Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:23][C:24]1[O:28][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]3[S:36][CH:37]=[CH:38][CH:39]=3)[CH:30]=2)=[N:26][C:25]=1[CH2:40][CH2:41]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:41][CH2:40][C:25]2[N:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]4[S:36][CH:37]=[CH:38][CH:39]=4)[CH:30]=3)[O:28][C:24]=2[CH3:23])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4cccs4)c3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCc2nc(-c3cccc(-c4cccs4)c3)oc2C)cc1)Oc1ccccc1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
3-(4-Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester (495 mg, 1.7 mmol) (see Ex. 1, Part C), toluene-4-sulfonic acid 2-[5-methyl-2-(3-thiophen-2-ylphenyl)oxazol-4-yl]ethyl ester (2.2 mmol) and Cs2CO3 (700 mg, 2.2 mmol) are combined in anhydrous DMF (25 mL) and stirred for 16 h at 55° C. under an atmosphere of nitrogen. The mixture was then cooled and diluted with ethyl acetate (100 mL), and washed with water then brine. The organic layer was dried with Na2SO4 and concentrated in vacuo to a viscous yellow oil. The residue was purified by flash column chromatography (100 g silica, 60×15 mL fractions, gradient elution 0–20% ethyl acetate in hexanes) to provide the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.90 (d, J=7.6 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.42–7.41 (m, 1H), 7.31 (d, J=5.2 Hz, 1H), 7.23–7.09 (m, 5H), 6.96 (t, J=7.2 Hz, 1H), 6.85–6.81 (m, 4H), 4.25 (t, J=6.8 Hz, 2H), 7.20 (q, J=7.2 Hz, 2H), 3.26 (d, J=14.0 Hz, 1H), 3.10 (d, J=14.0 Hz, 1H), 3.00 (t, J=6.8 Hz, 2.40 (s, 3H), 1.38 (s, 3H), 1.21 (t, J=7.2 Hz, 3H); MS (EI) 568.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[C:10](OCC)(=[O:15])[CH2:11][C:12]([CH3:14])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([C:10](=[O:15])[CH:11]=[C:12]([CH3:14])[S:9]2)=[CH:7][CH:8]=1
Reactant: COc1cccc(S)c1
Reactant: CCOC(=O)CC(C)=O
Product: COc1ccc2c(=O)cc(C)sc2c1
Temperature: 110 °C
Yield: 34 %

Procedure:
To a mixture of 3-methoxybenzenethiol (24 g, 28.5 mmol) in PPA (200 g) was added ethyl acetoacetate (22.8 g, 28.5 mmol) at room temperature under nitrogen. Then the reaction mixture was heated to 110° C. for 5 h with vigorous stirring and poured into ice-water (100 ml). The resultant mixture was extracted with ethyl acetate (500 ml×3). The combined organic phase was dried with anhydrous sodium sulfate, filtered and concentrated, then purified by silica gel column (PE/EtOAc=10/1) to afford desired product (2 g, 4%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]([F:25])([F:24])[C:14](=O)[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[Na+].[NH4+].[OH-]>C(Cl)Cl>[CH2:16]([C:15]1[C:14]([C:13]([F:12])([F:25])[F:24])=[N:1][C:2]2[C:3]([C:4]=1[OH:6])=[CH:7][C:8]([I:11])=[CH:9][CH:10]=2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: O=C(CCc1ccccc1)C(F)(F)F
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [NH4+]
Solvent: ClCCl
Product: Oc1c(Cc2ccccc2)c(C(F)(F)F)nc2ccc(I)cc12
Temperature: 100 °C

