Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:11]=2[N:10]([CH2:21][CH3:22])[C:9]1=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].BrN1C(=O)CCC1=O>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([CH:8]1[CH:14]=[CH:13][C:12]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:11]=2[N:10]([CH2:21][CH3:22])[C:9]1=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN1C(=O)C(C(=O)OC(C)(C)C)CCc2ccc(OC)cc21
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CCN1C(=O)C(C(=O)OC(C)(C)C)C=Cc2ccc(OC)cc21
Yield: 7.5 %

Procedure:
A mixture of 3(R,S)-tert-butoxycarbonyl-1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (0.80 g, 2.51 mmol) and N-bromosuccinimide (0.49 g, 2.76 mmol) in chloroform (20 mL) was heated at reflux for 5 hrs. The resulting reaction mixture was washed with saturated aqueous solution of NaHCO3 and water, dried over anhydrous Na2SO4, filtered and evaporated to dryness. The crude product was purified by flash chromatography on silica gel column eluted with EtOAc/n-hexane (3:7). The fractions containing the fast running component were collected and evaporated to dryness. The desired compound (60 mg, 8%) was obtained as a white crystalline powder.
Reaction SMILES: [CH2:1]([NH:18][C:19](=[O:39])[O:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][O:23][C@H:22]1[CH2:27][O:28][CH2:29][CH:30]([OH:38])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][OH:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(N(CC)CC)C.[C:47]1([CH3:57])[CH:52]=[CH:51][C:50]([S:53](Cl)(=[O:55])=[O:54])=[CH:49][CH:48]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([NH:18][C:19](=[O:39])[O:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][O:23][C@H:22]1[CH2:27][O:28][CH2:29][CH:30]([OH:38])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][S:53]([C:50]1[CH:51]=[CH:52][C:47]([CH3:57])=[CH:48][CH:49]=1)(=[O:55])=[O:54])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCCCCNC(=O)O[C@@H]1CCCO[C@H]1COCC(O)CCCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCNC(=O)O[C@@H]1CCCO[C@H]1COCC(O)CCCCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
0.458 g of dl-trans-2-[(2,8-dihydroxyoctyloxy)methyl]tetrahydropyran-3-yl N-heptadecylcarbamate (prepared as described in Preparation 75), 0.27 ml of triethylamine and 5 mg of 4-dimethylaminopyridine were dissolved in 10 ml of methylene chloride. 0.188 g of p-toluenesulfonyl chloride were added to the mixture, whilst ice-cooling, after which the mixture was stirred at room temperature for 14 hours. At the end of this time, the reaction mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through 12 g of silica gel and by medium pressure liquid chromatography through a Lobar B column. 0.492 g of the title compound was obtained, as a white wax, from the fractions eluted with mixtures of hexane and ethyl acetate ranging from 3:2 to 1:1 by volume.
Reaction SMILES: [CH:1]1([C:7]#[C:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH3:20])=[C:14]([O:21][CH3:22])[CH:13]=3)[CH2:6][CH2:5][CH2:4]CC1.[C:23](O)(=O)[CH3:24]>CO.[Pd]>[CH:8]1([C:9]2[C:10]([CH2:23][CH3:24])=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH3:20])=[C:14]([O:21][CH3:22])[CH:13]=3)[CH2:4][CH2:5][CH2:6][CH2:1][CH2:7]1
Reactant: CC(=O)O
Reactant: COc1cc2cc(C#CC3CCCCC3)cnc2cc1OC
Agent: [Pd]
Solvent: CO
Product: CCc1nc2cc(OC)c(OC)cc2cc1C1CCCCC1

