Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)=O.[CH2:25]([N:27]([CH2:30][CH2:31][CH2:32][C:33](=O)[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:28][CH3:29])[CH3:26]>C(O)C>[CH2:25]([N:27]([CH2:30][CH2:31][CH2:32][C:33]1[C:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=2)[C:4]2[C:3](=[CH:20][C:19]([O:21][CH3:22])=[C:18]([O:23][CH3:24])[CH:17]=2)[N:2]=1)[CH2:28][CH3:29])[CH3:26]
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Reactant: CCOC(=O)CC(=O)CCCN(CC)CC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(CCCN(CC)CC)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Yield: 13.6 %

Procedure:
A mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone hydrochloride (7.7 g), ethyl 6-(N,N-diethylamino)-3-oxohexanoate (5.0 g) and ethanol (100 ml) was stirred under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in chloroform. The chloroform layer was washed with an aqueous saturated solution of sodium bicarbonate and water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform-methanol (20:1, v/v) gave ethyl 2-[3-(N,N-diethylamino)propyl]-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (1.51 g, 14%). This compound was recrystallized from ethanol-hexane. Colorless prisms, mp. 96°-98° C.
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C[CH2:31][N:32](CC)CC.CN.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(Cl)Cl>[OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:32][CH3:31])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=C(O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Reactant: CCN(CC)CC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN
Solvent: ClCCl
Product: CNC(=O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Yield: 86.6 %

Procedure:
To a solution of 4-(((1R,2R)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (100 mg, 0.26 mmol), Et3N (157 mg, 1.56 mmol) and methyl amine (0.32 mL, 2.0 M solution in THF, 0.65 mmol) in DCM (5 mL), was added. T3P (0.33 mL, 50 wt % solution in ethyl acetate, 0.52 mmol) and then stirred at room temperature for 12 h. The reaction mixture was quenched with water (25 mL) and extracted with DCM (3×25 mL). The organic layer was washed with brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by CombiFlash using 20% ethyl acetate in chloroform as an eluent to yield 89 mg (86%) of the title compound as an off white solid.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:16]=[CH:15][N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][N:12]3[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH3:31][O:30][C:27]1[N:26]=[CH:25][C:24]([NH:23][C:2]2[C:7]([C:8]3[N:16]=[CH:15][N:14]=[C:13]4[C:9]=3[N:10]=[CH:11][N:12]4[CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:29][CH:28]=1
Reactant: Fc1ncccc1-c1ncnc2c1ncn2C1CCCCO1
Reactant: COc1ccc(N)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)cn1
Reaction time: 1 h
Yield: 71.7 %

Procedure:
A solution of 6-(2-fluoropyridin-3-yl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (196.6 mg, 657 μmol) and 3-amino-6-methoxypyridine (Aldrich, St. Louis, Mo.) (101.9 mg, 821 μmol) in THF (2.0 mL) was cooled in an ice bath and treated with LiHMDS (3.0 mL, 3.0 mmol). A blood-red solution was obtained. The mixture was stirred for 1 h, and then quenched with water (0.1 mL). The mixture was extracted into EtOAc from saturated aqueous NaHCO3, concentrated and purified by flash chromatography on silica (50% EtOAc/hexane; yellow band from column) to give 6-methoxy-N-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)pyridin-3-amine (190 mg, 71.7% yield) as a yellow crystalline solid. 1H NMR (400 MHz, CDCl3) δ 12.06 (s, 1H); 9.68 (dd, J=7.82, 1.76 Hz, 1H); 8.99 (s, 1H); 8.44 (d, J=2.54 Hz, 1H); 8.28 (dd, J=4.69, 1.76 Hz, 1H) 8.34 (s, 1H); 8.05 (dd, J=8.90, 2.64 Hz, 1H); 6.88 (dd, J=7.82, 4.69 Hz, 1H); 6.77 (d, J=8.80 Hz, 1H); 5.86 (dd, J=10.37, 2.35 Hz, 1H); 4.16-4.25 (m, 1H); 3.95 (s, 3H); 3.82 (s, 1H); 1.98-2.24 (m, 3H); 1.61-1.89 (m, 3H). m/z (ESI, +ve) 404.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([CH2:17][S:18][C:19]3[NH:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[N:20]=3)[C:11]=2[CH3:28])[CH2:4][O:3]1.C(N(CC)C(C)C)(C)C.[O-]O.C1(C(C)C)C=CC=CC=1.C(=O)([O-])[OH:51].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:29])[O:3][CH2:4][CH:5]([CH2:8][O:9][C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([CH2:17][S:18]([C:19]3[NH:20][C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)=[O:51])[C:11]=2[CH3:28])[CH2:6][O:7]1
Reactant: O=C([O-])O
Reactant: Cc1cnc(CSc2nc3ccccc3[nH]2)c(C)c1OCC1COC(C)(C)OC1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [O-]O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cnc(CS(=O)c2nc3ccccc3[nH]2)c(C)c1OCC1COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 63 %

