Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[O:16])=[CH:5][CH:4]=1.[C:24]([O-])(=[O:26])C.[Na+]>C(O)(=O)C>[OH:26][CH2:24][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=2)=[C:10]([C:15]([O:17][CH2:18][CH2:19][Si:20]([CH3:22])([CH3:23])[CH3:21])=[O:16])[CH:11]=1
Reactant: C[Si](C)(C)CCOC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: C[Si](C)(C)CCOC(=O)c1cc(CO)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.8 g of 4-bromomethyl-2'-(trimethylsilylethoxycarbonyl)biphenyl and 1.17 g of anhydrous sodium acetate are stirred overnight at 65° in glacial acetic acid and then boiled under reflux for 3 hours. The reaction mixture is evaporated, the residue is taken up in ethyl acetate and washed with water and sodium hydrogencarbonate, and the organic phase is dried and concentrated. The residue is introduced into 25 ml of ethanol, 6.3 ml of 1N NaOH are added and the mixture is stirred at room temperature for 30 minutes. It is evaporated in vacuo, and the residue is treated with ethyl acetate, washed with water and brine, dried and evaporated. Flash chromatography (N4) yields 4-hydroxymethyl-2-(trimethylsilylethoxycarbonyl)biphenyl as a colourless oil. 1H-NMR (DMSO): 0 ppm (s, 9 H), 0.75 ppm (t, 2 H), 4.1 ppm (t, 2 H), 4.73 ppm (d, 2 H), 5.27 ppm (t, 1H), 7.2-7.7 ppm aromatics.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH2:11][NH2:12]>O1CCOCC1>[NH:11]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[NH2:12]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: NN
Solvent: C1COCCO1
Product: NNc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.3 %

Procedure:
2-Chloro-5-nitropyridine (5 g, 31.5 mmol) and hydrazine (1.74 g, 34.7 mmol) were dissolved in 60 ml of dioxane, and the solution was stirred at room temperature for 16 hours. The precipitated yellow powder (m.p.: 198°-208° C.) was collected by filtration to obtain 502 mg of the intended product as a hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:12]3([F:16])[CH2:15][O:14][CH2:13]3)[N:8]2[CH3:11])=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]2[CH3:23])[N:3]=1.Cl[C:25]1N=C2C(N=C(C3(O)COC3)N2CC)=C(N2CCOC[C@@H]2C)N=1.CCCCCCC>C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:12]3([F:16])[CH2:15][O:14][CH2:13]3)[N:8]2[CH2:11][CH3:25])=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]2[CH3:23])[N:3]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(C1(F)COC1)n2C
Reactant: CCn1c(C2(O)COC2)nc2c(N3CCOC[C@@H]3C)nc(Cl)nc21
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCn1c(C2(F)COC2)nc2c(N3CCOC[C@@H]3C)nc(Cl)nc21

