Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:10]=1[CH2:11][N:12]([CH2:18][C@H:19]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][NH:20]1)[C:13](=[O:17])[CH:14](Cl)[CH3:15].CCOC(C)=O.CO>CN(C=O)C.C(Cl)Cl>[CH3:7][O:8][C:9]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:10]=1[CH2:11][N:12]1[C:13](=[O:17])[CH:14]([CH3:15])[N:20]2[CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[CH2:28][C@@H:19]2[CH2:18]1
Reactant: COc1ccc(CN(C[C@H]2Cc3ccccc3CN2)C(=O)C(C)Cl)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C[C@H]3Cc4ccccc4CN3C(C)C2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.2 %

Procedure:
Cesium carbonate (0.18 g) was added to a solution of N-(2,4-dimethoxybenzyl)-2-chloro-N-(((3R)-1,2,3,4-tetrahydroisoquinolin-3-yl)methyl)propanamide (0.18 g, 0.44 mmol) in DMF (4.7 ml). After stirring at ambient temperature for 3 h, the reaction was transferred to a separatory funnel with EtOAc. Extraction with EtOAc, washing the organic layer with water (3×) and brine and drying over MgSO4 afforded 0.15 g of crude product. Flash chromatography (SiO2, 0.2 to 10% MeOH in CH2Cl2) gave pure product (0.11 g, 68%). MS (ESI) 367 (M+H).
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:22]([O:24]CC)=[O:23])[CH:14]([C:18]([F:21])([F:20])[F:19])[O:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:22]([OH:24])=[O:23])[CH:14]([C:18]([F:19])([F:20])[F:21])[O:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1=Cc2ccc(Cc3ccccc3)cc2OC1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)C1=Cc2ccc(Cc3ccccc3)cc2OC1C(F)(F)F
Temperature: 40 °C
Yield: 95 %

Procedure:
The ester from Example 9k, Step 1 was added THF(7): EtOH(2): H2O(1) followed by LiOH (1.5 eq) and heated to 40° C. for 4 h. The reaction was cooled to room temperature, concentrated in vacuo. Acidified with HCl conc to pH 1, filtered solid and subjected solid to preparative reverse phase chromatography to produce the title compound (95%): ESHRMS m/z 333.0751 (M−H, C18H12O3F3 Calc'd 333.0733). 1HNMR (DMSO-d6/400 MHz), 13.13 (brs, 1H), 7.76 (s, 1H), 7.33 (d, 1H, J=7.5 Hz), 7.13-7.26 (m, 5H), 6.84-6.88 (m, 2H), 5.81 (q, 1H, J=7.1 Hz), 3.27 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([S:11][CH3:12])=[N:8][CH:9]=2)[NH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].CS(C)=O.Br[CH2:24][CH:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:34])[O-:33])[CH2:27][CH2:26]1>O.C1COCC1>[Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([S:11][CH3:12])=[N:8][CH:9]=2)[N:4]([CH2:24][CH:25]2[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:34])[O:33][C:10]([CH3:2])([CH3:5])[CH3:9])[CH2:27][CH2:26]2)[N:3]=1
Reactant: O=C([O-])NC1CCC(CBr)CC1
Reactant: CSc1ncc2c(Br)n[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CS(C)=O
Product: CSc1ncc2c(Br)nn(CC3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Temperature: 150 °C
Yield: 165.2 %

Procedure:
A 10 mL microwave tube was charged with 3-bromo-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidine (0.3 g, 1.22 mmol), K2CO3 (0.51 g, 3.66 mmol), and DMSO (2 mL). The mixture was stirred for 20 min before 4-(bromomethyl)cyclohexylcarbamate (0.45 g, 1.53 mmol) and THF (4 mL) was added. The resulting mixture was heated at 150° C. for 10 minutes in microwave. The reaction mixture was poured into water and extracted with Et2O (3×). The combined ether layer was dried (Na2SO4) and concentrated. The crude mixture was purified by Isco to provide tert-butyl 4-((3-bromo-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate (0.46 g, 83%) as a white solid. MS m/z 478.10 [M+Na]+.
