Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[C:2]1([SiH:8](Cl)Cl)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11]1[CH2:15]O[CH2:13][CH2:12]1.C=CC=C>CCOCC.C(O)CO>[C:2]1([SiH:8]2[CH2:13][CH:12]=[CH:11][CH2:15]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: Cl[SiH](Cl)c1ccccc1
Agent: C=CC=C
Agent: [Mg]
Solvent: OCCO
Solvent: CCOCC
Product: C1=CC[SiH](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 19 %

Procedure:
In a 500 mL two neck rb flask equipped with a reflux condenser, a Teflon covered magnetic stirring bar and a rubber septum was placed magnesium powder (9.6 g, 0.4 mol), phenyldichlorosilane (35.4g, 0.2 mol) and THF (300 mL). The reflux condenser was connected to a refrigeration unit. Ethylene glycol cooled to -20° C. was circulated through the reflux condenser. 1,3-Butadiene (15.1 g, 0.28 mol) was condensed at -78° C. into a volumetric flask which was sealed with a rubber septum. The 1,3-butadiene was transferred into the reaction via a cannula. The reaction mixture was stirred at rt for 24 h. Ether (2×100 mL) was added. The organic solution was decanted from the magnesium chloride salts. These were transferred to a sintered glass funnel and were washed with ether (100 mL). The combined organic solution was washed with water (2×50 mL), dried over anhydrous magnesium sulfate, filtered and the volatile solvents removed by evaporation under reduced pressure. The residue was purified by distillation through a 10 cm vacuum jacketed Vigreux column. A fraction, bp 87°/5 mm, 6.0 g, 19% yield, was collected.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH2:10]([N:12]([CH2:17][CH3:18])[CH2:13][CH2:14][CH2:15][NH2:16])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>O>[Cl:3][C:2]1[N:1]=[C:8]([NH:16][CH2:15][CH2:14][CH2:13][N:12]([CH2:17][CH3:18])[CH2:10][CH3:11])[N:7]=[C:5]([NH:16][CH2:15][CH2:14][CH2:13][N:12]([CH2:17][CH3:18])[CH2:10][CH3:11])[N:4]=1
Reactant: CCN(CC)CCCN
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCN(CC)CCCNc1nc(Cl)nc(NCCCN(CC)CC)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Following the procedure described in Japanese Patent Publication No. 39272/74, 50.0 ml of water was cooled to 3° C. and slowly 18.4 g (0.1 mole) of cyanuric chloride was added while maintaining 3°-5° C. by means of an external ice-water bath. Slowly 26.0 g (0.2 mole) of 3-(diethylamino)propylamine was added while maintaining 3°-12° C. by means of an ice-water bath. The resulting solution was stirred at ambient temperature for approximately eight hours and allowed to stand overnight. Slowly a 10 percent aqueous potassium carbonate solution was added to the reaction solution until it was slightly alkaline. The solid which precipitated was collected by filtration. The water wet filter cake was resuspended in water and dissolved by the addition of hydrochloric acid. Slowly 10 percent aqueous potassium carbonate was added until the mixture was slightly alkaline. The resulting solid was collected by filtration, washed with water and dried in vacuo to obtain 2-chloro-4,6-bis[3-(diethylamino)propyl]amino-1,3,5-triazine, a water-insoluble, white colored solid which melted at 119° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[O:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[C:9](S(C(F)(F)F)(=O)=O)=[C:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:7]=1.[Cl:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[O:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([C:38]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:33])[CH:39]=2)=[C:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:7]=1
Reactant: COc1nc(Oc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1S(=O)(=O)C(F)(F)F
Reactant: OB(O)c1cccc(Cl)c1
Product: COc1nc(Oc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1-c1cccc(Cl)c1