Procedure:
To 3-cyclohexylethynyl-6,7-dimethoxyquinoline (215 mg; 0.73 mmol) in 10mL CH3OH and 20 mL glacial acetic acid is added 22 mg 10% Pd/C. H2 is bubbled through the reaction mixture and then filtered, evaporated to dryness and diluted with distilled water. This is then neutralized with Na2CO3, extracted with EtOAc, washed with brine, dried (MgSO4), evaporated to dryness and chromatographed with 8:2/hexane: EtOAc to obtain 3-cyclohexyl-ethyl-6,7-dimethoxyquinoline.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:16]2[NH:15][C:14](=[O:17])[O:13][C:12]([CH3:19])([CH3:18])[C:11]=2[CH:10]=[CH:9][CH:8]=1.[Cl:20][C:21]1[CH:22]=[C:23]([SH:28])[CH:24]=[CH:25][C:26]=1[Cl:27]>>[Cl:20][C:21]1[CH:22]=[C:23]([S:28][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[C:16]3[NH:15][C:14](=[O:17])[O:13][C:12]([CH3:19])([CH3:18])[C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: CC1(C)OC(=O)Nc2c(OCCCCCl)cccc21
Reactant: Sc1ccc(Cl)c(Cl)c1
Product: CC1(C)OC(=O)Nc2c(OCCCCSc3ccc(Cl)c(Cl)c3)cccc21

Procedure:
Prepared analogously to Example 1 from 8-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 3,4-dichloro-thiophenol.
Reaction SMILES: [NH2:1][CH:2]([CH:5]([CH3:10])[C:6]([F:9])([F:8])[F:7])[CH2:3][OH:4].C(N(CC)CC)C.Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[F:7][C:6]([F:9])([F:8])[CH:5]([CH:2]1[CH2:3][O:4][C:19](=[O:21])[NH:1]1)[CH3:10]
Reactant: CC(C(N)CO)C(F)(F)F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C1COC(=O)N1)C(F)(F)F

Procedure:
To a solution of 2-amino-4,4,4-trifluoro-3-methylbutan-1-ol (580 mg, 3.69 mmol) in DCM (13 ml) was added triethylamine (1.132 ml, 8.12 mmol) and added dropwise a solution of triphosgene (329 mg, 1.107 mmol) in 1 mL in DCM (3 ml) over 10 min. The reaction mixture was washed with sat. NH4Cl solution (13 ml) dry, and concentrated in vacuo. Afforded 450 mg (It yellow solid). Used crude in the next step. 1H NMR (400 MHz, CDCl3) b 5.91 (d, J=13.3 Hz, 1H), 4.61-4.34 (m, 1H), 4.22-4.00 (m, 2H), 3.05 (q, J=7.3 Hz, 1H), 2.54-2.14 (m, 1H), 1.34 (t, J=7.3 Hz, 1H), 1.17 (d, J=7.1 Hz, 2H), 1.09 (d, J=7.1 Hz, 1H). MS 183.0507 m/z.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([N:28]([CH:38]3[CH2:40][CH2:39]3)CC3C=CC(OC)=CC=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[CH:22]=4)=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.[Br-].[Li+].[CH3:43][C:44]1([CH3:47])[CH2:46][O:45]1.C(O)(C(F)(F)F)=O>CO>[Cl:27][C:23]1[CH:22]=[C:21]([NH:20][C:18]([C:15]2[N:13]3[N:14]=[C:9]([NH:8][C@H:5]4[CH2:6][CH2:7][C@H:2]([NH:1][CH2:43][C:44]([OH:45])([CH3:47])[CH3:46])[CH2:3][CH2:4]4)[CH:10]=[C:11]([NH:28][CH:38]4[CH2:39][CH2:40]4)[C:12]3=[N:17][CH:16]=2)=[O:19])[CH:26]=[CH:25][N:24]=1
Reactant: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccnc(Cl)c4)cnc23)C2CC2)cc1
Reactant: CC1(C)CO1
Agent: [Br-]
Agent: [Li+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)CN[C@H]1CC[C@H](Nc2cc(NC3CC3)c3ncc(C(=O)Nc4ccnc(Cl)c4)n3n2)CC1
Reaction time: 0.17 h