Procedure:
A mixture of 2-amino-5-iodobenzoic acid (5.73 g, 21.8 mmol), 1,1,1-trifluoro-4-phenylbutan-2-one (5.30 g, 26.2 mmol, see reference Yang, D; Wong, M; Yan, Z. J. Org. Chem. 2000, 65, 4179-4184), and Eaton's reagent (16 mL) in a sealed pressure tube was heated at 100° C. for 1.5 hours. The reaction was then cooled to room temperature and ice-water and DCM were added. Then the pH was adjusted to pH 9 by the slow addition of 50% aqueous NaOH and concentrated NH4OH solutions (the mixture was periodically cooled in an ice-water bath to maintain the temperature below 40° C.). The precipitated solid was filtered, washed with water and Et2O, and air dried to provide the title compound as the crude product.
Reaction SMILES: NC1C=CC(F)=CC=1C(O)=O.FC1C=CC2NC(=O)OC(=O)C=2C=1.[NH2:25][C:26]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:27]=1[C:28]([NH:30][O:31][CH3:32])=[O:29].[Cl:38][C:39]1[CH:44]=[C:43](I)[C:42]([C:46]([F:49])([F:48])[F:47])=[CH:41][N:40]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[Cl:38][C:39]1[CH:44]=[C:43]([NH:25][C:26]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:27]=2[C:28]([NH:30][O:31][CH3:32])=[O:29])[C:42]([C:46]([F:47])([F:48])[F:49])=[CH:41][N:40]=1
Reactant: CONC(=O)c1cc(F)ccc1N
Reactant: FC(F)(F)c1cnc(Cl)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CONC(=O)c1cc(F)ccc1Nc1cc(Cl)ncc1C(F)(F)F
Temperature: 90 °C
Reaction time: 5 h
Yield: 40.5 %

Procedure:
Using the procedure in example 15.01, 2-amino-5-fluorobenzoic acid (1.5 g, 9.67 mmol) was converted into 6-fluoro-1H-3,1-benzoxazine-2,4-dione (1.2 g, 68.5%) as an pale yellow solid; and 6-fluoro-1H-3,1-benzoxazine-2,4-dione (1.05 g, 5.80 mmol) converted into 2-amino-5-fluoro-N-methoxybenzamide (0.344 g, 32.2%) as a yellow pale solid after purification by 2 flash chromatographies on silica gel (eluting with 0 to 50% EtOAc in DCM; eluting with 20% EtOAc in DCM). NMR Spectrum: (DMSOd6) 3.68 (s, 3H), 6.19 (bs, 2H), 6.72 (dd, 1H), 7.07 (ddd, 1H), 7.15 (dd, 1H), 11.48 (bs, 1H) 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (0.502 g, 1.63 mmol), 2-amino-5-fluoro-N-methoxybenzamide (0.344 g, 1.68 mmol), palladium(II) acetate (0.029 g, 0.13 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.151 g, 0.26 mmol) and cesium carbonate (0.638 g, 1.96 mmol) were weighed out in a microwave vial and sealed. Dioxane (10.3 ml) was added and argon bubbled through the reaction mixture followed by stirring at 90° C. for 5 hours. The reaction mixture was allowed to cool to room temperature, silica gel was added and the mixture was concentrated to afford the crude, which was purified by flash chromatography on silica gel eluting with 20 to 50% EtOAc. The solvent was evaporated to dryness to afford 2-[[2-chloro-5-(trifluoromethyl)-4-pyridyl]amino]-5-fluoro-N-methoxy-benzamide (0.240 g, 40%) as an yellow oil which crystallised on standing. NMR Spectrum: (DMSOd6) 3.62 (s, 3H), 6.85 (s, 1H), 7.43-7.51 (m, 2H), 7.60 (dd, 1H), 7.44 (s, 1H), 9.37 (bs, 1H), 11.88 (bs, 1H); Mass spectrum: MH+ 364
Reaction SMILES: Cl.[CH3:2][C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]=[C:6]([NH2:17])[C:5]=2[CH:4]=1.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[CH2:26][CH2:27][C@H:28]1[CH2:33]N[CH2:31][CH2:30][NH:29]1.C(N(CC)C(C)C)(C)C.CS(C)=O>C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[CH2:26][CH2:27][C@@H:28]1[NH:29][CH2:30][CH2:31][N:17]([C:6]2[C:5]3[CH:4]=[C:3]([CH3:2])[S:12][C:11]=3[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]=2)[CH2:33]1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Reactant: Fc1ccc(CC[C@H]2CNCCN2)c(F)c1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccc(F)cc2F)C1
Temperature: 105 °C
Reaction time: 48 h
Yield: 15.9 %