Procedure:
A toluene (4 ml) solution of 2-(((4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzimidazole (500 mg, 1.21 mmol), zirconium(IV) isopropoxide isopropanol complex (295 mg, 0.76 mmol) and N,N,N′,N′-(−)-tetramethyl-(D)-tartaramide (396 mg, 1.94 mmol) was stirred in a nitrogen atmosphere at 40° C. for one hour. After the solution was cooled to room temperature, N,N-diisopropylethylamine (91 μl, 0.52 mmol) was added and subsequently, cumene hydroperoxide (243 μl, 1.32 mmol as the content was regarded as 80%) was added dropwise to the mixture and then the mixture was stirred at room temperature for 22 hours. After a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium thiosulfate solution were added, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtrated, and concentrated. The residue was purified by silica gel column chromatography (NH silica gel: 30 g, elution solvent: ethyl acetate, ethyl acetate/methanol 7:3, 1;1 gradient). The fractions containing the title compound were collected with ethyl acetate and concentrated to obtain the title compound (328 mg, yield: 63%) as a colorless foam.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([F:11])[CH:5]=1)=[O:3].CC(C)=O.C(OCC)(=O)C>O1CCCC1>[F:11][C:6]1[CH:5]=[C:4]([C@H:2]([OH:3])[CH3:1])[CH:9]=[CH:8][C:7]=1[F:10]
Reactant: CC(=O)c1ccc(F)c(F)c1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: C[C@@H](O)c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
(S,R)-cis-1-amino-2-indanol (284.3 mg, 1.91 mmol, 0.1 eq) was dissolved in tetrahydrofuran (25 mL) in a dry two-necked round-bottomed flask fitted with a dropping funnel and nitrogen inlet. The solution was chilled to approximately 0° C. and N,N-diethylaniline-borane complex (3.50 mL, 19.2 mmol, 1 eq) added dropwise. The mixture was allowed to stir at 0° C. for 30 minutes at which time a solution of 3,4-difluoroacetophenone (2.40 mL) in tetrahydrofuran (40 mL) was added via the dropping funnel over approximately 90 minutes. The solution was allowed to slowly warm to room temperature and stirring continued overnight. Acetone (16 mL) was added to the reaction mixture and the solution allowed to stir for a further hour before being concentrated in vacuo. The residue was treated with toluene (100 mL) and washed with 1 M sulphuric acid (4×50 mL), water (2×50 mL) and brine (50 mL). The organic phase was then dried (Na2SO4) and concentrated in vacuo to afford the crude alcohol. Gradient flashmaster chromatography (20 g silica cartridge; 100% petroleum spirits to 100% ethyl acetate) afforded the desired alcohol as a clear oil (2.242 g, 74%).
Reaction SMILES: C[N:2]1[CH2:20][CH2:19][N:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=3[CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C@H:4]2[CH2:3]1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1(C)C=CC=CC=1>[CH2:3]1[C@@H:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][C:7]3[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[CH2:19][CH2:20][N:2]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CN1CCN2c3ccccc3Cc3ccccc3[C@H]2C1
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCN2c3ccccc3Cc3ccccc3[C@H]2C1
Yield: 97.6 %

