Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=O)[C:7]([CH3:14])=[N:6]2.COC1C=C2C(N=C(C)C(=O)N2)=CC=1.O=P(Cl)(Cl)[Cl:31]>>[Cl:31][C:8]1[C:7]([CH3:14])=[N:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2[nH]c(=O)c(C)nc2c1
Agent: COc1ccc2nc(C)c(=O)[nH]c2c1
Product: COc1ccc2nc(Cl)c(C)nc2c1
Yield: 38.7 %

Procedure:
A solution of 6-methoxy-3-methylquinoxalin-2(1H)-one & 7-methoxy-3-methylquinoxalin-2(1H)-one (1.2 g, 6.31 mmol) in POCl3 (10 ml) was refluxed for 3 h. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified by solid sodium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (20% ethyl acetate in pet ether) to get regioisomers as a mixture. The mixture of regioisomers were separated by SFC purification to afford 2-chloro-6-methoxy-3-methylquinoxaline (0.51 g, 38.7%) and 3-chloro-6-methoxy-2-methylquinoxaline (required isomer) (0.48 g, 36.5%) as off white solids.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[S:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][C:9]=3[NH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[H][H]>CO.CCOC(C)=O.[OH-].[OH-].[Pd+2]>[CH:1]1([C:7]2[C:8]3[S:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][C:9]=3[NH:10][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: O=C(O)c1cc2[nH]cc(C3=CCCCC3)c2s1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1cc2[nH]cc(C3CCCCC3)c2s1
Yield: 98 %

Procedure:
A solution (0.1 M) of 6-cyclohex-1-en-1-yl-4H-thieno[3,2-b]pyrrole-2-carboxylic acid in MeOH/AcOEt (2:1) was treated with 20% Pd(OH)2/C (10% wt.). The resulting suspension was stirred for 18 h under 45 psi of hydrogen then purged with nitrogen and filtered. The filtrate was concentrated to afford the title compound (98%) as a solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]([OH:5])[CH3:4].[Cl:8][C:9](Cl)([O:11]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>C(OCC)C>[Cl:8][C:9]([O:5][CH:3]([CH3:4])[C:2]([F:7])([F:6])[F:1])=[O:11]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(O)C(F)(F)F
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(OC(=O)Cl)C(F)(F)F
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a mixture of 1,1,1-trifluoro-2-propanol (114.1 mg, 1.0 mmol, Matrix Scientific) and triphosgene (98 mg, 0.33 mmol, Aldrich) in ethyl ether (10 mL) at −40° C. was added pyridine (80 μL, 1.0 mmol, EMD) in ethyl ether (1.0 mL) dropwise. The reaction mixture was warmed to 0° C. and stirred for 6 h. The flask containing the above reaction mixture was put into a refrigerator overnight and then filtered. The filtrate was concentrated in vacuo in ice both to colorless oil which was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]2[C:28](=O)[O:27][C:25](=[O:26])[C:24]2=[CH:30][CH:31]=1>ClCCl>[F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[C:28](=[O:27])[C:23]5=[CH:22][C:21]([Cl:20])=[CH:31][CH:30]=[C:24]5[C:25]4=[O:26])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Reactant: NCCN1CCC(c2noc3cc(F)ccc23)CC1
Solvent: ClCCl
Product: O=C1c2ccc(Cl)cc2C(=O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.63 g, 0.01 mole) and 4-chlorophthalic anhydride (1.82 g, 0.01 mole) in dichloromethane (100 ml) is stirred at room temperature for 3 hours. The solvent is removed under reduced pressure and the residual material is purified by flash chromatography. The product was purified further by recrystallization to give N-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-chlorophthalimide.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]([CH2:13][C:14]1[CH:15]=[C:16]2[N:31]=[C:30]([CH3:32])[N:29]([CH3:33])[C:17]2=[N:18][C:19]=1[N:20]([CH2:25][CH:26]1[CH2:28][CH2:27]1)[CH2:21][CH:22]1[CH2:24][CH2:23]1)[C:8]1[N:9]=[N:10][NH:11][N:12]=1.[H-].[Na+].CI.[C:47](OCC)(=O)C>CN(C=O)C>[F:42][C:2]([F:41])([F:1])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=1)[CH2:6][N:7]([CH2:13][C:14]1[CH:15]=[C:16]2[N:31]=[C:30]([CH3:32])[N:29]([CH3:33])[C:17]2=[N:18][C:19]=1[N:20]([CH2:25][CH:26]1[CH2:28][CH2:27]1)[CH2:21][CH:22]1[CH2:24][CH2:23]1)[C:8]1[N:12]=[N:11][N:10]([CH3:47])[N:9]=1
Reactant: Cc1nc2cc(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nn[nH]n3)c(N(CC3CC3)CC3CC3)nc2n1C
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1nc2cc(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c(N(CC3CC3)CC3CC3)nc2n1C
Reaction time: 0.25 h
Yield: 4.4 %

