Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@@H:12]([CH3:22])[O:11][C@H:10]1[N:23]1[CH:30]=[C:29]([I:31])[C:27]([NH2:28])=[N:26][C:24]1=[O:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)Cl.Cl[C:36]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:37]>>[Si:1]([O:8][C@@H:9]1[C@H:13]([O:14][Si:15]([C:18]([CH3:20])([CH3:21])[CH3:19])([CH3:17])[CH3:16])[C@@H:12]([CH3:22])[O:11][C@H:10]1[N:23]1[CH:30]=[C:29]([I:31])[C:27]([NH:28][C:36]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:37])=[N:26][C:24]1=[O:25])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCCCCOC(=O)Cl
Reactant: C[C@H]1O[C@@H](n2cc(I)c(N)nc2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Product: CCCCCOC(=O)Nc1nc(=O)n([C@@H]2O[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]2O[Si](C)(C)C(C)(C)C)cc1I
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a stirred solution of 5′-deoxy-2′,3′-bis-O-(tert-butyldimethylsilyl)-5-iodocytidine (116 mg, 0.200 mmol) in CH2Cl2 (2 ml) pyridine (84 μl, 1.00 mmol), N,N-dimethylamino-pyridine (6 mg, 0.05 mmol), and n-pentyl chloroformate (95 μl, 0.600 mmol) was added at room temperature under Ar. After stirring for 30 minutes, the reaction mixture was partitioned with dichloromethane and water and the organic phase was separated and the water phase was extracted with CH2Cl2 (15 ml×4). The combined organic phase was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was evaporated under reduced pressure. The crude product was purified by flash chromatography on SiO2 (eluent: 20% EtOAc/n-hexane) to give 2′,3′-bis-O-(tert-butyldimethylsilyl)-5′-deoxy-5-iodo-N4-(n-pentyloxycarbonyl)cytidine as a colorless amorphous solid. (132.4 mg, 91% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].C(N(CC)CC)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1>O1CCCC1>[Cl:5][CH2:4][CH2:3][CH2:2][N:23]1[CH2:22][CH2:21][N:20]([C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=2)[CH2:25][CH2:24]1
Reactant: ClCCCBr
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Fc1ccc(N2CCN(CCCCl)CC2)cc1
Reaction time: 16 h

Procedure:
26.1 g (0.166 mole) of 1-bromo-3-chloropropane and 33.6 g (0.333 mole) of triethylamine are added to 30.0 g (0.166 mole) of 1-(4-fluorophenyl)-piperazine in 50 ml of tetrahydrofuran. The reaction mixture is stirred for 16 hours at from 60° to 65° C., cooled and filtered, the solvent is stripped off under reduced pressure, and the crude product is distilled under reduced pressure from an oil pump. The product distils at 135°-145° C./0.05 mm Hg in a yield of 30.0 g (70%).
Reaction SMILES: [CH3:1][O-:2].[Na+].CO.[Br:6][C:7]1[C:8](Cl)=[N:9][CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1>O>[Br:6][C:7]1[C:8]([O:2][CH3:1])=[N:9][CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ncc([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium methoxide (28% methanol solution) (2 ml) was added to a methanol (2 ml) solution containing 3-bromo-2-chloro-5-nitropyridine (100 mg), followed by stirring at room temperature for 1 hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, and a yellow solid of 3-bromo-2-methoxy-5-nitropyridine (96 mg) was thus obtained.
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=O)[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[CH2:12]([N:16]=[C:17]=[O:18])[CH2:13][CH2:14][CH3:15]>>[CH2:12]([N:16]1[C:7](=[O:9])[CH:2]([CH2:3][C:4]([OH:6])=[O:5])[NH:1][C:17]1=[O:18])[CH2:13][CH2:14][CH3:15]
Reactant: NC(CC(=O)O)C(=O)O
Reactant: CCCCN=C=O
Agent: [Na+]
Agent: [OH-]
Product: CCCCN1C(=O)NC(CC(=O)O)C1=O
Reaction time: 2 h