Procedure:
A solution of 5.52 g of (S)-1,2,3,4,10,14b-hexahydro-2-methyldibenzo[c,f]pyrazino[1,2-a]azepine (prepared as described in preparation 6) in 30 ml of toluene was added dropwise to a solution of 6.8 g of ethyl chloroformate in 50 ml of toluene at 80° C. over a period of 10 minutes, and the mixture was heated under reflux for 3hours. At the end of this time, the crystals which precipitated were removed by filtration, and solvent was removed from the filtrate by evaporation under reduced pressure, to give 6.57 g (yield 98%) of the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[C:13]([NH2:23])[N:14]=[C:15]([O:18][CH2:19][CH2:20][O:21][CH3:22])[C:16]=3[N:17]=2)=[CH:4][CH:3]=1.[CH3:24]OCCO>>[NH2:23][C:13]1[N:14]=[C:15]([O:18][C@@H:19]2[CH2:24][CH2:22][O:21][CH2:20]2)[C:16]2[N:17]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:9]=[CH:10][C:11]=2[N:12]=1
Reactant: COCCO
Reactant: COCCOc1nc(N)nc2ccc(-c3ccc(F)cc3)nc12
Product: Nc1nc(O[C@@H]2CCOC2)c2nc(-c3ccc(F)cc3)ccc2n1

Procedure:
6-(4-fluoro-phenyl)-4-(2-methoxy-ethoxy)-pyrido[3,2-d]pyrimidin-2-ylamine (example 23) was obtained from 2-methoxy-ethanol; MS (m/z): 315 ([M+H]+, 100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19](OC(=O)C)(=[O:21])[CH3:20].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
To a solution of 3,9-diaza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (400 mg, 1.57 mmol) in DCM (16 mL) was added acetic anhydride (177 μL, 1.88 mmol) and triethylamine (656 μL, 4.71 mmol) and the mixture was stirred (rt, 16 h). The reaction mixture was diluted with DCM (16 mL), washed with water (3×10 mL) and brine (1×10 mL). The organic layer was dried, filtered and concentrated in vacuo to provide the 9-acetyl-3,9-diaza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (466 mg, 100%). This intermediate was dissolved in DCM (4 mL), treated with HCl (4 M in dioxane, 4 mL) and stirred (rt, 16 h). The dispersion was concentrated in vacuo to provide the title compound as a white powder (365 mg, 100%). MS (ESI): mass calcd. for C11H20N2O, 196.16; m/z found, 197.1 [M+H]+. 1H NMR (400 MHz, MeOD): 3.63-3.51 (m, 4H), 3.23-3.17 (m, 4H), 2.13 (s, 3H), 1.82-1.73 (m, 4H), 1.67-1.53 (m, 4H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]#N)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.CC(C[AlH]CC(C)C)C.Cl.C([O-])(O)=[O:22].[Na+]>C(Cl)Cl>[F:1][C:2]1[C:3]([CH:9]=[O:22])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: N#Cc1ncc(F)cc1F
Reactant: O=C([O-])O
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1ncc(F)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a solution of 3,5-difluoro-pyridine-2-carbonitrile (0.440 g, 3.14 mmol) (Niewoehner, U. et al. PCT Int. Appl. (2001), WO 2001068647) in dry CH2Cl2 (20 mL) cooled at −78° C., was added DIBAL-H (1.0 M in CH2Cl2, 3.2 mL, 3.2 mmol). After the mixture was stirred at −78° C. for 1 h, aqueous HCl (3 N, 10 mL) was added, and the mixture was warmed to room temperature. Saturated aqueous NaHCO3 (20 mL) was added, and the mixture was extracted with CH2Cl2 (3×20 mL). The extracts were combined and dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (CH2Cl2), affording afford 3,5-difluoro-pyridine-2-carbaldehyde as a colorless crystalline solid (0.0880 g, 20%). 1H NMR (CDCl3) δ 7.32-7.39 (m, 1H), 8.53 (d, 1H, J=2.4 Hz), 10.16 (s, 1H).
Reaction SMILES: [CH2:1]([N:4]([C@@H:33]([CH3:38])[C:34]([F:37])([F:36])[F:35])[S:5]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:15](C(OC(C)(C)C)=O)[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([CH:23]2[CH2:25][CH2:24]2)[CH:17]=3)=[N:12][CH:13]=1)(=[O:7])=[O:6])[CH:2]=[CH2:3].N1CCCC1>C(#N)C>[CH2:1]([N:4]([C@@H:33]([CH3:38])[C:34]([F:35])([F:37])[F:36])[S:5]([C:8]1[CH:13]=[N:12][C:11]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([CH:23]2[CH2:25][CH2:24]2)[CH:17]=3)=[CH:10][CH:9]=1)(=[O:6])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCN([C@@H](C)C(F)(F)F)S(=O)(=O)c1ccc(-c2cc3ccc(C4CC4)cc3n2C(=O)OC(C)(C)C)nc1
Solvent: CC#N
Solvent: C1CCNC1
Product: C=CCN([C@@H](C)C(F)(F)F)S(=O)(=O)c1ccc(-c2cc3ccc(C4CC4)cc3[nH]2)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.5 %

