Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]2[NH:15][C:16](C3C=CC(B4OC(C)(C)C(C)(C)O4)=CC=3)=[CH:17][N:18]=2)[CH2:3]1.Br[C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[CH:41]=[C:40]([C:45]1[NH:49][C:48]([C@@H:50]3[CH2:54][CH2:53][CH2:52][N:51]3[C:55](=[O:65])[C@@H:56]([NH:60][C:61](=[O:64])[O:62][CH3:63])[CH:57]([CH3:59])[CH3:58])=[N:47][CH:46]=1)[CH:39]=[CH:38]2.C([O-])([O-])=O.[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:8])[C@H:4]([C:14]2[NH:15][C:16]([C:35]3[CH:36]=[CH:37][C:42]([C:35]4[CH:44]=[CH:43][C:42]5[C:37](=[CH:38][CH:39]=[C:40]([C:45]6[NH:49][C:48]([C@@H:50]7[CH2:54][CH2:53][CH2:52][N:51]7[C:55](=[O:65])[C@@H:56]([NH:60][C:61]([O:62][CH3:63])=[O:64])[CH:57]([CH3:59])[CH3:58])=[N:47][CH:46]=6)[CH:41]=5)[CH:36]=4)=[CH:43][CH:44]=3)=[CH:17][N:18]=2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6C[C@H](O)CN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Temperature: 85 °C
Yield: 21.9 %

Procedure:
(2S,4S)-tert-butyl 4-hydroxy-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (200 mg, 0.44 mmol) and methyl (S)-1-((S)-2-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (219 mg, 0.44 mmol) were combined in DME (5 mL). Pd(PPh3)4 (51 mg, 0.0446 mmol) and K2CO3 (2M H2O, 0.73 mL, 1.45 mmol) were added, and the solution was degassed with N2 for 10 min. The solution was heated to 85° C. and stirred o/n. The following morning, the solution was cooled to rt. The solution was diluted with EtOAc, washed with sat. NaHCO3, brine, dried over MgSO4, and concentrated. The residue was purified by silica gel chromatography to yield product (36 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH3:9].[Li]CCCC.CN([CH:18]=[O:19])C>O1CCCC1>[Br:8][C:4]1[C:3]([CH3:9])=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:18]=[O:19]
Reactant: CN(C)C=O
Reactant: Cc1c(Br)cccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(Br)cccc1C=O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 100.5 %

Procedure:
To a solution of 1,3-dibromo-2-methylbenzene (3 g, 12.00 mmol) in Tetrahydrofuran (THF) (100 mL) stirred under nitrogen at −78° C. was added BuLi (9.00 mL, 14.40 mmol) dropwise. The reaction mixture was stirred at −78° C. for 20 min. DMF (1.115 mL, 14.40 mmol) was added dropwise. The reaction mixture was continuously stirred for 2 hours. The reaction was quenched with sat. aq. ammonia chloride solution. The aqueous layers were separated and extracted by EA for 3 times. The combined organic layers were washed by brine, dried over anhydrous sodium sulfate. The dried solution was concentrated in vacuo to afford 3-bromo-2-methylbenzaldehyde (D93) (2.4 g), which was used for the next step without further purification. MS (ES): C8H7BrO requires 197.9. found 199 (M+H+)
Reaction SMILES: [CH:1]([C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10]2[C:11]3[CH2:27][CH2:26][CH2:25][C:12]=3[N:13]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[C:21]([O:23]C)=O)[N:15]=2)[CH:5]=1)([CH3:3])[CH3:2].[NH3:28]>C1COCC1.O>[CH:1]([C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10]2[C:11]3[CH2:27][CH2:26][CH2:25][C:12]=3[N:13]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[C:21]([NH2:28])=[O:23])[N:15]=2)[CH:5]=1)([CH3:2])[CH3:3]
Reactant: N
Reactant: COC(=O)[C@H]1CCCN1c1nc2c(c(Nc3cc(C(C)C)[nH]n3)n1)CCC2
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1cc(Nc2nc(N3CCC[C@@H]3C(N)=O)nc3c2CCC3)n[nH]1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a solution of (R)-methyl 1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylate (500 mg, 1.351 mmol) in THF (10 mL) was added 28% aqueous ammonia (20 mL) and reaction mixture was allowed to stir at 60° C. for 24 h. The progress of reaction was monitored by LCMS. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2×100 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under vacuum to obtain a crude product which was purified by reverse phase HPLC to afford (R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (80 mg). 1H NMR (400 MHz, DMSO-d6, freebase) δ (ppm): 1.22 (d, 6H), 1.81-2.01 (m, 6H), 2.02-2.18 (m, 1H), 2.59-2.70 (m, 4H), 2.86-2.92 (m, 1H), 3.48 (brs, 1H), 3.67 (brs, 1H), 4.35 (d, 1H), 6.43 (brs, 1H), 6.85 (s, 1H), 7.18 (s, 1H), 8.78 (brs, 1H). The other enantiomer was prepared using the (R) chiral starting material.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)(=O)=O.[C-:18]#[N:19].[Na+]>CS(C)=O>[C:8]12([CH2:7][CH2:6][C:18]#[N:19])[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2
Reactant: CS(=O)(=O)OCCC12CC3CC(CC(C3)C1)C2
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCCC12CC3CC(CC(C3)C1)C2
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of Intermediate 44 (4.1 g, 16.01 mmol) in dimethyl sulfoxide (18 mL) was slowly added sodium cyanide (0.98 g, 20 mmol). The reaction mixture was stirred at 100° C. for 1.5 hours and at room temperature overnight. The crude was partitioned between ether and water and the organic layer was washed with water. The solvent was removed under reduced pressure and the title compound was obtained as a colourless solid (2.9 g, 98%) and used in the next step without further purification.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15]Cl.[OH:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[C:20]([CH3:25])[CH:19]=1>C(O)CCC>[OH:17][C:18]1[CH:24]=[CH:23][C:21]([N:22]2[C:3]3[C:12]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[N:6]=[C:5]([CH3:13])[C:4]=3[CH2:14][CH2:15]2)=[C:20]([CH3:25])[CH:19]=1
Reactant: Cc1cc(O)ccc1N
Reactant: Cc1nc2ccccc2c(Cl)c1CCCl
Agent: Cl
Solvent: CCCCO
Product: Cc1cc(O)ccc1N1CCc2c(C)nc3ccccc3c21
Yield: 12 %