Procedure:
DL-Aspartic acid (6.65 g, 0.05 mole) in 2N-NaOH (50 ml, 2 equiv.) was cooled to 0° C. and n-butyl isocyanate (7.5 g, 0.075 mole) added during 15 minutes to the stirred solution. Stirring was continued for 2 hours and the mixture left at room temperature overnight. The mixture was then filtered, acidified with concentrated hydrochloric acid (50 ml) and heated on a steam-bath for 30 minutes. The mixture was cooled, diluted with water and continuously extracted with ether for 21/2 hours. Removal of the ether gave a solid which was recrystallised from ether to yield the product as prisms, m.p. 132° C. Yield 8.8 g=82%.
Reaction SMILES: S1C2C(=NC=CC=2OC2C=CC(N)=CC=2)C=C1.F[C:19]1[CH:20]=[C:21]([NH:45][C:46]([NH:48][C:49](=[O:57])[CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[S:47])[CH:22]=[CH:23][C:24]=1[O:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]2[CH:32]=[C:33](C3C=CC(S(C)(=O)=O)=CC=3)[S:34][C:27]=12>>[C:51]1([CH2:50][C:49]([NH:48][C:46](=[S:47])[NH:45][C:21]2[CH:20]=[CH:19][C:24]([O:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]4[CH:32]=[CH:33][S:34][C:27]=34)=[CH:23][CH:22]=2)=[O:57])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)cc1
Agent: Nc1ccc(Oc2ccnc3ccsc23)cc1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3ccsc23)cc1
Yield: 34 %

Procedure:
Staring from the amine 213, following the procedure described above for the synthesis of compound 50 (scheme 10, example 55), title compound 170c was obtained in 34% yield. 1H NMR (400 MHz,DMSO-d6) δ ppm 12.35 (1H, s), 11.69 (1H, s), 8.47 (1H, d, J=5.28 Hz), 8.10 (1H, d, J=5.28 Hz), 7.70 (1H, s), 7.68 (1H, s), 7.54 (1H, d, J=5.28 Hz), 7.30-7.22 (7H, m), 6.61 (1H, d, J=5.28 Hz), 3.78 (2H, s). MS (m/z) 420.0 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH2:19][CH2:20][O:21][CH3:22])=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[CH2:23]([O:25][C:26](=[O:38])[CH2:27][N:28]1[C:36]2[C:31](=[CH:32][C:33]([OH:37])=[CH:34][CH:35]=2)[CH:30]=[CH:29]1)[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH2:23]([O:25][C:26](=[O:38])[CH2:27][N:28]1[C:36]2[C:31](=[CH:32][C:33]([O:37][CH2:2][C:3]3[C:4]([CH2:19][CH2:20][O:21][CH3:22])=[N:5][C:6]([C:9]4[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=4)=[N:7][CH:8]=3)=[CH:34][CH:35]=2)[CH:30]=[CH:29]1)[CH3:24]
Reactant: CCOC(=O)Cn1ccc2cc(O)ccc21
Reactant: COCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc2cc(OCc3cnc(-c4ccc(C(F)(F)F)cc4)nc3CCOC)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.5 %

