Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[N:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: Cc1ccc(-c2cccnn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-c2cccnn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyridazin-3-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 471 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH2:18][CH2:17][C:16](=O)[CH2:15][CH:14]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CC(O)=O.Cl.[CH2:25]([NH2:27])C.[OH-].[Na+]>ClCCCl>[CH3:25][NH:27][CH:16]1[CH2:17][CH2:18][C:13]([C:8]2[C:7]3[C:11](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[NH:10][CH:9]=2)=[CH:14][CH2:15]1
Reactant: O=C1CC=C(c2c[nH]c3cc([N+](=O)[O-])ccc23)CC1
Reactant: CCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CNC1CC=C(c2c[nH]c3cc([N+](=O)[O-])ccc23)CC1
Reaction time: 16 h
Yield: 103.9 %

Procedure:
A solution of compound 119 (0.5 g, 1.951 mmol) in 1,2-dichloroethane (10 mL) was treated with AcOH (0.11 mL, 1.951 mmol), ethylamine hydrochloride (0.159 g, 1.951 mmol), NaBH(OAC)3 (0.62 g, 2.926 mmol) at room temperature and stirred for over night (16 h). The reaction was basified with 2N NaOH (25 mL) and product was extracted into ethyl acetate (2×25 mL). The combined ethyl acetate layer washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2M NH3 in MeOH:CH2Cl2, 1:9) to obtain compound 126 (0.55 g, 99%) as a semi-solid. 1H NMR (DMSO-d6) δ 1.07 (t, 3H, J=7.2 Hz), 1.47-1.58 (m, 1H), 1.99-2.08 (m, 2H), 2.42-2.59 (m, 3H), 2.67-2.73 (m, 2H), 2.82-2.90 (m, 1H), 6.14 (brs, 1H), 7.81 (s, 1H), 7.86-7.97 (m, 2H), 8.31 (d, 1H, J=2.1 Hz); ESI-MS (m/z, %): 286 (MH+, 100), 241 (33).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]([NH:21][CH2:22][CH2:23]O)[N:18]=[C:17]([O:25][CH3:26])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCC(NC2N=C(Cl)N=C(OC)N=2)CC1)=O)(C)(C)C.N1CC[S:53][CH2:52][CH2:51]1.C(N(C(C)C)C(C)C)C.Cl.COC1N=C(NC2CCNCC2)N=C(NCCO)N=1>C(#N)C.O1CCOCC1.CO>[CH3:26][O:25][C:17]1[N:18]=[C:19]([N:21]2[CH2:22][CH2:23][S:53][CH2:52][CH2:51]2)[N:20]=[C:15]([NH:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[N:16]=1
Reactant: C1CSCCN1
Reactant: COc1nc(NCCO)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: COc1nc(Cl)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: COc1nc(NCCO)nc(NC2CCNCC2)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CO
Product: COc1nc(NC2CCNCC2)nc(N2CCSCC2)n1

Procedure:
The compound was prepared in analogy to the synthesis of 4-[4-(2-hydroxy-ethylamino)-6-methoxy-[1,3,5]triazin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (intermediate C26/step 2) from 4-(4-chloro-6-methoxy-[1,3,5]triazin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (intermediate C26/step 1) and thiomorpholine and N-ethyl diisopropylamine in acetonitrile at 50° C., followed by BOC cleavage with 4 M HCl in dioxane and methanol at rt in analogy to the procedure described for 2-[4-methoxy-6-(piperidin-4-ylamino)-[1,3,5]triazin-2-ylamino]-ethanol (intermediate C26/step 3). MS (ISP): 311.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Br)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:6]([O:5][C:3](=[O:4])[C:2]([CH3:16])([CH3:1])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:27][S:24]([C:21]1[CH:20]=[CH:19][C:18]([Cl:17])=[CH:23][CH:22]=1)(=[O:26])=[O:25])[CH3:7]
Reactant: CCOC(=O)C(C)(C)CCCCCCCBr
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(C)(C)CCCCCCCNS(=O)(=O)c1ccc(Cl)cc1
Yield: 53 %

