[N:3]=[C:2]([NH:27][CH2:26][C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[N:16]=[CH:17][CH:18]=[CH:19]3)[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=1
Reactant: NCc1ccc2ncccc2c1
Reactant: CC(=O)Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)Nc1cc(Cl)nc(NCc2ccc3ncccc3c2)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
To a mixture of N-(2,6-dichloro-3-nitropyridin-4-yl)acetamide (240 mg, 0.96 mmol) and quinolin-6-ylmethanamine (150 mg, 0.96 mmol) in CH3CN (10 mL) was added Et3N (0.5 mL). The reaction mixture was stirred at 80° C. for 1 h. After being cooled to room temperature, the mixture was purified by chromatography on silica gel eluting with DCM/MeOH=50/1 to afford the title compound (220 mg). MS (m/z): 372 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:6][C:5]([Cl:17])=[CH:4][N:3]=1.[BH4-].[Na+].O>C(O)C>[NH2:1][C:2]1[C:7]([CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[CH:6][C:5]([Cl:17])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1cc(Cl)cnc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)CCc1cc(Cl)cnc1N
Reaction time: 16 h
Yield: 65 %

Procedure:
To a solution of t-butyl (E)-3-(2-amino-5-chloro-3-pyridinyl)-2-propenoate (500 mg, 2.0 mmol) in ethanol (10 ml) at RT was added sodium borohydride (317 mg, 8.4 mmol) portionwise and the mixture stirred for 16 h. After the addition of water, the ethanol removed in vacuo and the mixture extracted with diethyl ether. The ethereal extracts were dried over MgSO4, evaporated to dryness and purified by column chromatography upon silica gel using hexane—EtOAc (7:3) as eluant to give t-butyl 3-(2-amino-5-chloro-3-pyridinyl)propanoate as a colourless oil (340 mg, 1.3 mmol).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][C@H:20]1[CH2:25][NH:24][CH2:23][C@@H:22]([CH3:26])[NH:21]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:24]3[CH2:23][C@H:22]([CH3:26])[NH:21][C@H:20]([CH3:19])[CH2:25]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: C[C@@H]1CNC[C@H](C)N1
Product: C[C@@H]1CN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)C[C@H](C)N1

Procedure:
NMR: (400 Mhz, CDCl3): 1.19-1.24 (6H, m, CH3), 2.61 (2H, t (J 10.72), CH2), 2.80 (3H, s, CH3), 2.88-2.90 (2H, m, CH2), 3.59 (2H, d (J 10.46), CH2), 3.93-4.00 (8H, m, CH2) 4.14 (2H, s, CH2), 7.12 (1H, s, ar), 7.51 (1H, t (J 7.80), ar), 7.60 (1H, d (J 8.29), ar), 8.32 (1H, d (J 6.73), ar), 9.04 (1H, s, ar), 10.10 (1H, b, NH) 6: Reaction between 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde and cis-2,6-dimethyl-piperazine using procedure C yielded 2-chloro-6-((3R,5S)-3,5-dimethyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine. This compound treated with methane sulphonyl chloride using standard conditions to yield 2-chloro-6-((3R,5S)-4-methanesulfonyl-3,5-dimethyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine. This compound was subjected to procedure A to yield the desired final compound which was purified using flash chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[CH:5][C:4]=1[C:14]([F:17])([F:16])[F:15].C(O)C>[Pd].O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:5][C:4]=1[C:14]([F:15])([F:17])[F:16]
Reactant: COc1ccc(C=CC(=O)O)cc1C(F)(F)F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(CCC(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
A mixture of 3-[4-methoxy-3-(trifluoromethyl)phenyl]acrylic acid (2.90 g, 11.8 mmol), 10% palladium on carbon (250 mg), ethanol (60 mL) and tetrahydrofuran (40 mL) was stirred under a hydrogen atmosphere (1 kg/cm2) at room temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-0/1) to give the title compound (2.40 g, yield 83%) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([O-])=O.B.[K]>CO.[Cu](Cl)Cl>[NH2:1][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Agent: Cl[Cu]Cl
Agent: B
Agent: [K]
Solvent: CO
Product: Nc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
To a solution of 4-nitrobenzylalcohol (4.59 g) in methanol (300 ml) was added copper chloride (I) (17.8 g) at room temperature, and then was gradually added potassium boron hydride (11.3 g) for 40 minutes. The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=3/1) to give 4-aminobenzylalcohol (1.31 g) as pale yellow crystals.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([C:16]([O:18]CC)=[O:17])=[CH:5][N:4]=1.[OH-].[Na+]>C(O)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([C:16]([OH:18])=[O:17])=[CH:5][N:4]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1ncc(C(=O)O)c(Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
A mixture containing 3.98 g (13.75 mmol) of the product prepared in step 20.1, 34.4 mL (34.4 mmol) of 1N NaOH and 35 mL of ethanol is stirred at room temperature overnight. The ethanol is evaporated off under reduced pressure and the residue is diluted in 100 mL of water. 65 mL of aqueous 1N HCl solution are added and the precipitate formed is drained by suction. The solid is rinsed with water and dried under vacuum. 2.88 g of the expected product are obtained in the form of a beige-coloured solid. Yield=92%.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:19]([O:21][CH3:22])=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=O)(C)(C)C.[ClH:23].O1CCOCC1>C(Cl)Cl>[ClH:23].[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][C@@H:9]([C:19]([O:21][CH3:22])=[O:20])[NH2:8])=[CH:16][CH:15]=1
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Yield: 84 %

Procedure:
The same procedures as in Example 29 were carried out from the compound obtained in Example 32 (50.6 g), 4 mol/L of hydrogen chloride-dioxane (123 mL), and methylene chloride (400 mL), to give the captioned compound (33.7 g, 84%) as crystals.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[C:17]([NH2:26])[C:16]=2[N:15]=[CH:14]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[C:17]([NH2:26])[C:16]=2[N:15]=[CH:14]1
Reactant: CC(C)(C)OC(=O)NCCCCn1cnc2c(N)nc3ccccc3c21
Solvent: O=C(O)C(F)(F)F
Product: NCCCCn1cnc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
One hundred ml of trifluoroacetic acid was added to 16.04 g (45.13 mmol) 1-[4-(tert-butoxycarbonylamino)butyl]-1H-imidazo[4,5-c]-quinoline-4-amine and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated to dryness. A 2N sodium hydroxide solution aqueous solution (120 ml) was added thereto and the mixture was stirred. The precipitate thus formed was collected by filtration and washed with water and diethyl ether to obtain 9.64 g (37.76 mmol) of 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinoline-4-amine shown below as a pale yellowish white solid. ##STR56## Its physicochemical properties were in agreement with those of the compound of Example 17.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][C:12]([OH:14])=O.C1N=C[N:17](C(N2C=NC=C2)=O)[CH:16]=1.CN.C(OCC)(=O)C>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][C:12]([NH:17][CH3:16])=[O:14]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(CC(=O)O)c(OC)c1
Agent: CN
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CNC(=O)Cc1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 73.3 %

Procedure:
A mixture of (2,4-dimethoxyphenyl)acetic acid (577 mg, 3.0 mmol) and N,N-carbonyldiimidazole (608 mg, 3.75 mmol) in DMF (10 mL) was stirred at room temperature for 45 min, aqueous 40% methyl amine (4.5 mL) was added and the reaction mixture was stirred at room temperature over the week-end. The reaction mixture was is partitoned between ethyl acetate and H2O. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-80% ethyl acetate in petroleum spirit) to give the subtitled compound (460 mg).