Procedure:
This compound was prepared in an analogous fashion to (S)-4-(2-chloro-8-(3-fluorooxetan-3-yl)-9-methyl-9H-pur-in-6-yl)-3-methylmorpholine, using (S)-3-(2-chloro-9-ethyl-6-(3-methylmorpholino)-9H-purin-8-yl)oxetan-3-ol as the starting material. LC-MS m/z (method C)=356/358 [M+H]+, RT=2.62 min; TLC (1:1 heptane:ethyl acetate): Rf=0.58.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].[Li]CCCC.Cl[Si](C)(C)C.[CH3:20][N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[C:8]=1[C:24]1([OH:27])[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]1)[NH2:5]
Reactant: Nc1cc(F)cc(F)c1
Reactant: CN1CCC(=O)CC1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCC(O)(c2c(F)cc(N)cc2F)CC1
Temperature: -74 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
To a stirred solution of 3,5-difluoroaniline (7.0 g, 54 mmol) in anhydrous THF (250 ml) under an atmosphere of nitrogen and cooled to −74° C. was added dropwise nBuLi (1.45M in hexanes, 78.6 ml, 0.114 mol) over a period of 10 minutes. The reaction was allowed to stir at −74° C. for 30 minutes. Chlorotrimethylsilane (12.4 g, 0.114 mol), in anhydrous THF (100 ml) was added dropwise over a period of 10 minutes. The solution was allowed to warm to ambient temperature and then stir for 40 minutes. The reaction was then cooled again to −74° C. and nBuLi (1.45M in hexanes, 43.0 ml, 62.4 mmol) was added dropwise over a period of 10 minutes. After stirring for a further 3.5 hours at −74° C., N-methyl-4-piperidone (7.90 g, 70.5 mmol) in anhydrous THF (50 ml) was added dropwise over a period of 10 minutes. The reaction was allowed to stir to ambient temperature over the weekend. The reaction was acidified with 10% HCl to pH<1 and extracted with diethyl ether. The aqueous phase was separated and treated with 40% NaOH to pH 12 then extracted with diethyl ether and the combined organic phases were washed with sat NaCl and then dried over MgSO4 and evaporated under reduced pressure. The resulting brown oil was triturated with cyclohexane to give the title compound as a pale yellow solid (9.30 g, 71%).
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[C:21]1([CH2:27][CH2:28][CH2:29][NH2:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH3-]C#N.[Na+]>Cl[Ti](Cl)(Cl)Cl>[C:21]1([CH2:27][CH2:28][CH2:29][NH:30][CH:2]2[C:10]3[C:5](=[CH:6][C:7]([O:11][C:12]4[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=4)=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3=O)nc1
Reactant: NCCCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3NCCCc2ccccc2)nc1
Yield: 58.6 %

Procedure:
Using a method similar to Example 1, using 6-(1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 4, 805 mg, 3.00 mmol), 3-phenylpropylamine (486 mg, 3.60 mmol), Ti(iPrO)4 (1.70 g, 6.00 mmol), TiCl4 (1.0M/DCM, 6.00 ml, 6.00 mmol), and NaBH3CN (377 mg, 6.00 mmol) gives the title compound (681 mg) as a light yellow solid. Mass spectrum (ion spray): m/z=388 (M+1); 1HNMR (CDCl3): 8.59 (s, 1H), 8.15 (d, 1H), 7.35 (d, 1H), 7.30-7.25 (m, 2H), 7.22-7.16 (m, 3H), 6.99 (s, 1H), 6.95 (d, 1H), 5.85 (br. s, 2H), 4.23 (t, 1H), 3.00 (m, 1H), 2.83 (m, 1H), 2.78 (t, 2H), 2.70 (m, 2H), 2.43 (m, 1H), 1.87 (m, 3H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH2:13]([O:16][C:17](=[O:30])[C@H:18]([CH2:27][CH2:28]O)[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:14]=[CH2:15].[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH2:13]([O:16][C:17](=[O:30])[CH:18]([CH2:27][CH2:28][N:35]1[C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]2[C:31]1=[O:41])[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:14]=[CH2:15]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=CCOC(=O)[C@H](CCO)NC(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=CCOC(=O)C(CCN1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Yield: 72.6 %

Procedure:
Diethyl azodicarboxylate (5.7 ml, 36.2 mmol, abbreviated as DEAD hereinafter) was added dropwise to a mixture of (±)-N-(tert-butoxycarbonyl)homoserine allyl ester (7.79 g, 30.0 mmol), phthalimide (4.41 g, 30 mmol), triphenylphosphine (9.45 g, 36.0 mmol) and tetrahydrofuiran (75 ml) at room temperature with stirring. This mixture was stirred for 1 hour. The solvent of the reaction mixture was evaporated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=4/1 as the eluent to afford the desired compound (8.46 g, yield 73%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[C:3](Br)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:9][CH2:10][CH2:11][CH2:12][NH2:13].[OH-].[Na+]>N1C=CC=CC=1>[NH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: NCCCN
Reactant: Cc1cccnc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: Cc1cccnc1NCCCN
Yield: 48.2 %