Procedure:
To a solution of 300 mg (0.91 mmol) 5-chloromethyl-4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidine and 199 mg (0.91 mmol) (5-hydroxy-indol-1-yl)-acetic acid ethyl ester in 5 ml DMF was added 443 mg (136 mmol) cesium carbonate. The reaction mixture was stirred at RT for 3 h and then taken up in ether, washed with 1N HCl and water. The crude product was purified by chromatography with AcOEt/heptane 1:4 to provide 152 mg of pure {5-[4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([S:36]([F:41])([F:40])([F:39])([F:38])[F:37])[CH:35]=1)[C:30](O)=[O:31])(=[O:26])=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:30](=[O:31])[C:29]2[CH:33]=[C:34]([S:36]([F:38])([F:39])([F:40])([F:41])[F:37])[CH:35]=[C:27]([S:24]([CH3:23])(=[O:26])=[O:25])[CH:28]=2)=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cc(S(C)(=O)=O)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
66 mg (0.228 mmol) of the compound of Example 6A and 74 mg (0.228 mmol) of the compound of Example 32A were dissolved in 1.5 ml of anhydrous DMF, and 104 mg (0.273 mmol) of HATU and 48 μl (0.273 mmol) of N,N-diisopropylethylamine were added in succession. The reaction mixture was stirred at RT for 4 h and then separated completely into its components by preparative HPLC (Method 9). The product fractions were combined and concentrated to dryness on a rotary evaporator. This gave the title compound in the form of its formic acid salt. For conversion into the salt-free form, the formate was dissolved in about 5 ml of methanol and passed over a bicarbonate cartridge (from Polymerlabs, Stratospheres SPE, PL-HCO3 MP SPE, capacity 0.9 mmol). After re-evaporation, the residue was triturated with a little diisopropyl ether at RT. Filtration with suction and drying of the solid under high vacuum gave 72.6 mg (53% of theory) of the title compound.
Reaction SMILES: CC1C=CC(CP(=O)OCC2C=CC=CC=2)=CC=1.[H-].[Na+].C([O:28][C:29]([CH:31]([CH2:45][CH2:46][C:47]([O:49]CC1C=CC=CC=1)=[O:48])[CH2:32][P:33]([CH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)(=[O:35])[OH:34])=[O:30])C1C=CC=CC=1>C1COCC1.CCOC(C)=O>[C:39]1([CH2:38][CH2:37][CH2:36][P:33]([CH2:32][CH:31]([CH2:45][CH2:46][C:47]([OH:49])=[O:48])[C:29]([OH:30])=[O:28])([OH:35])=[O:34])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(CCC(CP(=O)(O)CCCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: Cc1ccc(C[PH](=O)OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)CCC(CP(=O)(O)CCCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 163 %

Procedure:
To a solution of 4-methylbenzyl-O-benzylphosphinic acid (2, R=4-methylbenzyl) (2.16 g, 8.3 mmol) in THF (15 Ml) was added sodium hydride (0.10 g, 60% dispersion in oil) followed by dibenzyl 2-methylenepentanedioate (3) (3.24 g) at 0° C., and the mixture was stirred at room temperature for 4 hours. The reaction mixture was then diluted with EtOAc (50 Ml) and poured into 1 N Hcl (50 Ml). The organic layer was separated, dried over Na2SO4, and concentrated. This material was purified by silica gel chromatography (hexanes: EtOAc, 4:1 to 1:1) to give 3.41 g of 2,4-di(benzyloxycarbonyl)-butyl(4-methylbenzyl)-o-benzylphosphinic acid (4, R=4-methylbenzyl) as colorless oil (70% yield). Rf 0.61 (EtOAc).
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([C:7](=[O:17])[CH2:8][N:9]2[CH2:16][CH2:15][CH2:14][C@H:10]2[C:11](O)=[O:12])=[CH:3][CH:2]=1.C(N1CCOCC1)C.ClCCl.[C:35]([NH:39][C:40](=[O:47])[C@H:41]([C@H:43]([CH2:45][CH3:46])[CH3:44])[NH2:42])([CH3:38])([CH3:37])[CH3:36]>C(#N)C>[C:1]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:2]=[CH:3][C:4]([C:7](=[O:17])[CH2:8][N:9]2[CH2:16][CH2:15][CH2:14][C@H:10]2[C:11]([N:39]([C:35]([CH3:37])([CH3:36])[CH3:38])[C:40](=[O:47])[C@H:41]([C@H:43]([CH2:45][CH3:46])[CH3:44])[NH2:42])=[O:12])=[CH:5][CH:6]=1
Reactant: O=C(CN1CCC[C@H]1C(=O)O)c1ccc(-c2ccccc2)cc1
Reactant: CC[C@H](C)[C@H](N)C(=O)NC(C)(C)C
Agent: CCN1CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: CC[C@H](C)[C@H](N)C(=O)N(C(=O)[C@@H]1CCCN1CC(=O)c1ccc(-c2ccccc2)cc1)C(C)(C)C
Yield: 15.7 %