Procedure:
Combine 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (351.6 mg, 1.32 mmol), (S)-2-[2-(2,4-difluoro-phenyl)-ethyl]-piperazine (600.0 mg, 2.65 mmol), N,N-diisopropylethylamine (171.0 mg, 1.32 mmol), DMSO (0.6 ml), and toluene (2.4 ml). Stir and heat the mixture at 105° C. After 48 hours, cool the mixture to ambient temperature and then dilute it with ethyl acetate and water. Remove the organic layer and wash it with 1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give 91.8 mg (16%) of the title compound as a brown foam: mp 69°, dec; mass spectrum (ion spray): m/z=439.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:8](=[S:10])[NH2:9])[CH:7]=1.Br[CH2:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:8]2[S:10][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:9]=2)[CH:7]=1
Reactant: NC(=S)c1cc(Br)ccc1F
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(-c2cc(Br)ccc2F)n1
Temperature: 80 °C
Yield: 76 %

Procedure:
A mixture of 5-bromo-2-fluoro-benzenecarbothioamide (11.8 mmol, 2840 mg) and ethyl bromopyruvate (1.05 equiv., 12.4 mmol, 1.56 mL) in ethanol (30 mL) was heated at 80° C. overnight. The mixture was concentrated and the residue was purified on silica eluted with 0 to 20% EtOAc in Heptane to afford ethyl 2-(5-bromo-2-fluoro-phenyl)thiazole-4-carboxylate (2960 mg, 76.14% Yield) as a clear oil.
Reaction SMILES: [CH2:1]1[O:12][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:13]([NH2:16])[CH2:14][NH2:15]>C(O)C>[CH2:13]([NH:16][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:14][NH:15][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCC1CO1
Reactant: NCCN
Solvent: CCO
Product: CCCCCCCCCC(O)CNCCNCC(O)CCCCCCCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-undecene oxide (40 g.) and ethylenediamine (7.07 g.) and two recrystallizations of the resulting solid (14.9 g.) from ethanol gave N,N'-ethylenebis[2-hydroxyundecylamine] (I: R = CH3 (CH2)8, R' = H, X = (CH2)2, Z = H) (12.4 g., m.p. 130.2°-137.8° C.).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[N:9]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:10]([C:12]3[C:16]4=[N:17][C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=[C:15]4[N:14]([CH3:25])[CH:13]=3)=[CH:11][C:4]=12.[C:36]1([OH:42])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.ClCCl>[CH3:24][O:23][C:18]1[N:17]=[C:16]2[C:12]([C:10]3[N:9]([S:26]([C:29]4[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=4)(=[O:27])=[O:28])[C:5]4=[N:6][CH:7]=[CH:8][C:3]([CH2:2][O:42][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[C:4]4[CH:11]=3)=[CH:13][N:14]([CH3:25])[C:15]2=[CH:20][C:19]=1[O:21][CH3:22]
Reactant: Oc1ccccc1
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(CCl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: COc1cc2c(nc1OC)c(-c1cc3c(COc4ccccc4)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Temperature: 80 °C

