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]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[C:23]2=[O:38])[O:11][CH:10]1[C@H:39]([OH:71])[C@@H:40]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[NH:41][CH2:42][CH2:43][CH2:44][NH:45][C:46](=[O:63])[C@H:47]([CH2:59][CH:60]([CH3:62])[CH3:61])[NH:48]C(=O)OCC1C=CC=CC=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:48][C@@H:47]([CH2:59][CH:60]([CH3:62])[CH3:61])[C:46]([NH:45][CH2:44][CH2:43][CH2:42][NH:41][C@@H:40]([C@H:39]([CH:10]1[C@@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[C@@H:13]([O:14][Si:15]([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:16])[CH3:17])[C@H:12]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[C:23]2=[O:38])[O:11]1)[OH:71])[C:64]([O:66][C:67]([CH3:69])([CH3:70])[CH3:68])=[O:65])=[O:63]
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@H](CC(C)C)NC(=O)OCc4ccccc4)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@@H](N)CC(C)C)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Yield: 91.9 %

Procedure:
tert-Butyl (5S,12S)-12-[(R)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-isobutyl-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (234 mg, 0.228 mmol, obtained from Example 4) was hydrogenated in methanol (3 ml) using 10% palladium on carbon (58 mg) under atmospheric pressure to provide tert-butyl (2S,3R)-2-[(3-{[(2S)-2-amino-4-methylpentanoyl]amino}propyl)amino]-3-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl]-3-hydroxypropanoate (187 mg, 92%) as a white amorphous solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:32])=O)=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36][NH2:37]>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:29]=[CH:28][C:27]([C:30](=[O:32])[NH:37][CH2:36][CH2:35][N:34]([CH3:38])[CH3:33])=[CH:26][CH:25]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 71.4 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with N,N-dimethylethylenediamine (available from Aldrich Chemical Company, Inc.; 55 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(2-dimethylamino-ethylcarbamoyl)-biphenyl-2-carboxylic acid (81 mg, 73%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73 (t, J=5.4 Hz, 1H), 8.47 (s, 1H), 8.41 (d, J=2.0 Hz, 1H), 8.33 (d, J=2.0 Hz, 1H), 8.25 (dd, J=8.0, 1.8 Hz, 1H), 8.09 (dd, J=8.5, 2.0 Hz, 1H), 7.93 (d, J=8.3 Hz, 2H), 7.77 (d, J=8.5 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.3 Hz, 2H), 3.63 (q, J=5.8 Hz, 2H), 3.22-3.27 (m, 2H), 2.84 (s, 6H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C([NH:26][C@H:27]([C:29](O)=[O:30])[CH3:28])=O)(C)(C)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl.[NH2:40][C@H:41]([C:47]([OH:49])=[O:48])[CH2:42][CH2:43][C:44](=[O:46])[NH2:45].[OH-].[Na+].S(=O)(=O)(O)O>CCOCC.O.C1(C)C=CC=CC=1>[NH2:26][C@H:27]([C:29]([NH:40][C@H:41]([C:47]([OH:49])=[O:48])[CH2:42][CH2:43][C:44](=[O:46])[NH2:45])=[O:30])[CH3:28]
Reactant: C[C@H](NC(=O)C(C)(C)C)C(=O)O
Reactant: NC(=O)CC[C@H](N)C(=O)O
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Reaction time: 2 h
Yield: 52 %

Procedure:
Dissolve 10 mmol of triphenylphosphine with 10 ml of toluene, drop it into a mixed system composed of 10 mmol of tert-butylcarbonylalanine (Boc-Ala), 10 mmol of hexachloroethane and 20 ml of toluene. After reacting at 5° C. for 2 hours, drop it into a liquid mixture containing 15 mmol of glutamine, 20 ml of water and 60 ml of petrolium ether. While reacting, regulate pH to 12 with sodium hydroxide, the reaction temperature is 10° C., the reaction time after dropping is 1.5 hours. And then acidify it to regulate pH=1.5 with dilute sulfuric acid. The aqueous phase, after concentrated, reacts with hydrogen chloride/1,4-dioxane at room temperature for 5 hours. As the reaction is finished, add in 50 ml of ether, solids deposit, the product L-Ala-L-Gln with a yield of 52% is obtained by recrystallizing the solids with 1,4-dioxane-water.