Procedure:
A solution of N-[2-(biphenyl-4-yl)-2-oxoethyl] L-proline (50 mg, 0.16 mmol, 1.0 eq), N-ethylmorpholine (125 uL, 0.98 mmol, 6 eq) in acetonitrile (0.5 mL) was cooled to 0° C. and treated with a 50% solution of 1-n-propylphosphonic acid cyclic anhydride in dichloromethane (170 uL, 0.27 mmol, 1.6 eq) followed by L-isoleucine tert-butylamide (49 mg, 0.19 mmol, 1.1 eq). Purification by HPLC provided 12 mg (16%) of L-isoleucine, N-[1-(2-(biphenyl-4-yl)-2-oxoethyl)-L-prolyl] tert-butylamide.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[NH:10][C:9](=O)[C:8]3=[CH:18][S:19][CH:20]=[C:7]23)=[O:5])[CH2:3][CH2:2]1.B.[ClH:22].C(O)C>O1CCCC1>[ClH:22].[CH:1]1([C:4]([N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[NH:10][CH2:9][C:8]3=[CH:18][S:19][CH:20]=[C:7]23)=[O:5])[CH2:2][CH2:3]1
Reactant: O=C1Nc2ccccc2N(C(=O)C2CC2)c2cscc21
Agent: B
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(C1CC1)N1c2cscc2CNc2ccccc21

Procedure:
To 5.69 g. of 4-cyclopropylcarbonyl-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in 100 ml. of tetrahydrofuran is added 120 ml. of 1 M borane in tetrahydrofuran under argon, with stirring in an ice bath. The mixture is refluxed for 18 hours, then chilled and 60 ml. of 6 N hydrochloric acid is cautiously added. Most of the solvent is evaporated and 100 ml. of 5 N sodium hydroxide is added. The mixture is extracted with methylene chloride, dried over magnesium sulfate and evaporated giving a gum. Excess hydrochloric acid and ethanol are added to the gum and then evaporated giving a second gum. Ethanol is added to this second gum producing crystals which are recovered giving the desired product as colorless crystals, mp. 157°-159° C. (dec.).
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=[O:15])[CH2:10][C:11](=O)[NH2:12])=[O:7])[CH2:2][CH2:3][CH3:4].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[CH2:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=[O:15])[CH2:10][C:11]#[N:12])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N[C@H](CC(N)=O)C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCOC(=O)N[C@H](CC#N)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
N-Butyloxycarbonyl-D-asparagine (25 g, 108 mmol) was dissolved in 200 mL pyridine and 14 mL acetic anhydride and the solution was allowed to stir overnight at room temperature. After most of the pyridine was removed under reduced pressure, ethyl acetate was added and the solution was washed with citric acid and brine, dried (MgSO4), and concentrated to give 21 g (91%) oily product. ES-MS: calcd M+1 215.0; found 215.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][CH:7]=1.C(OC(C1(C(OC(C)C)=O)CC(OC)(OC)C1)=O)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:8]2)=[CH:6][CH:7]=1
Reactant: O=C(C=C(Nc1cccc(Cl)c1)c1ccccc1)C(F)(F)F
Agent: COC1(OC)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C1
Product: FC(F)(F)c1cc(-c2ccccc2)nc2cc(Cl)ccc12
Temperature: 0 °C

