Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=3)[CH2:12][CH2:11]2)=[N:2]1.[CH3:25][C:26]([CH3:31])=[CH:27][C:28](Cl)=[O:29]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C:18]3[CH:19]=[C:20]([NH:24][C:28](=[O:29])[CH:27]=[C:26]([CH3:31])[CH3:25])[CH:21]=[CH:22][CH:23]=3)[CH2:14][CH2:15]2)=[N:2]1
Reactant: CC(C)=CC(=O)Cl
Reactant: Nc1cccc(CCN2CCN(c3nsc4ccccc34)CC2)c1
Product: CC(C)=CC(=O)Nc1cccc(CCN2CCN(c3nsc4ccccc34)CC2)c1
Yield: 96.5 %

Procedure:
Starting from {3-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-phenyl}-amine (338 mg, 1 mmol) and 3,3 dimethyl acryloyl chloride (116 μL, 1.05 mmol) and following the procedure as outlined in Example 1, 406 mg of 3-methyl-but-2-enoic acid {3-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-phenyl}-amide was isolated as a light yellow solid in 100% purity @ 254 nm; LCMS (APCI): 421 [M+H]+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][C:6]=1[C:12]([F:15])([F:14])[F:13])([CH3:3])[CH3:2].[CH:16](O)=[O:17]>>[CH:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][CH:16]=[O:17])=[CH:7][C:6]=1[C:12]([F:13])([F:14])[F:15])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(N)cc1C(F)(F)F
Reactant: O=CO
Product: CC(C)Oc1ccc(NC=O)cc1C(F)(F)F
Temperature: 0 °C

Procedure:
A mixture of 54.8 g of 2B and 200 ml of 98% formic acid was refluxed for one hour, cooled and poured into ice water. The resulting mixture was extracted with ether. The extract was washed, successively, with aqueous soidum bicarbonate and water, dried and the solvent was evaporated under reduced pressure. The residue, a syrup, crystallized from 1/5 v/v ether/hexane to give N-(4-isopropoxy-3-(trifluoromethyl)phenyl)formamide (2C), as a tan solid, mp: 80°-82° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:13][CH2:14][C:15]([OH:17])=O)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].C[CH2:19][N:20](C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CN>C1COCC1.C(Cl)CCl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:13][CH2:14][C:15]([NH:20][CH3:19])=[O:17])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOc1ccc(CCC(=O)O)cc1OCC
Agent: CN
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CCOc1ccc(CCC(=O)NC)cc1OCC
Temperature: 70 °C

Procedure:
To a solution of 0.72 g of 3-(3,4-diethoxy-phenyl)-propionic acid in 10 mL THF were added 1.6 mL of DIPEA, 0.45 g of HOBt, 0.63 g of EDC and 10 mL of MeNH2 (2M in THF). The reaction mixture was heated in a closed vessel overnight at 70° C. Further additions of MeNH2 were done during the next 12 h. The mixture was then concentrated in vacuo, the residue was taken up in sat. aq. NaHCO3 and washed with EtOAc (2×). The organic layers were combined, washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by CC with EtOAc yielded 0.16 g of 3-(3,4-diethoxy-phenyl)-N-methyl-propionamide as solid.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:30][C:31]1[CH:35]=[CH:34][N:33]([CH2:36][C:37]([CH3:40])([OH:39])[CH3:38])[N:32]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:13]=[N:12]2)[C:8]([NH:30][C:31]2[CH:35]=[CH:34][N:33]([CH2:36][C:37]([OH:39])([CH3:40])[CH3:38])[N:32]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2C2CCCC2)cc1=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3C3CCCC3)cc2=O)n1
Yield: 75 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[4-(2-cyclopentyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 36) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-2-[4-(2-cyclopentyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide as a white solid (1.03 g, 75%); ES+-HRMS m/e calcd for C30H39N5O4 [M+H+] 534.3075 found 534.3076. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.09 (m, 1H), 1.20-1.80 (m, 14H), 1.81-2.02 (m, 3H), 2.27 (m, 1H), 3.04 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 5.46 (dd, J=4.4, J=10.7 Hz, 1H), 5.59 (d, J=2.8 Hz, 1H), 6.40 (d, J=2.2 Hz, 1H), 7.19 (m, 1H), 7.27-7.37 (m, 2H), 7.49 (dd, J=3.6, J=5.7 Hz, 1H), 7.52 (d, J=2.2 Hz, 1H), 8.16 (d, J=2.8 Hz, 1H), 10.80 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[CH2:4][CH:5]([N:7]1[C:20]2[CH:19]=[C:18]([C:21](=[S:23])[NH2:22])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6])[CH3:2].[CH2:26](N)[CH2:27][CH3:28].S>C(O)C>[CH2:24]([N:3]([CH2:1][CH3:2])[CH2:4][CH:5]([N:7]1[C:20]2[CH:19]=[C:18]([C:21](=[S:23])[NH:22][CH2:26][CH2:27][CH3:28])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6])[CH3:25]
Reactant: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Reactant: CCCN
Agent: S
Solvent: CCO
Product: CCCNC(=S)c1ccc2c(c1)N(C(C)CN(CC)CC)c1ccccc1S2
Temperature: 100 °C