Procedure:
A mixture of 3-methyl-2-bromopyridine (15 g), 1,3-diaminopropane (37.3 g) and pyridine (10 ml) was heated under reflux for 3 hr. After stripping, the residue was treated with 2N sodium hydroxide and the product extracted into chloroform. The extract was dried, stripped and the residue distilled at reduced pressure to give 2-(3-aminopropylamino)-3-methylpyridine (6.94 g) bp 100° C., 0.09 mm Hg. (ii) Sodium hydride (1.11 g) was dissolved in DMSO (20 ml) at 70°-75° C. The solution was cooled and 2-(3-aminopropylamino)-3-methylpyridine (6.94 g) in DMSO (10 ml) added at room temperature. Methyl iodide (6.56g) in DMSO (20 ml) was added dropwise maintaining the temperature at 20°-25° C. After a further 1 hr, water (100 ml) was added and the mixture extracted with chloroform. The chloroform extract was washed with 2N hydrochloric acid. The pH of the acid extract was raised to 9.5 and extracted with chloroform. The pH was raised further to 14 and again extracted with chloroform. After stripping the final extract, the residue was taken back up in water and the product extracted out again with ether. After drying (K2CO3), stripping the ether extract gave 2-[N-(3-aminopropyl)-N-methylamino]-3-methylpyridine (4.46 g) as an oil which was used without further purification. (iii) 2-[N-(3-aminopropyl)-N-methylamino]-3-methylpyridine (1.5 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one (1.46 g) were heated together under reflux in pyridine (10 ml) for 20 hr. The mixture was stripped and the residue triturated with water (pH adjusted to 7 with 6N hydrochloric acid) until a solid (2.1 g) was obtained. This was chromatographed (silica gel, 1-3% methanol/chloroform) and crystallised from acetone/water to give 2-[3-[N-methyl-N-(3-methylpyrid-2-yl)amino]-propylamino]-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one 1H2O, 0.48 g (22%) mp 83°-85° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](O)=[O:22])=[CH:15][CH:16]=2)[NH:11][N:10]=1.[CH3:28][C:29](=[CH2:32])[CH2:30][NH2:31].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:32][C:29](=[CH2:28])[CH2:30][NH:31][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[NH:18][C:14]1[CH:13]=[C:12]2[C:17]([C:9](/[CH:8]=[CH:7]/[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:10][NH:11]2)=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccccc1Nc1ccc2c(C=Cc3ccccn3)n[nH]c2c1
Reactant: C=C(C)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=C(C)CNC(=O)c1ccccc1Nc1ccc2c(/C=C/c3ccccn3)n[nH]c2c1
Reaction time: 8 h
Yield: 130.8 %

Procedure:
A solution of 2-[3-(2-Pyridin-2-yl-vinyl)-1H-indazol-6-ylamino]-benzoic acid (50.0 mg, 0.084 mmol), 2-methyl-allylamine (16.4 μL, 0.17 mmol), triethylamine (58 μl, 0.42 mmol), dissolved in DMF (0.8 mL), was treated with HATU (48 mg, 0.13 mmol). The mixture was stirred overnight, then purified by reverse phase HPLC yielding 45 mg (91%) of the title compound as a TFA salt (1.6 H2O, 1.3 TFA, effective MW=586.53). 1H NMR (DMSO-d6): δ 9.78 (1H, s), 8.72 (2H, m), 8.13 (4H, m), 7.70 (1H, d, J=7.1), 7.58 (2H, m), 7.41 (2H, m), 7.27 (1H, s), 7.06 (1H, d, J=7.1), 6.91 (1H, t, J=7.5), 4.42 (1H, m), 2.22 (2H, m), 2.08 (2H, m), 1.68 (2H, m). ESIMS (M+H+): 410.1.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.C(N(CC)C(C)C)(C)C.[CH2:30]([NH:34][CH2:35][C:36]1[CH:48]=[CH:47][C:39]([O:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:38]([CH3:49])[CH:37]=1)[CH2:31][CH2:32][CH3:33]>C(Cl)Cl>[CH2:30]([N:34]([CH2:35][C:36]1[CH:48]=[CH:47][C:39]([O:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:38]([CH3:49])[CH:37]=1)[C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCNCc1ccc(OCC(=O)OCC)c(C)c1
Reactant: CS(=O)(=O)c1nccc(-c2ccc(C(F)(F)F)cc2)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1nccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 100 °C
Yield: 21.9 %