Procedure:
To a solution of (S)-tert-butyl 2-(5-(N-allyl-N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)pyridin-2-yl)-6-cyclopropyl-1H-indole-1-carboxylate (500 mg, 0.91 mmol) in acetonitrile was added pyrrolidine (0.35 mL, 4.55 mmol). The mixture was stirred at room temperature for 5 hrs and the solvent was evaporated. The residue was purified on silica gel eluting with 0 to 10% ethyl acetate in CH2Cl2 to provide (S)-N-allyl-6-(6-cyclopropyl-1H-indol-2-yl)-N-(1,1,1-trifluoropropan-2-yl)pyridine-3-sulfonamide (370 mg, 91% yield). MS m/z 450.2 M+H+; 1H NMR (500 MHz, CDCl3): δ 9.28 (1H, s), 8.85 (1H, s), 7.96 (1H, d, J=5.5 Hz), 7.74 (1H, d, J=9.5 Hz), 7.49 (1H, d, J=5.5 Hz), 7.09 (1H, s), 7.01 (1H, s), 6.82-6.80 (1H, m), 5.75 (1H, m), 5.16-5.10 (2H, m), 4.64-4.62 (1H, m), 3.89 (2H, d, J=5.0 Hz), 2.00-1.96 (1H, m), 1.35 (3H, d, J=6.0 Hz), 0.98-0.96 (2H, m), 0.75-0.72 (2H, m).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[C:22]([CH3:34])=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[CH:25][CH:26]=1.O>CN(C)C=O>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:24]2[N:23]=[C:22]([CH3:34])[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)=[CH:26][CH:25]=2)=[CH:28][CH:29]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)ccc1CCl
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(Cl)cc2)ccc1COc1ccc(CCCCn2ccnn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
33 mg (0.83 mmol) of 60% sodium hydride were added to at 0° C. to a solution of 172 mg (0.85 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 8.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 200 mg (0.85 mmol) 3-chloromethyl-6-(4-chloro-phenyl)-2-methyl-pyridine (EP 0 284 174) were given to the reaction mixture and stirring continued at room temperature (r.t.) overnight. After addition of 16 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, water/methanol 1:1, and ether. The residue was dried at 40° C. in vacuum to give 305 mg (89%) of the title compound as white powder.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.CC1C=CC(S(O)(=O)=O)=CC=1>CCO>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]2[C:4](=[O:5])[NH:6][CH:16]([C:15]3[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=3)[NH:1][C:2]=2[N:10]=1
Reactant: NC(=O)c1ccc(Cl)nc1N
Reactant: O=Cc1cccc(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: O=C1NC(c2cccc(F)c2)Nc2nc(Cl)ccc21
Temperature: 25 °C
Yield: 52.3 %

