Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[C@H:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:3]1.CCN(CC)CC.[Br:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32](Cl)=[O:33]>C(Cl)Cl>[Br:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([NH:1][C@H:2]1[C@H:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][N:4]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:3]1)=[O:33]
Reactant: O=C(Cl)CCCCBr
Reactant: CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1NC(=O)CCCCBr
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.9 %

Procedure:
To a solution of trans-1-tert-butyl 4-ethyl 3-aminopiperidine-1,4-dicarboxylate 7 (2.5 g, 9.2 mmol, 1.0 equiv) in CH2Cl2 (50 mL), Et3N (2.5 mL, 18.4 mmol, 2.0 equiv) was added at rt. After the reaction solution was stirred at rt for 10 min, 5-bromovaleryl chloride (1.9 g, 9.6 mmol, 1.05 eq) was added. The reaction solution was stirred at rt for 2 h. The mixture was quenched with H2O (20 mL) and extracted with CH2Cl2 (50 mL×3). The organic layer was collected, concentrated in vacuo, and the residue was purified by column chromatography (silica, petroleum ether/EtOAc=1:1) to give (trans)-1-tert-butyl 4-ethyl 3-(5-bromopentanamido)piperidine-1,4-dicarboxylate 8 as yellow oil (3.2 g, yield: 80%). ESI-MS (M+H-56)+: 379.0. 1H NMR (400 MHz, CDCl3) δ: 5.99 (d, 1H), 4.39-4.38 (m, 1H), 4.15 (q, 2H), 3.79-3.74 (m, 1H), 3.66-3.60 (m, 1H), 3.41 (t, 2H), 3.30-3.26 (m, 1H), 3.21-3.14 (m, 1H), 2.78-2.74 (m, 1H), 2.19 (t, 2H), 1.99-1.85 (m, 3H), 1.80-1.72 (m, 3H), 1.45 (s, 9H), 1.27 (t, 3H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][N:10]=[C:9]([O:12][CH2:13][CH:14]([NH:17][C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][OH:16])[C:8]=2[CH:37]=1.[CH3:38]I>O1CCCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][N:10]=[C:9]([O:12][CH2:13][CH:14]([NH:17][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:15][O:16][CH3:38])[C:8]=2[CH:37]=1
Reactant: CI
Reactant: OCC(COc1noc2ccc(Cl)cc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC(COc1noc2ccc(Cl)cc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To a suspension of 0.44 g of 60% (w/w) sodium hydride in 49 ml of tetrahydrofuran is added 4.85 g of 5-chloro-3-(2-tritylamino-3-hydroxypropoxy)-1,2-benzoisoxazole at 20°-25° C. and they are refluxed for one hour. The reaction mixture is cooled to 5°-10° C., and thereafter, 1.56 g of methyl iodide is added, after which they are subjected to reaction at 20°-25° C. for five hours. The solvent is removed from the reaction mixture by distillation under reduced pressure, ethyl acetate and water are added to the residue obtained, and after shaking, the organic layer is separated. The separated organic layer is washed with a saturated saline solution and dried over anhydrous magnesium sulfate, after which the solvent is removed by distillation under reduced pressure. The residue obtained is crystallized from n-hexane and the crystals are collected by filtration, to obtain 5-chloro-3-(3-methoxy-2-tritylaminopropoxy)-1,2-benzoisoxazole.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=O)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].[OH:17][CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])[CH2:19][NH2:20]>>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:20][CH2:19][CH:18]([OH:17])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Reactant: NCC(O)c1ccccc1F
Product: COC(=O)COc1ccc(CC(C)NCC(O)c2ccccc2F)cc1

Procedure:
The compound was prepared as in Example 5 from 1-(4-carbomethoxymethoxyphenyl) propan-2-one (2.22 g) and 2-hydroxy-2-(2-fluorophenyl) ethanamine (1.55 g), and crystallised from hexane m.p. 60°-80° as a 55:45 mixture of diastereoisomers.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:21]([C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=2)=[CH:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[Cl-].[Na+].O>[CH:23]1([CH:22]=[C:21]([C:11]2[NH:10][C:14]3=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=[C:13]3[CH:12]=2)[C:28]2[CH:29]=[CH:30][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:32][CH:33]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1ccc2cc(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)n(S(=O)(=O)c3ccccc3)c2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2cc(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)[nH]c2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.1 %