Procedure:
A mixture of 2-(methylsulfonyl)-4-[4-(trifluoromethyl)phenyl]pyrimidine (0.3 g, 1 mmol), N,N-diisopropylethylamine (0.18 mL, 1 mmol) and ethyl {4-[(butylamino)methyl]-2-methylphenoxy}acetate (0.424 g, 1.53 mmol) was heated at 100° C. in a sealed reactivial for 18 h. The residue was dissolved in CH2Cl2 and purified by Biotage™ chromatography (Silica, 40 g) eluting 3:97 EtOAc:cyclohexane to afford the title compound as a pale yellow oil (110 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]([S:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH3:26])[CH:20]=2)[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])=[CH:4][N:3]=1.C([Li])CCC.CN(C)[CH:34]=[O:35].O>C1(C)C=CC=CC=1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([S:18][CH:9]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])[C:5]2[C:6]([CH3:8])=[CH:7][C:2]([CH:34]=[O:35])=[N:3][CH:4]=2)=[CH:20][C:21]=1[CH3:26]
Reactant: CN(C)C=O
Reactant: Cc1cc(SC(c2cnc(Br)cc2C)c2cc(F)ccc2F)ccc1Cl
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(SC(c2cnc(C=O)cc2C)c2cc(F)ccc2F)ccc1Cl
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 38.6 %

Procedure:
A solution of 2-bromo-5-[[(4-chloro-3-methylphenyl)thio](2,5-difluorophenyl) methyl]-4-methylpyridine (2.0 g, 4.4 mmol) in toluene (50 ml) was cooled to −78° C., and in an argon atmosphere, n-butyllithium (1.54 M hexane solution, 3.4 ml, 5.3 mmol) was added thereto. After stirring for 10 minutes at the same temperature, the mixture was allowed to warm to −40° C., stirred for 30 minutes, and cooled again to −78° C., and then N,N-dimethylformamide (409 μl, 5.3 mmol) was added. After stirring for 30 minutes at the same temperature, water was added, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, subsequently dried over anhydrous sodium sulfate, and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was subjected to flash silica gel column chromatography. The fraction obtained from an elution with hexane:ethyl acetate=95:5 was concentrated under reduced pressure to obtain the title compound (700 mg, 1.7 mmol, 40%) as a colorless oily substance.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([C:19](O)=[O:20])[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:22]1([NH2:28])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH:1]1([C:7]2[CH:8]=[C:9]([C:19]([NH:28][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:20])[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:17])([F:18])[F:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Reactant: NN1CCOCC1
Product: O=C(NN1CCOCC1)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-3-pyridinecarboxylic acid (example 12c) and 4-morpholinamine (CAN 4319-49-7) as starting materials; LC-MS (UV peak area/ESI) 99.0%, 388.1849 (M+H)+.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[C:14](=O)[CH2:15][CH2:16][N:17]1[CH2:22][CH:21]=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1.C(O)C.B.[Na].Cl>O1CCCC1>[CH3:2][C:3]1[N:7]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[CH:14]=[CH:15][CH2:16][N:17]1[CH2:18][CH:19]=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:22]1
Reactant: Cc1c(C(=O)CCN2CC=C(c3ccccc3)CC2)cnn1-c1ncccn1
Agent: B
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C=CCN2CC=C(c3ccccc3)CC2)cnn1-c1ncccn1
Temperature: 0 °C
Reaction time: 7 h
Yield: 26 %