Procedure:
A solution of 6-((trans)-4-aminocyclohexylamino)-N-(2-chloropyridin-4-yl)-8-(cyclopropyl(4-methoxybenzyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (100 mg, 0.178 mmol), lithium bromide (0.774 mg, 8.91 μmol) and 2,2-dimethyloxirane (12.85 mg, 0.178 mmol) in MeOH (5 mL) was stirred at 50° C. for 7 hrs. The reaction mixture was concentrated down, diluted in methanol (1 mL) and treated with TFA (0.824 mL, 10.69 mmol). After 10 minutes, the reaction mixture was concentrated, diluted with methanol and purified by preparative HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 30% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA) to isolate N-(2-chloropyridin-4-yl)-8-(cyclopropylamino)-6-((trans)-4-(2-hydroxy-2-methylpropylamino)cyclohexylamino)imidazo[1,2-b]pyridazine-3-carboxamide (41.9 mg, 0.082 mmol, 45.8% yield) as a white solid. LC/MS (BEH C18 2.1×50 mm 1.7u, Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2.2 min with 1 min hold time, Flow rate=2 mL/min, detection at 254 nm, Solvent A: 100% water/0.05% TFA; Solvent B: 100% ACN/0.05% TFA). Rt=0.71 minutes. [M+H]=513.3. 1H NMR (400 MHz, MeOD) δ ppm 8.47 (2H, s), 7.96-8.08 (1H, m), 7.52-7.70 (1H, m), 6.44 (1H, s), 3.69-3.92 (1H, m), 3.15-3.30 (1H, m), 3.05 (2H, s), 2.60-2.77 (1H, m), 2.36-2.48 (2H, m), 2.17-2.37 (2H, m), 1.60-1.80 (2H, m), 1.41-1.62 (2H, m), 1.35 (6H, s), 0.87-1.05 (2H, m), 0.63-0.78 (2H, m)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Clc1nc(NCc2ccc(Cl)c(Cl)c2)c2c3c(sc2n1)CCCC3
Reactant: c1cn[nH]c1
Product: Clc1ccc(CNc2nc(-n3cccn3)nc3sc4c(c23)CCCC4)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5,6,7,8-tetrahydro-4-(3,4-dichlorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5,6,7,8-tetrahydro-4-(3,4-dichlorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]2=[N:6][N:7]([C:9]3[CH:10]=[C:11]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=3[OH:20])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[N:8]=[C:4]2[CH:3]=1.[Br:27][C:28]1[CH:45]=[C:44]([Br:46])[CH:43]=[CH:42][C:29]=1[O:30][N:31]1[C:36]([CH3:38])([CH3:37])[CH2:35][CH:34](O)[CH2:33][C:32]1([CH3:41])[CH3:40]>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]2=[N:6][N:7]([C:9]3[CH:10]=[C:11]([CH:17]=[C:18]([C:21]([CH3:22])([CH3:23])[CH3:24])[C:19]=3[OH:20])[CH2:12][CH2:13][C:14]([O:16][CH:34]3[CH2:35][C:36]([CH3:38])([CH3:37])[N:31]([O:30][C:29]4[CH:42]=[CH:43][C:44]([Br:46])=[CH:45][C:28]=4[Br:27])[C:32]([CH3:41])([CH3:40])[CH2:33]3)=[O:15])[N:8]=[C:4]2[CH:3]=1
Reactant: CC(C)(C)c1cc(CCC(=O)O)cc(-n2nc3ccc(Cl)cc3n2)c1O
Reactant: CC1(C)CC(O)CC(C)(C)N1Oc1ccc(Br)cc1Br
Product: CC(C)(C)c1cc(CCC(=O)OC2CC(C)(C)N(Oc3ccc(Br)cc3Br)C(C)(C)C2)cc(-n2nc3ccc(Cl)cc3n2)c1O

Procedure:
The title compound is prepared according to the procedure of Example 3 using 3-(5-chlorobenzotriazol-2-yl)-5-tert-butyl-4-hydroxyhydrocinnamic acid and 1-(2,4-dibromophenoxy)-2,2,6,6-tetramethyl-4-hydroxypiperidine.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[C@:3]([C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)([OH:5])[CH3:4].[H][H]>[Pt]=O.CO>[CH3:1][CH:2]([CH3:12])[C@:3]([CH:6]1[CH2:11][NH:10][CH2:9][CH2:8][NH:7]1)([OH:5])[CH3:4]
Reactant: [H][H]
Reactant: CC(C)[C@@](C)(O)c1cnccn1
Agent: O=[Pt]
Solvent: CO
Product: CC(C)[C@@](C)(O)C1CNCCN1
Yield: 93.6 %