Procedure:
4-(3-Chloro-phenylamino)-1,1,1-trifluoro-4-phenyl-but-3-en-2-one (2.8 g, 0.0086 mole) and polyphosphoric acid (60 mL) in a 250 mL 3 neck round bottom flask was stirred mechanically under an atmosphere of Nitrogen at 165° C. internal temperature for 3 h. The reaction was poured over stirring ice water (600 ml). The product precipitated, and was collected by suction filtration, washed with water, and air dried overnight. The solids remaining in the Buchner funnel, and beaker from aqueous quench were rinsed into a flask concentrated in vacuo, then combined with the filtered sample and chromatographed on silica gel with 3:1 Hexanes/methylene chloride to afford the title compound as a white solid; 1H NMR (CDCl3, 400 MHz) δ 7.53-7.59 (m, 3H), 7.60-7.63 (dd, 1H, J=2.2 & J=9.1 Hz), 8.06-8.09 (dq, 1H, J=1.9 & J=9.0 Hz), 8.16-8.20 (m, 3H), 8.29 (d, 1H, J=2.1 Hz); 19F NMR 8-61.48; MS (ES+): 308.0 (100) [MH+], 310.0 (30) [M+2H+].
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([N:14]2[CH2:23][CH2:22][C:17]3([O:21][CH2:20][CH2:19][O:18]3)[CH2:16][CH2:15]2)=[C:11]([F:13])[CH:12]=1)=[O:5])[CH3:2].C[C:25](C)([O-:27])C.[Li+].C(OC(=O)CCC)[C@@H]1OC1>O1CCCC1>[O:21]1[C:17]2([CH2:16][CH2:15][N:14]([C:10]3[CH:9]=[CH:8][C:7]([N:6]4[CH2:2][C@H:1]([CH2:25][OH:27])[O:3][C:4]4=[O:5])=[CH:12][C:11]=3[F:13])[CH2:23][CH2:22]2)[O:18][CH2:19][CH2:20]1
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)Nc1ccc(N2CCC3(CC2)OCCO3)c(F)c1
Agent: CCCC(=O)OC[C@H]1CO1
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1O[C@@H](CO)CN1c1ccc(N2CCC3(CC2)OCCO3)c(F)c1
Reaction time: 0.08 h

Procedure:
5-Ethoxycarbonylamino-2-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)fluorobenzene (22.9 g, 0.071 M) was dissolved in dry tetrahydrofuran (250 ml) under nitrogen, cooled to −70°, and treated dropwise over 30 minutes with a solution of lithium t-butoxide (1M in tetrahydrofuran, 77.6 ml), keeping the temperature below −70°. After stirring for 5 minutes, (R)-glycidylbutyrate (11.19 g, 0.077 M) was added, and stirring continued at −65° for 1 hour, before allowing the temperature to rise to ambient over 16 hours. The precipitate was collected and washed with tetrahydrofuran to give the desired product (17.8 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[C:13]([CH3:18])[C:12]([C:19]([OH:21])=O)=[CH:11]3)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:44][N:45]([CH2:52][C:53]1[CH:59]=[CH:58][C:56]([NH2:57])=[CH:55][CH:54]=1)[CH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>CN(C=O)C.C(N(CC)CC)C>[CH3:44][N:45]([CH2:52][C:53]1[CH:54]=[CH:55][C:56]([NH:57][C:19]([C:12]2[C:13]([CH3:18])=[N:14][C:15]3[C:10]([CH:11]=2)=[CH:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[CH:17][CH:16]=3)=[O:21])=[CH:58][CH:59]=1)[CH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1
Reactant: Cc1ccc(-c2ccc3nc(C)c(C(=O)O)cc3c2)cc1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3nc(C)c(C(=O)Nc4ccc(CN(C)C5CCOCC5)cc4)cc3c2)cc1
Reaction time: 2 h
Yield: 39.5 %

Procedure:
To a solution of 6-(4-methylphenyl)-2-methylquinoline-3-carboxylic acid (120 mg) and 1-hydroxy-benzotriazole (88 mg) in DMF (5 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (125 mg) at room temperature, and the mixture was stirred for 2 hours. To the mixture was added a solution of 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline (105 mg) and triethylamine (0.2 ml) in DMF (5 ml), and the mixture was stirred for 18 hours and concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with chloroform. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethanol/ethyl acetate=1:2), and recrystallized from ethyl acetate-hexane to give N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-6-(4-methylphenyl)-2-methylquinoline-3-carboxamide (Compound 216) (82 mg) as pale yellow crystals.
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:10]=[C:11]([C@@H:15]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH2:16][OH:17])[CH:12]=[CH:13][CH:14]=1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(N(CC)CC)C>[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31]([O:17][CH2:16][C@@H:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=2)[O:18][C@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H](OC1CCCCO1)c1cccc(Cl)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@H](O[C@H]2CCCCO2)c2cccc(Cl)c2)cc1