Procedure:
Ethyl 2,2-dimethyl-9-bromononanoate (2.0 g, 0.007 mol) was treated with 4-chlorobenzenesulphonamide (3.44 g, 0.018 mol) and potassium carbonate (6.2 g, 0.045 mol) by the method described in Example 5(ii) to give the title compound (1.5 g) as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](C=O)[CH:2]=1.[Cl:9][C:10]1[C:14](C2C=NC=CC=2)=[N:13][S:12][N:11]=1.[H-].[Na+]>C1COCC1>[Cl:9][C:10]1[C:14]([C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][N:1]=2)=[N:13][S:12][N:11]=1
Reactant: O=Cc1cccnc1
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1nsnc1-c1ccccn1

Procedure:
3-(3-chloro-1,2,5-thiadiazol-4-yl-pyridine (compound 1) was synthesized from 3-pyridinecarboxaldehyde following, except with slight modification, from the published procedure as provided in Sauerberg et al, Journal Medicinal Chemistry, 1992, Vol.35, Page 2274. 3-(3-Chloro-1,2,5-thiadiazol-4-yl)pyridine was reacted with a diol (compound 2, wherein n=6, 7, 8, 9, 10 or 12) in the presence of sodium hydride in refluxing THF to yield bis[3-(pyridin-3-yl)-1,2,5-thiadiazol-4-yl]alkyl- diethers (compound 3, wherein n=6, 7, 8, 9, 19 or 12) in 75-90% yield. These diethers were treated with excess methyl iodide in acetone or chloroform to give bis-quaternary ammonium iodides (compound 4, wherein n =6, 7, 8, 9, 10 or 12) in 96-100% yield. The quaternary salts were then treated with 5 equivalents of sodium borohydride in a mixture of methanol and chloroform to yield the compounds 5, wherein n=6, 7, 8, 9, 10 or 12 in 50-60% yield. Dry hydrogen chloride gas was then bubbled through the methanolic solution of compounds 5 at 0° C. to give compounds 6, wherein n=6, 7, 8, 9, 10 or 12 in 95-100% yield.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]([CH3:16])[S:12]([CH3:15])(=[O:14])=[O:13])[N:10]=1)[C:5]([OH:7])=[O:6].Cl.[CH3:18][O:19][CH2:20][CH2:21][NH:22][CH2:23][C@@H:24]1[CH2:26][C@H:25]1[CH3:27].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC(N(C)C)=O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:18][O:19][CH2:20][CH2:21][N:22]([CH2:23][C@@H:24]1[CH2:26][C@H:25]1[CH3:27])[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]([CH3:16])[S:12]([CH3:15])(=[O:14])=[O:13])[N:10]=1)[C:5]([OH:7])=[O:6]
Reactant: CN(c1cc(C(=O)O)cc(Cl)n1)S(C)(=O)=O
Reactant: COCCNC[C@@H]1C[C@H]1C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CC(=O)N(C)C
Product: COCCN(C[C@@H]1C[C@H]1C)c1cc(C(=O)O)cc(N(C)S(C)(=O)=O)n1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
A suspension of 2-chloro-6-[methyl(methylsulfonyl)amino]isonicotinic acid (20 g, 75.6 mmol), trans (2-methoxyethyl)[(2-methylcyclopropyl)methyl]amine hydrochloride (17.65 g, 98.2 mmol), potassium phosphate (48.12 g, 226.7 mmol) in DMA (300 mL) was degassed with argon for 10 min. Pd(PtBu3)2 (1.93 g, 3.78 mmol) was added and the reaction mixture was degassed with argon for 10 min. The reaction mixture was stirred at 110° C. for 24 hours. The reaction was cooled to rt, filtered through celite, rinsed with EtOAc, diluted with water, the pH was adjusted to 3-4 with 1N HCl, extracted with EtOAc (×3). The organic layer was washed with aq LiCl, dried over sodium sulfate and concentrated in vacuo to give 2-{(2-methoxyethyl)[(trans-2-methylcyclopropyl)methyl]amino}-6-[methyl(methylsulfonyl)amino]isonicotinic acid. 1H NMR (400 MHz, CDCl3) δ 7.05 (s, 1H), 7.62 (s, 1H), 3.76 (t, J=6.3 Hz, 2H), 3.60 (t, J=6.3 Hz, 2H), 3.52-3.43 (m, 1H), 3.39 (s, 3H), 3.36 (s, 3H), 3.38-3.30 (m, 1H), 3.18 (s, 3H), 1.23 (d, J=6.1 Hz, 3H), 0.82-0.64 (m, 2H), 0.46-0.39 (m, 1H), 0.32-0.25 (m, 1H).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]2[CH:45]=[C:46]([N:49]3[CH2:54][CH2:53][CH2:52][N:51]([CH2:55][C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)[C:50]3=[O:62])[CH:47]=[CH:48][C:5]=2[N:4]=1)[CH3:2].CO>Cl>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:13][CH:14]=2)[C:6]2[CH:45]=[C:46]([N:49]3[CH2:54][CH2:53][CH2:52][N:51]([CH2:55][C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)[C:50]3=[O:62])[CH:47]=[CH:48][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccc(N3CCCN(Cc4ccccc4)C3=O)cc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CO
Product: CCc1nc2ccc(N3CCCN(Cc4ccccc4)C3=O)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 55 from 4'-[[2-ethyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-benzimidazol-1-yl]methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl and methanol in methanolic hydrochloric acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=3)[O:21][N:20]=2)[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[NH3+]N.C(OCC)(=O)C>C(O)C.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=3)[O:21][N:20]=2)[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN(C)CCCOc2noc(-c3ccc([N+](=O)[O-])cc3)n2)cc1OC
Agent: [Ni]
Agent: N[NH3+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(CCN(C)CCCOc2noc(-c3ccc(N)cc3)n2)cc1OC
Temperature: 50 °C
Yield: 23.6 %

