Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[NH2:11][C:12]1[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[O:9])[CH:3]=1
Reactant: Cc1ccccc1N
Reactant: O=C(Cl)c1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)c1cc(Cl)ncn1

Procedure:
A cooled (0° C.) solution of 6-chloropyrimidine-4-carbonyl chloride (26.76 g; 151 mmol), obtained as described above for Intermediate 7 step 1, in anhydrous DCM (270 ml) was treated dropwise over 25 minutes with a solution of o-toluidine (13.6 ml; 126.0 mmol) and DIEA (43.4 ml; 252 mmol) in anhydrous DCM (100 mL). At the end of addition, the reaction mixture was washed with water then brine, dried over MgSO4, filtered and dried under vacuum to afford the title compound used without further purification as a brown solid. 1H NMR (300 MHz, DMSO-d6) δ 10.47 (1H, br s), 9.32 (1H, d, J=1.0 Hz), 8.25 (1H, d, J=1.0 Hz), 7.65-7.63 (1H, m), 7.34-7.19 (3H, m), 2.31 (3H, s). MS (ESI+): 248.0; MS (ESI−): 246.1. HPLC (Condition A): Rt 4.19 min (HPLC purity 96.0%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:40])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:35][C:36]([OH:39])([CH3:38])[CH3:37])[S:21]([C:24]1[CH:25]=[C:26]([CH2:30][C:31]([O:33]C)=[O:32])[CH:27]=[CH:28][CH:29]=1)(=[O:23])=[O:22].[OH-].[Li+].O1CCCC1>O>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:40])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:35][C:36]([OH:39])([CH3:38])[CH3:37])[S:21]([C:24]1[CH:25]=[C:26]([CH2:30][C:31]([OH:33])=[O:32])[CH:27]=[CH:28][CH:29]=1)(=[O:22])=[O:23]
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCN(CC(C)(C)O)S(=O)(=O)c3cccc(CC(=O)OC)c3)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCN(CC(C)(C)O)S(=O)(=O)c3cccc(CC(=O)O)c3)c2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
By the same manner to Example 2-12, the compound obtained in Example 2-22 (70 mg) and lithium hydroxide (20 mg) were added to tetrahydrofuran (4 ml) and water (2 ml) and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure and partitioned between 2M hydrochloric acid and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layer was dried and concentrated under reduced pressure to give the titled compound as a white solid. Yield: 23 mg (34%); MS APCI+ve 565 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:8][CH2:9][CH2:10][OH:11])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]([C:16]1[S:25][C:19]2[N:20]=[C:21](Cl)[N:22]=[CH:23][C:18]=2[C:17]=1[CH3:26])=[O:15]>>[CH3:12][O:13][C:14]([C:16]1[S:25][C:19]2[N:20]=[CH:21][N:22]=[C:23]([NH:1][C:2]3[C:3]([O:8][CH2:9][CH2:10][OH:11])=[N:4][CH:5]=[CH:6][CH:7]=3)[C:18]=2[C:17]=1[CH3:26])=[O:15]
Reactant: COC(=O)c1sc2nc(Cl)ncc2c1C
Reactant: Nc1cccnc1OCCO
Product: COC(=O)c1sc2ncnc(Nc3cccnc3OCCO)c2c1C

Procedure:
Prepared analogously to example 28.1 from 2-(3-aminopyridin-2-yloxy)ethanol (175 mg) and chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (121 mg)
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][C:9]2[C:4](=[C:5]([F:22])[C:6]([F:21])=[C:7]([F:20])[CH:8]=2)[N:3]=1.CO[CH:25](OC)[N:26]([CH3:28])[CH3:27]>C(OCC)(=O)C>[Cl:1][C:2]1[C:11]([C:12]([C:13](=[CH:25][N:26]([CH3:28])[CH3:27])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:19])=[CH:10][C:9]2[C:4](=[C:5]([F:22])[C:6]([F:21])=[C:7]([F:20])[CH:8]=2)[N:3]=1
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)c1cc2cc(F)c(F)c(F)c2nc1Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(F)c(F)c2nc1Cl
Reaction time: 2 h