Procedure:
Platinum oxide (4.673 g, 20.58 mmol) was placed in a Parr bottle. Methanol (140 mL) was added under an atmosphere of nitrogen followed by (R)-(+)-3-methyl-2-(pyrazin-2-yl)butan-2-ol (17.1 g, 102.9 mmol). The reaction mixture was shaken in a PARR hydrogenator overnight with a hydrogen pressure of 60 psi. Lc/Ms after this time indicate that the reaction was complete. The suspension was filtered through a pad of celite under a nitrogen atmosphere, rinsing with methanol. The crude mixture was concentrated in vacuo. The residue was re-dissolved in dichloromethane, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as viscous light yellow oil (16.6 g, 93%); 1H NMR (CDCl3) 0.82-1.08 (9H, m), 1.81 (1H, m), 2.20-3.17 (10H, m); MS ES(+) 173.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[CH3:11][O:12][CH:13](OC)OC>>[CH3:11][O:12][CH:13]=[C:5]1[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:9]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COC(OC)OC
Product: COC=C1C(=O)OC(C)(C)OC1=O

Procedure:
2,2-Dimethyl-1,3-dioxane-4,6-dione (100 g) was heated in trimethylorthoformate (500 ml) at 100° C. for 2 h. The solution was evaporated under reduced pressure to give an oil. The oil was triturated with 1:1 isohexane/diethyl ether (400 ml) and the solid was filtrated and dried in vacuo to give the sub-title compound (99.8 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[OH-].[NH4+:13]>>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH2:13]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1ccc([N+](=O)[O-])cc1F
Temperature: 135 °C

Procedure:
A mixture of 10.0 grams (0.063 mole) of 3,4-difluoronitrobenzene and 40 mL of aqueous 29% ammonium hydroxide was placed in a pressure bottle and sealed. The mixture was stirred and heated at 135° C. for about 18 hours. The bottle and contents were then cooled and the bottle opened. A solid was collected by filtration and washed, first with water and then with petroleum ether. The solid was dried, yielding 9.4 grams of 2-fluoro-4-nitroaniline.
Reaction SMILES: [C:1]1([C:7]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)=[N:18][C:10]3[O:11][CH2:12][C:13]4[N:14]([CH:15]=[N:16][N:17]=4)[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:38]N1C(=O)CCC1=O>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[C:33]([O:32][C:31](=[O:37])[NH:30][C:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:19]3[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][C:9]4[N:14]5[C:15]([Br:38])=[N:16][N:17]=[C:13]5[CH2:12][O:11][C:10]=4[N:18]=3)=[CH:21][CH:22]=2)[CH2:27][CH2:28][CH2:29]1)([CH3:34])([CH3:36])[CH3:35]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3cnnc3CO4)cc2)CCC1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(Br)nnc3CO4)cc2)CCC1
Yield: 68.5 %

Procedure:
A mixture of tert-butyl 1-(4-(8-phenyl-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutylcarbamate (200 mg, 0.404 mmol) and 1-bromopyrrolidine-2,5-dione (114.9275 mg, 0.646 mmol) in DCM (12 ml) and CCl4 (18 ml) was heating at 50 degree for 24 h. The mixture was concentrated and the residue was partitioned between ethyl acetate (40 ml) and water (40 ml). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (30 ml). The combined organic phase was washed with water (50 ml) brine (30 ml) and concentrated to give product 159 mg. 1H NMR (500 MHz, CDCl3): 8.55 (s, 1H), 7.22-7.35 (m, 9H), 5.58 (s, 2H), 5.1 (br, 1H), 2.4-2.5 (m, 4H), 2.01-2.11 (m, 1H), 1.79-1.89 (m, 1H), 1.24-1.43 (br, 9H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([NH:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:14]=[C:13]([O:28][CH3:29])[N:12]=2)=[CH:7][C:3]=1[CH:4]=[N:5]O.[ClH:30]>C(O)(=O)C.CCOC(C)=O.[Zn]>[ClH:30].[NH2:5][CH2:4][C:3]1[CH:7]=[C:8]([C:11]2[N:12]=[C:13]([O:28][CH3:29])[N:14]=[C:15]([NH:17][CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH:16]=2)[CH:9]=[CH:10][C:2]=1[F:1]
Reactant: COc1ccc(CCNc2cc(-c3ccc(F)c(C=NO)c3)nc(OC)n2)cc1
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(CCNc2cc(-c3ccc(F)c(CN)c3)nc(OC)n2)cc1
Reaction time: 1 h