Procedure:
5 g of 3-{3-[N-(2-(3,4-dimethoxyphenyl)-ethyl)-N-methylamino]-propyloxy)-5-(4-nitrophenyl)-1,2,4-oxadiazole (for preparation, see Example 67) were dissolved in 500 ml ethanol. 4 ml of hydrazinium hydroxide and a catalytic quantity of Raney nickel were added to the solution and the reaction mixture was heated at 50° C. for 30 minutes. The catalyst was then filtered off and the filtrate was concentrated to dryness. The remaining residue was reacted with 10% aqueous sodium carbonate solution and shaken with ethyl acetate. The organic phase was dried with sodium sulfate, filtered, and concentrated. The crude oily title compound that remained as a residue was purified by medium-pressure chromatography over silica gel (Lichroprep Si 60®) using 99:1 ethyl acetate/methanol as the eluent. 1.1 g of the title compound were obtained as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH:18]2[O:20][CH2:19]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(COc2ccc(OCC3CO3)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
25 g of p-benzyloxyphenol, 165 ml of epichlorohydrin, and 34.5 g of potassium carbonate were refluxed while stirring for 4 hours. The mixture was cooled down to room temperature and filtered, whereupon it was evaporated to dryness. The product was recrystallized from the smallest possible amount of diisopropyl ether. M.p. 68° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Mg].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.[Li+].[Cl-].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: BrCCCCBr
Reactant: COc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li+]
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CCCCBr)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
After starting the Grignard reaction by adding 5.00 ml 4-bromoanisole to a mixture of 4.86 g (0.20 mol) magnesium turnings and 100 ml THF, 20.00 ml 4-bromoanisole (total: 25.0 ml (37.4 g; 0.20 mol) were added at a pace sufficient to maintain reflux temperature. The reaction mixture was heated to reflux for additional 3 h, cooled to r.t. and dropped at 0° C. within 1 h to a stirred solution prepared by mixing 129.6 g (71.6 ml, 0.60 mol) 1,4-dibromo-butane in 200 ml THF with a freshly prepared solution of 0.17 g (4.0 mmol) LiCl and 0.267 g (2.0 mmol) Cu(II)Cl2 in 20 ml THF. Stirring was continued for 12 h at r.t. followed by the addition of 100 ml of a 20% ammonium chloride solution and 200 ml ethyl acetate. The water phase was extracted twice with 50 ml ethyl acetate, all organic phases were combined, dried over sodium sulphate and evaporated. The resulting oil was fractionated by vacuum distillation. Yield: 27.7 g (57%), b.p. 112–115° C./0.15 mbar.
Reaction SMILES: [Br:1][C:2]1[C:10](OS(C(F)(F)F)(=O)=O)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:19].C(OCC)(=O)C.O.[CH3:27][N:28](C)C=O>[C-]#N.[Zn+2].[C-]#N.[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:1][C:2]1[C:10]([C:27]#[N:28])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:19]
Reactant: CN(C)C=O
Reactant: O=C1CCc2c1ccc(OS(=O)(=O)C(F)(F)F)c2Br
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(c1Br)CCC2=O
Temperature: 70 °C