Procedure:
This derivative was prepared by the method described in Example 132 using 2-(3,4-difluorophenoxy)-4-methoxy-5-trifluoromethansulfonyl-6-[2,4-dichlorophenyl]pyrimidine (27 mg, 0.05 mmol) as described in Reference Example 17 and 3-chlorobenzeneboronic acid (Lancaster, 16 mg, 0.1 mmol). HPLC Rt=4.82 min. 1H-NMR 500 MHz (CDCl3): 3.88 (s, 3H), 6.45 (d, J=8 Hz, 1H), 6.51 (s, 1H), 6.67 (d, J=8 Hz, 1H), 6.71 (s, 1H), 6.95 (m, 1H), 7.05 (t, J=9 Hz, 1H), 7.8 (m, 2H), (7.39 s, 2H).
Reaction SMILES: C([O:3][C:4](=[O:22])[C@@H:5]([O:20][CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][CH2:31][NH2:32].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][CH2:31][NH:32][C:17]([C:14]([CH3:15])([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:20][CH3:21])[C:4]([OH:3])=[O:22])=[CH:12][CH:11]=1)[CH3:16])=[O:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OC
Reactant: NCCc1ccccc1F
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OC(C)(C)C(=O)NCCc2ccccc2F)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (PREPARATION 5, step 2) and 2-(2-fluoro-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C22H26FNO5 [M−H]−: 402.
Reaction SMILES: [F:1][C:2]1[C:19]([F:20])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[O:7])=[C:4]([OH:21])[CH:3]=1.[C:22]1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[F:20][C:19]1[C:2]([F:1])=[CH:3][C:4]2[O:21][CH2:22][N:8]([C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=3)[C:6](=[O:7])[C:5]=2[CH:18]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)c1cc(F)c(F)cc1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1c2cc(F)c(F)cc2OCN1c1ccc([N+](=O)[O-])cc1
Yield: 0.7 %

Procedure:
To 4,5-difluoro-2-hydroxy-N-(4-nitrophenyl)benzamide (0.13 g, 0.44 mmol) in toluene (5 ml) was added paraformadehyde (0.3 g, 10 mmol) and p-toluenesulfonic acid (0.01 g, 0.05 mmol) and the reaction heated to 120° C. for 3 hr with azeotropic removal of water. Saturated sodium bicarbonate (10 ml) was added and product extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated to give 0.11 mg (81%) of 6,7-difluoro-3-(4-nitrophenyl)-2,3-dihydrobenzo[e][1,3]oxazin-4-one. RP-HPLC: 2.54 min; ES-MS (M+H)+=307.0; 1H-NMR (MeOH-d4) δ (ppm): 5.78 (s, 2 H), 7.04 (dd, 1 H), 7.64 (d, 2 H), 7.82 (dd, 1 H), 8.3 (d, 2 H).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([N:23]2[CH2:27][CH:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:25]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)=[N:24]2)=[O:22])=[CH:16][CH:15]=1.IC>O1CCCC1.CCCCCC.C(O)(=O)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([N:23]2[CH2:27][C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([CH3:1])[C:25]([C:34]3[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=3)=[N:24]2)=[O:22])=[CH:16][CH:15]=1
Reactant: CC(C)NC(C)C
Reactant: O=C(Nc1ccc(Cl)cc1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CI
Solvent: C1CCOC1
Product: CC1(c2ccccc2)CN(C(=O)Nc2ccc(Cl)cc2)N=C1c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 99 %

Procedure:
To 2.1 g of diisopropylamine dissolved in 15 ml of tetrahydrofuran and cooled in an ice salt bath was added 8.0 ml of a 2.7 molar solution of n-butyllithium in hexane. After stirring for 5 minutes a solution of 4.2 g of N,3-bis-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (Example D) in 15 ml of tetrahydrofuran was added and the resulting solution stirred for 15 minutes. To this solution was added 1.0 ml of iodomethane and, after 15 minutes 1.0 ml of acetic acid was added. The reaction mixture was partitioned between diethyl ether and water and the organic layer was dried over anhydrous magnesium sulfate. The resulting solution was filtered evaporated in vacuo to give 4.3 g of N,3-bis-(4-chlorophenyl)-4-phenyl-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide, melting point 151°-158° C. NMR and IR data were consistent with the structure.
Reaction SMILES: Cl[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].[CH3:16][N:17]([CH2:19][C@@H:20]1[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]1)[CH3:18]>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:26][C@H:23]1[CH2:24][CH2:25][C@@H:20]([CH2:19][N:17]([CH3:18])[CH3:16])[CH2:21][CH2:22]1
Reactant: CN(C)C[C@H]1CC[C@@H](N)CC1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Product: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@@H](CN(C)C)CC1

