Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C@H:5]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[CH2:24]([S:36][CH:37](O)[CH3:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>>[CH2:1]([O:3][C:4](=[O:23])[C@H:5]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:38][CH2:37][S:36][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:18][CH:17]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1ccccc1
Reactant: CCCCCCCCCCCCSC(C)O
Product: CCCCCCCCCCCCSCCOc1ccc(C[C@H](NC(=O)c2ccccc2)C(=O)OCC)cc1
Yield: 66.5 %

Procedure:
N-Benzoyl-L-tyrosine ethyl ester (4.0 g, 12.76 mmol) and dodecanylthioethanol [Patent Application WO 99/15129] (3.15 g, 12.76 mmol) were reacted as described in Example 2 for the preparation of 1-[2-{2-[bis(4-chlorophenyl)ethyl]methylamino}ethoxy]-4-bromo-benzene and gave the title material (4.6 g, 66%) as a white solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[O:5]([CH2:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:18][CH2:19][C:20](Cl)=[O:21]>ClCCCl>[Cl:18][CH2:19][C:20]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:12][C:13]2[NH:17][N:16]=[N:15][N:14]=2)=[CH:7][CH:8]=1)=[O:21]
Reactant: O=C(Cl)CCl
Reactant: c1ccc(OCc2nnn[nH]2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(CCl)c1ccc(OCc2nnn[nH]2)cc1
Reaction time: 8 h

Procedure:
Aluminium chloride (30.3 g) was added to a stirred mixture of the product of step (i) above (10 g) and chloroacetyl chloride (19.3 g) in dry 1,2-dichloroethane and stirring continued overnight. The mixture was concentrated to about half volume on the steam bath, cooled and added to an ice/hydrochloric acid mixture. After stirring for 15 minutes the solid was collected and, on recrystallisation from methanol/water, gave 5-(4-chloroacetylphenoxymethyl)tetrazole, 7.5 g: m.p. 194°-196° C.; NMR (d6DMSO) δ7.99 (2H, d), 7.20 (2H, d), 5.61 (2H, s), 5.11 (2H, s); m/e 251 (M-H)-, 1 Cl pattern; calculated for C10H9ClN4O2 : C, 47.5; H, 3.6; N, 22.2. found: C, 47.3; H, 3.7; N, 22.2%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:12]=[CH:11][NH:10][C:5]2=[N+:6]([O-])[C:7]=1[CH3:8].C([O-])(O)=O.[Na+].O=P(Cl)(Cl)[Cl:20]>>[Br:1][C:2]1[C:3]([Cl:20])=[C:4]2[N:12]=[CH:11][NH:10][C:5]2=[N:6][C:7]=1[CH3:8]
Reactant: Cc1c(Br)cc2nc[nH]c2[n+]1[O-]
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1nc2[nH]cnc2c(Cl)c1Br
Temperature: 0 °C

