Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C@@H:10]([CH2:16][CH2:17][CH3:18])[NH:11][C:12](=O)[CH2:13][CH3:14].[OH-].[Na+]>O1CCCC1>[CH2:12]([NH:11][C@@H:10]([CH2:9][OH:8])[CH2:16][CH2:17][CH3:18])[CH2:13][CH3:14]
Reactant: CCC[C@@H](NC(=O)CC)C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCN[C@@H](CO)CCC
Temperature: 4 °C
Reaction time: 0.2 h
Yield: 97.2 %

Procedure:
Lithium aluminum hydride (5.47 g) was added to tetrahydrofuran (144 mL) with stirring at 4° C. and then stirred under ice-cooling for 15 minutes. A solution of (R)—N-propionylnorvaline methyl ester (15.87 g) in tetrahydrofuran (85 mL) was added dropwise to the resulting suspension over 70 minutes under stirring at 4° C. and then stirred for 15 minutes under ice-cooling. The suspension was refluxed and stirred for 2 hours and then stirred under ice-cooling for 20 minutes, and an aqueous solution (25 mL) of 1 mol/L sodium hydroxide was added dropwise thereto over 12 minutes and stirred under ice-cooling for 5 minutes. The suspension was refluxed and stirred for 1 hour. The suspension was filtered and washed with ethyl acetate (23 mL). The insoluble matter was subsequently washed twice with hot ethyl acetate (115 mL). The filtrate and the washings were combined and dried over anhydrous sodium sulfate for 12 hours and then concentrated under reduced pressure to give (R)—N-propylnorvalinol (11.97 g, 97% yield) as a yellow oil.
Reaction SMILES: [C:1]1([C:7]2[N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:10][O:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Pd]>[C:1]1([CH:7]2[CH2:12][O:11][CH2:10][CH2:9][N:8]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCOCC1c1ccccc1
Reaction time: 18 h

Procedure:
Tert-butyl 5-phenyl-2H-1,4-oxazine-4(3H)-carboxylate (170 mg, 0.65 mmol) was dissolved in methanol (10 ml). 10% Pd/c (100 mg) was added and the mixture stirred under hydrogen for 18 hours. The catalyst was removed by filtration and the filtrate concentrated to give crude tert-butyl 3-phenylmorpholine-4-carboxylate. The crude product was dissolved in DCM (10 ml) and TFA (1 ml) was added. The mixture was stirred at room temperature for 4 hours. The mixture was then concentrated and the crude purified by reverse phase HPLC (90/10 acetonitrile/water). The subtitle compound was obtained as a white solid (130 mg, 73%); 1H-NMR (d6-DMSO) 3.26 (2H, brm), 3.72-3.81 (2H, m), 4.00-4.03 (2H, m), 4.49 (1H, m), 7.45-7.53 (5H, m), 9.27 (2H, brs); 13C-NMR (d6-DMSO) 43.5, 57.7, 62.8, 68.2, 127.7, 128.9, 129.3; MS ES(+) 164.1 (M++1); HRMS m/z calcd for C10H13NO+H+ 164.1075 [M+H+]. Found 164.1082. IR λmax=1659 cm−1.
Reaction SMILES: [N:1]1([C:7]2[O:8][C:9]3[C:14]([C:15](=[O:17])[CH:16]=2)=[CH:13][CH:12]=[CH:11][C:10]=3OS(C(F)(F)F)(=O)=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:26]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[C:29]([O:28][C:26](=[O:27])[NH:33][CH2:34][C:35]1[CH:36]=[CH:37][C:38]([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:9]=2[O:8][C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:16][C:15]3=[O:17])=[CH:39][CH:40]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: O=c1cc(N2CCOCC2)oc2c(OS(=O)(=O)C(F)(F)F)cccc12
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2cccc3c(=O)cc(N4CCOCC4)oc23)cc1
Temperature: 80 °C