Procedure:
To a solution of (6-{[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-methyl}-2,3-dimethyl-3H-imidazo[4,5-b]pyridin-5-yl)-bis-cyclopropylmethyl-amine (0.220 g, 3.7 mmol.) in DMF (8 mL) was added 60% sodium hydride (0.017 g, 0.741 mmol.) at 0° C. and the resulting reaction mixture was stirred at the same temperature for 15 min. and then methyl iodide (0.046 mL, 0.0741 mmol.) was added and continued to stir for 30 min. The crude product was extracted with ethyl acetate (250 mL), washed with water (250 mL×2) and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography using 230-400 mesh silica gel eluting with 1:1 hexane: ethyl acetate yielded 0.010 gm (yield: 4.4%) of pure colorless gummy compound.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)=[CH2:5].[F-].[Cs+].[OH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:34])[CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][C:28]2[O:31][CH2:32][O:33][C:27]=2[CH:26]=1>CS(C)=O>[OH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:34])[CH2:23][CH:24]([C:25]1[CH:30]=[CH:29][C:28]2[O:31][CH2:32][O:33][C:27]=2[CH:26]=1)[CH2:3][C:4]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)=[O:5]
Reactant: O=C(C=Cc1ccc2c(c1)OCO2)c1ccccc1O
Reactant: C=C(O[Si](C)(C)C)c1ccsc1
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Product: O=C(CC(CC(=O)c1ccccc1O)c1ccc2c(c1)OCO2)c1ccsc1
Temperature: 70 °C

Procedure:
1-Trimethylsilyloxy-1-(thiophen-3-yl)ethylene (7.0 mmol; prepared according to J. Chem. Soc., Perkin Trans. I 1989, 1585) and CsF (0.27 g, 1.76 mmol) were added to a suspension 1-(2-hydroxyphenyl)-3-(3,4-methylenedioxyphenyl)-2-propen-1-one on Wang resin (2.0 g, 1.76 mmol) in dimethyl sulfoxide (30 mL). The reaction mixture was heated to 70° C. for 3 h and the reaction was quenched with 10% AcOH/CH2Cl2. The resin was filtered, washed with DMF (×2) and alternating MeOH and CH2Cl2(×5), and dried under high vacuum overnight to give 1-(2-hydroxyphenyl)-3-(3,4-methylenedioxyphenyl)-5-(thiophen-3-yl)-1,5-pentanedione on Wang resin.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]1[CH2:13][CH2:12][C:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([Br:21])=[CH:16][N:15]=2)=[CH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:25]I.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:22])[N:7]([CH:8]1[CH2:13][CH2:12][C:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([Br:21])=[CH:16][N:15]=2)=[CH:10][CH2:9]1)[CH3:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: Cc1cc(Br)cnc1C1=CCC(NC(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Br)cnc1C1=CCC(N(C)C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h