Procedure:
A mixture of 2-fluoro-5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzaldehyde oxime [860 mg, Example 26(a)] in acetic acid (10 mL) is treated with zinc powder (0.6 g, 9.2 mmol). After 1 hour at 20° C., the reaction mixture is filtered through Celite, concentrated, diluted with 1 M sodium hydroxide solution, and extracted with ethyl acetate. The extracts are dried over magnesium sulfate, filtered, and subjected to chromatography on silica gel eluting with 10% MeOH in DCM to provide the free base, which is treated with saturated HCl in EtOAc afford [6-(3-aminomethyl-4-fluoro-phenyl)-2-methoxy-pyrimidin-4-yl]-[2-(4-methoxy-phenyl)-ethyl]-amine hydrochloride [720 mg, Example 27]. LCMS: RT=1.88 minutes, MS: 383 (M+H). IC50=41 nM
Reaction SMILES: [C:1](=[O:14])(OC1C=CC=CC=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22].C(Cl)Cl>CCO>[C:3]([O:2][C:1]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])=[O:14])([CH3:4])([CH3:5])[CH3:6]
Reactant: NCCCCCCN
Reactant: CC(C)(C)OC(=O)Oc1ccccc1
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCCCCN
Temperature: 78 °C

Procedure:
tert-Butyl phenyl carbonate (25.60 mL, 138.0 mmoles) was added to a stirred solution of 1,6-diaminohexane (15.30 g, 131.7 mmoles) in absolute EtOH (150 mL) in a 250 mL RB flask. The apparatus was fitted with a condenser and heated to 78° C. overnight under a blanket of nitrogen and then allowed to cool to room temperature. The solvent was stripped off the reaction mixture in vacuo (rotary evaporator) yielding a pale pink oily residue. CH2Cl2 (200 mL) was added to the residue and the resultant solution extracted with 3×200 mL portions of de-ionised water. For each extraction the pH of the aqueous phase was monitored and adjusted with HCl (aq, 2M) such that the pH of the aqueous layer was 3<pH<7 [only required for 1st extraction, needing ca. 60-70 mL HCl (aq, 2M)]. The aqueous phases were collected in a Erlenmeyer flask containing aqueous NaOH (aq, 100 mL, 3M). Ensuring that the pH of the collected aqueous extracts was ≧14 the resulting aqueous phase was extracted with CH2Cl2 (3×150 mL). These organic phases were recombined, evaporated to a volume of ca. 200 mL and subjected to the above pH modulated purification protocol for a second time by first extracting with water [3×200 mL, 3<pH<7 modulation with HCl (aq, 2M), again only required for 1st extract needing ca. 45-55 mL HCl (aq, 2M)], basicifying these aqueous extracts with NaOH (100 mL, 3M) and extracting with CH2Cl2 (3×150 mL). The CH2Cl2 extracts were combined, reduced in volume to 200 mL and then dried over anhydrous MgSO4, filtered, and stripped to dryness on a rotary evaporator for a period of 20 minutes to yield 6-(tert-butoxycarbonylamino)hexylamine as a peach oil. This peach oil was then subjected to a short path distillation using a Kugelrohr apparatus with an oven temperature of 180° C. and at a vacuum pressure of 0.160 torr, the receiver bulb was cooled by means of a dry-ice/acetone bath. Yield: 13.1 g (46%, colourless oil). 1H NMR (CDCl3) δ 1.14 (s, 2H, —NH2), 1.26-1.37 (m, 4H, —CH2—), 1.37-1.52 (s+m, 9H+4H, t-Bu+—CH2—), 2.67 (t, 2H, >NCH2—), 3.09 (q, 2H, —C(═O)NCH2—), 4.60 (bs, 1H, —C(═O)NH—).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[Cl:11][C:12]1[C:13]([CH3:22])=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>>[C:1]([C:4]1[S:8][C:7]([NH:9][S:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([Cl:11])[C:13]=2[CH3:22])(=[O:19])=[O:20])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: CC(=O)c1sc(N)nc1C
Product: CC(=O)c1sc(NS(=O)(=O)c2cccc(Cl)c2C)nc1C