Procedure:
A solution of 4-chloro-3-chloroethyl-2-methylquinoline hydrochloride (1.28 g, 4,6 mmol) and 4-hydroxy-2-methylaniline (1.13 g. 9.2 mmol) in n-butanol(20 ml) was heated at reflux under a nitrogen atmosphere for 20 hours, thenevaporated. Chromatography (silica gel, 5-7% methanolic ammonia in dichloromethane) and recrystallisation from aqueous methanol gave 1-(4-hydroxy2-methylphenyl)-4-methyl-2,3-dihydropyrrolo[3,2-c]quinoline (0.16 g), m.p. 315°-318°.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[CH2:7][C:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])([CH3:10])[O:9][C:4]=2[C:3]=1[CH2:19][CH2:20][CH3:21].[CH3:22]OC(OC)OC.S(=O)(=O)(O)O>>[OH:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[CH2:7][C:8]([CH2:11][CH2:12][C:13]([O:15][CH3:22])=[O:14])([CH3:10])[O:9][C:4]=2[C:3]=1[CH2:19][CH2:20][CH3:21]
Reactant: COC(OC)OC
Reactant: CCCc1c(O)ccc2c1OC(C)(CCC(=O)O)CC2=O
Agent: O=S(=O)(O)O
Product: CCCc1c(O)ccc2c1OC(C)(CCC(=O)OC)CC2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the title compound of Example 3 (4.3 g, 14.7 mmole), 6 ml of trimethylorthoformate, and 1.4 ml of sulfuric acid was stirred at room temperature for two hours. The reaction mixture was poured onto stirred ice/water and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate, and concentrated to an oil. The oil was purified by chromatography on silica gel, giving 3.7 g of the title compound as a crystalline solid, m.p. 101.5°-102.5°. Structure assignment was consistent with nmr and infrared spectra. ##STR7##
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1Cl)([O-:3])=[O:2].[CH3:15][NH2:16]>C(O)C>[N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[NH:16][CH3:15])([O-:3])=[O:2]
Reactant: CN
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Solvent: CCO
Product: CNc1c([N+](=O)[O-])cc(C)cc1[N+](=O)[O-]

Procedure:
0.05 mol (18 g) of 2,6-dinitro-4-methylchlorobenzene is added gradually, whilst stirring, to 40 ml of a 33% strength solution of methylamine in ethanol. The temperature rises to 50° C. and the expected derivative precipitates immediately. When the addition has ended, the stirring is maintained for 5 minutes and the 2,6-dinitro-4-methyl-N-methylaniline is then filtered off and washed with water; after recrystallisation from alcohol and drying in vacuo, it melts at 132° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=O)[CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:14])=O>>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([Cl:14])=[O:10])[CH2:3][CH2:2]1
Reactant: O=C(O)CC1CCOCC1
Reactant: O=C(Cl)C(=O)Cl
Product: O=C(Cl)CC1CCOCC1