Procedure:
To a solution of N-[4-(5-bromo-3-methylpyridin-2-yl)cyclohex-3-en-1-yl]carbamic acid-tert-butyl ester (11.2 g) in N,N-dimethylformamide (90 ml) was added sodium hydride (1.46 g) under ice-cooling, and stirred at the same temperature for 0.5 hours. Then methyl iodide (5.7 ml) was added thereto, and stirred at the same temperature for 2 hours. After completion of the reaction, water was added thereto, and the precipitated solid was collected by filtration to give N-[4-(5-bromo-3-methylpyridin-2-yl)cyclohex-3-en-1-yl]-N-methylcarbamic acid-tert-butyl ester.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1>C1COCC1>[OH:2][CH:1]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH3:17])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13]
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Solvent: C1CCOC1
Product: Cc1ccccc1C(O)c1cnccc1-c1cccc(C#N)c1

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (15 mg, 0.075 mmol) in THF (1 mL) at −78° C. was added 0.5 M 4-methylphenylmagnesium bromide in THF (0.3 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-{3-[hydroxy-(2-methyl-phenyl)-methyl]-pyridin-4-yl}-benzonitrile as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:17][CH2:16][C@@H:15]3[C@H:10]([O:11][CH2:12][CH2:13][NH:14]3)[CH2:9]2)=[CH:6][C:5]([C:18]#[N:19])=[CH:4][C:3]=1[NH:20][C:21]1[N:26]=[C:25]([NH:27][CH2:28][CH3:29])[C:24]2=[N:30][CH:31]=[C:32]([C:33]#[N:34])[N:23]2[N:22]=1.CCN(C(C)C)C(C)C.[C:44](Cl)(=[O:47])[O:45][CH3:46]>CO>[Cl:1][C:2]1[C:3]([NH:20][C:21]2[N:26]=[C:25]([NH:27][CH2:28][CH3:29])[C:24]3=[N:30][CH:31]=[C:32]([C:33]#[N:34])[N:23]3[N:22]=2)=[CH:4][C:5]([C:18]#[N:19])=[CH:6][C:7]=1[N:8]1[CH2:17][CH2:16][C@@H:15]2[C@H:10]([O:11][CH2:12][CH2:13][N:14]2[C:44]([O:45][CH3:46])=[O:47])[CH2:9]1
Reactant: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@H]4NCCO[C@@H]4C3)c2Cl)nn2c(C#N)cnc12
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H]4[C@@H](C3)OCCN4C(=O)OC)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(+/−)-2-((2-chloro-5-cyano-3-((4aR,8aR)-hexahydro-1H-pyrido[3,4-b][1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 371)(10 mg, 0.021 mmol, was taken up in MeOH (1 mL) and DIPEA 20 μL was added. The reaction was stirred at 5° C. (ice bath) and methyl carbonochloridate (1.617 μl, 0.021 mmol) was added; the reaction stirred at 25° C. 1 hr. The solvents removed and the crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 20-mM ammonium acetate; Gradient: 40-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford (+/−)-(4aR,8aR)-methyl 6-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)octahydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate (7.8 mg).
Reaction SMILES: [CH3:1][C:2]([O:13][CH2:14][C@H:15]1[CH2:17][O:16]1)([CH3:12])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[N:5]1.C(OCC)(=O)C.[H][H]>C(O)C>[CH3:12][C:2]([O:13][CH2:14][C@H:15]1[CH2:17][O:16]1)([CH3:1])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH2:9])=[N:5]1
Reactant: [H][H]
Reactant: CC(C)(Cn1ccc([N+](=O)[O-])n1)OC[C@H]1CO1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(Cn1ccc(N)n1)OC[C@H]1CO1
Yield: 103.1 %