Procedure:
A solution of 6-bromo-5-methyl-3H-imidazo[4,5-b]pyridine 4-oxide (1.00 equivalent) in POCl3 (excess) is stirred at 80° C. for 16 hours. The reaction mixture is concentrated in vacuo to give the crude material that is poured into ice-water. The resulting aqueous solution is neutralized with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to afford the desired product. The product is purified by trituration or flash column chromatography if further purification is necessary.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([NH2:10])=[C:4]([Cl:11])[N:3]=1.[F:12][C:13]([F:18])([F:17])[C:14](O)=O>>[Cl:1][C:2]1[N:7]=[C:6]2[C:5]([N:10]=[C:14]([C:13]([F:18])([F:17])[F:12])[N:8]2[CH3:9])=[C:4]([Cl:11])[N:3]=1
Reactant: CNc1nc(Cl)nc(Cl)c1N
Reactant: O=C(O)C(F)(F)F
Product: Cn1c(C(F)(F)F)nc2c(Cl)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2,6-dichloro-N4-methylpyrimidine-4,5-diamine (400 mg) and trifluoroacetic acid (8 mL) was stirred for 8 hours while heating to reflux. Furthermore, the reaction mixture was stirred at 120° C. for 1.5 hours under microwave irradiation. After the reaction mixture was concentrated under reduced pressure, phenylphosphonic dichloride (1.8 mL) was added to the residue, and the mixture was stirred 180° C. for 2 hours. After the reaction mixture was cooled to room temperature, cold water (20 mL) was added thereto, then, the mixture was stirred, and the precipitate was collected by filtration. The obtained solid was purified by silica gel column chromatography (Hex:EtOAc=100:0 to 90:10), whereby 2,6-dichloro-9-methyl-8-(trifluoromethyl)-9H-purine (435 mg) was obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][CH:18]([OH:35])[C:19](=[O:34])[NH:20][CH2:21][C:22]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([O:30][CH3:31])=[CH:24][C:23]=1[O:32][CH3:33])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:43]1([CH3:53])[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:44]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:13]([O:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:17][CH:18]([O:35][S:49]([C:46]1[CH:47]=[CH:48][C:43]([CH3:53])=[CH:44][CH:45]=1)(=[O:51])=[O:50])[C:19](=[O:34])[NH:20][CH2:21][C:22]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([O:30][CH3:31])=[CH:24][C:23]=1[O:32][CH3:33])([CH3:14])([CH3:16])[CH3:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(OC)c(CNC(=O)C(O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(OC)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(OC)c(CNC(=O)C(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)OS(=O)(=O)c2ccc(C)cc2)c(OC)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
To a stirred solution of 10 (0.546 g, 1.09 mmol) in CH2Cl2 (10 mL) cooled with ice bath (0° C.) was added Et3N (0.76 mL, 5.45 mmol), p-toluenesulfonyl chloride (TsCl, 0.416 g, 2.18 mmol) and catalytic amount 4-dimethylaminopyridine (DMAP, 0.11 mmol, 0.013 g). After maintaining at 0° C. for 15 min., the ice bath was removed, the reaction kept at r.t. overnight and then submitted to standard workup with CH2Cl2. The crude product was purified by FC (EtOAc/Hexanes, 40/60 to 50/50, V/V) to provide a pale white solid 11 (0.68 g, 96%). HPLC of 11: isomer one: 50%, Rt=12.53 min; isomer two: 50%, Rt=18.72 min; [column: Lux 3u Cellulose-1 (150×4.6 mm), UV detector, 210 nm, 5% 2-propanol in hexanes; flow rate: 1.0 mL/min]. 1HNMR (200 MHz, CD2Cl2) δ 7.72 (d, 2H, J=8.2 Hz), 7.28 (d, 2H, J=8.2 Hz), 6.79 (d, 1H, J=20.6 Hz), 6.15 (s, 2H), 5.14 (br s, 1H), 4.83 (t, 1H, J=6.8 Hz), 4.50-3.94 (m, 3H), 3.82 (s, 6H), 3.81 (s, 3H), 2.41 (s, 3H), 2.28-2.11 (m, 2H), 1.43 (s, 9H), 1.42 (s, 9H). 13C NMR (50 MHz, CD2Cl2) δ 171.0, 167.3, 161.8, 159.9, 155.8, 146.3, 133.3, 130.6, 128.5, 128.4, 106.6, 106.4, 91.3, 82.8, 82.5, 80.2, 78.0, 77.7, 56.4, 56.0, 35.7, 35.3, 32.9, 28.7, 28.3, 22.0. HRMS calcd for C31H45N2O11S (M+H)4: 653.2744. found: 653.2734, 653.2739.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39].C(N(CC)CC)C>CN(C)C=O>[O:29]=[C:27]1[NH:26][C:25](=[O:30])[CH:24]([CH2:23][C:22]2[CH:31]=[CH:32][C:19]([O:18][CH2:17][C:15]3[N:14]([CH3:33])[C:13]4[CH:34]=[C:9]([O:8][C:7]5[CH:35]=[CH:36][C:4]([NH:3][S:38]([CH3:37])(=[O:40])=[O:39])=[CH:5][CH:6]=5)[CH:10]=[CH:11][C:12]=4[N:16]=3)=[CH:20][CH:21]=2)[S:28]1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NS(C)(=O)=O)cc3)cc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 39.4 %