Procedure:
A solution of 10-(1-diethylamino-2-propyl)-2-phenothiazinecarbothioamide acid fumarate, L series (0.56 g) and propylamine (1.4 cc) in absolute ethanol (10 cc) is saturated with hydrogen sulphide and heated for 16 hours to a temperature in the region of 100° C. After cooling, the mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual orange oil is purified by chromatography on a column (height: 25 cm; diameter: 1 cm) of silica gel (0.04-0.063 mm) with a slight excess pressure of nitrogen (40 kPa), eluting with a mixture (80:20 by volume) (150 cc) of ethyl acetate and cyclohexane and collecting 15-cc fractions. The combined fractions 4 to 7 are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 10-(1-Diethylamino-2-propyl)-N-propyl-2-phenothiazinecarbothioamide, L series (0.5 g) is thereby obtained in the form of a yellow oil. 0.25 g of this product is dissolved in isopropyl ether (25 cc) and a 0.3N solution (2.2 cc) of hydrochloric acid in isopropyl ether is added dropwise, with stirring and at a temperature in the region of 5° C. Stirring is maintained for 1 hour at a temperature in the region of 5° C. The precipitate is drained, washed with isopropyl ether (3×5 cc) and dried under reduced pressure (5 mm Hg; 4 kPa) at 40° C. 10-(1-Diethylamino-2-propyl)-N-propyl-2-phenothiazinecarbothioamide hydrochloride, L series (0.24 g) is thereby obtained in the form of a yellow solid, m.p. 95°-100 C. (melts forming a paste), the NMR characteristics of which are identical to those of the product described in Example 6.
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=O)[C:7]3=[C:8]2[C:3](=[C:4]([Br:16])[CH:5]=[CH:6]3)[CH:2]=1)=[O:12].Cl.[NH2:18][OH:19]>N1C=CC=CC=1>[Br:16][C:4]1[CH:5]=[CH:6][C:7]2[C:14](=[O:13])[N:18]([OH:19])[C:11](=[O:12])[C:9]3[C:8]=2[C:3]=1[CH:2]=[CH:1][CH:10]=3
Reactant: NO
Reactant: O=C1OC(=O)c2ccc(Br)c3cccc1c23
Agent: Cl
Solvent: c1ccncc1
Product: O=C1c2cccc3c(Br)ccc(c23)C(=O)N1O
Yield: 82.6 %

Procedure:
4-Bromo-1,8-naphthalic anhydride (1.6 g, 5.8 mmol) and hydroxylamine hydrochloride (0.8 g, 11.5 mmol) were reacted in pyridine (30 mL) following the procedure of Example 1 to give 1.4 g of the title compound , mp 248-251° C.;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([NH2:23])=[O:22])[CH2:17][CH2:16]1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([NH:23][C:12]2[CH:11]=[CH:10][C:5]([CH2:6][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:4][CH:3]=2)=[O:22])[CH2:17][CH2:16]1
Reactant: C1CCNCC1
Reactant: COc1cc2ncnc(N3CCN(C(N)=O)CC3)c2cc1OC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(N3CCN(C(=O)Nc4ccc(CN5CCCCC5)cc4)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 92 %