Procedure:
A mixture of 1-[2-methyl-2-((R)-1-oxiranylmethoxy)-propyl]-3-nitro-1H-pyrazole (0.3 g, 1.24 mmol), and ethyl acetate (15 mL), ethanol (15 mL) was subjected to the H-Cube (Thales Nano) at 1 mL/min at 10° C., 10 psi hydrogen. The first time through not completely reduced. Resubjected and complete reduction of nitro group by NMR. Solvent was removed under reduced pressure to afford 1-[2-methyl-2-((R)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3ylamine as an oil (0.27 g, 100%).
Reaction SMILES: C(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH3:21][O:22][C:23](=[O:35])[C@@H:24]([CH2:33][OH:34])[NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].[O:36]1[CH:41]=[CH:40][CH2:39][CH2:38][CH2:37]1>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(OCC)(=O)C>[C:29]([O:28][C:26]([NH:25][C@H:24]([CH2:33][O:34][CH:37]1[CH2:38][CH2:39][CH2:40][CH2:41][O:36]1)[C:23]([O:22][CH3:21])=[O:35])=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: COC(=O)[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](COC1CCCCO1)NC(=O)OC(C)(C)C
Yield: 95.3 %

Procedure:
To a 2 L three neck flask fitted with a magnetic stirbar, under argon, was added CH2Cl2 (500 mL), PPTs (pyridinium-p-toluene sulfonate) (2 g, 0.008 mol). After dissolving the PPTs by stirring, N-(tert-butoxycarbonyl)-D-serine methyl ester 1 (97.9 g, 0.446 mol) was added to give a clear yellow solution. DHP (3,4-dihydro-2H-pyran) (105 mL, 1.16 mol) was added in one portion. The clear yellow solution was stirred at room temperature over 60 hr to give a slightly cloudy yellow mixture. The mixture was evaporated to give an off-white solid. Ethyl acetate (650 mL) was added to the residue and stirred for 20 minutes to dissolve. The solution was washed with 1.2M HCl (1×500 mL) to pH 4, sat. NaHCO3 (1×600 mL plus 1λ300 mL) to pH 7, brine (1×500 mL), dried over MgSO4 (20 g), filtered and concentrated under reduced pressure to give 129 g (96%) of product 2 as a waxy white solid. 1H NMR (60 MHz, CDCl3) δ 5.2-5.7 (br m, 1H), 3.4-4.8 (m, 9H), 1.4-1.8 (m, 15H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:16][C:17]1[CH:22]=[C:21]([C:23]2[CH:24]=[N:25][C:26]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:27][CH:28]=2)[CH:20]=[CH:19][C:18]=1[OH:36]>O1CCOCC1.N1C=CC=CC=1.CN(C1C=CN=CC=1)C.[OH-].[Na+]>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:36][C:18]1[CH:19]=[CH:20][C:21]([C:23]2[CH:24]=[N:25][C:26]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:27][CH:28]=2)=[CH:22][C:17]=1[F:16]
Reactant: Oc1ccc(-c2cnc(Nc3ccccc3)nc2)cc1F
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COc1cc2nccc(Oc3ccc(-c4cnc(Nc5ccccc5)nc4)cc3F)c2cc1OC
Temperature: 180 °C

Procedure:
A mixture of 4-chloro-6,7-dimethoxyquinoline (0.064 g, 0.28 mmol) and 2-fluoro-4-(2-(phenylamino)pyrimidin-5-yl)phenol (Step 3, 0.48 g, 0.17 mmol) in dioxane (1.0 mL) and pyridine (0.5 mL) was treated with a catalytic amount of DMAP (0.12 g, 0.1 mmol). The mixture was heated under microwave irradiation at 180° C. for 30 min. After cooling to RT, the mixture was diluted with NaOH (0.2 N, 6 mL), and the suspension was filtered. The resulting solid was further purified on silica with 0-5% (NH3-MeOH in DCM) to afford the title compound as a white solid. MS (ESI pos. ion) m/z: 469. Calc'd for C27H21FN4O3: 468.16.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:71][N:72]([CH3:77])[CH2:73][CH2:74][NH:75][CH3:76]>CN1C(=O)CCC1>[CH3:71][N:72]([CH3:77])[CH2:73][CH2:74][N:75]([CH3:76])[C:32](=[O:34])[C:31]1[CH:35]=[CH:36][C:28]([NH:27][C:26]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([C:9]3[N:10]=[C:11]([N:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)[N:12]=[C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[N:8]=3)=[CH:24][CH:23]=2)=[O:37])=[CH:29][CH:30]=1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: CNCCN(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCN(C)C(=O)c1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)nc(N4CCOCC4)n3)cc2)cc1
Yield: 50.2 %