Procedure:
Trifluoro-methanesulfonic acid 4-bromo-1-oxo-indan-5-yl ester (10.30 g, 28.68 mmol) is stirred in 50 mL of dry N,N-dimethylformamide under argon atmosphere. Zinc cyanide (1.01 g, 8.60 mmol), 1,1-bis(diphenylphosphino) ferrocene (1.58 g, 2.86 mmol) and tris(dibenzylideneacetone)dipalladium(0) (1.32 g, 1.44 mmol) are added the reaction mixture is warmed at 70° C. for 1 h. The reaction mixture is partioned between ethyl acetate and water, the organic phase is washed with brine, washed with water, dried over sodium sulfate and concentrated under vacuum. The crude product obtained is purified by flash chromatography (cyclohexane/ethyl acetate 99/01→50/50) to give the title compound (Yield: 2.2 g).
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[NH:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22].[C:26](Cl)(=[O:30])[C:27](Cl)=[O:28]>CO>[C:21]([C:20]1[CH:19]=[C:18]([N:17]2[C:8]3[CH:9]=[CH:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[C:7]=3[NH:6][C:27](=[O:28])[C:26]2=[O:30])[CH:25]=[CH:24][CH:23]=1)#[N:22]
Reactant: N#Cc1cccc(Nc2ccc3ccccc3c2N)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cccc(-n2c(=O)c(=O)[nH]c3c4ccccc4ccc32)c1
Temperature: 25 °C
Yield: 9.5 %