Procedure:
A suspension of 26.7 g of ethyl 3-(2-chloro-6,7,8-trifluoro-3-quinolyl)-3-oxopropionate in 270 cm3 of ethyl acetate and 32 cm3 of N,N-dimethylformamide dimethyl acetal is heated at a temperature close to 75° C., with stirring, for 2 hours. The reaction mixture is concentrated to dryness under reduced pressure (20 kPa) at about 50° C. The dry extract is taken up in 175 cm3 of diisopropyl ether, drained and washed with twice 85 cm3 of the same solvent. 19.32 g of ethyl 2-(2-chloro-6,7,8-trifluoro quinoline-3-carbonyl)-3-dimethylaminoacrylate are obtained in the form of an orange solid melting at 118° C., which is used for the subsequent steps without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:22][C:23]([C:25]2[CH:29]=[C:28]([OH:30])[N:27]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:38])[C@@H:13]([NH:22][C:23]([C:25]2[CH:29]=[C:28]([O:30][CH2:40][C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:42])[N:27]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3cccc(F)c3)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)n(-c3cccc(F)c3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4.0 g 4-((S)-3-tert-Butoxycarbonyl-2-{[1-(3-fluoro-phenyl)-5-hydroxy-1H-pyrazole-3-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid ethyl ester in 20 ml DMF were added 1.242 ml benzyl bromoacetate and 4.884 g cesium carbonate. After stirring at RT for 12 h the solution was reduced to a volume of 50 ml, diluted with 200 ml ethyl acetate and extracted with aqueous LiCl (4% w/w) and aqueous NaHCO3. The crude product obtained after evaporation of the solvent was used in the subsequent reaction.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[OH-].[K+].C(O)C>O>[CH2:12]([C:7]1[C:6]([C:4]([OH:5])=[O:3])=[C:10]([CH3:11])[O:9][N:8]=1)[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1c(CCc2ccccc2)noc1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1onc(CCc2ccccc2)c1C(=O)O

Procedure:
A mixture of 300 g. (1.30 mole) 3-phenethyl-5-methyl-isoxazole-4-carboxylic acid ethyl ester, 146 g. (1.60 mole) potassium hydroxide 1500 ml. ethanol and 500 ml. water is stirred for 2 hours at room temperature and 2 additional hours at reflux. The ethanol is evaporated in vacuo and the aqueous solution is cooled and acidified with hydrochloric acid. The resulting solid is filtered and washed with water and triturated with methanol to give 3-phenethyl-5-methyl-isoxazole-4-carboxylic acid; m.p. 154° to 156° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][C:15]#[N:16])[CH:9]=1.N1CCCCC1>CO>[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[CH:6][C:2]2[NH:1][CH:5]=[CH:4][CH:3]=2)[C:15]#[N:16])[CH:9]=1
Reactant: N#CCc1cccnc1
Reactant: O=Cc1ccc[nH]1
Solvent: CO
Solvent: C1CCNCC1
Product: N#CC(=Cc1ccc[nH]1)c1cccnc1
Yield: 47.8 %