Procedure:
207 mg of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-[4-phenyl-1,2,3,6-tetrahydro-1-pyridyl]-1-propanone hydrochloride was dissolved in a solvent mixture comprising 10 ml of ethanol and 10 ml of tetrahydrofuran. After ice-cooling to 0° C., 319 mg of sodium boron hydride was added thereto in portions for 7 hours. After decomposing the sodium boron hydride by adding conc. hydrochloric acid, the solvent was removed by evaporation. Then the residue was neutralized by adding an aqueous solution of sodium hydroxide and extracted with chloroform. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was dissolved in 7 ml of tetrahydrofuran. Then 250 mg of tosic acid monohydrate was added and the mixture was heated under reflux for 60 minutes. After evaporating the solvent, the residue was neutralized by adding an aqueous solution of sodium hydroxide and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (chloroform:methanol=100:1-3). Then the product was converted into hydrochloride by adding 0.3 ml of a 1N hydrochloric acid/ethanol solution and recrystallized from methanol/ethyl acetate. Thus 47 mg of the title compound was obtained in the form of a pale yellow solid product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([Br:8])=[C:4](Cl)[N:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([NH:15][CH3:16])=[O:14].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([NH:15][CH3:16])=[O:14])[C:5]([Br:8])=[CH:6][N:7]=1
Reactant: CNC(=O)c1ccccc1N
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Br
Yield: 76 %

Procedure:
In a similar fashion as outlined in Example 191a, 2,6-dichloro-5-bromopyrimidine was reacted with 2-amino-N-methylbenzamide and N,N-diisopropylethylamine in isopropyl alcohol (microwave −120° C., 10 minutes) to afford 2-(2-chloro-5-bromo-pyrimidin-4-ylamino)-N-methyl-benzamide as a yellow solid in 76% yield. MS: 342.96 (M+H); 1H NMR (d6-dmso): δ 11.96 (s, 1H), δ 8.85 (br s, 1H), δ 8.57 (s, 1H), δ 8.47 (d, J=9 Hz, 1H), δ 7.79 (d, J=8 Hz, 1H), δ 7.57 (t, J=8 Hz, 1H), δ 7.22 (t, J=8 Hz, 1H), δ 2.78 (d, J=5 Hz, 3H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C@H:7]1[CH2:12][CH2:11][C@@H:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[C:15](=[O:20])[CH2:14]2)[CH2:9][CH2:8]1>ClCCl>[CH3:1][S:2]([O:6][C@H:7]1[CH2:8][CH2:9][C@@H:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[C:15](=[O:20])[CH2:14]2)[CH2:11][CH2:12]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CN1CCN([C@H]2CC[C@@H](O)CC2)CC1=O
Solvent: ClCCl
Product: CN1CCN([C@H]2CC[C@@H](OS(C)(=O)=O)CC2)CC1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
0.24 ml methanesulphonic acid chloride are added dropwise at 0° C. to 500 mg (cis)-1-hydroxy-4-(4-methyl-3-oxo-piperazin-1-yl)-cyclohexane and 0.52 ml N,N-isopropyl-ethylamine in 10 ml dichloromethane and stirred for 1.5 hours at ambient temperature. The product is purified by column chromatography.
Reaction SMILES: [C:1]([C:3]1([CH2:9][C:10]([OH:12])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].[H][H]>CO.[C].[Rh]>[CH2:6]1[CH2:5][CH2:4][C:3]([CH2:1][NH2:2])([CH2:9][C:10]([OH:12])=[O:11])[CH2:8][CH2:7]1
Reactant: [H][H]
Reactant: N#CC1(CC(=O)O)CCCCC1
Agent: [Rh]
Solvent: CO
Product: NCC1(CC(=O)O)CCCCC1
Yield: 65.1 %