Procedure:
A mixture of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-6-methoxy-1H-pyrrolo[2,3-b]pyridine (300 mg, 0.56 mmol) and tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 20 mL, 20 mmol) was stirred for 12 h at room temperature. The mixture was poured into brine (15 mL), extracted with ethyl acetate (2×100 mL), washed with a saturated aqueous ammonium chloride solution (3×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to give 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-6-methoxy-1H-pyrrolo[2,3-b]pyridine (0.22 g, 100%) as a solid which was used in the next step without purification: LC/MS m/e calcd for C22H24N2O3S [M+H]+ 397.51, observed 397.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:18][C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[C:9]([NH:11][C@H:12]([CH:16]=O)[CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[N:32][CH:33]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:18][C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[C:9]([NH:11][C@H:12]([CH2:16][NH:27][C:28]2[CH:33]=[N:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH:13]([CH3:14])[CH3:15])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](C=O)NC(=O)[C@@H](CC(=O)N1CCOCC1)c1ccc(F)cc1
Reactant: COc1ccc(N)cn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(NC[C@@H](NC(=O)[C@@H](CC(=O)N2CCOCC2)c2ccc(F)cc2)C(C)C)cn1

Procedure:
2-(S)-(4-Fluoro-phenyl)-N-(1-(S)-formyl-2-methyl-propyl)-4-morpholin-4-yl-4-oxo-butyramide (350 mg, 0.96 mmol, 1.0 eq.) and 5-Amino-2-methoxy-pyridine (240 μL, 1.92 mmol, 2.0 eq.) dissolved in MeOH (2.5 mL) and acetic acid (106 mL, 1.92 mmol, 2.0 eq.) added via syringe at room temperature. Sodium cyanoborohydride (121 mg, 1.92 mmol, 2.0 eq.) added in portion and the reaction monitored the reaction by LC/MS. Upon completion, solvents were evaporated and dissolved in EtOAc (100 mL) washed with brine, dried over MgSO4, filtered and evaporated. Purification by preparative mass-directed HPLC provided the title compound as a white solid after evaporation and lyophilization (2.6 mg, 5.6 □mol, 0.6%). HPLC-MS calcd. for C25H33FN4O4 (M+H+) 473.3, found 473.5.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([F:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:19]=[O:21])=[C:11]([F:16])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCc1ccc(N)c(F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCc1ccc(N=C=O)c(F)c1

Procedure:
In analogy to the procedure described in example 9.1, 3-(4-amino-3-fluoro-phenyl)-propionic acid tert-butyl ester was reacted with triphosgene in the presence of Et3N in CH2Cl2 under reflux conditions for 20 h to give the title compound as yellow oil which was used in the next step without further purification. MS: m/e=265.1 [M+].
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([CH3:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C.O>[CH3:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH3:10]
Reactant: Cc1ccccc1O
Reactant: Cc1ccccc1CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1COc1ccccc1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
α-bromo-o-xylene (2.0 g, 10.81 mmol) was added to a solution of 2-methyl-phenol (1.06 g, 9.82 mmol) and cesium carbonate (7.99 g, 24.55 mmol) in DMF (20 mL). The reaction was stirred at 80° C. overnight. The reaction mixture was acidified with 25 mL 1N HCl(aq) and poured into copious water. The aqueous layer was extracted with ethyl acetate and the organic layer was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified via radial chromatography (20% ethyl acetate in hexanes) to yield 1.82 g (88%) of 2-(2-methyl-benzyloxy)toluene (31.1). LC/MSD m/e: 213.2 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:20])[N:8]([CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:28]([O:30][CH2:31][C:32]([Cl:35])([Cl:34])[Cl:33])=[O:29].C(OCC)(=O)C>C1COCC1.O>[Cl:33][C:32]([Cl:35])([Cl:34])[CH2:31][O:30][C:28](=[O:29])[NH:20][C:7]1[N:8]([CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15])[N:9]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(N)n(CCO[Si](C)(C)C(C)(C)C)n1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(CCO[Si](C)(C)C(C)(C)C)n1
Temperature: 0 °C
Yield: 100 %