Procedure:
A mixture of pyrrole-2-carboxaldehyde (2.85 g; 30 mmol), 3-pyridylacetonitrile (3.54 g; 30 mmol), and piperidine (2 mL) in methanol (50 mL) was refluxed for 18 hours. The dark precipitate formed was separated by filtration. Dark solid was treated with charcoal in hot methanol to obtain 2.8 g (48%) of the title compound as a yellow solid, m.p. 139°-142° C. Anal. Calcd. for C12H9N3 : C, 73.83; H, 4.65; N, 21.52. Found: C, 73.71; H, 4.57; N, 21.76. Mass spectrum: (EI; M+) m/z 195. 1H-NMR (DMSO-d6 ; 200 MHz) δ 11.5 (s, 1H), 8.8 (d, 1H), 8.5 (d, 1H), 7.92-7.96 (m, 1H), 7.8 (s, 1H), 7.43-7.52 (m, 1H), 7.2 (d, 2H), 6.38-6.4 ppm (q, 1H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH:7]1[CH2:23][O:22][C:10]2=[CH:11][CH:12]=[C:13]3[C:17]([N:16]([CH2:18][C@@H:19](O)[CH3:20])[N:15]=[CH:14]3)=[C:9]2[CH2:8]1)[CH3:5])[CH3:2].C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[N-:40]=[N+:41]=[N-:42].[Na+]>C1COCC1>[N:40]([C@H:19]([CH3:20])[CH2:18][N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]3[O:22][CH2:23][CH:7]([O:6][CH:4]([O:3][CH2:1][CH3:2])[CH3:5])[CH2:8][C:9]3=2)[CH:14]=[N:15]1)=[N+:41]=[N-:42]
Reactant: CCOC(C)OC1COc2ccc3cnn(C[C@H](C)O)c3c2C1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(C)OC1COc2ccc3cnn(C[C@@H](C)N=[N+]=[N-])c3c2C1
Temperature: 95 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a solution of the product from Step G (0.35 g, 1.09 mmol) and triethylamine (0.55 g, 5.47 mmol) in anhydrous THF (50 ml) at 0° C. was added methanesulfonic anhydride (0.47 g, 2.73 mmol). The mixture was stirred for 1 h and sodium azide (0.71 g, 10.9 mmol) was added. The reaction mixture was evaporated to a residue that was dissolved in anhydrous DMF (80 mL) and heated at 95° C. for 3 h. The mixture was cooled, poured into a saturated solution of sodium bicarbonate (80 mL), and extracted with EtOAc (3×80 mL). The combined extracts were dried (MgSO4) and evaporated to a residue that was purified by chromatography (silica, 10% EtOAc/hexane) to give an oil (0.30 g, 80%): LC/MS (+APCI) m/z 346 (M+H).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[F:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1>CSC.O1CCCC1>[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:6]2[CH2:5][CH2:4][CH:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2](=[O:1])[CH2:7]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)CC1CCC=CC1=O
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: CSC
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCC(c2ccc(F)cc2)CC1=O
Reaction time: 0.33 h

Procedure:
This ester (4 g, 0.022 mmol), copper (I) bromide-dimethyl sulfide complex (4.88 g, 0.023 mmol) in dimethyl sulfide (20 ml) and tetrahydrofuran (120 ml) was cooled to −40° C. under nitrogen and treated dropwise with 4-fluorophenylmagnesium bromide (1M solution in THF, 43.9 ml) so that the temperature did not rise above −40° C. Reaction was stirred for 20 minutes before quenching with 1N HCl (300 ml) and extracting the products with ether (3×300 ml). Combined organic phase washed with saturated sodium chloride, dried over magnesium sulfate and evaporated to dryness. The crude oil was purified by silica chromatography eluting with hexane-ethyl acetate mixtures (10-20%), to give ethyl [4-(4-fluorophenyl)-2-oxo-cyclohexyl]acetate as a colourless oil, 2.8 g. 1H NMR δ (ppm) (CDCl3): 7.26-7.11 (2H, m), 7.04-6.94 (2H, m), 4.18-4.11 (2H, m), 3.55-3.44 (1H, m), 3.00-2.90 (1H, m), 2.80-2.73 (2H, m), 2.69-2.55 (1H, m), 2.28-2.17 (2H, m), 2.10-1.88 (2H, m), 1.61-1.42 (1H, m) and 1.31-1.25 (3H, m).
Reaction SMILES: O1CC[CH2:3][CH2:2]1.[C:6]([O:10][C:11](=[O:47])[N:12]([CH2:36][C:37]1[CH:46]=[CH:45][C:40]2[O:41][CH2:42][CH2:43][O:44][C:39]=2[CH:38]=1)[CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]2[C:30]3[C:25](=[C:26]([CH:33]=[O:34])[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=3)[CH:24]=[CH:23][C:22]2=[O:35])[CH2:15][CH2:14]1)([CH3:9])([CH3:8])[CH3:7].C([Mg]Br)C.O1CCCC1.[Cl-].[NH4+]>C(Cl)(Cl)Cl.O>[C:6]([O:10][C:11](=[O:47])[N:12]([CH2:36][C:37]1[CH:46]=[CH:45][C:40]2[O:41][CH2:42][CH2:43][O:44][C:39]=2[CH:38]=1)[CH:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][N:21]2[C:30]3[C:25](=[C:26]([CH:33]([OH:34])[CH2:2][CH3:3])[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=3)[CH:24]=[CH:23][C:22]2=[O:35])[CH2:17][CH2:18]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: C1CCOC1
Reactant: COc1cc(C=O)c2ccc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCC(O)c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Reaction time: 1.5 h