Procedure:
To a solution of 2-amino-6-chloronicotinamide (200 mg, 1.17 mmol) and 3-fluorobenzaldehyde (160 mg, 1.29 mmol) in 20 mL of EtOH was added PTSA (20 mg, 0.12 mmol), and then the mixture was heated at reflux for 16 h. The solution was cooled to room temperature and filtered to give the product of 7-chloro-2-(3-fluorophenyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (170 mg, yield: 52%) without further purification. 1H-NMR (CDCl3, 400 MHz) δ 8.09 (d, J=8.0 Hz, 1H), 7.41˜7.44 (m, 1H), 7.29˜7.36 (m, 2H), 7.15˜7.19 (m, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.03 (s, 1H), 5.75 (s, 1H), 5.35 (s, 1H). MS (M+H)+: 278/280.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[CH2:15])=[CH:12][CH:11]=1.ClCCC1C=CC=CC=1.P(=O)(O)(O)O>>[CH3:15][CH:14]1[C:13]2[C:12](=[CH:11][CH:10]=[CH:17][CH:16]=2)[CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:1]1
Reactant: C=Cc1ccccc1
Reactant: C=Cc1ccc(Cl)cc1
Agent: ClCCc1ccccc1
Agent: O=P(O)(O)O
Product: CC1CC(c2ccccc2)c2ccccc21

Procedure:
A mixture of 90 parts of styrene, 234 parts of p-chlorostyrene and 66 parts of p-chloroethylbenzene is added to 722 parts of 93 per cent strength by weight phosphoric acid at 35° to 40° C over 5 hours. After a further 2 hours at 35° to 40° C the organic phase is separated off and washed with 200 parts of 3 per cent strength by weight sodium hydroxide solution. Fractional distillation gives 16 parts of 1-methyl-3-phenylindan, 78 parts of 1-methyl-3-(p-chloro)-phenylindan (b.p. 166° to 170° C (10 mm), nD25 : 1.5869) and 13 parts of 1-methyl-3-(p-chloro)-phenyl-5-chloroindan (b.p. 197° to 204° C (10 mm)).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:54]1[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=1.[CH2:60]([N:62]1[C:66]2[N:67]=[CH:68][C:69]([C:72]3[CH2:79][C:75]4([CH2:78][CH2:77][CH2:76]4)[O:74][N:73]=3)=[C:70]([NH2:71])[C:65]=2[CH:64]=[N:63]1)[CH3:61]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:60]([N:62]1[C:66]2[N:67]=[CH:68][C:69]([C:72]3[CH2:79][C:75]4([CH2:76][CH2:77][CH2:78]4)[O:74][N:73]=3)=[C:70]([NH:71][C:54]3[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=3)[C:65]=2[CH:64]=[N:63]1)[CH3:61]
Reactant: CCn1ncc2c(N)c(C3=NOC4(CCC4)C3)cnc21
Reactant: Brc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCn1ncc2c(Nc3ccncc3)c(C3=NOC4(CCC4)C3)cnc21
Temperature: 25 °C

Procedure:
2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (0.3 equivalent), palladium acetate (0.09 equivalent) and cesium carbonate (1.5 equivalent) is added to 4-bromo pyridine (1 equivalent) in anhydrous dioxane under inert atmosphere. 1-Ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (1.3 equivalent) (example 36) is added and the reaction mixture is stirred at reflux for about 10-12 hours. It is cooled to room temperature and filtered through celite. The reaction mixture is extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous sodium sulphate and concentrated in vacuo. The crude compound is purified by column chromatography.
Reaction SMILES: [NH2:1][CH:2]([C:4]([OH:6])=[O:5])[CH3:3].C(N(CC)CC)C.C[Si](Cl)(C)C.[CH2:19]([CH:21]([CH2:25][CH3:26])[C:22](Cl)=[O:23])[CH3:20].[OH-].[Na+]>ClCCl.O>[CH3:20][CH2:19][CH:21]([CH2:25][CH3:26])[C:22]([NH:1][CH:2]([CH3:3])[C:4]([OH:6])=[O:5])=[O:23]
Reactant: CCC(CC)C(=O)Cl
Reactant: CC(N)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)C(=O)NC(C)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
24.5 g (0.275 mol) of D,L-alanine are initially charged in 250 ml of dichloromethane, and 61.2 g (0.605 mol) of triethylamine are added. The mixture is cooled to 0° C., and 65.7 g (0.605 mol) of trimethylsilyl chloride are added. The mixture is stirred at room temperature for one hour and at 40° C. for one hour. The mixture is cooled to −10° C., and 37 g (0.275 mol) of 2-ethylbutyryl chloride are slowly added dropwise. The mixture is stirred at −10° C. for two hours and at room temperature overnight. The mixture is cooled in an ice bath, and 150 ml of water are added. 50 g (1.25 mol) of NaOH, dissolved in 100 ml of water, are added and the aqueous phase is separated off and concentrated. The residue is again taken up in water and acidified with concentrated hydrochloric acid, the aqueous solution is extracted repeatedly with dichloromethane and the organic phase is dried over Na2SO4 and concentrated.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[I-].[CH3:11][S+](C)C.O.[OH-].[K+]>C(#N)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[CH2:11][O:7]2)=[CH:4][CH:3]=1
Reactant: C[S+](C)C
Reactant: O=Cc1ccc(Br)cc1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: Brc1ccc(C2CO2)cc1
Temperature: 55 °C