Procedure:
A mixture of 5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg), methanesulfonyl chloride (88 mg), triethylamine (234 mg) and anhydrous N,N-dimethylformamide (8 ml) was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=3:1→4:1→1:0 as the eluant and the product was recrystallized from ethyl acetate to afford the title compound (159 mg, mp 224.8-226.5° C.).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C:6]([CH3:18])([CH2:8][CH2:9][C:10]([O:13][C:14](=[O:17])[CH2:15]Cl)([CH3:12])[CH3:11])[CH3:7])=[O:4].[CH2:19]([CH2:21][NH2:22])[OH:20]>C(Cl)Cl>[OH:20][CH2:19][CH2:21][NH:22][CH2:2][C:3]([O:5][C:6]([CH3:18])([CH2:8][CH2:9][C:10]([O:13][C:14](=[O:17])[CH2:15][NH:22][CH2:21][CH2:19][OH:20])([CH3:12])[CH3:11])[CH3:7])=[O:4]
Reactant: CC(C)(CCC(C)(C)OC(=O)CCl)OC(=O)CCl
Reactant: NCCO
Solvent: ClCCl
Product: CC(C)(CCC(C)(C)OC(=O)CNCCO)OC(=O)CNCCO
Temperature: 20 °C
Reaction time: 18 h