Procedure:
To 20 mL of a tetrahydrofuran solution containing 0.65 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-formyl-7-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 8.8 mL of 1 mol/L ethylmagnesium bromide/tetrahydrofuran was added at −78° C. and stirred for 1.5 hours. To the reaction mixture, aqueous saturated ammonium chloride solution, water and chloroform were added. The organic layer was separated, washed sequentially with aqueous saturated sodium hydrogen carbonate solution and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=20:1], to give 200 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-(1-hydroxypropyl)-7-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7](OC)=[O:8].[NH3:15]>CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([NH2:15])=[O:8]
Reactant: N
Reactant: COC(=O)c1cc(O)ccc1[N+](=O)[O-]
Solvent: CO
Product: NC(=O)c1cc(O)ccc1[N+](=O)[O-]

Procedure:
Methyl 5-hydroxy-2-nitrobenzoate (48 g) in 340 ml methanol was heated 30 hours at 107° in a pressure vessel with 140 ml NH3. The mixture was cooled and concentrated to dryness on the rotovap. Water was added (200 ml) and the solid filtered and dried to give 12 g product, m.135-8.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[CH:5]=[CH:4][C:3]=1[C:16](=O)[CH3:17].[NH2:19][OH:20]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[CH:5]=[CH:4][C:3]=1[C:16](=[N:19][OH:20])[CH3:17]
Reactant: NO
Reactant: CC(=O)c1ccc(Oc2ccccc2Cl)cc1Cl
Solvent: CCO
Product: CC(=NO)c1ccc(Oc2ccccc2Cl)cc1Cl

Procedure:
A mixture of 2.4 g (8.54 mmol) of 1-[2-chloro-4-(2-chloro-phenoxy)-phenyl]-ethanone and 0.76 mL hydroxylamine solution (50% in water) in 60 mL ethanol was refluxed for 24 hours. Then the mixture was evaporated to dryness and the residue was purified by chromatography (silica gel column, methylene chloride).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[S:18])[S:12][CH2:13][C:14](=O)[CH2:15][Cl:16].[H][H]>>[Cl:16][CH2:15][C:14]1[N:10]([C:3]2[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=2[F:1])[C:11](=[S:18])[S:12][CH:13]=1
Reactant: O=C(CCl)CSC(=S)Nc1ccc(F)c(F)c1F
Reactant: [H][H]
Product: Fc1ccc(-n2c(CCl)csc2=S)c(F)c1F