Procedure:
A mixture of 4-bromobenzaldehyde (intermediate 29, 25.25 g, 136 mmol), trimethylsulfonium iodide (28.71 g, 141 mmol), water (6.5 ml, 361 mmol) and potassium hydroxide (15.56 g, 277 mmol) in acetonitrile (140 ml) was warmed to 55° C. for 2.5 hours. The resulting solution was partitioned between water and diethyl ether, and the organic layer was washed with water, diluted hydrochloric acid, and brine, and dried over sodium sulfate. Crude product of 2-(4-bromo-phenyl)-oxirane (intermediate 30) was obtained by removal of organic solvent under reduced pressure, which was used for next reaction without purification.
Reaction SMILES: [C:1](#[N:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(C#N)CCCCCCCCCC.[CH2:21]([CH2:23]N)[OH:22]>O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH2:2]([C:1]1[O:22][CH2:21][CH2:23][N:7]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC#N
Reactant: NCCO
Agent: CC(=O)[O-]
Agent: CCCCCCCCCCCC#N
Agent: [Zn+2]
Solvent: O
Product: CCCCCC1=NCCO1
Yield: 58.1 %

Procedure:
9.72 g (100 mmoles) of hexanenitrile was substituted for undecyl cyanide in Example 1 and the reaction was repeated with 6.11 g (100 mmoles) of ethanolamine and 549 mg (2.5 mmoles) of zinc acetate dihydrate under identical conditions. At the end of the reaction the product was worked up as before and distilled at 73° C./10 mm to give 8.2 g (60%) of 2-pentyl-2-oxazoline.
Reaction SMILES: [CH3:1][C:2](=[N:7][OH:8])[C:3]([CH3:6])=[N:4][OH:5].[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(N(CC)CC)C>O1CCOCC1>[CH3:9][S:10]([O:5][N:4]=[C:3]([CH3:6])[C:2]([CH3:1])=[N:7][O:8][S:10]([CH3:9])(=[O:12])=[O:11])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=NO)C(C)=NO
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=NOS(C)(=O)=O)C(C)=NOS(C)(=O)=O
Yield: 77.3 %

Procedure:
To 300 ml of 1,4 dioxane in a round-bottom flask was added 11.6 g (0.1 mole) of dimethylglyoxime. When the solid had completely dissolved, 22.9 g (0.2 mole) of methanesulfonyl chloride was added. The mixture was stirred and 20.2 g (0.2 mole) triethylamine was added dropwise. The reaction mixture was stirred for 51/2 hours during which time a precipitate was formed. The dioxane was removed by evaporation under reduced pressure. The residue was stirred in ice water, then filtered. The solid product was dissolved in dichloromethane and dried over anhydrous sodium sulfate. The slurry was filtered and the solvent was removed in a rotary evaporator. The solid residue was stirred in cold ethanol, then filtered and dried in a vacuum oven, giving 21.05 g (77% yield) of di-(methanesulfonyl)-dimethylglyoxime with mp 169-172° C.