Procedure:
To a solution of 0.3 g of 3-[4-chloromethyl-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridine in 30 cm3 of acetonitrile, at a temperature in the region of 20° C., are added 0.066 cm3 of phenol and 0.486 g of potassium carbonate. The reaction medium is heated at 80° C. for 18 hours. After cooling, the reaction medium is filtered through a sinter funnel and the filtrate is concentrated under reduced pressure. The residue obtained is taken up in 5 cm3 of water and 10 cm3 of dichloromethane. After separation of the phases by settling, the organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. After purification by flash column chromatography (SiO2, dichloromethane/ethyl acetate 97.5/2.5 by volume as eluents), 0.140 g of 5,6-dimethoxy-1-methyl-3-[4-phenoxymethyl-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-pyrrolo[3,2-b]pyridine is obtained with the following characteristics:
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][OH:24])[N:18]=[C:17]([O:25][CH3:26])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:27]([O:31]C(N1CCC(NC2N=C(Cl)N=C(OC)N=2)CC1)=O)([CH3:30])([CH3:29])[CH3:28].NCC(OC(C)(C)C)=O.C(N(C(C)C)C(C)C)C.Cl.COC1N=C(NC2CCNCC2)N=C(NCCO)N=1>C(#N)C.O1CCOCC1.CO>[C:27]([O:31][C:23](=[O:24])[CH2:22][NH:21][C:19]1[N:18]=[C:17]([O:25][CH3:26])[N:16]=[C:15]([NH:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[N:20]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: COc1nc(Cl)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Reactant: COc1nc(NCCO)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: CC(C)(C)OC(=O)CN
Agent: COc1nc(NCCO)nc(NC2CCNCC2)n1
Agent: Cl
Solvent: CO
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1nc(NCC(=O)OC(C)(C)C)nc(NC2CCNCC2)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 tert-butyl glycinate 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): 339.2 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH2:10].[CH:25]([CH2:27][CH:28]([CH3:34])[C:29](OCC)=[O:30])=O>>[OH:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[C:29](=[O:30])[CH:28]([CH3:34])[CH2:27][CH:25]=[N:10][CH2:9][CH2:8]1
Reactant: CCCCCCCCCCCCCCC(O)CNCCNCCN
Reactant: CCOC(=O)C(C)CC=O
Product: CCCCCCCCCCCCCCC(O)CNCCN1CCN=CCC(C)C1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 339.5 g (1 mole) of N-(2-hydroxy)hexadecyldiethylenetriamine and 144.2 g (1 mole) of ethyl 3-formyl-2-methylpropionate. At 140° to 160° C., 18 g of water and 46 g of ethanol were distilled off to obtain 4-(2-hydroxyhexadecyl)aminoethyl-6-methyl-2,3,6,7-tetrahydro-1,4-diazocin-5-one.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[F:12]/[C:13](=[CH:17]\[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)/[C:14](O)=[O:15]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:14](=[O:15])/[C:13](/[F:12])=[CH:17]/[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:4]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)/C(F)=C/c1ccccc1
Agent: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)/C(F)=C/c1ccccc1

Procedure:
Prepared as free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and Z-2-fluoro-3-phenylpropenoic acid; MS (ES+) 275 (MH+).
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[CH:24]=[CH:23][N:22]([CH2:25][CH3:26])[C:14]=3[N:15]=[C:16](S(C)(=O)=O)[N:17]=2)=[CH:7][CH:6]=1>CS(C)=O>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[CH:24]=[CH:23][N:22]([CH2:25][CH3:26])[C:14]=3[N:15]=[C:16]([C:1]#[N:2])[N:17]=2)=[CH:7][CH:6]=1
Reactant: [C-]#N
Reactant: CCn1ccc2c(Nc3ccc(Cl)cc3)nc(S(C)(=O)=O)nc21
Agent: [Na+]
Solvent: CS(C)=O
Product: CCn1ccc2c(Nc3ccc(Cl)cc3)nc(C#N)nc21
Temperature: 90 °C