Reaction SMILES: Br[Si](C)(C)C.[CH2:6]([C:10]1[N:11]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]3[NH:45][N:44]=[N:43][N:42]=3)=[CH:31][CH:30]=2)[C:12]([C:16]([O:18][CH2:19][P:20]([O:25]CC)([O:22]CC)=[O:21])=[O:17])=[C:13]([Cl:15])[N:14]=1)[CH2:7][CH2:8][CH3:9].CO>C(#N)C>[CH2:6]([C:10]1[N:11]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]3[NH:45][N:44]=[N:43][N:42]=3)=[CH:31][CH:30]=2)[C:12]([C:16]([O:18][CH2:19][P:20](=[O:21])([OH:22])[OH:25])=[O:17])=[C:13]([Cl:15])[N:14]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCc1nc(Cl)c(C(=O)OCP(=O)(OCC)OCC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: CC#N
Product: CCCCc1nc(Cl)c(C(=O)OCP(=O)(O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromotrimethylsilane (1.70 mL, 13.1 mmol) was added to a stirred, 0° C. mixture of (diethoxyphosphoryl)methyl 2-butyl-4-chloro-1-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylate (3.49 g, 5.95 mmol) in acetonitrile and the mixture was stirred at room temperature for 1 hour. Methanol (20 mL) was added, stirred for 30 minutes then concentrated in vacuo to afford the title compound as crude, which was used in the subsequent step without further purification. LC-MS: m/z 531.0 (M+H).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]=[C:13]([C:18]4[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=4)/[CH:21]=[CH:22]/[C:23](O)=[O:24])[NH:12][C:11]=3[N:10]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:9]2=[O:36])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CN(C)C=O.ClCCl>[CH:1]1([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]=[C:13]([C:18]4[CH:28]=[CH:27][CH:26]=[C:20](/[CH:21]=[CH:22]/[C:23]([N:12]5[CH:11]=[CH:15][N:14]=[CH:13]5)=[O:24])[CH:19]=4)[NH:12][C:11]=3[N:10]([CH2:29][CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)[C:9]2=[O:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)/C=C/c1cccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(/C=C/c1cccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)c1)n1ccnc1
Reaction time: 18 h
Yield: 146.3 %

Procedure:
A slurry of (E)-3-[1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]cinnamic acid (from step (a), 0.50 g) in anhydrous N,N-dimethylformamide (10 mL) was heated briefly to near reflux under nitrogen. N,N′-carbonyldiimidazole (Aldrich, 0.202 g, 1.22 mmol) was then added to the pale yellow slurry, which thinned and turned orange as a gas evolved. Within minutes the slurry turned a bright yellow and thickened as a yellow solid formed. The mixture was stirred for 18 h, diluted with dichloromethane (30 mL), and filtered. The bright yellow solid was washed with dichloromethane (30 mL), and dried at 40° C. to provide (E)-1,3-bis(cyclohexylmethyl)-8-(3-(2-(1H-imidazol-1-ylcarbonyl)vinyl)phenyl)-9H-purin-2,6(1H,3H)-dione as a yellow powder (0.403 g). To a mixture of this compound (0.40 g, 0.74 mmol) and nonaethylene glycol monomethyl ether, (part (a) of example 10, 0.350 g) in N,N-dimethyl fornamide (10 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (Aldrich, 0.112 g). The resulting solution was stirred at 55° C. for 20 h. The solution was cooled to room temperature and adjusted to pH 7 by addition of 1N HCl. Chloroform (50 mL) was added and the solution was washed with water (2×20 mL). The combined organic layers were washed with brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residual waxy solid was chromatrographed on silica gel eluted with 10% methanol/chloroform to give (E)-3-[1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]cinnamic acid nonaethylene glycol methyl ether ester as a white waxy solid (0.421 g, 63%); 1H-NMR (DMSO-d6) δ: 8.53 (s, 1, aryl CH), 8.13 (d, J=7.7, 1, aryl CH), and 7.80 (d, J=8.5, 1, aryl CH), 7.71 (d, J=16, 1, CH═) 7.58, (m, 1, aryl CH), 6.78, (d, J=15.9, 1, CH═) 4.28 (m,2, CH2O), 3.91, (d, J=7.2, 2, CH2N), 3.77 (d, J=7.2, CH2N), 3.68 (m, 2, CH2O), 3.70-3.40 (m, 32, 16 CH2), 3.21 (s, 3, CH3), 2.1-1.6 and 1.4-1.0 (m, 22, cyclohexyl CH2 and CH).