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][OH:7])=[N+:2]=[N-:3].[H-].[Na+].[CH2:10]([O:13][C:14]1[N:19]=[C:18](OCC=C)[N:17]=[C:16]([O:24][CH2:25][CH:26]=[CH2:27])[N:15]=1)[CH:11]=[CH2:12]>C1COCC1>[N:1]([CH2:4][CH2:5][CH2:6][O:7][C:18]1[N:19]=[C:14]([O:13][CH2:10][CH:11]=[CH2:12])[N:15]=[C:16]([O:24][CH2:25][CH:26]=[CH2:27])[N:17]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCCO
Reactant: C=CCOc1nc(OCC=C)nc(OCC=C)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOc1nc(OCC=C)nc(OCCCN=[N+]=[N-])n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
To 3-azido-1-propanol (8.7 g, 85.7 mmol) in THF (200 mL) was added sodium hydride (5.6 g, 128.6 mmol) at −78° C. The reaction mixture was stirred at −78° C. for about 30 minutes and then allowed to equilibrate at room temperature and stirred for an additional 3 hours. The reaction mixture was recooled to −78° C. and added to a solution of 2,4,6-triallyloxy-1,3,5-triazine (21.4 g, 85.7 mmole) in THF (200 mL). The reaction mixture was stirred at room temperature for about 16 hours. The reaction mixture was evaporated to a brown residue. The residue was purified by flash column chromatography over silica gel using EtOAc/hexane as the eluent. The pure fractions were pooled together and evaporated to dryness to give 8.5 g (36%) of the title compound. TLC (Rf: 0.5; 20% EtOAc/Hexane, I2). 1H NMR (CDCl3) δ2.1 (m, 2H, CH2), 3.5 (t, 2H, CH2), 4.5 (t, 2H, CH2), 4.9 (m, 4H, CH2), 4.3 (m. 4H, CH2), 6.0 (m, 2H, CH).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C(Cl)Cl.CC([O-])=O.[K+].Br[C:39]1[S:40][C:41]2[C:47]([C:48]3[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=3)=[C:46]([C@H:55]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])[C:56]([O:58][CH2:59][CH3:60])=[O:57])[C:45]([CH3:66])=[CH:44][C:42]=2[N:43]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].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>[C:62]([O:61][C@@H:55]([C:46]1[C:45]([CH3:66])=[CH:44][C:42]2[N:43]=[C:39]([C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[CH:3]=3)[S:40][C:41]=2[C:47]=1[C:48]1[CH:49]=[CH:50][C:51]([Cl:54])=[CH:52][CH:53]=1)[C:56]([O:58][CH2:59][CH3:60])=[O:57])([CH3:63])([CH3:64])[CH3:65]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc([N+](=O)[O-])c(F)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A microwave vial was charged with 4-bromo-2-fluoro-1-nitrobenzene (690 mg, 3.14 mmol), bis(pinacolato)diboron (946 mg, 3.73 mmol), PdCl2(dppf).CH2Cl2 (242 mg, 0.30 mmol), then KOAc (926 mg, 9.44 mmol). The vial was flushed with argon, diluted with dioxane (11 mL), sealed, then heated to 100° C. for 1 hour. The reaction mixture was allowed to cool to room temperature and then a portion of this cooled solution (6.1 mL, 1.74 mmol) was added to a vial that was charged with (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (437 mg, 0.88 mmol) and Pd(PPh3)4 (102 mg, 0.09 mmol). The mixture was diluted with dioxane (2 mL) and to this was added 2M aqueous K2CO3 (1.50 mL, 3.00 mmol). The vial was sealed, heated to 100° C. for 1 hour, and then allowed to cool to room temperature. The mixture was diluted with EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (5-30% EtOAc/Hex gradient) to afford the desired product. LCMS-ESI+: calc'd C28H27ClFN2O5S: 557.1 (M+H+); Found: 557.1 (M+H+).