Procedure:
Sodium cyanide (0.103 g) was added to a solution of the product from step (iii) (0.37 g) in dimethylsulphoxide (10 ml) and heated at 90° C. for 48 h. The mixture was partitioned between ethyl acetate and water, the organics dried (MgSO4) and evaporated under reduced pressure. The residue was purified by RPHPLC eluting with 29-95% acetonitrile in aqueous trifluoroacetic acid. Yield 0.14 g
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[C:22](=[O:23])[N:21]([CH3:24])[CH2:20][CH2:19][N:18]3[CH3:25])=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.CN1CCN(C)C(C2C=CC(N)=CC=2)C1=O>>[Br:1][C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C@@H:17]3[C:22](=[O:23])[N:21]([CH3:24])[CH2:20][CH2:19][N:18]3[CH3:25])=[CH:15][CH:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: CN1CCN(C)C(c2ccc(Nc3nc(Br)cn(C)c3=O)cc2)C1=O
Agent: CN1CCN(C)C(c2ccc(N)cc2)C1=O
Product: CN1CCN(C)[C@H](c2ccc(Nc3nc(Br)cn(C)c3=O)cc2)C1=O

Procedure:
The (R)-isomer of compound 14 can be prepared from the (+)-isomer of 1,4-dimethyl-3-(4-aminophenyl)piperazin-2-one using the same procedure.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:16](=[O:28])[NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])[N:19]=1)[CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)(C)(C)C.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>ClCCl>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[NH2:7][C@@H:8]([CH2:9][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)[C:16]([NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH2:23][C:24]([OH:27])([CH3:25])[CH3:26])[N:19]=1)=[O:28]
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)Cn1ccc(NC(=O)[C@@H](N)CC2CCCCC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A solution of {(S)-2-cyclohexyl-1-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-ylcarbamoyl]-ethyl}-carbamic acid t-butyl ester (0.61 g 1.5 mmol) in dichloromethane (10 mL) was treated with trifluoroacetic acid (5 mL). The mixture was stirred at room temperature for 0.5 h, and concentrated to afford (S)-2-amino-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide trifluoroacetate (630 mg, 100%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.C([Li])CCC.[CH3:17][C:18]1([CH3:28])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]([CH:26]=[O:27])=[CH:19]1>O1CCCC1>[CH:8]1[C:9]2[C:4](=[CH:3][C:2]([CH:26]([C:20]3[C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23][C:18]([CH3:28])([CH3:17])[CH:19]=3)[OH:27])=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Brc1ccc2cnccc2c1
Reactant: CC1(C)C=C(C=O)C(C)(C)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)C=C(C(O)c2ccc3cnccc3c2)C(C)(C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
A solution of 6-bromoisoquinoline (416 mg, 2 mmol) in tetrahydrofuran (8 mL) was added dropwise into n-butyl lithium (1.6 M in hexane, 1.25 mL, 2 mmol) at −78° C. and the reaction was stirred for 30 minutes. A solution of the product of Example 10g (150 mg, 1 mmol) in tetrahydrofuran (2 mL) was added and the reaction was stirred at −78° C. for 1 hour and then slowly warmed to room temperature. The mixture was quenched with the addition of saturated aqueous ammonium chloride and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound (167.3 mg, Yield: 63%). 1H NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 8.52 (d, J=6.0 Hz, 2H), 7.96 (d, J=8.8 Hz, 2H), 7.49 (d, J=8.4 Hz, 1H), 5.49 (s, 1H), 5.32 (d, J=15.2 Hz, 1H), 1.63-1.44 (m, 4H), 1.21 (s, 3H), 1.01 (s, 3H), 0.97 (s, 3H), 0.91 (s, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11](=[O:24])[C:12](C(OC)=O)([CH3:19])[CH2:13][C:14]([O:16]CC)=[O:15])=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1>Br>[CH3:1][C:2]1[C:10]([C:11](=[O:24])[CH:12]([CH3:19])[CH2:13][C:14]([OH:16])=[O:15])=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: CCOC(=O)CC(C)(C(=O)OC)C(=O)c1c(C)nn2ccccc12
Agent: Br
Product: Cc1nn2ccccc2c1C(=O)C(C)CC(=O)O
Temperature: 0 °C
Yield: 80.5 %