Procedure:
Into toluene (20 ml) were added (R)-2-(3-chlorophenyl)-2-(3,4,5,6-tetrahydro-[2H]-pyran-2-yloxy)ethanol obtained in 3) above (6.0 g) and triethylamine (4.7 g) and further, under ice-cooling and dropwise, p-toluenesulfonyl chloride (4.9 g), and the resulting mixture was stirred at the same temperature for 1 hour. The reaction mixture was washed with water and the organic layer was further washed with a saturated aqueous sodium chloride solution and dried with anhydrous magnesium sulfate. The desiccant was filtered off and then the solvent was distilled off to obtain a colorless oily compound mentioned above (9.1 g, 94.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[NH2:11][NH2:12]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:11][NH2:12])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: NN
Reactant: CSc1nc(Cl)cc(Cl)n1
Solvent: C1CCOC1
Product: CSc1nc(Cl)cc(NN)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
33 g (169.2 mmol) of 4,6-dichloro-2-(methylthio)pyrimidine are introduced into 300 ml of THF at −20° C., and 169 ml of a 1M solution of hydrazine in THF is added dropwise at a rate such that the temperature does not rise above −15° C. The mixture is stirred at 0° C. for a further 2 h. After the reaction is complete, the solvent is distilled off and the residue is stirred with diethyl ether. 18.4 g (57% of theory) of the product are obtained as a solid.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]=C)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:26].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]=[O:26])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1ccc2c(c1)OCCc1sc(-c3ncnn3C(C)C)nc1-2
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C=O)ccc1-2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-vinyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.200 g, 0.591 mmol) in tetrahydrofuran (20 mL) and water (10 mL) was added osmium tetraoxide (0.0473 mmol, 4% wt in water, 0.3 ml) followed by sodium metaperiodate (0.253 g, 0.00118 mol) slowly. The mixture was stirred at room temperature for 6 hours. The reaction was quenched with saturated sodium thiosulfate, then diluted with ethyl acetate and extracted 3 times with ethyl acetate. The organic phases were combined, dried with Na2SO4 and concentrated to give 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carbaldehyde. MS (ESI+) 341.1
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[O:9][CH2:8][CH2:7][C:6]=2[CH:14]=1.[F:15][C:16]1[C:17]([NH:26][C:27]2[C:32]([Cl:33])=[CH:31][N:30]=[C:29](Cl)[N:28]=2)=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([NH:21][CH3:22])=[O:20]>CC(O)C.Cl.O1CCOCC1>[F:15][C:16]1[C:17]([NH:26][C:27]2[C:32]([Cl:33])=[CH:31][N:30]=[C:29]([NH:1][C:2]3[CH:3]=[CH:4][C:5]4[N:11]([CH3:12])[C:10](=[O:13])[O:9][CH2:8][CH2:7][C:6]=4[CH:14]=3)[N:28]=2)=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([NH:21][CH3:22])=[O:20]
Reactant: CN1C(=O)OCCc2cc(N)ccc21
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)CCOC(=O)N3C)ncc1Cl
Temperature: 120 °C

Procedure:
A mixture of 2-amino-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one and 3-fluoro-2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide in IPA (3 mL) was treated with 4 drops of 4N HCl/dioxane and microwave-heated at 120° C. for 90 minutes. The mixture was concentrated and purified by semipreparative HPLC to afford 3-fluoro-2-[5-chloro-2-(5-methyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide: 1H NMR (300 MHz, CDCl3) δ 8.87 (s, 1H), 8.08 (s, 1H), 7.30 (m, 5H), 6.91 (d, 2H), 6.10 (bq, 1H), 4.41 (t, 2H), 3.35 (s, 3H), 2.92 (d, 3H), 2.81 (t, 2H); MS (m/e) 471 (M+1).