Procedure:
Trifluoro-methanesulfonic acid 2-morpholin-4-yl-4-oxo-4H-chromen-8-yl ester [E] (380 mg, 1.0 mmol), 4-(N-Boc-aminomethyl)phenylboronic acid (280 mg, 1.1 mmol, 1.1 eq), potassium carbonate (275 mg, 2.0 mmol, 2 eq) and tetrakis triphenylphosphine palladium (0) (60 mg, 0.05 mmol 0.05 eq) were stirred in dioxane (4 ml) and heated to 80° C. for 4 hours. The cooled reaction was then filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography eluting with 0-3% methanol in dichloromethane to afford [4-(2-morpholin-4-yl-4-oxo-4H-chromen-8-yl)-benzyl]-carbamic acid tert-butyl ester [F]. Yield 238 mg, 54%.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[NH2:9][C@@H:10]([CH3:25])[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12].C(N(CC)CC)C>C(Cl)Cl.[Cl-].[Na+].O>[CH3:25][C@H:10]1[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:12][C:2](=[O:3])[NH:9]1
Reactant: C[C@H](N)C(O)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C[C@@H]1NC(=O)OC1(c1ccccc1)c1ccccc1
Reaction time: 5 h
Yield: 76.5 %

Procedure:
Trichloromethyl chloroformate (6.37 g, 32.19 mmol) was added to a mixture of (S)-2-amino-1,1-diphenyl-1-propanol (10) (6.65 g, 29.26 mmol) and triethylamine (6.31 g, 62.3 mmol) in CH2Cl2 at 0° C. The reaction mixture was stirred for 5 h at the same temperature, poured into a brine solution (150 ml), and diluted with more dichloromethane. After collecting insoluble impurities through the Buchner funnel, the organic layer was separated and the aqueous layer was washed once with a mixture of dichloromethane and AcOEt. The combined organic extracts were dried over MgSO4/K2CO3 and concentrated under reduced pressure. The resulting crude product was washed with diethyl ether, water, AcOEt and diethyl ether again, to obtain the title compound (11) (5.67 g, 76%) as a white solid. m.p. 264–266° C. [α]D25=−279.71° (c, 0.0414 in DMSO). δH 0.82 (3H, d, 3J=6.30 Hz, CH3), 4.65 (1H, q, 3J=6.0 Hz, CH—NH2), 7.10–7.70 (10H, m, Ar—H), 7.93 (1H, broad s, NH). δC 19.6 (CH3), 55.9 (CH—NH2), 85.6 (C—O), 126.3, 126.4, 128.1, 128.6, 128.8 and 129.1 (o-, m- and p-Ar), 140.6 and 144.2 (α-Ar), 157.6 (C═O). ir 3254 (NH), 1745 and 1725 (C═O). m/e (CI—NH3) 254 (MH+, 9%), 271 (MNH4+, 55%), 52 (100%).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:18])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:17][O:16][CH2:15]2)[CH2:10][CH2:9]1.C(=O)(OC(C)(C)C)[NH2:20].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=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].O1CCOCC1>[F:18][C:6]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH2:10][CH2:9]2)=[C:2]([NH2:20])[CH:3]=[N:4][CH:5]=1
Reactant: Fc1cncc(Cl)c1N1CCN(C2COC2)CC1
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Nc1cncc(F)c1N1CCN(C2COC2)CC1
Temperature: 115 °C
Reaction time: 2 h