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (500 mg, 2.1 mmol) was reacted with cis-4-[(dimethylamino)methyl]cyclohexanamine (300 mg, 2.0 mmol) to afford the desired product (400 mg, 55%) as a yellow solid: ESI MS m/z 361 [M+H]+;
Reaction SMILES: [F:1][C:2]([C:5]1[N:9]([C:10]2[CH:11]=[C:12]([CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)[CH:18]=2)[C:13](O)=[O:14])[N:8]=[N:7][N:6]=1)([F:4])[CH3:3].[NH2:26][C@H:27]([CH3:30])[CH2:28][OH:29]>>[F:1][C:2]([C:5]1[N:9]([C:10]2[CH:11]=[C:12]([CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)[CH:18]=2)[C:13]([NH:26][C@@H:27]([CH3:30])[CH2:28][OH:29])=[O:14])[N:8]=[N:7][N:6]=1)([F:4])[CH3:3]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-n3nnnc3C(C)(F)F)c2)nc1
Reactant: C[C@@H](N)CO
Product: Cc1ccc(-c2cc(C(=O)N[C@@H](C)CO)cc(-n3nnnc3C(C)(F)F)c2)nc1

Procedure:
3-[5-(1,1-Difluoro-ethyl)-tetrazol-1-yl]-5-(5-methyl-pyridin-2-yl)-benzoic acid was reacted with (R)-2-amino-propan-1-ol using the procedure of step 4 of Example 5, to afford 3-[5-(1,1-Difluoro-ethyl)-tetrazol-1-yl]-N-((S)-2-hydroxy-1-methyl-ethyl)-5-(5-methyl-pyridin-2-yl)-benzamide, MS (M+H)=403.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]([O:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH3:6])=[O:4].[CH2:17]([O:29][C:30]1[CH:31]=[N:32][C:33]([C:36]2[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][CH:37]=2)=[N:34][CH:35]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C@H:5]([O:7][C:8]([C:9]1[CH:10]=[CH:11][C:12]([O:15][C:40](=[O:41])[C:39]2[CH:38]=[CH:37][C:36]([C:33]3[N:34]=[CH:35][C:30]([O:29][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:31][N:32]=3)=[CH:44][CH:43]=2)=[CH:13][CH:14]=1)=[O:16])[CH3:6])=[O:4]
Reactant: COC(=O)[C@@H](C)OC(=O)c1ccc(O)cc1
Reactant: CCCCCCCCCCCCOc1cnc(-c2ccc(C(=O)O)cc2)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCOc1cnc(-c2ccc(C(=O)Oc3ccc(C(=O)O[C@H](C)C(=O)OC)cc3)cc2)nc1
Temperature: 25 °C
Yield: 22.4 %