Procedure:
Dissolve 5-tert-butyl-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2H-pyrazol-3-ylamine (5.5 g, 0.018 mol) in THF (100 mL) under N2 and cool to 0° C. Add pyridine (1.6 mL, 1.1 equiv.) via syringe followed by dropwise addition of 2,2,2-trichloroethyl chloroformate (2.7 mL, 1.1 equiv.). Stir the reaction at 0° C. for one hour then remove the cooling bath and allow the reaction to stir for a total of 5 hours. Dilute the reaction with ethyl acetate and water. Wash the organic layer with water then saturated aqueous saturated sodium chloride and then dry over magnesium sulfate, filter, and concentrate in vacuo to give a residue (8.7 g, 100%) that is used without further purification. MS (ES), m/z 474 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([CH:11]([OH:14])[CH2:12][CH3:13])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I[CH3:16]>CN(C=O)C>[CH3:16][O:14][CH:11]([CH2:12][CH3:13])[CH:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:10]
Reactant: CI
Reactant: CCC(O)C(C)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(OC)C(C)c1ccccc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 57.9 %

Procedure:
A 2 L reaction flask was charged with NaH (29.5 g, 0.73 mol) in oil dispersion (60%) and DMF (500 mL) under N2. The mixture was heated to 40° C. 2-Phenyl-pentan-3-ol (100 g, 0.61 mol) was fed to the mixture over 1 hour. The reaction was aged for 1 hour at 40° C. Iodomethane (103 g, 0.73 mol) was then fed into the reaction mixture over 2 hours. The reaction mixture was further aged for 8 hours, and quenched subsequently with saturated NH4Cl solution (300 mL). The layers were separated. The organic layer was washed with saturated NaHCO3 (300 mL) and brine (300 mL) to provide a crude product, which was purified by distillation to afford (2-methoxy-1-methylbutyl)-benzene (63 g, 58% yield).
Reaction SMILES: [CH3:1][N:2]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1[N+:17]([O-])=O>[Pd].C(OCC)(=O)C.CO>[NH2:17][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:7]=1[NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(NCCCN(C)CCc2ccccn2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(NCCCN(C)CCc2ccccn2)c(N)c1
Reaction time: 4 h

Procedure:
Methyl 4-({3-[methyl(2-pyridin-2-ylethyl)amino]propyl}amino)-3-nitrobenzoate (9.1 g) in solution in an ethyl acetate/methanol mixture and 10% palladium on carbon (910 mg) are added together in an autoclave. After stirring for 4 hours under a hydrogen atmosphere (3 bars), the catalyst is eliminated by filtration on Celite and the filtrate is concentrated under reduced pressure at 40° C. in order to produce the expected compound in the form of an oil (8.2 g, 98% yield).
Reaction SMILES: CS(C)=O.Cl[C:6]1[N:7]([CH2:28][CH:29]2[CH2:31][CH2:30]2)[C:8]2[C:13]([N:14]=1)=[C:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:11]=[C:10]([C:21]1[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=1)[N:9]=2.[S:32]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)([CH3:35])(=[O:34])=[O:33]>ClCCl.CO>[CH:29]1([CH2:28][N:7]2[C:6]([N:39]3[CH2:40][CH2:41][N:36]([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:37][CH2:38]3)=[N:14][C:13]3[C:8]2=[N:9][C:10]([C:21]2[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=2)=[N:11][C:12]=3[N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:31][CH2:30]1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CC4)c3n2)cn1
Solvent: CO
Solvent: CS(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CC2)CC1
Reaction time: 4 h
Yield: 66.7 %

Procedure:
A dimethyl sulfoxide solution (1.0 ml) of 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]pyrimidin-2-amine (101.9 mg, 0.26 mmol) and N-mesylpiperazine (125.8 mg, 0.77 mmol) was heated at 140° C. and stirred for 4 hours followed by the addition of N-mesylpiperazine (83.8 mg, 0.51 mmol) and the resulting mixture was further stirred at 140° C. for 3 hours. The reaction mixture was left standing to cool followed by the addition of dichloromethane-methanol (10:1) and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the reaction mixture was filtrated, then the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (dichloromethane:methanol=15:1) to give the title compound (89.2 mg, 68%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:12])=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5](O)=[O:6].O1CCCC1.B(F)(F)F.O1CCCC1.O>C(Cl)Cl>[NH2:1][C:2]1[C:3]([Cl:12])=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[CH2:5][OH:6]
Reactant: Nc1cc(Cl)cc(C(=O)O)c1Cl
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: Nc1cc(Cl)cc(CO)c1Cl
Temperature: 8 °C
Reaction time: 1 h
Yield: 11.5 %