Procedure:
To an anhydrous tetrahydrofuran (18 mL) solution of 3-(1-amino-2-naphthylamino)benzonitrile (200 mg, 0.771 mmol) was added an anhydrous tetrahydrofuran (2 mL) solution of oxalyl chloride (66 μL, 0.771 mmol) under cooling in an ice-bath. The mixture was stirred under cooling in an ice-bath for 30 minutes and at room temperature for one hour. After addition of methanol (1 mL), the solvent was removed by evaporation under reduced pressure. The mixture was suspended by chloroform, and washed with a saturated aqueous sodium hydrogen carbonate solution. The precipitated solid was collected by filtration, and washed with water. The obtained solid was purified by silica gel chromatography (chloroform/methanol=9/1) to obtain the titled compound as a white powder (23 mg, yield 10%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].Cl.[NH2:33]O.Cl>CO.CO.O.O.C(OCC)(=O)C>[O:3]=[C:4]1[CH:5]=[C:6]([C@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[CH2:9]2)[O:7][NH:33]1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2cccc(C(F)(F)F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cccc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
A solution of Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-(trifluoromethyl)benzyl)-piperidine-1-carboxylate (2.45 g, 5.90 mmol) in MeOH (7 mL) was added to a solution of NaOH (307 mg, 7.67 mmol) in MeOH/H2O (8 ml/0.5 mL) at −30° C. After 10 min hydroxylamine hydrochloride (0.82 g, 11.80 mmol) and NaOH (472 mg, 11.80 mmol) were added in MeOH (8 mL) and H2O (8 mL). Stirring was continued at −30° C. for 30 min. The reaction solution was poured into 6 M HCl 60 mL) at 80° C. and heated for 30 min. The reaction mixture was dissolved between water and ethyl acetate. The organic phase was isolated, dried with Na2SO4, filtered through celite and the solvent was evaporated. Purification using prepLC (pH=3, large column 40-55% MeCN over 20 min) Cis-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(3-(trifluoromethyl)benzyl)piperidine-1-carboxylate (1.27 g, 56%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.86-2.15 (m, 4H), 2.68 (dd, 1H), 2.86 (dd, 1H), 2.96-3.06 (m, 1H), 3.12-3.25 (m, 1H), 3.58 (s, 3H), 3.95-4.08 (m, 1H), 4.25-4.37 (m, 1H), 5.75 (s, 1H), 7.23-7.32 (m, 1H), 7.35-7.41 (m, 2H), 7.43-4.49 (m, 1H). MS m/z 385 (M+H)+
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]([CH2:26][CH3:27])[CH2:15][CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[N:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1>>[CH2:26]([N:14]([CH2:15][CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:4]1[N:3]=[C:2]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[CH:7]=[C:6]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)[N:5]=1)[CH3:27]
Reactant: CCN(CCc1c[nH]c2ccccc12)c1nc(Cl)cc(N2CCCCC2)n1
Reactant: Cc1ccc(N)cc1
Product: CCN(CCc1c[nH]c2ccccc12)c1nc(Nc2ccc(C)cc2)cc(N2CCCCC2)n1
Temperature: 160 °C

Procedure:
A mixture of N-[4-chloro-6-(1-piperidinyl)-2-pyrimidinyl]-N-ethyl-N-[2-(1H-indol-3-yl)ethyl]amine (33.4 mg, 0.087 mmol) and p-toluidine (47 mg, 0.43 mmol) was heated neat under argon at 160° C. in a sealed tube for 12 hours. The crude material was purified by preparative TLC, eluting with hexane/ethyl acetate (4:1). N2-Ethyl-N2-[2-(1H-3-indolyl) ethyl]-N4-(4-methylphenyl)-6-piperidino-2,4-pyrimidinediamine was obtained, from a band at Rf=0.37, as a solid (15 mg, 0.033 mmol, 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[N:17]=[C:16](I)[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[N:9]=2)[CH:7]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[NH2:66][C:67]1[CH:72]=[CH:71][N:70]=[CH:69][C:68]=1[CH3:73].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[N:17]=[C:16]([NH:66][C:67]3[CH:72]=[CH:71][N:70]=[CH:69][C:68]=3[CH3:73])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[N:9]=2)[CH:7]=1
Reactant: Fc1ccc(Cl)cc1-c1nc(I)c2c(n1)CCCC2
Reactant: Cc1cnccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1CCCC2
Temperature: 80 °C
Yield: 85.2 %

Procedure:
The crude 2-(5-chloro-2-fluorophenyl)-4-iodo-5,6,7,8-tetrahydroquinazoline (130 mg, 0.35 mmol, 1 eq) was dissolved in dioxane (5 ml) and to this was added Pd(OAc)2 (4 mg, 0.02 mmol, 0.05 eq) followed by BINAP (16 mg, 0.03 mmol, 0.075 eq), 4-amino-3-picoline (49 mg, 0.45 mmol, 1.3 eq) and Cs2CO3 (170 mg, 0.52 mmol, 1.5 eq). The reaction mixture was heated to 80° C. for 15 h. The reaction mixture was cooled to r.t. and filtered through Celite® and the crude material was purified by flash column chromatography (1:1/ethyl acetate:hexane) to afford [2-(5-chloro-2-fluorophenyl)-5,6,7,8-tetrahydroquinazolin-4-yl]-(3-methylpyridin-4-yl)-amine, 38 (110 mg, 86%).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)[C:5]([OH:7])=[O:6].N([O-])=[O:18].[Na+]>O>[OH:18][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=N[O-]
Reactant: Nc1cc(C(=O)O)cc(N2CCCC2=O)c1
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(O)cc(N2CCCC2=O)c1
Temperature: 90 °C