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([F:6])([F:5])I.[C:9]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]=[CH2:21])=[CH:16][CH:15]=1)(=[O:11])[CH3:10].C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[C:9]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][C:3]([F:6])([F:5])[C:2]([F:8])([F:7])[F:1])=[CH:18][CH:19]=1)(=[O:11])[CH3:10]
Reactant: FC(F)(F)C(F)(F)I
Reactant: C=Cc1ccc(COC(C)=O)cc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(=O)OCc1ccc(CCC(F)(F)C(F)(F)F)cc1
Yield: 31.3 %

Procedure:
At −78° C., pentafluoroiodoethane (2.09 g, 8.51 mmol)) was condensed into a pressure bottle. Toluene (5 mL), 4-ethenylbenzenemethanol acetate (1 g, 5.67 mmol), and tributyltin hydride (1.53 mL, 5.67 mmol) were added. The pressure bottle was sealed and irradiated for 30 hours using a 75 W lamp. The solvent was removed in vacuo. Flash chromatography of the residue gave 525 mg of 4-(3,3,4,4,4-pentafluorobutyl)benzenemethanol acetate; 1H NMR (300 MHz, CDCl3) δ 7.32 (d, 2H), 7.21 (d, 2H), 5.09 (s, 2H), 2.91 (m, 2H), 2.32 (m, 2H), 2.10 (s, 3H) ppm.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]2[CH2:21][C@@H:20]([CH3:22])[CH2:19][CH2:18][CH2:17][C@@H:16]2[CH3:23])[C:10]=1[F:24].[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]2[CH2:21][C@@H:20]([CH3:22])[CH2:19][CH2:18][CH2:17][C@@H:16]2[CH3:23])[C:10]=1[F:24])[C:4]#[C:5][CH3:6]
Reactant: C[C@H]1CCC[C@H](C)N(c2ncnc(Cl)c2F)C1
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1ncnc(N2C[C@@H](C)CCC[C@@H]2C)c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
0.10 g of sodium hydride (60% oil suspension) was suspended in 3 ml of tetrahydrofuran. 0.5 ml of tetrahydrofuran solution of 0.15 g of 2-butyn-1-ol was added dropwise at room temperature therein, and the mixture was stirred for 10 minutes. Into the mixture was added dropwise 0.5 ml of tetrahydrofuran solution of 0.31 g of 1-(6-chloro-5-fluoropyrimidin-4-yl)-trans-2,6-dimethyl-hexahydro-1H-azepine at room temperature, and stirred for 6 hours at 6° C. After the reaction mixture was cooled to near room temperature, the reaction mixture was poured into a saturated ammonium chloride aqueous solution, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.34 g of 1-(6-(2-butynyloxy)-5-fluoropyrimidin-4-yl)-trans-2,6-dimethyl-hexahydro-1H-azepine (hereinafter, referred to as Compound (42)).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[CH:8][O-].[Na+].[C:11]([CH2:13][C:14]([NH2:16])=[O:15])#[N:12].N1CCCCC1>O>[OH:1][C:2]12[NH:16][C:14](=[O:15])[CH:13]([C:11]#[N:12])[CH:8]=[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7]2
Reactant: N#CCC(N)=O
Reactant: O=C1CCCCC1=C[O-]
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: O
Product: N#CC1C=C2CCCCC2(O)NC1=O
Temperature: 40 °C
Reaction time: 96 h
Yield: 217.7 %

Procedure:
Sodium 2-oxocyclohexylidenemethanolate (15 g), 2-cyanoacetamide (4.3 g) and piperidine (1.0 ml) were suspended in water (35 ml), and the mixture was stirred at 40° C. for 4 days. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was suspended in methanol, and insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give the object compound (21.4 g).