Procedure:
Into a 1 liter three-neck flask was introduced 40 g (0.19 mole) of 3-amino-2,5-dichlorobenzoic acid and 150 ml of tetrahydrofuran. The solution was cooled to 8°-10° C. in an ice bath. A borontrifluoride-tetrahydrofuran (1M) solution (280 ml) was added dropwise over a period of 1 hr. After being stirred at 8° C. for an additional 1 hr. the solution was allowed to warm up slowly to room temperature. The reaction flask was then cooled again in an ice bath and 50 ml of water was added through a dropping funnel. The mixture was taken into 1 liter of methylene chloride and washed once with NaHCO3 and twice with water, then dried over calcium sulfate. The methylene chloride solution afforded 19.2 g of crude solid product, mp 111-121. Five grams of the crude solid was recrystallized from acetonitrile to yield 4.2 g of 3-amino-2,5-dichlorobenzyl alcohol; mp 121-127; nmr (DMSO-d6) δ 4.50 (D, 2H), 5.34 (t, 1H), 5.52 (S, 2H), 6.73 (S, 2H); ir (CHCl3) 3490, 3380, 3240, 1630 and 1598 Cm-1.
Reaction SMILES: Br[C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[F:18])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.[CH3:19][N:20]1CCCC1=O.[C-]#N.[Na+]>O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:3]2[C:2]([C:19]#[N:20])=[C:10]3[C:5]([CH2:6][CH2:7][CH2:8][CH2:9]3)=[N:4]2)=[C:12]([F:18])[CH:13]=1
Reactant: CN1CCCC1=O
Reactant: Fc1cc(Cl)ccc1-n1nc2c(c1Br)CCCC2
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#Cc1c2c(nn1-c1ccc(Cl)cc1F)CCCC2

Procedure:
4.7 Parts of 3-bromo-2-(4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-2H-indazole [from Example 1-d] was combined with 1.5 parts of cuprous cyanide in 60 parts of N-methylpyrrolidinone and heated to 190° for 2 hours. After cooling to 30°, the reaction mixture was digested in a solution of 15 parts of sodium cyanide in 150 parts of water at 65°-70° for 2 hours, then extracted with 250 parts of toluene four times. The combined toluene extracts were washed with 500 parts of water 4 times, followed by 100 parts saturated aqueous sodium chloride. After drying with anhydrous sodium sulfate, the solution was evaporated at 50° and 50 mm. Hg to yield 4.4 parts of a brown oil. After crystallization from methylcyclohexane, 1.1 parts of 2-(4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-2H-indazole-3-carbonitrile melting at 83°-84° were isolated.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([C:14]#[N:15])[C:5]=1[N:16]1[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=[CH:17]1.O.O.O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:13])[F:12])[CH:7]=[C:6]([C:14]#[N:15])[C:5]=1[N:16]1[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[N:18]([Br:1])[CH2:17]1
Reactant: N#Cc1cc(C(F)(F)F)cc(Cl)c1-n1cnc(C(F)(F)F)cc1=O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1cc(C(F)(F)F)cc(Cl)c1N1CN(Br)C(C(F)(F)F)=CC1=O
Reaction time: 6 h

Procedure:
Bromine (35mg) was added to a stirred solution of 1-(2-chloro-6-cyano-4-trifluoromethylphenyl)-4-trifluoromethylpyrimidin-6-one (70mg) and sodium acetate trihydrate (77mg) in acetic acid (3.5ml). After stirring for 6 hours, the reaction mixture was allowed to stand overnight, whereupon the solvent was evaporated under reduced pressure. The residual solid was dissolved in ethyl acetate and washed with water, followed by aqueous sodium bicarbonate solution and finally brine. After drying over anhydrous magnesium sulphate the solvent was evaporated under reduced pressure to give 1-(2-chloro-6-cyano-4-trifluoromethylphenyl)-3-bromo-4-trifluoromethylpyrimidin-6-one as a colourless solid.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)[CH:3]([CH3:5])[CH3:4].C(N(C(C)C)C(C)C)C.[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>CN(C)C=O>[C:24]([NH:28][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[C:6]([CH:2]([OH:1])[CH:3]([CH3:4])[CH3:5])[CH:7]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)N
Reactant: CC(C)C(O)c1cccc(C(=O)O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C(O)c1cccc(C(=O)NC(C)(C)C)c1
Yield: 82.5 %