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.[Br:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([S:33]([F:38])([F:37])([F:36])([F:35])[F:34])[CH:32]=1)[C:27](O)=[O:28].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.O>[Br:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([S:33]([F:38])([F:34])([F:35])([F:36])[F:37])[CH:32]=1)[C:27]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:28]
Reactant: O=C(O)c1cc(Br)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: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(NC(=O)c2cc(Br)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
10.0 g (34.6 mmol) of the compound of Example 6A and 11.3 g (34.6 mmol) of the compound of Example 15A were dissolved in 120 ml anhydrous DMF, and 15.8 g (41.5 mmol) of HATU and 7.2 ml (41.5 mmol) of N,N-diisopropylethylamine were added in succession. The reaction mixture was stirred at RT overnight (about 15 h) and then stirred into 1.6 liters of water. After 40 minutes, the resulting precipitate was filtered off with suction, washed thoroughly with a further 0.5 liter of water and finally dissolved in 1.8 liters of ethyl acetate. The organic solution was washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate, the mixture was filtered and the solvent was removed on a rotary evaporator. The crude product obtained in this manner was purified by filtration with suction (about 330 g of silica gel, mobile phase gradient cyclohexane/ethyl acetate 1:1→1:3). This gave 11.95 g (57% of theory) of the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C@@H:5]1[CH2:10][O:9][CH2:8][CH2:7][NH:6]1.C(N(CC)CC)C.[CH2:18]1[O:20][CH2:19]1>CO.C1(C)C=CC=CC=1>[CH3:2][O:3][CH2:4][C@H:5]1[N:6]([CH2:18][CH2:19][OH:20])[CH2:7][CH2:8][O:9][CH2:10]1
Reactant: COC[C@@H]1COCCN1
Reactant: C1CO1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC[C@@H]1COCCN1CCO
Reaction time: 48 h

Procedure:
To a mixed solution of (3R)-3-(methoxymethyl)morpholine hydrochloride (4.71 g) and triethylamine (4.11 ml) in methanol (110 ml) was added 5.8M ethylene oxide (22 ml) in toluene solution at room temperature. After the reaction mixture was stirred at the same temperature for two days, it was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using mixed solvents of dichloromethane and methanol (20:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give 2-[(3R)-3-methoxymethylmorpholino]ethanol (4.67 g) as an oil.
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][CH:7]=1>CS(C)=O>[C:1]([CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][CH:7]=1)#[N:2]
Reactant: [C-]#N
Reactant: BrCc1ccc(Oc2ccccc2)c2ccccc12
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ccc(Oc2ccccc2)c2ccccc12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
Sodium cyanide (3.7 g; 75 mMol) was dissolved in DMSO (50 mL, dried over molecular sieves). The mixture was heated in an oil bath maintained at 50° C., and 15.7 g (50 mMol) of 1-bromomethyl-4-phenoxynaphthalene, prepared as described above, in 75 mL of DMSO was added dropwise. After addition was complete, stirring was continued for 0.5 hours. The temperature was raised to 70° C., and stirring was continued for 1.0 hour. The oil bath was turned off, and the stirring was continued overnight. The mixture was poured onto ice, and extracted with ether. The combined organic extractions were washed with brine and dried over magnesium sulfate. The product was obtained as a white, crystalline solid (6.24 g; 49% yield). mass 259. A sample was purified for analysis by medium pressure chromatography on silica gel, eluting with ethyl acetate:hexane/1:9.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1.[CH2:27]1[O:42][C:41]2[CH:40]=[CH:39][C:31]([CH2:32][N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[CH:30][C:29]=2[O:28]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:27]1[O:42][C:41]2[CH:40]=[CH:39][C:31]([CH2:32][N:33]3[CH2:38][CH2:37][N:36]([CH2:2][C:3]4[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]5[CH:18]=[CH:17][CH:16]=[C:15]([C:19]6[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=6)[CH:14]=5)=[CH:5][CH:4]=4)[CH2:35][CH2:34]3)=[CH:30][C:29]=2[O:28]1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CCl)cc3)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CN4CCN(Cc5ccc6c(c5)OCO6)CC4)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
In DMF (3 ml) was dissolved (E)-N-[4—(chloromethyl)—phenyl]-3—(4-methylphenyl)cinnamamide (200 mg), and to the solution were added 1—(3,4-methylenedioxybenzyl)-piperazine (158 mg) and potassium carbonate (382 mg). The mixture was stirred at room temperature for 16 hours, and to the mixture was added water (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give (E)-N-[4-[1—(3,4-methylenedioxybenzyl)-4-piperazinylmethyl]phenyl]-3—(4-methylphenyl)cinnamamide (Compound 57) (266 mg) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:3]=1.O.[NH2:27][NH2:28]>C(O)C>[NH2:13][C:12]1[C:11]2[C:10](=[CH:9][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH:5]=3)=[CH:15][CH:14]=2)[NH:28][N:27]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2cc(NCc3ccccc3Cl)nc(N)n2)cc1F
Solvent: O
Solvent: CCO
Product: Nc1nc(NCc2ccccc2Cl)cc(-c2ccc3c(N)n[nH]c3c2)n1
Temperature: 100 °C
Yield: 18.2 %

Procedure:
To 4-(2-amino-6-{[(2-chlorophenyl)methyl]amino}-4-pyrimidinyl)-2-fluorobenzonitrile (800 mg, 2.27 mmol) in ethanol (2 mL) was added hydrazine monohydrate (3 mL, 74 mmol), and the reaction mixture was heated to 100° C. for 1 hour in a BiotageInitiator® microwave synthesizer. Upon cooling, the reaction mixture was concentrated in vacuum and purified by RPHPLC (BiotageSP1) (gradient: 30% CH3CN/H2O to 60% CH3CN/H2O) to afford the title compound (151 mg) as an off-white solid. LC-MS (ES) m/z=366 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 4.61 (d, J=5.6 Hz, 2H), 5.37 (s, 2H), 6.07 (s, 2H), 6.40 (s, 1H), 7.34-7.27 (m, 2H), 7.46-7.41 (m, 4H), 7.70 (d, J=8.8 Hz, 1H), 7.84 (s, 1H), 11.52 (s, 1H).