Procedure:
In a pressure tube containing 1-(3-chloro-5-fluoro-4-pyridyl)-4-(oxetan-3-yl)piperazine (800 mg, 2.944 mmol) was added dioxane (6 mL). To this solution was added tert-butyl carbamate (517.3 mg, 4.416 mmol), Cs2CO3 (1.918 g, 5.888 mmol), xantphos (85.17 mg, 0.1472 mmol) followed by Pd2(dba)3 (134.8 mg, 0.1472 mmol). The tube was sealed and heated thermally for 60 h at 115° C. The reaction mixture was cooled to RT and filtered on a pad of celite. The cake was washed with EtOAc and the combined filtrate was concentrated in vacuo to a black oil. The residue was taken up in DCM (2 ml) and TFA (3 ml) was added. The resulting dark brown clear solution was stirred at RT for 2 h and then concentrated in vacuo. The residue was loaded onto a SCX-2 (10 g) cartridge. Flushed with MeOH (×3, CV) before eluting the desired product with 2M NH3 in MeOH (×3 CV). The basic eluent was concentrated in vacuo to afford a dark brown oil that was purified by chromatography on silica eluting with DCM-DCM:MeOH:NH3(90:10:1) a gradient of 100-0 to 30:70. Fractions containing product were collected and concentrated in vacuo to afford 5-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-amine as a light brown solid. 295 mg: MS (ES+) 253.2.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O>C(O)(=O)C.CCO>[Cl:12][C:13]1[C:20]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[N:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(NN=Cc1cccc(C(F)(F)F)c1Cl)c1ccc(O)cc1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
To a solution of 4-hydroxy-benzoic acid hydrazide (0.3 g, 0.002 mol) and 2-chloro-3-(trifluoromethyl)benzaldehyde (0.42 g, 0.002 mol) in abs. EtOH (10 mL) was added 1 drop of acetic acid. The reaction mixture was refluxed for 4 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by EtOAc to give white solid 0.64 g, in 93% yield, mp: 261.5° C. 1H NMR (CD3OD) δ 8.89 (s, 1H), 8.51 (d, 1H), 7.85 (m, 3H), 7.56 (t, 1H), 6.89 (d, 2H). 13C NMR (CDCl3) δ 166.9, 163.1, 144.3, 135.7, 132.8, 132.5, 131.0, 130.3, 130.1, 128.5, 125.4, 124.3, 123.2, 116.4. Anal. Calcd for C15H10ClF3N2O2. ½H2O: C, 51.22; H, 2.86; N, 7.96; CI, 10.08; F, 16.20. Found: C, 51.17; H, 3.04; N, 7.53; CI, 10.25; F, 15.93.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([OH:19])[C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C>[CH2:28]([O:19][C:13]1[C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:8]2[CH2:7][CH2:6][N:5]([C:3](=[O:4])[C:2]([F:1])([F:20])[F:21])[CH2:11][CH2:10][C:9]=2[CH:12]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: O=C(N1CCc2cc(O)c([N+](=O)[O-])cc2CC1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(N1CCc2cc(OCc3ccccc3)c([N+](=O)[O-])cc2CC1)C(F)(F)F
Reaction time: 3 h

Procedure:
1.30 g (4.27 mmol) 2,2,2-trifluoro-1-(7-hydroxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethanone are placed in 20 ml DMF and at room temperature 0.65 g (4.70 mmol) potassium carbonate and 0.508 ml (4.27 mmol) benzylbromide are added and the mixture is stirred for 3 h. Then it is filtered and the filtrate is concentrated by evaporation i.vac., the residue is triturated with water, suction filtered and dried at 45° C. in the circulating air dryer.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([NH:25][CH:26]3[CH2:31][N:30]4[N:32]=[CH:33][C:34]([C:35]([OH:37])=O)=[C:29]4[CH2:28][CH2:27]3)=[O:24])=[C:16]2[CH:15]=1.C[CH2:39][N:40]=[C:41]=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.CNC.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([NH:25][CH:26]3[CH2:31][N:30]4[N:32]=[CH:33][C:34]([C:35](=[O:37])[N:40]([CH3:41])[CH3:39])=[C:29]4[CH2:28][CH2:27]3)=[O:24])=[C:16]2[CH:15]=1
Reactant: O=C(O)c1cnn2c1CCC(NC(=O)c1cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)cc13)C2
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)C(=O)c1cnn2c1CCC(NC(=O)c1cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)cc13)C2
Reaction time: 0.25 h