Procedure:
To the solution of 1.33 g (6.0 mmol) 3-amino-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid in 15 ml water and 0.75 ml (13.3 mmol, 2.2 eq) concentrated sulfuric at 0° C. are added 0.56 g (8.2 mmol, 1.35 eq) sodium nitrit. After addition of 10 ml water the reaction is heated to 90° C. After cooling to rt the reaction is extracted with EtOAc, the organic layer is dried over sodium sulfate and the solvent is evaporated at reduced pressure to give the product.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])=[O:11])[S:8][C:4]=2[CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CCO>[Br:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:11])[S:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CCCNC(=O)Nc1nc2ccc(Br)cc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCCNC(=O)Nc1nc2ccc(Br)cc2s1
Temperature: 20 °C
Reaction time: 3 h
Yield: 15.4 %

Procedure:
To a solution of ethyl 4-([(6-bromo-1,3-benzothiazol-2-yl)amino]carbonylamino)-butanoate (175 mg, 0.453 mmol) in THF/EtOH (1/1, 3 mL) was added 2 M NaOH (2.26 mL, 4.53 mmol). The reaction mixture was stirred at about 20° C. for about 3 hrs then 2 M HCl was added until pH<6 and a white precipitate was formed. The precipitate was filtered off and washed with H2O. 25 mg (15%) pure product was isolated.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].CC(C)([O-])C.[K+].[N+:17](C1C=CC(C(ON)=O)=CC=1)([O-])=O.C([O-])(O)=O.[Na+]>CN(C=O)C>[NH2:17][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ncc[nH]1
Reactant: NOC(=O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nccn1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of ethyl 1H-imidazole-2-carboxylate (701 mg, 5 mmol) in DMF (20 ml) was dropwise added potassium tert-butoxide (5.50 ml, 5.50 mmol). The reaction turned cloudy in the middle of the addition. The mixture was stirred for 30 minutes before O-(4-nitrobenzoyl)hydroxylamine (911 mg, 5.00 mmol) in DMF (10 mL) was added dropwise. The reaction turned dark blue and then brown and finally orange as the addition continued. The reaction was stirred at room temperature overnight and poured into aqueous NaHCO3 (150 mL) to form a clear yellow solution which was extracted with CH2Cl2 (4×200 ml). The organic layers were combined and evaporated in vacuo to provide ethyl 1-amino-1H-imidazole-2-carboxylate (760 mg, 98% yield) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[C:5]2([CH3:14])[CH3:13].[CH:15](O)=O>>[CH3:13][C:5]1([CH3:14])[C:4]2[C:8](=[CH:9][C:10]3[NH:11][CH:15]=[N:1][C:2]=3[CH:3]=2)[NH:7][C:6]1=[O:12]
Reactant: O=CO
Reactant: CC1(C)C(=O)Nc2cc(N)c(N)cc21
Product: CC1(C)C(=O)Nc2cc3[nH]cnc3cc21

Procedure:
288 mg. (1.51 mmole) 5,6-diamino-3,3-dimethylindolin-2-one and 66 mg. (1.43 mmole) formic acid are heated for 1 hour at 100° C. After the addition of a further 24 mg. (0.52 mmole) formic acid, the reaction mixture is further heated to 100° C. for 60 minutes. Thereafter, trituration is carried out with 0.5 ml. amounts of diethyl ether, followed by suction filtration. There are obtained 277 mg. (91% of theory) of the title compound in the form of pale crystals; m.p. 278°-280° C.