Procedure:
In 10 ml of toluene was suspended 593.5 mg (2.16 mmol) of 6,7-dimethoxy-4-piperazinylquinazoline obtained by the method described in South African Patent No. 67 06512 (1968), and 362.6 ml (2.16 mmol) of 4-(chloromethyl)phenyl isocyanate was added thereto, followed by stirring at room temperature for 3 hours. After the reaction mixture was filtered, the obtained crystals were washed with diisopropyl ether and dried under reduced pressure to give 916.8 mg (2.08 mmol, 96%) of N-[4-(chloromethyl)phenyl]-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboxamide. In 10 ml of dimethylformamide was dissolved 422.9 mg (0.96 mmol) of the obtained N-l4-(chloromethyl)phenyl]-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboxamide, and 0.28 ml (2.83 mmol) of piperidine was added thereto, followed by stirring at room temperature for 7 hours. Then, the reaction mixture was poured into water and the precipitated crystals were collected by filtration, followed by purification by silica gel column chromatography to give 430.9 mg (0.88 mmol) of the desired compound as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1Br.[Cl:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][C:16]=1[Cl:17].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.[Pd]>[Cl:10][C:11]1[CH:12]=[C:13]([C:7]2[CH:6]=[CH:5][C:4]([CH3:9])=[CH:3][C:2]=2[F:1])[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: Cc1ccc(Br)c(F)c1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(-c2ccc(Cl)c(Cl)c2)c(F)c1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
3-fluoro-4-bromotoluene (50 g, 0.265 mol) and 3,4-dichlorophenylboronic acid (53 g, 0.278 mol) were dissolved in ethanol (970 ml) and sodium carbonate (56.1 g, 0.529 mol) was added. Palladium 10% on charcoal (6.6 g) was added, and the mixture was refluxed for 4 hours under nitrogen atmosphere. The reaction mixture was cooled, filtered and concentrated, isopropyl acetate (250 ml) was added, and then the solution was concentrated again. The residue was dissolved in isopropyl acetate (250 ml) and 1M sodium hydroxide (250 ml). The organic phase was separated, washed with water (125 ml), neutralized with hydrogen chloride 3 M, washed with brine (250 ml), and concentrated. The residue was mixed with acetonitrile/water 1/1 v/v (150 ml), heated to 40° C. to dissolve and then cooled to 0 to 5° C., and stirred for 30 minutes at this temperature. The compound 3′,4′-dichloro-2-fluoro-4-methyl-biphenyl crystallized as a powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:10]=[CH:9][C:8]([N:11]2[CH2:26][CH2:25][C:14]3[N:15]=[CH:16][N:17]=[C:18]([O:19][C@H:20]4[CH2:24][CH2:23][NH:22][CH2:21]4)[C:13]=3[CH2:12]2)=[CH:7][C:4]=1[C:5]#[N:6].C(N(CC)CC)C.[C:34](Cl)(=[O:37])[O:35][CH3:36]>C(Cl)Cl>[CH3:36][O:35][C:34]([N:22]1[CH2:23][CH2:24][C@H:20]([O:19][C:18]2[C:13]3[CH2:12][N:11]([C:8]4[CH:9]=[N:10][C:3]([O:2][CH3:1])=[C:4]([C:5]#[N:6])[CH:7]=4)[CH2:26][CH2:25][C:14]=3[N:15]=[CH:16][N:17]=2)[CH2:21]1)=[O:37]
Reactant: COc1ncc(N2CCc3ncnc(O[C@H]4CCNC4)c3C2)cc1C#N
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CC[C@H](Oc2ncnc3c2CN(c2cnc(OC)c(C#N)c2)CC3)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.3 %