Procedure:
To a solution of compound (61) (0.898 g, 3 mmol) in 5 ml, of methylene chloride at 0° C., ethanolamine (40) (2.504 g, 41 mmol) was added drop wise over the course of one hour. The solution was then allowed to warm to 20° C. and stirred for 18 hours. On completion, the reaction was diluted with CH2Cl2 (15 mL) and washed with brine (1×20 mL) and dried. The solvent was evaporated to get clear yellow oil. (0.380 g) 1H NMR (400 MHz, CDCl3): δ 1.35 (s, 12H), 1.79 (s, 4H), 2.68-2.71 (t, J=5.1, 4H), 3.08 (b, 4H), 3.26 (s, 4H), 3.58-3.60 (t, J=5.1, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH:5]([NH:26]C=O)[CH:6]=[C:7]([CH2:15][P:16]([O:22]C(C)C)([O:18]C(C)C)=[O:17])[CH2:8][CH2:9][N:10]([C:12](=[O:14])[CH3:13])[CH3:11])[CH3:2].C[Si](C)(C)Br.C(O)C>ClCCl>[CH2:1]([O:3][C:4](=[O:29])[CH:5]([NH2:26])[CH:6]=[C:7]([CH2:15][P:16]([OH:22])([OH:18])=[O:17])[CH2:8][CH2:9][N:10]([C:12](=[O:14])[CH3:13])[CH3:11])[CH3:2]
Reactant: CCOC(=O)C(C=C(CCN(C)C(C)=O)CP(=O)(OC(C)C)OC(C)C)NC=O
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(N)C=C(CCN(C)C(C)=O)CP(=O)(O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
8.2 g (18.9 mmol) of 6-(N-acetyl-N-methylamino)-4-diisopropylphosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester are dissolved in 40 ml of dichloromethane, and 9.8 ml (75.6 mmol) of trimethylbromosilane are added dropwise at room temperature. The mixture is left to stand at room temperature for 24 hours, 40 ml of ethanol are added dropwise, the mixture is left to stand for a further 24 hours and is concentrated by evaporation, the residue is dissolved in 40 ml of ethanol, and a mixture of 40 ml of propylene oxide and 40 ml of ethanol is added dropwise. A suspension forms, which is stirred for a further one hour at room temperature and for one hour at 0° and is then filtered with suction. Drying yields 6-(N-acetyl-N-methylamino)-2-amino-4-phosphonomethyl-hex-3-enoic acid ethyl ester having a melting point of 222°-223° C. (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:17]3[CH:18]=[C:19]([F:23])[C:20]([F:22])=[CH:21][C:16]=3[N:15]=[C:14]2[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[OH:31])=[CH:8][CH:7]=1.Br[CH2:34][CH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:17]3[CH:18]=[C:19]([F:23])[C:20]([F:22])=[CH:21][C:16]=3[N:15]=[C:14]2[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[O:31][CH2:34][CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:8][CH:7]=1
Reactant: COC(=O)COc1ccc(Cn2c(-c3ccc(Cl)cc3O)nc3cc(F)c(F)cc32)cc1
Reactant: BrCC1CCCC1
Product: COC(=O)COc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from {4-[2-(4-chloro-2-hydroxy-phenyl)-5,6-difluoro-benzoimidazol-1-ylmethyl]-phenoxy}-acetic acid methyl ester and bromomethyl-cyclopentane (CAS Reg. No. 3814-30-0). Brown sticky solid (57%). MS (Turbo Spray): m/z=540.9 (M+H).
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.N1(C=O)CC[O:13][CH2:12]C1.Cl.CCOCC>C1COCC1>[Cl:8][C:5]1[N:4]=[C:3]([Cl:9])[C:2]([CH:12]=[O:13])=[CH:7][N:6]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: O=CN1CCOCC1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1cnc(Cl)nc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
A solution of isopropyl magnesium chloride lithium chloride complex in THF (2M, 184 mL, 368 mmol) was added drop-wise over about 30 min to a 2 L round-bottomed flask charged with a solution of 5-bromo-2,4-dichloropyrimidine (49.6 g, 218 mmol) in THF (1000 mL) at about −78° C. The reaction was allowed to stir at about −78° C. for about 30 min. Morpholine-4-carbaldehyde (75.0 g, 653 mmol) was then added drop-wise at about −78° C. over about 30 min. The reaction was allowed to stir for about 30 min at about −78° C. then allowed to warm to about −35° C. and stirred for about 30 min. Aqueous HCl (1N, 250 mL) and Et2O (500 mL) were added and the reaction mixture was allowed to warm to ambient temperature. The organic layer was separated and the aqueous layer was further extracted with Et2O (200 mL). The combined organic layers were dried over anhydrous MgSO4, filtered through a silica gel pad on a fritted funnel, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using DCM (100%) as the eluent to provide 2,4-dichloropyrimidine-5-carbaldehyde (27.3 g, 71%) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.34 (s, 1H), 9.30 (s, 1H).
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:42])[C:6]1[CH:16]=[C:15]([C:17]2[CH:18]=[C:19]3[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])=[N:24][N:23]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:20]3=[N:21][CH:22]=2)[CH:14]=[C:8]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH:7]=1.O>O.CO>[CH3:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:25]1[C:19]2[C:20](=[N:21][CH:22]=[C:17]([C:15]3[CH:14]=[C:8]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH:7]=[C:6]([CH:16]=3)[C:5]([OH:42])=[O:4])[CH:18]=2)[N:23]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:39])[CH3:40])[N:24]=1
Reactant: COC(=O)c1cc(C(=O)N(C)C)cc(-c2cnc3c(c2)c(-c2ccccc2OC)nn3COCC[Si](C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cc(C(=O)O)cc(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.7 %