Procedure:
In a 50 ml round flask were charged 191 mg (0.85 mmol) of (R)-4-hydroxybenzoic acid 1-(methoxycarbonyl)-ethyl ester as prepared in Example 1-2), 360 mg (0.935 mmol) of 4-(5-dodecyloxypyrimidin-2-yl)benzoic acid, 10.4 mg (0.085 mmol) of N,N-dimethyl-4-aminopyridine, and 20 ml of methylene chloride, followed by stirring at 25 ° C. To the mixture was added 193 mg (0.935 mmol) of DCC to conduct a reaction at 25° C. for 18 hours. After completion of the reaction, the solid was removed by filtration, and the filtrate was washed successively three times with 10 ml portions of water, three times with 10 ml portions of a 5% acetic acid aqueous solution, and three times with 10 ml portions of water. The organic solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography using a 20:1 (by volume) mixture of methylene chloride and diethyl ether. Recrystallization from hexane gave 110 mg (0.19 mmol) of Compound (35) in a yield of 22%.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([CH:17]([CH2:26][C:27]([O-:29])=O)[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:6][O:7][C:8]=2[CH:9]2[CH2:12][CH:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10]2)[CH2:3][CH2:2]1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=1[NH2:38].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(=O)(O)[O-].[Na+]>O.CN(C=O)C>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=1[NH:38][C:27]([CH2:26][CH:17]([C:5]1[C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:8]([CH:9]2[CH2:10][CH:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:12]2)[O:7][N:6]=1)[CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[O:29]
Reactant: Cc1ccc(Cl)c(N)c1
Reactant: CC(C)CC1CC(c2onc(C(CC(=O)[O-])CC(=O)OC(C)(C)C)c2C2CC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)c(NC(=O)CC(CC(=O)OC(C)(C)C)c2noc(C3CC(CC(C)C)C3)c2C2CC2)c1
Yield: 33.5 %

Procedure:
Mono-tert-butyl 3-[4-cyclopropyl-5-(3-isobutylcyclobutyl)isoxazol-3-yl]glutarate (2.83 g) and DMF (28 mL) were mixed. After an addition of 2-chloro-5-methylphenylamine (1.184 g), HOBt.H2O (1.28 g) and WSC.HCl (1.60 g) to the resultant solution, the mixture was stirred at RT for 2 days. To the reaction mixture was added saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and brine, then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (Eluent: ethyl acetate/hexane=1/15→1/10→1/8) to give the title compound (1.241 g).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([N+]([O-])=O)[CH:14]=1.CC[O-].[Na+].[Na]>CCO>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([NH:2][CH:3]2[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4]2)[CH:14]=1
Reactant: NC1Cc2ccccc2C1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)cc1NC1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 36.1 %

Procedure:
26 g of 2-aminoindane hydrochloride and then 20 g of 4-chloro-1,2-dinitrobenzene are added to a solution of sodium ethylate, prepared from 0.61 g of sodium and 200 ml of EtOH, and the mixture is stirred for 48 hours at RT. The solvent is evaporated off under vacuum, the residue is extracted with AcOEt, washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum to give 10.3 g of the expected product after crystallization from EtOH. M.p.=108° C.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([O:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=2)=[C:5]([I:11])[C:6](=[O:10])[NH:7][C:8]=1[CH3:9].NC(N)=[S:23].[OH-].[Na+].Cl>CS(C)=O>[CH3:20][C:15]1[CH:14]=[C:13]([CH:18]=[C:17]([CH3:19])[CH:16]=1)[O:12][C:4]1[C:3]([CH2:2][SH:23])=[C:8]([CH3:9])[NH:7][C:6](=[O:10])[C:5]=1[I:11]
Reactant: NC(N)=S
Reactant: Cc1cc(C)cc(Oc2c(CCl)c(C)[nH]c(=O)c2I)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1cc(C)cc(Oc2c(CS)c(C)[nH]c(=O)c2I)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of compound 125 (1.5 g; 0.0037 mol) and thiourea (0.31 g; 0.00408 mol) in DMSO (30 ml) was stirred at room temperature for 1 hour. NaOH 3N was added. The mixture was stirred for 15 minutes, acidified with HCl 3N and extracted with ethylacetate (EtOAc). The organic layer was separated, dried on magnesium sulfate (MgSO4), filtered and the solvent was evaporated. The residue was taken up in DIPE and filtered. The precipitate (1.2 g) was purified by column chromatography over silica gel (eluent: EtOAc 100%; 35–70 μm) and dried to yield 0.3 g (20%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[CH:7][C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[C:10]([CH2:16]Br)[CH:9]=3.[C:18]([O-:21])(=[O:20])[CH3:19].[K+]>CN(C=O)C.C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[CH:7][C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[C:10]([CH2:16][O:21][C:18](=[O:20])[CH3:19])[CH:9]=3
Reactant: CC(=O)[O-]
Reactant: BrCc1ccc2c(ccc3ccc(Br)cc32)c1
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)OCc1ccc2c(ccc3ccc(Br)cc32)c1
Temperature: 80 °C
Yield: 96.5 %