Procedure:
To a stirred solution of 6-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamido)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carboxylic acid (45 mg, 0.08 mmol) in dry DMF (1 mL) was added EDCI (28.7 mg, 0.09 mmol), HOBt (12 mg, 0.88 mmol) and stirring was continued at 25° C. for 15 min. To the above reaction added dimethylamine hydrochloride (7.8 mg, 0.1 mmol) followed by DIPEA (0.05 ml, 0.26 mmol), stirring was continued at 25° C. for 16 h. Reaction mixture was diluted with DCM (50 mL), washed it with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford title compound as white solid. MS (ESI): m/z 534.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:17](I)[CH2:18][CH2:19][CH3:20]>CN(C=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:17][CH2:18][CH2:19][CH3:20])[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: CCCCI
Reactant: Brc1ccc(Nc2ncccn2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCN(c1ccc(Br)cc1)c1ncccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, N-(4-bromophenyl)pyrimidin-2-amine (160 mg) was added to a suspension of sodium hydride (33 mg) in anhydrous DMF (3 ml), and the resulting mixture was stirred at room temperature for 30 minutes. The reaction solution was cooled to 0° C. and n-butyl iodide (0.080 ml) was added thereto, followed by stirring the resulting mixture at room temperature for 1 hour. Saturated brine was added to the reaction solution and the resulting mixture was extracted 3 times with ethyl acetate. Organic layers were washed 3 times with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: ethyl acetate/hexane=1/10) to obtain N-(4-bromophenyl)-N-butylpyrimidin-2-amine (194 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:27][CH2:28][CH2:29][OH:30])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:26]=[CH:25][C:20]([C:21](OC)=[O:22])=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:27][CH2:28][CH2:29][OH:30])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([CH2:21][OH:22])=[CH:25][CH:26]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc([C@H](C)N2CC[C@](CCCO)(c3ccc(F)cc3)OC2=O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(CO)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 32.3 %

Procedure:
Methyl 4-((S)-1-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)benzoate (10 mg, 0.024 mmol) was dissolved in dry THF (4 mL) and cooled to 0° C. LiAlH4 (2 mg, excess) was added slowly. After 10 min, the mixture was warmed to rt and stirred for 2 h. LC-MS found reaction completed. The mixture was quenched with water, diluted with EtOAc (5 mL), washed with 1% aq HCl (2 mL). After concentration, the residue was purified by prep HPLC to afford (R)-6-(4-fluorophenyl)-3-((S)-1-(4-(hydroxymethyl)phenyl)ethyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (3.0 mg, 32%). LC-MS Method 1 tR=1.2 min, m/z=410 (M+Na); 1H NMR (CDCl3) 7.23 (m, 2H), 7.14 (d, 2H), 7.03 (q, 2H), 6.95 (t, 2H), 5.66 (m, 1H), 4.61 (s, 2H), 3.59 (t, 2H), 1.53 (d, 3H).
Reaction SMILES: Cl[C:2]1[CH:19]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:20])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=3.[CH3:21][C:22]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:23]=1[NH2:24]>CC(O)C>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:17][CH3:18])[C:6]1=[CH:19][C:2](=[N:24][C:23]3[C:25]([CH3:30])=[CH:26][C:27]([CH3:29])=[CH:28][C:22]=3[CH3:21])[NH:3][C:4](=[O:20])[N:5]1[CH2:14][CH2:13]2
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: COc1cc2c(cc1OC)-c1cc(Cl)nc(=O)n1CC2
Solvent: CC(C)O
Product: COc1cc2c(cc1OC)-c1cc(=Nc3c(C)cc(C)cc3C)[nH]c(=O)n1CC2
Temperature: 25 °C