Procedure:
The compound (4.63 g) of Example 9 was dissolved into 47% hydrobromic acid (50 ml) and the solution was refluxed for 1 hour under heat. This was poured into ice water and extracted with methylene chloride. After the organic layer was dried over anhydrous sodium sulfate, solvent was distilled off under reduced pressure. The residue was purified by means of silica gel column chromatography (developing solvent, methylene chloride:ethanol=10:1) to obtain aimed product (2.76 g) as purple powder.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([S:11][C:12]#N)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[BH4-].[Na+].[OH-].[K+].[Cl:18][C:19]1([Cl:25])[CH2:21][C:20]1(CCl)[CH3:22]>C(O)C.C(Cl)(Cl)Cl.O>[N+:1]([C:4]1[CH:10]=[C:9]([S:11][CH2:12][C:20]2([CH3:22])[CH2:21][C:19]2([Cl:25])[Cl:18])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Reactant: CC1(CCl)CC1(Cl)Cl
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC1(CSc2ccc(N)c([N+](=O)[O-])c2)CC1(Cl)Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.5 %

Procedure:
To a stirred mixture 9.75 g (0.05 mole) of 2-nitro-4-thiocyanoaniline in 500 ml of absolute ethanol under N2, there is added 2.1 g of sodium borohydride in portions. The mixture is stirred at room temperature for 3 hours. 3.25 g (0.05 mole) of KOH in 30 ml of absolute ethanol is added. The mixture is stirred for 1 minute. A solution of 8.7 g (0.05 mole) of 1,1-dichloro-2-chloromethyl-2-methylcyclopropane in 15 ml of absolute ethanol is added and the mixture is refluxed for 3 hours. Equal amounts of H2O and CHCl3 are added until two layers are formed. The organic layer is separated, dried (MgSO4), and the solvent removed in vacuo to give a red oil which is triturated with 10 ml of absolute ethanol to yield 9.6 g of 2-nitro-4-[(2,2-dichloro-1-methylcyclopropyl)methyl]thioaniline as a solid, m.p. 76-78° C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]3[N:21]([C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=4)[N:22]=[CH:23][C:16]=23)[CH2:10][CH2:9]1)(C)(C)C>Cl.O1CCOCC1>[CH3:33][S:30]([C:27]1[CH:28]=[CH:29][C:24]([N:21]2[C:17]3=[N:18][CH:19]=[N:20][C:15]([NH:14][CH:11]4[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]4)=[C:16]3[CH:23]=[N:22]2)=[CH:25][CH:26]=1)(=[O:32])=[O:31]
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-n2ncc3c(NC4CCC(N)CC4)ncnc32)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 103.5 %

Procedure:
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (30 mg, 0.06 mmol) was dissolved in 4M HCl in dioxane (2 mL) and then stirred overnight at 40° C. The resulting solution was evaporated to provide compound A54 as a white solid (24 mg, 100%). Exact mass calculated for C18H22N6O2S 386.2, found 387.2 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][C:12](=[N:15]O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.COCCO[AlH2-]OCCOC.[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCC(=NO)CC2)cc1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(N2CCC(N)CC2)cc1
Yield: 82.4 %

Procedure:
A mixture of 1-(4-methoxy-phenyl)-piperidin-4-one oxime (4.55 g, 20.6 mmol), “Red-Al®” (70% in toluene, 23.4 ml) and toluene (10 ml) was heated at 140° for 2 h. After cooling, the reaction mixture was poured on H2O (100 ml). Extraction of the solution with CH2Cl2, drying of the organic layer, evaporation of the solvent and purification of the residue by chromatography (SiO2, CH2Cl2—MeOH—aq. NH3 140:10:1) gave 1-(4-methoxy-phenyl)-piperidin-4-yl-amine (3.5 g, 89%, white crystals, MS: m/e=207.2 (M+H+)).