Procedure:
Commercially available (tetrahydro-pyran-4-yl)-acetic acid and oxalyl chloride were processed as described for example 9A to afford the title compound. MS (DCI/NH3) m/z 159 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([CH2:13][C:14]([F:17])([F:16])[F:15])[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21].S(Cl)(Cl)=O.[CH3:26]O.O>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([CH2:13][C:14]([F:17])([F:16])[F:15])[CH:7]=[C:6]([C:18]([O:20][CH3:26])=[O:19])[C:5]2=[O:21]
Reactant: Cc1cc(F)cc2c(=O)c(C(=O)O)cn(CC(F)(F)F)c12
Reactant: CO
Solvent: O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cn(CC(F)(F)F)c2c(C)cc(F)cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2.3 g of 6-fluoro-1,4-dihydro-8-methyl-4-oxo-1-(2,2,2-trifluoroethyl)-3-quinolinecarboxylic acid in 25 ml of pyridine, at 0°, was added 1.1 ml of thionyl chloride. The resulting slurry was stirred at room temperature for 0.5 hour and subsequently treated with 5 ml of methanol. After 1 hour, the reaction mixture was poured into 200 ml of water; the resulting white solid was filtered, washed with water, and dried to give 2.0 g of 6-fluoro-1,4-dihydro-8-methyl-4-oxo-1-(2,2,2-trifluoroethyl)-3-quinolinecarboxylic acid, methyl ester, m.p. 168°-171°.
Reaction SMILES: [Mg].BrBr.[CH2:4](Br)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Br[CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[Cl-].[NH4+]>O1CCCC1>[CH3:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCC/C=C\CCBr
Reactant: CCCCCCCBr
Agent: BrBr
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCC/C=C\CCCCCCCCCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.1 %