Procedure:
To the stirred solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2yl)phenyl)ureido)benzoic acid (150 mg; 0.297 mmol), Hunig's base (303 μL, 1.782 mmol), HBTU (563 mg, 1.485 mmol) in 2 mL of NMP was reacted according to example 68 with N1,N1,N2-trimethylethane-1,2-diamine (154 μL, 1.188 mmol) to give N-(2-(dimethylamino)ethyl)-4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)-N-methylbenzamide as a white solid (88 mg, 50% yield); MS (ESI) m/z=590.2.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[NH2:22][CH:23]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:24]#[N:25]>>[C:24]([CH:23]([NH:22][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH2:26][CH:27]([CH3:29])[CH3:28])#[N:25]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC(C)CC(N)C#N
Agent: Cl
Product: CC(C)CC(C#N)NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and 2-amino-4-methylpentanenitrile hydrochloride (CAN 72177-82-3) as starting materials. MS (EI): m/e=379.1 [M+H]+.
Reaction SMILES: N.[CH3:2][C:3]1[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:5][N:6]([CH:8]([CH2:12][CH2:13][CH3:14])[C:9]([OH:11])=O)[CH:7]=1.[CH3:21][CH:22]([N:26]1[CH:30]=[C:29](C)C(C2C=CC=CC=2)=N1)C(O)=O>>[CH2:22]([N:26]([CH2:30][CH3:29])[C:9](=[O:11])[CH:8]([CH2:12][CH2:13][CH3:14])[N:6]1[CH:7]=[C:3]([CH3:2])[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:5]1)[CH3:21]
Reactant: Cc1cn(C(C)C(=O)O)nc1-c1ccccc1
Reactant: CCCC(C(=O)O)n1cc(C)c(-c2ccccc2)n1
Agent: N
Product: CCCC(C(=O)N(CC)CC)n1cc(C)c(-c2ccccc2)n1

Procedure:
Following the procedure of Example 68, but substituting diethylamine for aqueous ammonia and 4-methyl-3-phenyl-α-propylpyrazole-1-acetic acid for α,4-dimethyl-3-phenylpyrazole-1-acetic acid, there was obtained N,N-diethyl-4-methyl-3-phenyl-α-propylpyrazole-1acetamide having a melting point of 65°-67° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:20]=[CH:19][C:17]([O-:18])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Na+].Br[CH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1>CC(C)=O>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([O:18][CH2:23][C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=3)=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([O-])cc2)CC1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(COc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Temperature: 60 °C

Procedure:
Sodium 4-(1-BOC-piperazin-4-yl)phenoxide (1 equivalent) and methyl 4-bromomethylbenzoate (1 equivalent) were combined in dry acetone and heated to reflux at 60° C. for 18 hours. The slurry was filtered and the filtrate was then concentrated to provide the crude methyl 4-[4-(1-BOC-piperazin-4-yl)phenoxymethyl]benzoate, that was used without purification.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14](=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].Cl[Si:28]([CH3:31])([CH3:30])[CH3:29]>C1COCC1>[CH3:29][Si:28]([CH3:31])([CH3:30])[O:26][C:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH2:13]
Reactant: C[Si](C)(C)Cl
Reactant: CCCCCCCCCCCC(C)=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C=C(CCCCCCCCCCC)O[Si](C)(C)C
Temperature: 10 °C
Yield: 99.1 %