Procedure:
To a solution of 2-methoxy-5-[4-((S)-pyrrolidin-3-yloxy)-7,8-dihydro-5H-pyrido[4,3-d]py rimidin-6-yl]-nicotinonitrile (prepared using intermediate 11 and method 1b, process step 2, example 1) (25.0 mg, 0.071 mmol) and triethylamine (0.04 mL, 0.29 mmol) in CH2Cl2 (2 mL) was added methyl carbonochloridate (0.006 mL, 0.078 mmol) and the mixture stirred at room temperature for 18 h. Diluted with CH2Cl2 (2 mL) and washed with sat. NaHCO3(aq) (1 mL). The organic layer was filtered through a phase separation tube and evaporated in vacuo. Purification was performed by reverse phase Gilson HPLC (Method A) and subsequent neutralization of the combined fractions by elution through an Isolute® SCX-2 cartridge, eluting with methanol, then with 2M ammonia in methanol. Basic fractions were concentrated in vacuo gave (S)-3-[6-(5-cyano-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylic acid methyl ester (10 mg, 35% yield) as a yellow powder. 1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.09-2.31 (m, 2H) 2.91 (t, 2H) 3.45-3.75 (m, 9H) 3.93 (s, 3H) 4.17 (s, 2H) 5.58-5.65 (m, 1H) 8.09 (d, 1H) 8.27 (d, 1H) 8.61 (s, 1H) LCMS: [M+H]+=411.1, Rt(1)=1.58 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[O:16]1[CH2:18][CH:17]1[CH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.[H-].[Na+]>CN(C)C=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:18][CH:17]([OH:16])[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: c1cncc(CCC2CO2)c1
Reactant: Oc1ccc(Cc2ccc(O)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1ccc(Cc2ccc(OCC(O)CCc3cccnc3)cc2)cc1
Yield: 21 %

Procedure:
Prepared according to the method described in Example 5 from bis(4-hydroxyphenyl)methane (1.6 g), (±)-3-(2-oxiranylethyl)pyridine (1.24 g) and sodium hydride (60% dispersion in oil; 0.319 g) in dimethylformamide (25 ml) at 100° C. for 2 hours to give the title compound as a white solid (0.587 g).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([CH3:12])=[CH:4][C:3]=1[N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]2=[N:14]1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:34]Br>C(Cl)(Cl)(Cl)Cl>[OH:1][C:2]1[C:7]([C:8]([CH3:9])([CH3:11])[CH3:10])=[CH:6][C:5]([CH2:12][Br:34])=[CH:4][C:3]=1[N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]2=[N:14]1
Reactant: BrBr
Reactant: Cc1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(CBr)cc(-n2nc3ccccc3n2)c1O
Temperature: 25 °C

Procedure:
2-(2′-hydroxy-3′-tert-butyl-5′-bromomethyphenyl)benzotriazole was prepared from the bromination of 2-(2′-hydroxy-3′-tert-butyl-5′-methyphenyl)benzotriazole using azobis isobutyronitrile (AIBN) as an initiator. In a 500 ml three-necked round bottomed flask, 6.274 g (0.0223 mol) 2-(2′-hydroxy-3′-tert-butyl-5′-methyphenyl)benzotriazole and 100 mg of AIBN were taken and dissolved in 150 ml of dry carbon tetrachloride. In a separate conical flask 4.18 g (1.5 ml, 0.03 mol) of bromine was dissolved in 75 ml of dry carbon tetrachloride and solution was transferred to a cylindrical funnel with pressure equalizing tube. Three-necked round-bottomed flask containing solution of 2-(2′-hydroxy-3′-tert-butyl-5′-methyphenyl)benzotriazole was kept in oil-bath with temperature 50° C. Nitrogen was bubbled through the solution for creating inert atmosphere. Cylindrical funnel containing bromine solution was mounted on the three-necked round-bottomed flask. Solution in the flask was continuously stirred with the help of magnetic stirrer. Bromine solution was added, drop-by-drop, from funnel to the flask for a span of 4-5 hours till all the solution was poured out. After that heating was stopped and the final reaction mixture was allowed to cool at room temperature. Product was separated by solvent evaporation. Finally the product was purified by recrystallization from acetone. The yield of 2-(2′-hydroxy-3′-tert-butyl-5′-bromomethyphenyl)benzotriazole was 6.6 g (82%)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]3[NH:24][C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:26]([CH3:28])[N:27]=3)[CH2:18]2)[N:3]=1.[NH2:35][NH2:36]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:11]([C:12]([NH2:13])=[N:35][NH:36]3)=[CH:14][CH:15]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]3[NH:24][C:25]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[C:26]([CH3:28])[N:27]=3)[CH2:18]2)[N:3]=1
Reactant: NN
Reactant: Cc1nc(C2CN(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)CCO2)[nH]c1-c1ccccc1
Solvent: CCO
Product: Cc1nc(C2CN(c3cc(-c4ccc5c(N)n[nH]c5c4)nc(N)n3)CCO2)[nH]c1-c1ccccc1
Reaction time: 1 h
Yield: 87.5 %