Procedure:
A 1-liter reactor was charged with 5.0 g (0.206 mole) of magnesium and 150 g of tetrahydrofuran, and the reaction was initiated by adding a piece of bromine and 35.6 g (0.2 mole) of n-heptyl bromide dropwise thereto under an atmosphere of nitrogen. After completion of the addition, the mixture was stirred for 2 hours under reflux of tetrahydrofuran and the resulting liquid was transferred to a 300-ml dropping funnel. Next, 30 g of tetrahydrofuran, 0.4 g of cuprous chloride and 49.5 g (0.18 mole) of 1-bromo-cis-3-tetradecene were placed in another 1-liter reactor and cooled to 0° C. Then, the above-described Grignard reagent was added dropwise thereto so that the temperature did not exceed 10° C. After completion of the reaction, 100 g of a saturated aqueous ammonium chloride solution was added and the resulting mixture was allowed to separate into two layers. The organic layer was recovered, freed of tetrahydrofuran under reduced pressure, and distilled to obtain 22.3 g of cis-10-henicosene (purity 95.1%, yield 75%, b.p. 171°-175° C./2 mmHg). MS(m/e): 56(100%), 294 (M+, 10%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][OH:3].C(N(CC)CC)C.[CH3:15][C:16]([Si:19](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:18])[CH3:17]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:19]([O:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])([C:16]([CH3:18])([CH3:17])[CH3:15])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 500ml round-bottom flask equipped with a magnetic stir-bar, N2inlet was added ethyl glycolate (10g, 96.0mmoles, 1eq) and dry CH2Cl2(200ml, 0.5M). This was followed by the addition of triethylamine (40ml, 0.288moles, 3eq) and DMAP (1.17g, 9.6mmoles, 10mol %) followed by the dropwise addition of TBDPSCl (27.5ml, 0.106moles, 1.1eq) in dry CH2Cl2(20ml). The reaction mixture was allowed to stir at room temperature overnight at which time the reaction mixture was diluted with CH2Cl2and washed with 1N HCl, saturated sodium bicarbonate, H2O and dried over Na2SO4. After filtration the volatiles were removed in vacuo to yield 30g (91%) of titled compound.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[C:5]([NH2:18])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:19][C:20]1[C:25]([C:26](O)=[O:27])=[C:24]([F:29])[C:23]([CH2:30][NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:22][CH:21]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:19][C:20]1[C:25]([C:26]([NH:18][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[N:3]=[C:2]([CH3:1])[N:11]=[C:10]3[N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:27])=[C:24]([F:29])[C:23]([CH2:30][NH:31][C:32](=[O:37])[C:33]([CH3:35])([CH3:34])[CH3:36])=[CH:22][CH:21]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: Cc1nc(N2CCOCC2)c2cccc(N)c2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(N2CCOCC2)c2cccc(NC(=O)c3c(Cl)ccc(CNC(=O)C(C)(C)C)c3F)c2n1
Yield: 25.1 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 2-methyl-4-morpholinoquinazolin-8-amine (Intermediate-51, 100 mg, 0.41 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 176 mg, 0.61 mmol), oxalyl chloride (115 mg, 0.92 mmol), DMF (1 drop) and DIPEA (159 mg, 1.23 mmol) in CH2Cl2 (5 mL) to afford 53 mg of the title product. 1H NMR (400 MHz, DMSO-d6): δ 10.36 (s, 1H), 8.69 (d, J=7.6 Hz, 1H), 8.14-8.11 (t, J=5.7 Hz, 1H), 7.76-7.74 (d, J=8.4 Hz, 1H), 7.50-7.46 (t, J=8.1 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.37-7.33 (t, J=8.0 Hz, 1H), 4.30 (d, J=5.7 Hz, 2H), 3.77 (d, J=4.7 Hz, 2H), 3.73 (d, J=4.6 Hz, 2H), 3.30 (s, 3H), 1.13 (s, 9H); MS (m/z): 514.29 (M+H)+.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[C:13]([NH:32][C@@H:33]([C:39]([O:41][CH3:42])=[O:40])[CH2:34][C:35](OC)=[O:36])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[C:13]([NH:32][C@@H:33]([C:39]([O:41][CH3:42])=[O:40])[CH2:34][C:35](=[O:36])[CH2:1][P:2]([O:5][CH3:6])([O:3][CH3:4])=[O:7])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COP(C)(=O)OC
Reactant: COC(=O)C[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)[C@@H](CC(=O)CP(=O)(OC)OC)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
Dissolve dimethyl methylphosphonate (83mL, 0.766 mol) in anhydrous tetrahydrofuran (800 mL), cool to -78° C. and place under an inert atmosphere. Add, by dropwise addition over 15 minutes, n-butyllithium (306 mL of a 2.5M solution, 0,766 mol). Stir the resulting clear solution for a further 0.5 hour. While maintaining the solution at -78° C, add by dropwise addition over 15 minutes, to another solution of (R)-dimethyl N-tritylaspartate (71 g, 0.182 mol) in anhydrous tetrahydrofuran (200 mL) also at -78° C. Stir for a further 0.5 hours, quench with acetic acid (45 mL) and warm to room temperature. Add ethyl acetate (500 mL) and saturated sodium bicarbonate (250 mL). Separate the organic phase, filter through silica gel and evaporate the solvent to give a solid residue. Crystallize (t-butylmethyl ether/hexane) to give the title compound as a white solid (61.0 g, 69%). 1H NMR (CDCl3) δ7.5-7.25 (m, 15 H), 3.82 (s, 3H), 3.79 (s, 3H), 3.75 (t, 3H), 3.08 (d, 2H), 2.88 (m, 2H), 1.65 (bs, 1H).
Reaction SMILES: [NH2:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12].[F:18][C:19]([F:26])([F:25])[C:20](SCC)=[O:21]>CO>[F:18][C:19]([F:26])([F:25])[C:20]([NH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12])=[O:21]
Reactant: N[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O
Reactant: CCSC(=O)C(F)(F)F
Solvent: CO
Product: O=C(N[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a suspension of 2′-amino,2′-deoxyuridine (2.0 g, 8.22 mmoles) in methanol (150 ml) was added S-ethyl trifluorothioacetate (1.6 ml, 12.48 mmoles, 1.5 eq.). This mixture was stirred at room temperature overnight. Nitrogen was bubbled through the reaction mixture for 2 h to remove volatile thio-byproducts. The mixture was evaporated to dryness and the solid was recrystallized from methanol/chloroform to yield 2.3 g (82%) of 2′-trifluoroacetylamino,2′-deoxyuridine. The analytical data agreed with the literature (Imazawa and Eckstein (1979) supra).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:15]CC2C=CC=CC=2)=[C:8]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=1)(=[O:3])[CH3:2].C([O-])=O.[NH4+]>CO>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:15])=[C:8]([NH:10][S:11]([CH3:14])(=[O:12])=[O:13])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(=O)c1ccc(O)c(NS(C)(=O)=O)c1