Procedure:
A mixture of 3-(1-hydroxy-2-methylpropyl)benzoic acid (677 mg, 3.49 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyl uronium hexafluorophosphate (1.73 g, 4.54 mmol), N-ethyl-N-isopropylpropan-2-amine (1.21 mL, 6.97 mmol) and tert-butylamine (510 mg, 6.97 mmol) in N,N-dimethylformamide (12.0 mL) was subjected to microwave irradiation at 100° C. for 10 minutes. The reaction mixture was concentrated under vacuum and purified with silica column chromatography (eluting with 9% to 33% ethyl acetate in heptane) to afford the title compound (718 mg). MS (ESI) m/z 250.4 [M+H]+
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][Br:7].[Cl:8][C:9]1[CH:28]=[CH:27][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([OH:26])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[C:11]([F:29])[CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][O:26][C:20]1[CH:19]=[C:18]2[C:23]([C:14]([NH:13][C:12]3[CH:27]=[CH:28][C:9]([Cl:8])=[CH:10][C:11]=3[F:29])=[N:15][CH:16]=[N:17]2)=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: BrCCOCCBr
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCOCCBr
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.3 %

Procedure:
2-Bromoethyl ether (1.57 ml, 12 mmol) was added to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (1 g, 3.1 mmol), (prepared as described for the starting material in Example 2), and potassium carbonate (1.73 g, 12 mmol) in DMF (10 ml). The mixture was stirred for 18 hours at ambient temperature and was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and then brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography on silica eluting with methylene chloride/acetonitrile/methanol (60/38/2). The purified product was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 7-(2-(2-bromoethoxy)ethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (763 mg, 52%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[N:13][C:12]([C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=3)=[N:11][C:10]=2[C:9]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C>O.CO.ClCCl>[CH2:1]([N:8]1[CH2:16][C:15]2[C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[N:13][C:12]([C:23]3[CH:24]=[CH:25][C:26]([NH2:29])=[CH:27][CH:28]=3)=[N:11][C:10]=2[C:9]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2nc(-c3ccc([N+](=O)[O-])cc3)nc(N3CCOCC3)c2CN1Cc1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CN(Cc2ccccc2)C3=O)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
6-benzyl-4-morpholino-2-(4-nitrophenyl)-5H-pyrrolo[3,4-d]pyrimidin-7(6H)-one (cy) (0.112 g, 0.260 mmol), stannous chloride dihydrate (0.310 g, 1.36 mmol) and ethanol (2.00 mL) were combined and stirred at 80° C. for 1 hour. The mixture was diluted with H2O and 10% MeOH in dichloromethane, extracted 3 times with 10% MeOH in dichloromethane. The combined organic extract was dried over Magnesium sulfate and concentrated to give compound cz (0.083 g, 80%): LC-MS: m/z=+434 (M+H)+; 1H NMR (400 MHz, DMSO) δ 9.10 (s, 2H), 7.24 (d, J=8.6, 2H), 7.14 (s, 2H), 6.91 (d, J=8.6, 2H), 4.64 (d, J=27.1, 4H), 3.80-3.60 (m, 11H).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]1)[C:14](=[O:28])[NH:15][C:16]1[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=1.[F:36][C:37]([F:47])([F:46])[O:38]C1C=CC(S)=CC=1>>[CH3:26][C:22]([S:21][C:18]1[S:17][C:16]([NH:15][C:14]([N:13]([C@H:29]2[CH2:30][CH2:31][C@H:32]([CH3:35])[CH2:33][CH2:34]2)[CH2:12][CH2:11][CH2:10][S:9][C:4]2[CH:3]=[CH:8][C:7]([O:38][C:37]([F:47])([F:46])[F:36])=[CH:6][CH:5]=2)=[O:28])=[N:20][CH:19]=1)([CH3:27])[C:23]([OH:25])=[O:24]
Reactant: COc1ccccc1SCCCN(C(=O)Nc1ncc(SC(C)(C)C(=O)O)s1)[C@H]1CC[C@H](C)CC1
Reactant: FC(F)(F)Oc1ccc(S)cc1
Product: CC(C)(Sc1cnc(NC(=O)N(CCCSc2ccc(OC(F)(F)F)cc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis 2-{2-[3-[3-(2-methoxy-phenylsulfanyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using 4-trifluoromethoxy -thiophenol.