Procedure:
A solution of n-butyllithium (12.6 mL, 27.7 mmol, 2.2 M in hexane) was added dropwise via syringe to a cooled (-78° C.) solution of diisopropylamine (4.1 mL, 29 mmol) in dry THF (200 mL). The resulting solution was stirred (15 minutes -78° C.), then a solution of 2-tridecanone (5.0 g, 25 mmol) in dry THF (50 mL) was added dropwise via a drop-in funnel. The resulting mixture was stirred (30 minutes, -78° C.), then a solution of chlorotrimethylsilane (3.5 mL, 28 mmol) in dry THF (40 mL) was added in one portion. The dry ice bath was removed and the resulting mixture was warmed to 10° C., then quenched with saturated sodium bicarbonate (100 mL). Dichloromethane (400 mL) and water (80 mL) were added and the layers were separated. The organic layer was washed with brine (1×200 mL), dried (MgSO4), and concentrated in vacuo to yield 6.7 g (98%) of the title compound as a milky oil which was used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[CH2:21][CH2:20][N:19](CC4C=CC=CC=4)[CH2:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO.O.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[CH2:21][CH2:20][NH:19][CH2:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(Nc2ncnc3c2CCN(Cc2ccccc2)C3)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1ccc(Nc2ncnc3c2CCNC3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
A mixture of N-(4-tert-butylphenyl)-7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (0.359 g, 0.96 mmol), prepared as described in Example 2, ammonium formate (0.304 g, 4.82 mmol) and palladium (10% wt. on activated carbon, 40 mg) in MeOH (5 mL) was stirred at r.t. for one h and then at 60° C. for two h. The mixture was cooled to r.t. and filtered over celite. The filtrate was concentrated under reduced pressure to give a white solid which was dissolved in water. The mixture was extracted twice with a 3:1 mixture of chloroform:isopropanol. The combined organic extracts were dried over sodium sulfate and concentrated to dryness to give 0.26 g (96%) of the title compound which was used directly without further purification.
Reaction SMILES: Cl[C:2]([F:27])([F:26])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([NH:18][CH:19]([CH3:21])[CH3:20])[C:4]=1[C:22]([O:24][CH3:25])=[O:23].C(N(CC)CC)C>C(O)C>[F:27][CH:2]([F:26])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([NH:18][CH:19]([CH3:21])[CH3:20])[C:4]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1NC(C)C
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1NC(C)C
Yield: 89.8 %

Procedure:
This compound was prepared as described in Example 54: 2.7 g (0.006 mol) of product of Example 60, 0.65 g (0.006 mol) of triethylamine and 0.12 g of C (10%) in 30 ml of ethanol were reacted affording an oil residue which was kugelrohr distilled at 80 Pa. pot temperature 104° C., to give 2.07 g (89.8%) of product as a white solid; mp 53°-55° C.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[CH2:21]([N:28]1[CH2:32][CH2:31][CH2:30][C:29]1=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])(O)=O.[Na+]>C1COCC1.C(O)(=O)C>[CH2:21]([N:28]1[CH2:32][CH2:31][CH:30]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C1CCNCC1
Reactant: O=C1CCCN1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: c1ccc(CN2CCC(N3CCCCC3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
12.7 g (60.0 mmol) NaBH(OAc)3 and 2.3 mL acetic acid are added to a solution of 4.94 mL (50.0 mmol) piperidine and 8.03 mL (50.0 mmol) N-benzylpyrrolidinone in 200 mL THF. The reaction is stirred overnight at RT. The reaction solution is combined with 200 mL saturated NaHCO3 solution and extracted twice with 200 mL EtOAc. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. The purification is carried out by column chromatography on silica gel (EtOAc/MeOH/NH3 8:2:0.2).