Procedure:
A mixture of 4-{2-amino-6-[2-(4-methyl-5-phenyl-1H-imidazol-2-yl)-4-morpholinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (100 mg, 0.220 mmol) and hydrazine (0.348 mL, 10.98 mmol) in ethanol (2 mL) was heated under microwave conditions with stirring for 1 hour. The mixture was concentrated, and the crude product was purified by RPHPLC to afford the title compound (90 mg) as a pale yellow solid. LC-MS (ES) m/z=468 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 2.35 (s, 3H), 3.04-3.22 (m, 2H), 3.66-3.75 (m, 1H), 4.04 (d, J=11.2 Hz, 1H), 4.32 (d, J=12.8 Hz, 1H), 4.52-4.58 (m, 1H), 4.70 (s, 1H), 5.38 (s, 2H), 6.20 (s, 2H), 6.70 (s, 1H), 7.17-7.28 (m, 1H), 7.34-7.46 (m, 2H), 7.52-7.66 (m, 3H), 7.71 (d, J=8.4 Hz, 1H), 7.96 (s, 1H), 11.52 (s, 1H), 12.20 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([Cl:1])=[N:3][C:4]=2[NH2:11]
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Reactant: BrCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1nc(Cl)nc2c1ncn2Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
2-Chloroadenine (1.53 g, 9.0 mmol), 3-bromobenzyl bromide (2.48 g, 9.92 mmol), potassium carbonate (1.38 g, 10 mmol) were combined in DMF (10 mL) and stirred at ambient temperature overnight. The mixture was diluted with ethyl acetate (200 mL) and washed with water and brine. The organic layer was dried with Na2SO4 and evaporated to dryness. The residue was triturated with diethyl ether/ethyl acetate 4:1 and filtered giving 9-(3-bromobenzyl)-2-chloro-9H-purin-6-amine (Compound 53) (2.3 g) as off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21][N:22]=[N+]=[N-])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[H][H]>C1COCC1.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21][NH2:22])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: [N-]=[N+]=NC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Agent: [Pd]
Solvent: C1CCOC1
Product: NC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Yield: 93.9 %

Procedure:
To a solution of C—[(R)-7-(3-fluoro-benzenesulfonyl)-chroman-2-yl]-methyl azide (1.76 g, 5.07 mmol) in 30 mL of THF was added 10% Pd/C (0.176 g). The reaction mixture was hydrogenated at 1.5 atmospheric pressure of hydrogen for 18 hours. The mixture was filtered and the filtrated was evaporated under reduced pressure. The residue was purified by flash chromatography (methylene chloride/MeOH 7:3) to give 1.53 g (94%) of C—[(R)-7-(3-Fluoro-benzenesulfonyl)-chroman-2-yl]-methylamine. MP=257.1-258.9° C.; MS (M+H)=322.
Reaction SMILES: [CH2:1]([C:5]([CH3:22])([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][OH:21])=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(N(CC)CC)C>[CH2:1]([C:5]([CH3:22])([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCC(C)(Cc1ccc(OCCO)cc1)C(=O)OCC
Solvent: CCN(CC)CC
Product: CCCCC(C)(Cc1ccc(OCCOS(C)(=O)=O)cc1)C(=O)OCC