Procedure:
3-Chloro-2-oxopropyl N-(2,3,4-trifluorophenyl)-dithiocarbamate (4.0 g) is added to 30% hydrogen chloridemethanol solution (15 ml), and the mixture is refluxed for 3 hours. The solvent is distilled off under reduced pressure, and cold water is added to the residue and the mixture is extracted with chloroform. The extract is washed with saline solution, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue is recrystallized from cyclohexane to give the title compound (2.6 9) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12]Cl)=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:15])=[C:7]([Cl:14])[CH:8]=2)[N:3]=1.[NH2:16][C:17]1[N:21]=[C:20]([SH:22])[NH:19][N:18]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[C:11]([CH2:12][S:22][C:20]2[NH:19][N:18]=[C:17]([NH2:16])[N:21]=2)=[N:10][C:9]2[C:4]([N:3]=1)=[CH:5][C:6]([Cl:15])=[C:7]([Cl:14])[CH:8]=2
Reactant: ClCc1nc2cc(Cl)c(Cl)cc2nc1Cl
Reactant: Nc1n[nH]c(S)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1n[nH]c(SCc2nc3cc(Cl)c(Cl)cc3nc2Cl)n1
Reaction time: 8 h

Procedure:
2,6,7-Trichloro-3-chloromethylquinoxaline (105 mg, 0.37 mmol) and 3-amino-5-mercapto-1,2,4-triazole (48 mg, 0.41 mmol) were dissolved in DMF (3 ml). Triethylamine (0.2 ml, 1.1 mmol) was added and the dark brown solution was allowed to stand at room temperature overnight. After evaporation of the solvent under reduced pressure, the residue was taken up in ethyl acetate and water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were concentrated in vacuo, and the residue was purified by flash column chromatography using ethyl acetate to afford the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.C(N(CC)CC)C.[C@:23]12([CH3:35])[C:29]([CH3:31])([CH3:30])[CH:26]([CH2:27][CH2:28]1)[CH2:25][CH:24]2[C:32](Cl)=[O:33]>ClCCl>[C@:23]12([CH3:35])[C:29]([CH3:30])([CH3:31])[CH:26]([CH2:27][CH2:28]1)[CH2:25][CH:24]2[C:32]([NH:1][CH:2]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1)=[O:33]
Reactant: NC(Cn1ccnc1)c1ccc(Cl)cn1
Reactant: CC1(C)C2CC[C@@]1(C)C(C(=O)Cl)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@@]1(C)C(C(=O)NC(Cn1ccnc1)c1ccc(Cl)cn1)C2
Reaction time: 1.5 h

Procedure:
To a solution of 0.38 g of 1-amino-1-(5-chloro-2-pyridyl)-2-(1H-imidazol-1-yl)ethane (racemic compound, see A) above) in 4 ml of dry dichloromethane is added 0.26 g (0.36 ml) of triethylamine. The mixture is stirred and cooled to -79°. Then 0.44 g of (1S)(-)-camphanic acid chloride are added in such a way that the temperature does not exceed -74°. Stirring is continued for additionally 90 minutes without further cooling. For working up the mixture is poured onto ice-water, extracted three times with dichloromethane and washed with brine. After drying with sodium sulfate the solvent is evaporated. A mixture of the two diastereomeric amides is obtained which is separated by chromatography over silica gel (dichloromethane/methanol/heptane=10/1/5). The two compounds are obtained as white crystals:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][NH:10][C:11](=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].Cl[C:22]([O:24][CH3:25])=[O:23]>O1CCCC1>[CH3:8][O:9][N:10]([C:22]([O:24][CH3:25])=[O:23])[C:11](=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: COC(=O)Cl
Reactant: CCCCCCCCC(=O)NOC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCC(=O)N(OC)C(=O)OC
Temperature: 25 °C