Procedure:
4 N aqueous lithium hydroxide (0.43 ml, 1.71 mmol) was added to 5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-isophthalamic acid methyl ester (0.80 g, 1.43 mmol) in water/methanol(3:1) and stirred at room temperature for 16 hours, water was added and the mixture was extracted with ethyl acetate (3×), the combined organic layers were dried over magnesium sulfate and purified by silica gel chromatography to give 5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-isophthalamicacid (717 mg, 92% yield) of an off white powder. MS: m/z 546.7 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:6][C:5]([C:15]#[N:16])=[CH:4][C:3]=1[NH:17]C(=O)OC(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:17][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([CH2:8][N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[C:2]=1[Cl:1])[C:15]#[N:16]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(CN2CCOCC2)c1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(N)c(Cl)c(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
A solution of tert-butyl (2-chloro-5-cyano-3-(morpholinomethyl)phenyl)carbamate (45 mg, 0.128 mmol) in a mixture of DCM (2 mL) and TFA (2 mL) was left stirring at RT for 1 hr. The solvent was removed and the residue was dissolved in MeOH and applied onto an SCX column. This was washed with MeOH and the product was eluted with 2N NH3 in MeOH. The solvent was removed to leave 3-amino-4-chloro-5-(morpholinomethyl)benzonitrile (32 mg, 100% yield).
Reaction SMILES: [OH:1][C:2]1[C:19]2[C@@H:18]3[C@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C:13](=[O:20])[CH2:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:21][CH3:22])[CH:3]=1.S(OC)(O[CH3:27])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:27][O:1][C:2]1[C:19]2[C@@H:18]3[C@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C:13](=[O:20])[CH2:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:21][CH3:22])[CH:3]=1
Reactant: COc1cc(O)c2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc2c(c(OC)c1)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Reaction time: 6 h

Procedure:
A suspension of 1-hydroxy-3-methoxyestra-1,3,5(10)-trien-17-one (2.5 g, 8.3 mM), dimethyl sulfate (1.3 g, 10.3 mM) and potassium carbonate (1.2 g) in 250 ml of anhydrous acetone is refluxed with vigorous stirring for 6 hrs. An additional 0.5 g of dimethyl sulfate is added and the suspension refluxed for 14 hrs. The reaction mixture is filtered while warm and the solids washed well with acetone. The combined acetone filtrates are evaporated in vacuo and the residue is recrystallized from methanol-H2O. Two recrystallizations give 1,3-dimethoxyestra-1,3,5(10)-trien-17-one, yield 1.91 g (73%); m.p. 132°-133°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH3:9][C:10]([CH3:12])=O>>[CH2:12]([N:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[N:6][C:5]1=[O:8])[CH:10]=[CH2:9]
Reactant: CC(C)=O
Reactant: O=c1ncc(Cl)c[nH]1
Product: C=CCn1cc(Cl)cnc1=O
Yield: 64 %

Procedure:
1-Allyl-5-chloropyrimid-2-one was prepared from 5-chloropyrimid-2-one as above in 64% yield. m.p. 130°-131° C. (acetone) (Found: C, 49.22; H, 4.13. Calc. for C7H7ClN2O: C, 49.28; H, 4.13).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]([CH3:12])[C:9](=O)[CH2:8][CH2:7]2.S([O-])([O-])(=O)=O.[Mg+2].[CH2:20]([NH2:23])[CH2:21][CH3:22]>ClCCl>[CH3:12][CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[Br:1])[CH2:7][CH2:8][C:9]1=[N:23][CH2:20][CH2:21][CH3:22]
Reactant: CC1C(=O)CCc2cccc(Br)c21
Reactant: CCCN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CCCN=C1CCc2cccc(Br)c2C1C
Temperature: 25 °C

Procedure:
To a solution of 8-bromo-1-methyl-2-tetralone (4.05 gm, 16.9 mMol) in dichloromethane (60 mL) were added magnesium sulfate (3.0 gm, 25 mMol) and n-propylamine (2.0 mL, 24.4 mMol). The mixture was stirred at room temperature for twenty hours. The reaction mixture was filtered through a bed of celite and the filtrate concentrated in vacuo to give 1-methyl-2-n-propylimino-8-bromo-1,2,3,4-tetrahydronaphthalene as a dark residue.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:9].CON(C)[C:13]([C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=1)=[O:14]>>[Cl:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][C:13]([C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=1)=[O:14]
Reactant: CON(C)C(=O)c1ccc(I)cc1
Reactant: ClCc1ccccc1Cl
Product: O=C(Cc1ccccc1Cl)c1ccc(I)cc1