Reaction SMILES: O1CCOCC1.Cl.[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)=[CH:14][N:13]=[C:12]([C:29]2[CH:30]=[C:31]([CH:41]=[CH:42][CH:43]=2)[CH2:32][NH:33]C(=O)OC(C)(C)C)[C:11]=1[F:44])#[N:9]>ClCCl>[NH2:33][CH2:32][C:31]1[CH:30]=[C:29]([C:12]2[C:11]([F:44])=[C:10]([C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)=[CH:14][N:13]=2)[C:8]#[N:9])[CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(-c2ncc(-c3ccc(Oc4ccccc4)cc3)c(C#N)c2F)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)cnc(-c2cccc(CN)c2)c1F
Reaction time: 3 h

Procedure:
A 1 M dioxane solution of HCl (3 mL, 3.00 mmol) was added to a solution of tert-butyl 3-(4-cyano-3-fluoro-5-(4-phenoxyphenyl)pyridin-2-yl)benzylcarbamate (54.6 mg, 0.110 mmol) in dichloromethane (3 mL). After 3 h at room temperature, the mixture was concentrated and pumped under vacuum to give 2-(3-(aminomethyl)phenyl)-3-fluoro-5-(4-phenoxyphenyl)isonicotinonitrile as brown solid, assumed as bis-HCl salt (48 mg, 93% yield). 1H NMR (500 MHz, methanol-d4) δ ppm 8.80 (1H, s), 8.16 (1H, s), 8.08 (1H, br. s), 7.72 (2H, δ, J=8.25 Hz), 7.65 (2H, δ, J=3.85 Hz), 7.42 (2H, t, J=7.70 Hz), 7.20 (1H, t, J=7.29 Hz), 7.16 (2H, δ, J=7.97 Hz), 7.10 (2H, δ, J=7.97 Hz), 4.25 (2H, s); MS (ES+) m/z: 396 (M+H); LC retention time: 3.768 min (analytical HPLC Method A).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:9]=[C:10]1[CH2:19][C:12]2([CH2:15][CH:14]([C:16]([OH:18])=[O:17])[CH2:13]2)[CH2:11]1.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl.C(#N)C>[O:9]=[C:10]1[CH2:11][C:12]2([CH2:15][CH:14]([C:16]([O:18][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[O:17])[CH2:13]2)[CH2:19]1
Reactant: BrCc1ccccc1
Reactant: O=C1CC2(C1)CC(C(=O)O)C2
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1CC2(C1)CC(C(=O)OCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (bromomethyl)benzene (564 mg) in CHCl3 (1 mL) was added to a stirred solution of 6-oxospiro[3.3]heptane-2-carboxylic acid (462 mg) and DIPEA (0.576 mL) in acetonitrile (2 mL) and CHCl3 (2 mL) and the mixture was stirred at rt overnight. The reaction mixture was evaporated to dryness and then purified by silica gel FCC (1:1 DCM:hexanes) to afford benzyl 6-oxospiro[3.3]heptane-2-carboxylate as a clear oil.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([O:20][CH3:21])[CH:11]=1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>C(Cl)Cl.C(OCC)(=O)C.CCCCCC>[Si:22]([O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([O:20][CH3:21])[CH:11]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1ccc(CO)cc1OC
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1OC
Reaction time: 2 h

Procedure:
15.5 ml (0.110 mol) of triethylamine and 616 mg '5.04 mmol) of 4-N,N-dimethylaminopyridine were added to a solution of 19.8 g (0.101 mol) of methyl 4-hydroxymethyl-2-methoxybenzoate [prepared as described in step (i) above] and 16.91 g (0.112 mol) of t-butyldimethylsilyl chloride in 150 ml of methylene chloride, and the resulting mixture was stirred for 2 hours. At the end of this time, the reaction mixture was diluted with a mixture of ethyl acetate and hexane, and the diluted mixture was washed with ice-cooled 1 N aqueous hydrochloric acid, with water, with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, giving 32.20 g (a quantitative yield) of the title compound as an oily substance.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[C:8]([Cl:19])[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH:20]1[CH2:23][CH:22]([N:24]2[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]2)[CH2:21]1>>[Cl:19][C:8]1[N:9]=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:11]2[N:12]=[C:3]([CH2:2][N:20]3[CH2:23][CH:22]([N:24]4[CH2:29][CH2:28][C:27]([F:30])([F:31])[CH2:26][CH2:25]4)[CH2:21]3)[CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: FC1(F)CCN(C2CNC2)CC1
Reactant: Clc1nc(N2CCOCC2)c2nc(CBr)ccc2n1
Product: FC1(F)CCN(C2CN(Cc3ccc4nc(Cl)nc(N5CCOCC5)c4n3)C2)CC1

Procedure:
4-(6-(Bromomethyl)-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine 7 (0.1 g) was reacted with 1-(azetidin-3-yl)-4,4-difluoropiperidine via General Procedure B to give 80 mg 4-(2-chloro-6-((3-(4,4-difluoropiperidin-1-yl)azetidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)morpholine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[CH2:13]([O:15][C:16]([C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:19][C@H:20]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21](Cl)=[O:22])=[O:17])[CH3:14]>O>[CH2:13]([O:15][C:16]([C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:19][C@H:20]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:21]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:22])=[O:17])[CH3:14]
Reactant: NCCC(=O)O
Reactant: CCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)NCCC(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The solution of 1.5 g of 3-aminopropionic acid and 1.8 g of sodium carbonate in 30 ml of water at 0° is added to 2.2 g of 4-ethoxycarbonyl-(R*,R*)-2,4-dibenzylbutyryl chloride and the mixture is stirred at room temperature for 4 hours. The mixture is extracted with ether, and the aqueous layer is acidified with 2N hydrochloric acid. The acidic solution is extracted with ethyl acetate, washed with saturated brine, dried (magnesium sulfate), filtered and concentrated. The residue is recrystallized from ether to yield N-[4-ethoxycarbonyl-(R*,R*)-2,4-dibenzylbutyryl]-3-aminopropionic acid, melting at 84°-86°; NMR (CDCl3) δ10.5 (1H, CO2H), 6.1 (t, 1H, J=6 Hz, NH), 4.1 (q, 2H, J=8 Hz, OCH2), 1.08 (t, 3H, J=8 Hz, CH3).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH3:14])[C@H:9]1[CH2:15][CH3:16])C1C=CC=CC=1.[ClH:17]>CO.[OH-].[OH-].[Pd+2]>[ClH:17].[CH2:15]([C@@H:9]1[C@@H:10]([CH3:14])[O:11][CH2:12][CH2:13][NH:8]1)[CH3:16]
Reactant: CC[C@@H]1[C@@H](C)OCCN1Cc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CC[C@H]1NCCO[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Pd(OH)2 (15.0 mg, 10% on carbon) was added to a solution of (2R,3R)-4-benzyl-3-ethyl-2-methylmorpholine (110 mg, 0.50 mmol) in MeOH (10 mL) under N2. Hydrogen was bubbled through the reaction mixture for one minute and then the reaction was stirred at rt under hydrogen (1 atm) for 2 hours. Then, N2 was bubbled through the reaction for 1 minute. A solution of HCl (3M, 3 mL, 9 mmol) in methanol was added. The reaction mixture was stirred at room temperature for 30 minutes and concentrated in vacuo to afford (2R,3R)-3-ethyl-2-methylmorpholine hydrochloride. 1H NMR (300 MHz, DMSO-d6) δ 9.45-9.34 (br s, 1H), 3.84-3.91 (m, 1H), 3.68-3.78 (m, 1H), 3.53-3.61 (m, 1H), 3.08-3.21 (m, 1H), 2.93-3.01 (m, 1H), 2.70-2.85 (m, 1H), 1.45-1.81 (m, 2H), 1.13 (d, J=6.3 Hz, 3H), 0.90-1.05 (m, 3H). MS APCI calc'd for C7H15NO [M+H]+ 130. found 130.
Reaction SMILES: [S:1](Cl)([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH3:18][O:19][CH:20]([O:23][CH3:24])[CH2:21][NH2:22].CCN(CC)CC>C(Cl)Cl>[CH3:18][O:19][CH:20]([O:23][CH3:24])[CH2:21][NH:22][S:1]([C:4]1[C:16]2[C:8](=[C:9]([N:10]([CH3:12])[CH3:11])[CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: COC(CN)OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(CNS(=O)(=O)c1cccc2c(N(C)C)cccc12)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of dansyl chloride (270 mg, 1.00 mmol) in CH2Cl2 (10 mL) was added aminoacetaldehyde dimethyl acetal (130 μL, 1.2 mmol) and Et3N (170 μL, 1.2 mmol); the solution was allowed to stir for 1 h at 25° C. The reaction mixture was then evaporated to dryness under reduced pressure and the material left was purified by silica gel chromatography using a gradient of MeOH (0→1%) in CH2Cl2 as the eluent. Fractions containing the product were collected and evaporated to dryness under low pressure affording 11 (318 mg, 940 μmol) as a solid in a yield of 94%. 1H NMR (300 MHz, DMSO-d6): δ 8.45 (dt, J=8.5, 1.1 Hz, 1H), 8.29 (dt, J=8.8, 0.9 Hz, 1H), 8.16 (t, J=5.5 Hz, 1H), 8.10 (dd, J=7.3, 1.1 Hz, 1H), 7.61 (t, J=8.5 Hz, 1H), 7.58 (t, J=8.5 Hz, 1H), 7.25 (dd, J=7.6, 0.7 Hz, 1H), 4.11 (t, J=5.5 Hz, 1H), 3.06 (s, 6H), 2.89 (t, J=5.5 Hz, 2H), 2.81 (s, 6H). 13C NMR (75 MHz, DMSO-d6): δ 151.2, 136.2, 129.3, 128.9, 127.9, 127.7, 123.5, 119.1, 115.0, 102.4, 53.3, 44.9, 43.9. +ESI-HRMS: Calcd for C16H22N2O4S [M+H]+ 339.1373. found 339.1374.