Procedure:
In a similar manner to that described in Reference example 3(g), a reaction was carried out using ethyl 2-butyl-3-[4-(2-hydroxyethoxy)phenyl]-2-methylpropionate (2.73 g), which is the product of Reference example 10(d), triethylamine (1.85 ml) and methanesulfonyl chloride (0.75 ml) and the reaction mixture was treated to afford the desired compound (3.17 g) as a syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[O:28]([NH2:30])[CH3:29]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([NH:30][O:28][CH3:29])=[O:14]
Reactant: CON
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1Cl
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CONC(=O)Cc1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Yield: 85 %

Procedure:
2-(2-Chloro-4-nitrophenyl)acetic acid (67.2 mmol) was dissolved in DMF (500 mL) to give a colorless solution. CDI (87 mmol) was added in one portion. The mixture was stirred at room temperature until bubbling of the solution ceased. Methoxylamine hydrochloride (87 mmol) was added poroom temperatureion wise, and the resulting mixture was stirred at room temperature over night. The resulting suspension was concentrated under reduced pressure to 100 mL and then diluted with EtOAc (1200 mL). The resulting solution was washed with water (2×700 mL) and the aqueous layer was extracted back with EtOAc (2×600 mL). The organic layers were combined and washed with sat. aq. NaHCO3 (1×1200 mL) and sat. aq. NaCl (1×1200 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-(2-chloro-4-nitrophenyl)-N-methoxyacetamide as a solid (85%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:23](=[CH:24][CH:25]=1)[O:22][C:11]1([CH2:14][N:13]([C:15]([O:17]C(C)(C)C)=O)[CH2:12]1)[CH2:10][C:9]2=[O:26].C(Cl)(=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:23](=[CH:24][CH:25]=1)[O:22][C:11]1([CH2:14][N:13]([C:15](=[O:17])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:12]1)[CH2:10][C:9]2=[O:26]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(=O)OC(C)(C)C)C1)O2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(=O)c3ccccc3)C1)O2
Yield: 97.2 %

Procedure:
A suspension of Intermediate 4 (280 mg, 0.90 mmol) in DCM (7.5 ml) was treated with benzoyl chloride (0.16 ml, 1.4 mmol) and DIPEA (0.32 ml, 1.8 mmol) as described in Example 36, Step A, giving (E)-3-[1′-benzoyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid methyl ester as a white solid (330 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[C:29]([N+:34]([O-])=O)[CH:28]=2)[C:14]([N:16]2[CH2:22][CH2:21][C:20]3[S:23][CH:24]=[N:25][C:19]=3[CH2:18][CH2:17]2)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:37].[CH:38](O)=O>[Pd]>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]3[NH:33][CH:38]=[N:34][C:29]=3[CH:28]=2)[C:14]([N:16]2[CH2:22][CH2:21][C:20]3[S:23][CH:24]=[N:25][C:19]=3[CH2:18][CH2:17]2)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:37]
Reactant: Nc1ccc(CC(NS(=O)(=O)c2cc(Cl)c(N)c(Cl)c2)C(=O)N2CCc3ncsc3CC2)cc1[N+](=O)[O-]
Reactant: O=CO
Agent: [Pd]
Product: Nc1c(Cl)cc(S(=O)(=O)NC(Cc2ccc3[nH]cnc3c2)C(=O)N2CCc3ncsc3CC2)cc1Cl

Procedure:
Prepared from 4-amino-N-[1-((4-amino-3-nitro-phenyl)methyl)-2-(5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepin-6-yl)-2-oxo-ethyl]-3,5-dichloro-benzenesulphonamide and cyclising with formic acid in the presence of palladium/charcoal analogously to Example 1.