Procedure:
A mixture of 3-bromo-7-(bromomethyl)-phenanthrene (2.249 g, 6.425 mmol) and potassium acetate (1.26 g, 12.8 mmol) in 60 ml of DMF was heated at 80° C. for 7 hours. After cooling to RT, the reaction mixture was diluted with ethyl ether, washed with water and brine, dried (MgSO4) and evaporated to give 2.042 g (97%) of the title compound as a white solid which was used in the following reaction without purification.
Reaction SMILES: C([O-])(O)=O.[Na+].[NH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[CH2:11][OH:12].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(Cl)Cl>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:6]2[CH2:10][CH2:9][CH2:8][C@@H:7]2[CH2:11][OH:12])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: OCC1CCCN1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1)N1CCC[C@@H]1CO
Temperature: 20 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
To a mixture of sat aq. NaHCO3 (44 g, 0.53 mol), CH2Cl2 (400 mL) and pyrrolidin-2-yl-methanol (53 g, 0.53 mol) was added a solution of 4-bromo-benzenesulfonyl chloride (127 g, 0.50 mol) in CH2Cl2 (100 mL). The reaction was stirred at 20° C. overnight. The organic phase was separated and dried over Na2SO4. Evaporation of the solvent under reduced pressure provided (R)-(1-(4-bromophenylsulfonyl)pyrrolidin-2-yl)methanol (145 g, crude), which was used in the next step without further purification. 1H NMR (CDCl3, 300 MHz) δ 7.66-7.73 (m, 4H), 3.59-3.71 (m, 3H), 3.43-3.51 (m, 1H), 3.18-3.26 (m, 1H), 1.680-1.88 (m, 3H), 1.45-1.53 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23](=O)[CH2:24][C:25]([O:27]CC)=O)=[C:10]1[C:31]([O:33][CH2:34][CH3:35])=[O:32].N12CCCC1=NCCC2.Cl.[NH2:46][C:47]([NH2:49])=[NH:48]>C(O)C>[NH2:48][C:47]1[NH:49][C:25](=[O:27])[CH:24]=[C:23]([CH2:22][O:21][CH2:20][C:11]2[NH:12][C:13]([CH3:19])=[C:14]([C:15]([O:17][CH3:18])=[O:16])[CH:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=3[Cl:1])[C:10]=2[C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:46]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)CC(=O)COCC1=C(C(=O)OCC)C(c2cccc(Cl)c2Cl)C(C(=O)OC)=C(C)N1
Agent: C1CN=C2CCCN2C1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1=C(COCc2cc(=O)[nH]c(N)n2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Yield: 27.3 %

Procedure:
A solution of ethyl 4-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxy}acetoacetate (0.74 g), 1,5-diazabicyclo[4.3.0]non-5-ene (0.25 g) and guanidine hydrochloride (0.14 g) in ethanol (30 ml) was heated under reflux for 5.5 hours and then evaporated. The residue was dissolved in chloroform and the solution washed successively with water, 10% aqueous sodium carbonate solution and water, dried over anhydrous magnesium sulphate and evaporated. The residue was triturated with ethyl acetate and the resulting precipitate collected, washed thoroughly with diethyl ether, recrystallized from ethyl acetate/ethanol and dried to give the title compound (0.20 g), m.p. 222°-225° C. Found: C,52.10; H,4.56; N,10.54. C23H24Cl2N4O6 requires C,52.78; H,4.62; N,10.70%.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:15]([O-])([OH:17])=[O:16].O>OS(O)(=O)=O>[CH3:1][C:2]1[C:10]([N+:15]([O-:17])=[O:16])=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(C(F)(F)F)cc1C(=O)O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(C(=O)O)cc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 76 %