Procedure:
A solution of 3 g (1-cyanocyclohexyl)-acetic acid in 10.5 mL methanol is hydrogenated at 10 bar hydrogen pressure and 30° C. in the presence of rhodium-carbon (5%) over a period of five hours. The reaction mixture is filtered and the filtrate evaporated on a rotary evaporator at 30° C. The crystalline residue is stirred with isopropanol and the crystallizate is filtered off with suction and dried to constant weight in a vacuum drying cabinet at 30° C. 2.0 g of the title compound are obtained (65.2% of theory); m.p. 152° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)[C:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(O)(=O)C>[Fe].CO>[CH2:1]([C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[C:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CC(=O)OC)n1Cc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCc1nc(Cl)c(CC(=O)OC)n1Cc1ccc(N)cc1
Yield: 98.5 %

Procedure:
A mixture of methyl 2-butyl-4-chloro-1-(4-nitrobenzyl)imidazole-5-acetate (5.00 g, 13.7 mmol, 1 eq), iron (2.67 g, 47.8 mmol, 3.5 eq), glacial acetic acid (5.47 mL, 95.3 mmol, 7 eq), and methanol (250 mL) was refluxed for 5.5 hours. The solvent was removed by rotary evaporation. The residue was diluted with water (300 mL) and extracted five times with 300 mL portions of ethyl acetate. The organic layers were dried and concentrated. The residue was flash chromatographed in 75:25 hexane/ethyl acetate over silica gel to give 4.53 g of a golden yellow oil which crystallized after standing for several days. NMR (200 MHz, CDCl3) δ 6.72 (d, 2H, J=7 Hz); 6.60 (d, 2H, J=7 Hz); 4.99 (s, 2H); 3.61 (s, 3H); 3.47 (s, 2H); 2.60 (t, 2H, J=7 Hz); 1.68 (m, 2H); 1.35 (m, 2H); 0.86 (t, 3H, J=7 Hz). Mass spectrum shows M+=335/337. Mass Calcd. for C17H22N3O2Cl: 335.1400. Found: 335.1407.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:9].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.C>O.C1(C)C=CC=CC=1>[Cl:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1
Reactant: Fc1cccc(Cl)c1Br
Reactant: Cc1ccc(N)cc1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(Nc2c(F)cccc2Cl)cc1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 103.2 %

Procedure:
A mixture of 2-bromo-1-chloro-3-fluorobenzene (32 g, 153 mmol), p-toluidine (16.4 g, 153 mmol), sodium tert.butylate (27.5 g, 286 mmol), (±)-BINAP [2,2′-Bis-(diphenylphosphino)-1,1′-binaphthalin, 0.66 g, 1.1 mmol) and toluene (250 ml) is stirred under nitrogen for about 30 minutes. After the addition of Palladium-bis-(dibenzylidenaceton) (0.8 g, 1 mmol), the mixture is heated to 110° C. (slight reflux) for 14-20 hours. The mixture is then cooled to 30° C., water (60 ml), concentrated hydrochloric acid (60 ml) as well as charcoal and cellite (5 g each) are added and stirring is continued for an hour. The mixture is filtered and the filtrate is separated into the phases. The organic phase is washed with water (3 times, 70 ml each) and concentrated in vacuo to obtain 37.2 g of crude (2′-chloro-6′-fluorophenyl)-(4-methylphenyl)-amine. The product can be used in the next step (Step 1.2) as such; alternatively in can be kugelrohrdistilled in vacuo.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C([O:12][C:13](=[O:24])[NH:14][C@H:15]([CH3:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)(C)(C)C>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[CH3:23][C@@H:15]([NH:14][C:13](=[O:12])[OH:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: C[C@H](Cc1ccccn1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](Cc1ccccn1)NC(=O)O
Reaction time: 2 h

Procedure:
TFA (4 mL) was added to a CH2Cl2 solution (10 mL) of 7-3 (120 mg, 0.48 mmol) and the solution stirred under ambient conditions for 2 h and concentrated to dryness. The residue was azeotroped with toluene (3×25 mL) to provide 7-4 as a light-yellow semi-solid.