Procedure:
2-Chloro-9,10-dimethoxy-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-4-one, prepared according to Preparation 1, (38.5 g, 0.13 mol) and 2,4,6-trimethylaniline (52.7 g, 0.39 mol) in propan-2-ol (3 l) was stirred and heated at reflux, under nitrogen, for 24 h. After cooling to room temperature, the solution was evaporated in vacuo and the residue was purified by column chromatography on silica gel, eluting with CH2Cl2/MeOH, initially 98:2, changing to 96:4 once the product began to elute from the column. The title compound was obtained with a slight impurity, (just above the product on tlc). Yield 34.6 g, 67%.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:5]=[C:4](O)[CH:3]=1.P(Cl)(Cl)([Cl:19])=O.O>ClCCl>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:5]=[C:4]([Cl:19])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)nc(Nc2ccc(F)cc2)n1
Solvent: O
Solvent: ClCCl
Product: Cc1cc(Cl)nc(Nc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
A reaction mixture of 6-methyl-4-hydroxy-2-(4-fluorophenylamino)pyrimidine (1.74 g, 7.93 mmol) and phosphorus oxychloride was stirred for 1 hour at a room temperature and then dissolved in dichloromethane. Water was added dropwise to the reaction mixture and stirred for 30 minutes. The separated organic layer was washed with 2N NaOH solution, dried over anhydrous magnesium sulfate, and then concentrated under a reduced pressure to give 1.57 g of the titled compound. (Yield 83.5%)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[NH2:28][C@H:29]1[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]1>>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([NH:28][C@H:29]3[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N[C@H]2CCCN(C(=O)OC(C)(C)C)C2)nc(N2CCOCC2)n1
Yield: 90 %

Procedure:
Reaction of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole with tert-butyl (3S)-3-amino-1-piperidinecarboxylate as in Example 28 gave tert-butyl (3S)-3-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-1-piperidinecarboxylate in 90% yield: 1H NMR (DMSO-d6) (rotamers) δ8.12-7.58 (m, 3H), 7.38 and 7.38 (2t, J=8.2 Hz, 1H), 6.95 and 6.94 (2d, J=7.8 Hz, 1H), 3.97 (s, 3H), 3.78-3.69 (m, 10H), 2.99-2.94 and 2.85-2.83 (2m, 2H), 1.97-1.93 and 1.78-1.76 (2m, 2H), 1.58-1.19 (m, 11H).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:8]=3[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]=2[N:6]=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1>O1CCOCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:8]2[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]3[N:6]=[C:2]([NH:29][CH:26]4[CH2:28][CH2:27]4)[S:3][C:4]=3[CH:11]=[CH:10][C:9]=2[CH:12]=1
Reactant: NC1CC1
Reactant: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(Cl)nc32)c(=O)[nH]c1=O
Solvent: C1COCCO1
Product: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(NC4CC4)nc32)c(=O)[nH]c1=O
Temperature: 100 °C

Procedure:
A mixture of the product from example 44 step (viii) (0.25 g) and cyclopropylamine (0.44 ml) in dry 1,4-dioxane (3 ml) was heated at 100° C. for 34 h. The solvent was removed under reduced pressure and the residue partitioned between water and ethyl acetate. The organic extracts were dried (MgSO4) and evaporated under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:26]3[S:27][C:28]4[C:34]([O:35][CH3:36])=[CH:33][C:32]([CH3:37])=[CH:31][C:29]=4[CH:30]=3)[C:9]([Cl:25])=[C:10]([CH2:11][N:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[N:6]2[N:5]=[CH:4][N:3]=1.[ClH:38]>O1CCOCC1>[ClH:25].[ClH:38].[ClH:25].[Cl:25][C:9]1[C:8]([C:26]2[S:27][C:28]3[C:34]([O:35][CH3:36])=[CH:33][C:32]([CH3:37])=[CH:31][C:29]=3[CH:30]=2)=[C:7]2[N:6]([C:10]=1[CH2:11][N:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1)[N:5]=[CH:4][N:3]=[C:2]2[NH2:1]
Reactant: COc1cc(C)cc2cc(-c3c(Cl)c(CN4CCN(C(=O)OC(C)(C)C)CC4)n4ncnc(N)c34)sc12
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(C)cc2cc(-c3c(Cl)c(CN4CCNCC4)n4ncnc(N)c34)sc12