Procedure:
The title compound was prepared from α,2-dichlorotoluene and O,N-dimethyl-4-iodobenzenehydroxamic acid (see Preparation 30) by a similar method to that of Preparation 20(i) as a colourless solid, m.p. 105-106° C., which was characterised by 1H-N.M.R. spectroscopy.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(OCC)(=O)C.N1C=CC=CC=1>[C:14]([N:2]1[CH2:3][CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1]1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N1CCc2c([nH]c3ccccc23)C1
Reaction time: 0.5 h

Procedure:
2-acetyl-1,2,3,4-tetrahydro-β-carboline was prepared as follows: 1 g of 1,2,3,4-tetrahydro-β-carboline (Sigma) was dissolved in a minimum of ethyl acetate, and pyridine 3 mL) was added along with acetic anhydride (1.5 mL). After 30 minutes, the mixture was dried and the resulting 2-acetyl-1,2,3,4-tetrahydro-β-carboline was recrystallized from acetone.
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:11]=[CH:12][CH:13]=2)=[C:5]([F:21])[CH:4]=1.[H][H]>[Pt].[C].CC(O)C>[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])=[C:5]([F:21])[CH:4]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)n1cccc1-c1ccc(N)cc1F
Agent: [Pt]
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCCC1c1ccc(N)cc1F

Procedure:
5 ml of water and 660 mg of 5% platinum-carbon catalyst were added to a 2-propanol (50 ml) solution of 2.2 g of t-butyl 2-(4-amino-2-fluoro-phenyl)-pyrrole-1-carboxylate, and stirred in a hydrogen atmosphere under a pressure of 50 kgf/cm2 at 50° C. for 1 day. The catalyst was removed through filtration through Celite, the solvent was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/1) to obtain the entitled compound as a brown oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:23])=[C:7]([C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1.O>[C:24]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:23])=[C:7]([C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1)(=[O:26])[CH3:25]
Reactant: Nc1ccc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1ccc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2c1
Reaction time: 24 h

Procedure:
A solution of 100 mg of 7-amino-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide in 1 mL of anhydrous pyridine is treated with 0.032 mL of acetic anhydride. After 24 h, an additional 0.005 mL of acetic anhydride is added and the mixture is stirred for an additonal 48 h. The mixture is diluted with 2 mL of distilled water and the precipitate is collected by filtration. It is washed with two 1 mL portions of distilled water and dried in a stream of air. It is dried at 20 torr/75°C./16 h. The product is obtained as 78 mg of a tan solid.
Reaction SMILES: [CH:1]([C:4]1[O:8][N:7]=[C:6]([CH:9](O)[CH3:10])[CH:5]=1)([CH3:3])[CH3:2].C1(C)C=CC(S([Cl:21])(=O)=O)=CC=1.O>N1C=CC=CC=1>[Cl:21][CH:9]([C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[O:8][N:7]=1)[CH3:10]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)c1cc(C(C)O)no1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)c1cc(C(C)Cl)no1
Reaction time: 5 h
Yield: 57.3 %

Procedure:
5.66 g of 1-(5-i-propyl-isoxazol-3-yl)ethanol was dissolved in 30 ml of pyridine, and 7.20 g of 4-toluenesulfonyl chloride was then added under ice-cooling. The mixture was stirred for 5 hours under ice-cooling. After water was added, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.63 g of 3-(1-chloroethyl)-5-i-propylisoxazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][OH:19].[C:20]1(O)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][O:19][C:28]1[C:29]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCCO
Reactant: Oc1cccc2ccccc12
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCCOc1cccc2ccccc12
Reaction time: 72 h

Procedure:
To a mixture of Example 1B (10.87 g), 1-naphthol (5.77 g) and triphenylphosphine (10.5 g) in THF (100 mL) was added di-tert-butyl azodicarboxylate (9.21 g). The mixture was stirred for 3 days, concentrated, redissolved in dichloromethane, washed with water and brine and dried (MgSO4), filtered and concentrated. The concentrate was purified by flash column chromatography on silica gel with 0-10% ethyl acetate in hexanes. The product was recrystallized from hexanes.