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[F:12][C:13]([F:36])([F:35])[C:14]([NH:16][C:17]1[N:21]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[C:24]([Cl:33])[C:23]=2[Cl:34])[N:20]=[CH:19][CH:18]=1)=[O:15]>C(O)(=O)C>[N+:8]([C:18]1[CH:19]=[N:20][N:21]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[C:24]([Cl:33])[C:23]=2[Cl:34])[C:17]=1[NH:16][C:14](=[O:15])[C:13]([F:36])([F:35])[F:12])([O-:11])=[O:9]
Reactant: O=C(Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)c(Cl)c1Cl)C(F)(F)F
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(Nc1c([N+](=O)[O-])cnn1-c1c(Cl)cc(C(F)(F)F)c(Cl)c1Cl)C(F)(F)F
Reaction time: 20 h
Yield: 77.6 %

Procedure:
2.4 ml (0.0258 mol) of acetic anhydride and 1.1 ml (0.025 mol) of 98% strength nitric acid are added in succession to 10 g (0.0235 mol) of 5-trifluoroacetamido-1-(2,3,6-trichloro-4-trifluoromethyl-phenyl)-pyrazole in 20 ml of glacial acetic acid at room temperature. After the mixture has been stirred for 20 hours, it is concentrated in vacuo, the residue is taken up in 100 ml of methylene chloride and the mixture is extracted with 400 ml of 5% strength aqueous sodium carbonate solution. The aqueous phase is acidified and extracted with 200 ml of methylene chloride. The combined organic phases are dried over sodium sulphate and freed from the solvent in vacuo. 8.6 g (77.6% of theory) of 4-nitro-5-trifluoroacetamido-1-(2,3,6-trichloro-4-trifluoromethyl-phenyl)-pyrazole of melting point 136°-137° C. are obtained.
Reaction SMILES: C([C@@H:4]1[C:13](=[O:14])[C:12]2[CH:11]=[CH:10][N:9]3[C:15]([CH3:19])=[C:16]([CH3:18])[N:17]=[C:8]3[C:7]=2[N:6]([C:20](=[O:22])[CH3:21])[C@H:5]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=O)C.[BH4-].[Na+].C(=O)([O-])[O-:32].[K+].[K+]>CO>[C:20]([N:6]1[C:7]2[C:8]3=[N:17][C:16]([CH3:18])=[C:15]([CH3:19])[N:9]3[CH:10]=[CH:11][C:12]=2[C@@H:13]([OH:14])[C@H:4]([OH:32])[C@H:5]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)[C@@H]1C(=O)c2ccn3c(C)c(C)nc3c2N(C(C)=O)[C@H]1c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: CC(=O)N1c2c(ccn3c(C)c(C)nc23)[C@@H](O)[C@H](O)[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
64 g of (8R,9R)-8,10-diacetyl-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridin-7-one (crude product) are dissolved in 250 ml of methanol. 12.3 g of sodium borohydride are introduced with ice cooling. After stirring for 1 h, 23 g of potassium carbonate are added to the reaction mixture and it is stirred for a further 2 h at room temperature. It is then added to ice water and the precipitate is filtered off with suction. After washing the precipitate with acetone and ether, 37 g of the title compound are isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.[Cl-].[Cl:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:20]=1[CH:21]=[N+:22]([CH3:24])[CH3:23].ClC1C=CC=C(F)C=1C=O.CNC>>[Cl:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:20]=1[CH:21]([N:22]([CH3:24])[CH3:23])[C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: C[N+](C)=Cc1c(F)cccc1Cl
Reactant: Clc1ccc(-c2cc3ccccc3[nH]2)cc1
Agent: CNC
Agent: O=Cc1c(F)cccc1Cl
Agent: [Cl-]
Product: CN(C)C(c1c(F)cccc1Cl)c1c(-c2ccc(Cl)cc2)[nH]c2ccccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-(4-chlorophenyl)-indole and (2-chloro-6-fluoro-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 24 from 2-chloro-6-fluoro-benzaldehyde and dimethylamine.