Procedure:
Intermediate 60A (65 mg, 0.12 mmol) was stirred in 1 ml of a 4 M solution of hydrogen chloride in 1,4-dioxane for 2 h at rt. The suspension was evaporated to dryness, and the crude product was purified by preparative RP-HPLC (Reprosil C18, gradient 10-95% acetonitrile/0.1% aq. hydrochloric acid) affording 49 mg (74% of th.) of the title compound.
Reaction SMILES: CS([C:5]1[S:6][C:7]([C:10]([F:13])([F:12])[F:11])=[N:8][N:9]=1)(=O)=O.[CH3:14][N:15]([C:22](=[O:25])[CH2:23][OH:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CC)(CC)CC)C.CC(C)=O>[F:11][C:10]([F:13])([F:12])[C:7]1[S:6][C:5]([O:24][CH2:23][C:22]([N:15]([CH3:14])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:25])=[N:9][N:8]=1
Reactant: CN(C(=O)CO)c1ccccc1
Reactant: CS(=O)(=O)c1nnc(C(F)(F)F)s1
Agent: CC[N+](CC)(CC)CC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC(C)=O
Product: CN(C(=O)COc1nnc(C(F)(F)F)s1)c1ccccc1
Reaction time: 20 h
Yield: 90.8 %

Procedure:
5.8 g (0.025 mol) of 2-methylsulphonyl-5-trifluoromethyl-1,3,4-thiadiazole, 4.4 g (0.026 mol) of N-methyl-2-hydroxyacetanilide, 3.8 g (0.038 mol) of potassium carbonate, 0.5 g of tetraethylammonium bromide and 50 ml of acetone are mixed in a 100 ml three-necked flask equipped with a stirrer and a thermometer, and the mixture is stirred for 20 hours at 20°-25° C. The undissolved salts are then filtered off and washed with acetone and the whole of the filtrate is freed of solvent in vacuo. The residue is taken up in 100 ml of diethyl ether, washed with dilute hydrochloric acid, dried over sodium sulphate and filtered, and the filtrate is freed of solvent in vacuo. The remaining oil crystallizes completely after a short time. 7.2 g (90.8% of theory) of 2-(5-trifluoromethyl-1,3,4-thiadiazol-2-yloxy)-N-methylacetanilide of melting point 63° C. are obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=[CH:9][NH:8][N:7]=1)=[O:5])C.O.[OH-].[Li+]>C1COCC1.O>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:10]1[C:6]([C:4]([OH:5])=[O:3])=[N:7][NH:8][CH:9]=1
Reactant: CCOC(=O)c1n[nH]cc1-c1ccc(Cl)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1n[nH]cc1-c1ccc(Cl)cc1Cl
Yield: 108.1 %

Procedure:
A solution of 4-(2,4-dichloro-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (205 mg; 0.72 mmol) and lithium hydroxide monohydrate (125 mg; 2.9 mmol) in 1:1 THF/water (10 ml) was heated at 60° C. overnight. The THF was removed by evaporation, the aqueous phase acidified with 1 M hydrochloric acid then extracted with ethyl acetate (20 ml). The ethyl acetate layer was dried (MgSO4), filtered and evaporated to give 200 mg of 4-(2,4-dichloro-phenyl)-1H-pyrazole-3-carboxylic acid. (LC/MS: [M+H]+256.85).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:22](=O)([O:26]CC)[O:23][CH2:24][CH3:25].[O-]CC.[Na+]>C(O)C>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:22]([O:23][CH2:24][CH3:25])=[O:26])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCOC(=O)OCC
Reactant: CCCCCCCCOc1ccc(CC(=O)OCC)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCOc1ccc(C(C(=O)OCC)C(=O)OCC)cc1

Procedure:
The obtained ethyl 4-n-octyloxyphenylacetate (79 g), ethanol (140 ml), diethyl carbonate (300 ml) and sodium ethoxide (19.3 g) are mixed, and the mixture is heated with stirring while ethanol is distilling off. The reaction mixture is transferred into ice water and is acidified with hydrochloric acid. The organic layer is separated and the solvent is distilled off to give diethyl 4-n-octyloxyphenylmalonate (91.6 g).