Procedure:
In an atmosphere of nitrogen 10% Pd—C (1.17 g) was added to a mixture of compound of example 39c (11.7 g; 36.67 mmol) and ammonium formate (11.56 g; 116.23 mmol) in methanol (110 mL) It was refluxed for 3 h. The catalyst was filtered and the filtrate concentrated and purified using flash chromatography (silica gel, 10% CH3CN in chloroform). Yield, 8.3 g (84.2%); mp, 202° C.: MS (ESI−): 228 (M−1); analysis: C9H11NO4S requires C, 47.15; H, 4.84; N, 6.11; S, 13.98; found: C, 47.39; H, 4.72; N, 6.53; S, 13.53%.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[N:3]=1.ClC1C=C(O)C=CC=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[OH:40]>>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[O:40][C:2]1[C:7]([C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[N:3]=1
Reactant: O=C(c1ccc(C(F)(F)F)nc1Cl)N1CCCc2ccccc21
Reactant: Oc1cc(Cl)ccc1Cl
Agent: Oc1cccc(Cl)c1
Product: O=C(c1ccc(C(F)(F)F)nc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21

Procedure:
The title compound was prepared in analogy to Example 25, Step 2, replacing (2-chloro-5-fluoro-pyridin-3-yl)-(3,4-dihydro-2H-quinolin-1-yl)-methanone with (2-chloro-6-trifluoromethyl-pyridin-3-yl)-(3,4-dihydro-2H-quinolin-1-yl)-methanone and 3-chloro-phenol with 2,5-dichloro-phenol ([CAS RN 583-78-8]). MS (ISP): 467.1 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[N+:14]([O-])([OH:16])=[O:15].C(=O)(O)[O-].[Na+]>OS(O)(=O)=O.O=S(=O)=O>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:3])=[O:4]
Reactant: O=[N+]([O-])O
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: CS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of 3-methylsulfonylbenzoic acid (16.3 g) in 20% oleum (100 ml) was cooled (ice-bath) and fuming nitric acid (>90%; 90 ml) was added dropwise. The resulting mixture was stirred for 4 days at room temperature and was then poured onto crushed ice. The acids were partially neutralised by addition of solid sodium bicarbonate (to ˜pH2). The solid precipitate was filtered off and dried to give, as a pale beige solid D11 (15.6 g).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17](Cl)=[O:18].[Br:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH2:30][CH2:29]1)[NH2:24]>>[Br:20][C:21]1[CH:22]=[C:23]([NH:24][C:17]([C:3]2[CH:4]=[N:5][N:6]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)[C:2]=2[CH3:1])=[O:18])[CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:35][CH2:36][O:37][CH2:38][CH2:39]2)[CH2:30][CH2:29]1
Reactant: Nc1ccc(N2CCC(N3CCOCC3)CC2)c(Br)c1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(C(F)(F)F)cc1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(Br)c2)cnn1-c1ccc(C(F)(F)F)cc1
Yield: 60.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxylic chloride (1.7 g) and 3-bromo-4-(4-morpholinopiperidin-1-yl)aniline (2.0 g), the title compound (2.1 g) was obtained, melting point: 220–230° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][CH2:31][C@@H:3]12.[CH2:32]([N:34](C(C)C)C(C)C)[CH3:33].Cl.C(N)C>CN(C=O)C>[CH2:32]([NH:34][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][CH2:31][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:18][CH2:17]2)=[N:20][CH:21]=1)[CH3:33]
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)nc1
Reactant: CCN(C(C)C)C(C)C
Agent: CCN
Agent: Cl
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.2 %

Procedure:
(S)-6-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinic acid (75 mg, 0.178 mmol) was taken up in DMF (0.9 mL). To the mixture was added N-ethyl-N-isopropylpropan-2-amine (93 μl, 0.53 mmol), O-(7-Azabenzotriazole-1-yl)-N, N,N′N′-tetramethyluronium hexafluorophosphate (101 mg, 0.266 mmol), and ethanamine hydrochloride (15.9 mg, 0.195 mmol). The reaction was stirred at room temperature overnight. The reaction was purified via HPLC (10-80 MeCN/H2O, TFA buffered). The fractions were collected and lyophilized to yield 27.4 mg (34%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.84 (s, 1H), 10.03 (br. s., 1H), 8.64 (s, 1H), 8.35 (t, J=5.2 Hz, 1H), 8.04 (d, J=9.1 Hz, 1H), 7.83 (s, 1H), 6.90-7.11 (m, 2H), 4.40-4.71 (m, 3H), 4.26 (s, 2H), 3.98 (d, J=11.1 Hz, 1H), 2.96-3.57 (m, 8H), 2.61-2.74 (m, 1H), 2.08 (d, J=11.9 Hz, 1H), 1.87 (d, J=12.4 Hz, 1H), 1.33-1.73 (m, 4H), 1.11 (t, 3H). [M+H] calc'd for C24H31N7O2, 450. found, 450.