Procedure:
To a stirred solution of 2-methyl-5-(trifluoromethyl)benzoic acid (2.00 g, 9.80 mmol) in H2SO4 (20 mL, 12 N) was added HNO3 (2 mL, 12N) at 0° C. After stirring for 3 hours, water was added and resulting precipitate was collected. The solid was washed with water and dried to give the titled compound as a white solid (1.90 g, 76% yield). 1H-NMR (400 MHz, CDCl3) δppm; 8.43 (s, 1H), 8.15 (s, 1H), 2.77 (s, 3H); MS (ES) [M−H] 247.8.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]([OH:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:22][C:23]([CH3:27])([CH3:26])[CH2:24]O>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][O:21][CH:8]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(N)CO
Reactant: OC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N)COC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 16 %

Procedure:
Trifluoroacetic acid (25 ml) was added to a solution of benzhydrol (9.2 g) and 2-amino-2-methylpropanol (4.5 g) in methylene chloride (5 ml) and the mixture was stirred at room temperature for 3 hours and evaporated. The residue was partitioned between water and ethyl acetate and the organic layer was washed with water, dried over magnesium sulphate and evaporated. The residue was triturated with hexane and recrystallised from ethyl acetate to give the title compound as a colourless solid (2.98 g, 16%), m.p. 160°-161°.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH2:7][C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:23])[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:37]=[CH:36][C:30]([O:31][CH2:32][C:33](O)=[O:34])=[CH:29][CH:28]=1>>[NH2:23][C:12]1[N:13]=[C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:33](=[O:34])[CH2:32][O:31][C:30]3[CH:36]=[CH:37][C:27]([Cl:26])=[CH:28][CH:29]=3)[CH2:21][CH2:22]2)[C:15]2[N:16]=[C:8]([CH2:7][CH2:6][C:5]3[CH:24]=[CH:25][C:2]([Br:1])=[CH:3][CH:4]=3)[S:9][C:10]=2[N:11]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(CCc3ccc(Br)cc3)sc2n1
Reactant: O=C(O)COc1ccc(Cl)cc1
Product: Nc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(CCc3ccc(Br)cc3)sc2n1
Yield: 29 %

Procedure:
This compound was prepared from 2-(4-bromophenethyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-chlorophenoxyacetic acid in a yield of 29%, according to the procedure for the synthesis of example 50.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:7]([C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=2)[OH:8])[CH:9]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: O=Cc1cc(Br)ccc1F
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)cc1)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.3 %

Procedure:
A solution of 5-bromo-2-fluorobenzaldehyde (10.2 g, 50 mmol) in anhydrous tetrahydrofuran (200 mL) was cooled to −78° C. A solution of 4-chlorophenyl-magnesium bromide (1M in diethyl ether, 60 mL, 60 mmol) was added via syringe over 8 minutes. Stirring was continued at low temperature for 5 minutes and the reaction was warmed up to room temperature and stirred for 1 hour at this temperature. The solution was cooled in an ice-water bath and quenched by addition of saturated aqueous ammonium chloride solution (40 mL). The organic phase was decanted and the aqueous residue was concentrated under reduced pressure to remove any remaining organic solvent. The aqueous phase was extracted with ethyl acetate (200 mL×2) and the extracts were combined with the decanted tetrahydrofuran solution. This solution was washed with brine (25 mL) and was dried (sodium sulfate), filtered and concentrated under reduced pressure, giving crude (5-bromo-2-fluorophenyl)-(4-chlorophenyl)-methanol (15.2 g, 96% yield) as a yellow solid.