Procedure:
The title compound was prepared from 5-acetyl-2-amino-4-methylthiazole and 3-chloro-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (10.8 mg) with purity >90%. LCMS (pos) m/z 345.0.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[NH2:11][C:12]1[CH:16]=[C:15]([CH3:17])[NH:14][N:13]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>C(O)CCC>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([NH:11][C:12]2[NH:13][N:14]=[C:15]([CH3:17])[CH:16]=2)[CH:7]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: [I-]
Agent: [Na+]
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc(Cl)cc(Nc2cc(C)n[nH]2)n1
Temperature: 120 °C
Reaction time: 15 h

Procedure:
To a solution of 4,6-dichloro-2-methylsulfanyl-pyrimidine (5 g, 25.6 mmol) and 3-amino-5-methylpyrazole 2.61 g, 26.9 mmol) in BuOH (60 mL) is added diisopropylethylamine (4.69 mL, 26.9 mmol) followed by sodium iodide (3.84 g, 25.6 mmol). The reaction mixture is stirred for 15 hours at 120° C. The solvent is then removed in vacuo and the residue is purified by flash chromatography (SiO2, hexane/AcOEt gradient) to give [6-chloro-2-methylsulfanyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][C@@H:18]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([N+:31]([O-])=O)[CH:25]=2)[CH2:19]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C>[Pd].CO>[NH2:31][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[Cl:30])[CH2:23][N:20]1[CH2:21][CH2:22][C@@H:18]([NH:17][C:15](=[O:16])[CH2:14][NH:13][C:11](=[O:12])[C:10]2[CH:34]=[C:35]([C:38]([F:40])([F:41])[F:39])[CH:36]=[CH:37][C:9]=2[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:19]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)c([N+](=O)[O-])c2)C1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)c(N)c2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]-1-(4-chloro-3-nitrobenzyl)pyrrolidine prepared above, 10% Pd-activated carbone (22 mg), ethyl acetate (2.7 mL) and methanol (0.3 mL) was stirred under a hydrogen atmosphere at room temperature for 15 h. The Pd catalyst was filtered off, and the filtrate was concentrated to afford (R)-1-(3-amino-4-chlorobenzyl)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (89.7 mg, quant.): Any remarkable by-products were not detected in TLC.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[OH:10].[F:11][C:12]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:13]=1[C:14](Cl)=[O:15]>>[OH:10][C:3]1[C:4]([Cl:9])=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[NH:1][C:14](=[O:15])[C:13]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:12]=1[F:11]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1F
Reactant: Nc1cc(Cl)cc(Cl)c1O
Product: O=C(Nc1cc(Cl)cc(Cl)c1O)c1cc([N+](=O)[O-])ccc1F

Procedure:
Prepared by the method of Example 15a), from 2-amino-4,6-dichlorophenol (409 mg, 2.3 mmol) and 2-fluoro-5-nitrobenzoyl chloride (468 mg, 2.3 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:19])[C:8](=[O:18])[N:9]2[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].CO[CH:25]1[CH2:29][CH2:28][CH:27](OC)O1>C(O)(=O)C>[CH2:16]([O:15][C:13]([CH2:12][N:9]1[C:10]2[C:5](=[CH:4][C:3]([N+:20]([O-:22])=[O:21])=[C:2]([N:1]3[CH:25]=[CH:29][CH:28]=[CH:27]3)[CH:11]=2)[NH:6][C:7](=[O:19])[C:8]1=[O:18])=[O:14])[CH3:17]
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(N)cc21
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(-n3cccc3)cc21
Temperature: 0 °C
Yield: 82.9 %

Procedure:
30 g (97 mmol) of 7-amino-1-(ethoxycarbonylmethyl)-6-nitro-2,3(1H,4H)-quinoxalinedione and 16.1 g (121.5 mmol) of 2,5-dimethoxytetrahydrofuran in 500 ml of acetic acid were heated at 80° C. for 1 h. The mixture was then poured into ice-water, and the precipitate was filtered off with suction to yield 28.8 g (83%) of the product.