Procedure:
A 100 mL round-bottom flask equipped with a magnetic stir bar, argon inlet and pressure equalizing addition funnel is charged with tetrahydrofuran (14.0 mL), triethylamine (2.13 g, 1.5 eq) and N-methoxynonanamide (1.96 g, 1 eq). The reaction is cooled in an ice bath and methyl chloroformate (1.88 g, 1.4 eq) is added dropwise. The reaction is allowed to warm to room temperature overnight. The tetrahydrofuran is removed under vacuum and the residue is diluted with methylene chloride (25 mL). The reaction is washed with 0.1 M hydrochloric acid solution 1×20 mL), saturated aqueous sodium bicarbonate (3×20 mL)and brine 1×20 mL). The organic layer is dried over sodium sulfate, filtered and concentrated under vacuum.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].P(Cl)(Cl)[Cl:12]>ClCCCl.ClC(Cl)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:12])=[O:5]
Reactant: O=C(O)c1ccccc1Br
Reactant: ClP(Cl)Cl
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: O=C(Cl)c1ccccc1Br

Procedure:
To a mixture of 50.2 g (0.25 mole) of 2-bromobenzoic acid in 200 ml of 1,2-dichloroethane was added 13.7 g (0.10 mole) of phosphorous trichloride in 100 ml of dichloroethane. The mixture was heated at reflux for 4 hours to provide 2-bromobenzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].I([Cl:19])(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>C1COCC1>[Cl:19][CH2:14][C:13]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[Cl:1])=[N:10][C:9]([Cl:12])=[CH:8][CH:7]=2)=[O:15]
Reactant: O=I(=O)Cl
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(CCl)c1cnc2ccc(Cl)nc2c1Cl
Temperature: 70 °C
Reaction time: 5 h
Yield: 33.3 %

Procedure:
To a solution of 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (3.0 g, 12 mmol) in THF (120 mL) was added benzyltrimethylammonium dichloroiodate (4.3 g, 12 mmol) and the reaction mixture was stirred at 70° C. for 5 h. The reaction mixture was cooled, diluted with satd. aq. sodium bicarbonate and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by column chromatography (silica, dichloromethane/ethyl acetate) to afford the desired product (1.1 g, 32%) as an off-white solid. ESI MS m/z 275 [M+H]+.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:4]1.[CH:30](=O)[CH3:31]>>[Cl:14][C:11]1[C:12]([CH3:13])=[C:7]([CH:5]2[CH2:4][N:3]([CH2:30][CH3:31])[CH2:6]2)[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]2[C:21]3=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]3[C:19]([CH3:27])=[N:18]2)[CH3:16])[CH:10]=1
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Reactant: CC=O
Agent: Cl
Product: CCN1CC(c2c(C)c(Cl)cc(C(C)n3nc(C)c4c(N)ncnc43)c2OC)C1

Procedure:
This compound was prepared using procedures analogous to those for Example 1, with racemic 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride from Example 2, Step 1 and acetaldehyde instead of acetone. The crude purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. The product was isolated as a racemic mixture. LCMS calculated for C21H28ClN6O (M+H)+: m/z=415.2; Found: 415.1
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]1([C:16]2[N:17]=[C:18]([CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]3=[O:34])[O:19][C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1.CCCCCC.C([Li])CCC>[C:10]1([C:16]2[N:17]=[C:18]([CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]3([C:7]3[CH:2]=[CH:3][CH:4]=[C:5]([O:8][CH3:9])[CH:6]=3)[OH:34])[O:19][C:20]=2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccc(Br)cc1
Reactant: O=C1CCCCC1Cc1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc(C2(O)CCCCC2Cc2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a solution of 4-bromoanisole (1.00 g) in tetrahydrofuran (4 ml), n-butyllithium hexane solution (1.56M, 3.4 ml) was added at −78° C. under a flow of nitrogen. After stirring for 0.5 hour, a solution of 2-[(4,5-diphenyloxazol-2-yl)methyl]cyclohexan-1-one (1.36 g) in tetrahydrofuran (3 ml) was added below −50° C. to the reaction mixture and stirred for 0.5 hour. After usual workup, the crude product was purified by column chromatography (silica gel 50 g, eluent; hexane/ethyl acetate=9 then 4) to give 2-[(4,5-diphenyloxazol-2-yl)methyl]-1-(3-methoxyphenyl)-1-cyclohexanol (1.01 g) as a foam.