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9].[CH3:11][C:12](C)([O-])[CH3:13].[K+].[I-].[K+].C(Br)C=C>C1COCC1>[CH2:13]([CH:1]([OH:10])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9])[CH:12]=[CH2:11]
Reactant: CC(C)(C)[O-]
Reactant: OCCOCCOCCO
Agent: [I-]
Agent: [K+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC(O)COCCOCCO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Allyl-triethylene glycol was prepared according to the literature method with modifications (Setz O, et al. Angew Chem Int Ed Engl. 1995, 34, 803-805). Thus, the mixture of triethylene glycol (11.83 g, 78.8 mmol), potassium t-butoxide (4.42 g, 39.4 mmol) and potassium iodide (0.65 g, 3.94 mmol) in THF (500 mL) was stirred at room temperature for 0.5 h, into which was added dropwise allyl bromide (4.767 g, 39.4 mmol) in THF (120 mL) over a period of 1.5 h. After continuing to be stirred at room temperature for 36 h, the mixture was filtered through a celite pad. The crude product, obtained after removal of solvents under vacuum, was purified by a silica gel column chromatography eluting with hexane/ethyl acetate (1:1) to afford the product (4.9 g, 25.8 mmol, 65% yield) with chemical structure confirmed by 1H NMR and MS.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:17]=3)[CH2:12][CH2:11][N:10]=2)=[N:5][N:4]=[N:3]1.[BH4-].[Na+]>CO>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1SCC1=NCCc2cc(OCc3ccccc3)c(OCc3ccccc3)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1nnnc1SCC1NCCc2cc(OCc3ccccc3)c(OCc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 1-(1-methyl-1H-tetrazol-5-yl)-thiomethyl- 6,7-dibenzyloxy-3,4-dihydroisoquinoline (1g) in methanol (10 ml) was added sodium borohydride (120 mg), and the mixture was stirred for 1.5 hours at room temperature. After the reaction precipitated crystals were collected by filtration and washed with methanol to give 1-(1-methyl-1H-tetrazol-5-yl)thiomethyl- 6,7-dibenzyloxy-1,2,3,4-tetrahydroisoquinoline (0.88 g). This crystals were recrystallized from ethanol to give crystals, mp 106° to 108°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[C:17]([OH:19])[C:16]3[C:20]4[CH2:21][N:22]([CH2:30][C:31]([NH:33][C:34]([NH2:36])=[O:35])=[O:32])[CH2:23][CH2:24][C:25]=4[C:26]([CH3:29])([CH3:28])[O:27][C:15]=3[CH:14]=2)[CH3:12])=[CH:4][CH:3]=1.[ClH:37].[O:38]1[CH2:43][CH2:42][N:41]([CH2:44][CH2:45][CH2:46][C:47](O)=[O:48])[CH2:40][CH2:39]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:37].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[C:17]([O:19][C:47](=[O:48])[CH2:46][CH2:45][CH2:44][N:41]3[CH2:40][CH2:39][O:38][CH2:43][CH2:42]3)[C:16]3[C:20]4[CH2:21][N:22]([CH2:30][C:31]([NH:33][C:34]([NH2:36])=[O:35])=[O:32])[CH2:23][CH2:24][C:25]=4[C:26]([CH3:29])([CH3:28])[O:27][C:15]=3[CH:14]=2)[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(CCCc1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)NC(N)=O)CC1
Reactant: O=C(O)CCCN1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CC(CCCc1ccc(F)cc1)c1cc(OC(=O)CCCN2CCOCC2)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)NC(N)=O)CC1

Procedure:
The above-titled compound was prepared according to the method of Example 8 by reacting equimolar quantities of {{8-[5-(4-fluorophenyl)-2-pentyl]-10-hydroxy-5,5-dimethyl-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridin-2-yl}acetyl}urea and 4-morpholinobutyric acid hydrochloride in the presence of dicyclohexylcarbodiimide.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][N:7]([CH3:37])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[CH2:34][C@@:32]3([CH3:33])[C@@H:28]([CH2:29][CH2:30][C:31]3=[O:35])[C@H:27]3[C:18]2=[C:19]2[C:24]([CH2:25][CH2:26]3)=[CH:23][C:22](=[O:36])[CH2:21][CH2:20]2)=[CH:13][CH:12]=1.C(=O)(O)[O-].[Na+]>ClCCl.N1C=CC=CC=1>[Cl:4][C:23]1[C:22](=[O:36])[CH2:21][CH2:20][C:19]2[C:24]=1[CH2:25][CH2:26][C@@H:27]1[C:18]=2[C@@H:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][N:7]([CH3:6])[CH3:37])=[CH:16][CH:15]=2)[CH2:34][C@@:32]2([CH3:33])[C@H:28]1[CH2:29][CH2:30][C:31]2=[O:35]
Reactant: CN(C)CCOc1ccc([C@H]2C[C@]3(C)C(=O)CC[C@H]3[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)CCOc1ccc([C@H]2C[C@]3(C)C(=O)CC[C@H]3[C@@H]3CCC4=C(Cl)C(=O)CCC4=C32)cc1
Reaction time: 0.5 h

Procedure:
6 ml of sulphuryl chloride at 10% in dichloromethane is added under an inert atmosphere, at ambient temperature to a solution of 1.08 g of 11β-[4-(2-(dimethylamino) ethoxy) phenyl]-estra-4,9-diene-3,17-dione in 11 ml of pyridine and agitation is carried out for 30 minutes at approximately −36° C. The reaction medium is poured into sodium bicarbonate, followed by extraction, washing, drying and evaporating under reduced pressure until 1.84 g of crude product is obtained, which is purified by chromatography, eluting with an ethyl acetate/triethylamihe mixture 80/20. 616 mg of expected pure product is obtained. (Rf AcOEt/TEA 8/2=0.35).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[F:7][C:8]1[C:16]([F:17])=[C:15]2[C:11]([C:12]([NH2:18])=[N:13][NH:14]2)=[CH:10][CH:9]=1>N1C=CC=CC=1>[F:7][C:8]1[C:16]([F:17])=[C:15]2[C:11]([C:12]([NH:18][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[N:13][NH:14]2)=[CH:10][CH:9]=1
Reactant: CCCC(=O)Cl
Reactant: Nc1n[nH]c2c(F)c(F)ccc12
Solvent: c1ccncc1
Product: CCCC(=O)Nc1n[nH]c2c(F)c(F)ccc12
Temperature: 3 °C
Reaction time: 76 h

Procedure:
0.61 cm3 of butyryl chloride is added to 1 g of 6,7-difluoro-1H-indazole-3-amine described above, in 15 cm3 of pyridine, after having cooled to about 3° C., and the mixture is then left at ambient temperature for 76 hours. The reaction medium is concentrated under reduced pressure (2 kPa; 40° C.) and the residue is taken up in 25 cm3 of ethyl acetate and 25 cm3 of water. The organic phase is washed with 25 cm3 of distilled water and then with 25 cm3 of saturated aqueous sodium chloride solution. After drying over magnesium sulfate, filtering and concentrating under reduced pressure (2 kPa; 40° C.), the residue obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40–60 μm; diameter 3 cm), eluting with a dichloromethane/methanol mixture (98/2 by volume). The fractions containing the expected product are combined and then evaporated under reduced pressure (2 kPa; 40° C.); after drying (90 Pa ; 40° C.), 596 mg of N-(6,7-difluoro-1H-indazol-3-yl)butanamide are obtained in the form of a white solid melting at 191° C.