Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:40])[CH:10]([CH:21]([C:26](=[O:39])[NH:27][CH:28]([C:33](=[O:38])[NH:34][CH:35]1[CH2:37][CH2:36]1)[C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH:23]([CH3:25])[CH3:24])[C:11](OCC1C=CC=CC=1)=O)C1C=CC=CC=1.[H][H].N1CCCCC1.C=O>C(O)C.[Pd]>[CH:35]1([NH:34][C:33]([CH:28]([NH:27][C:26]([CH:21]([C:10](=[CH2:11])[C:9]([OH:40])=[O:8])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:39])[C:29]([CH3:30])([CH3:32])[CH3:31])=[O:38])[CH2:37][CH2:36]1
Reactant: [H][H]
Reactant: CC(C)CC(C(=O)NC(C(=O)NC1CC1)C(C)(C)C)C(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: C=C(C(=O)O)C(CC(C)C)C(=O)NC(C(=O)NC1CC1)C(C)(C)C
Temperature: 25 °C

Procedure:
2-[1-(1-Cyclopropylcarbamoyl-2,2-dimethyl-propylcarbamoyl)-3-methyl-butyl]-malonic acid dibenzyl ester (14.53 g, 25.7 mmol) was dissolved in ethanol (200 ml) and the solution was placed under a blanket of argon. 10% Palladium on charcoal (3.2 g) was added and a fine stream of hydrogen gas was passed through the suspension for 3h with stirring. TLC showed that all the starting material had been consumed. The system was purged with argon and the catalyst was removed by filtration. The filtrate was cooled and stirred in an ice bath and treated with piperidine (2.39 g, 28.1 mmol) which was added dropwise, followed by 37% formaldehyde solution (22.6 ml, ca. 257 mmol). The reaction mixture was allowed to warm slowly to room temperature, then stirred overnight. The solvents were removed under reduced pressure and the residual oil was partitioned between ethyl acetate (300 ml) and 1 M hydrochloric acid (300 ml). The organic layer was separated, washed with 1M HCl and brine, dried over MgSO4, filtered and evaporated to dryness. The remaining pale brown foam (4.40 g, crude) contained a number of minor impurities but was used in Step C without purification. 1H-NMR; δ (CDCl3), 8.34 (1H, d, J=10.0 Hz), 7.37 (1H, m), 6.47 (1H, s), 5.99 (1H, s), 4.50 (1H, d, J=9.9 Hz), 4.07 (1H, m), 2.73 (1H, m), 1.79 (1H, m), 1.52 (2H, m), 1.00-0.82 (1 5H, br m), 0.78 (2H, m) and 0.55 (2H, m).
Reaction SMILES: [CH3:1][S:2]([C:5](C(OC)=O)([CH2:16][CH2:17][CH2:18][CH:19]([O:32][C:33](=[O:35])[CH3:34])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:4])=[O:3].[Cl-].[Na+].CS(C)=O>O>[CH3:1][S:2]([CH:5]([CH2:16][CH2:17][CH2:18][CH:19]([O:32][C:33](=[O:35])[CH3:34])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:3])=[O:4]
Reactant: COC(=O)CCCCCCC(CCCC(COc1cccc(C(F)(F)F)c1)OC(C)=O)(C(=O)OC)S(C)(=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)CCCCCCC(CCCC(COc1cccc(C(F)(F)F)c1)OC(C)=O)S(C)(=O)=O
Temperature: 185 °C
Yield: 190 %

Procedure:
A mixture of methyl 8-methylsulfonyl-8-methoxycarbonyl-12-acetoxy-13-(3-trifluoromethylphenoxy)tridecanoate (5.82 g., 0.01 mole), sodium chloride (0.59 g., 0.01 mole), dimethylsulfoxide (8 ml.), and water (0.2 ml.) is heated in an oil bath at 185° C. for 10 hours under nitrogen. The reaction mixture is then concentrated in vacuo on a steam bath. The dark-colored residue is diluted with water, acidified with 6N hydrochloric acid, and extracted with ether. The ether extracts are washed with water, dried with anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (9.90 g., 0.019 mole, 94%).
Reaction SMILES: C(O[C:4](=O)[C@@H:5](OC)[CH2:6][C:7]1[CH:12]=[CH:11][C:10](OCC(O)=O)=[CH:9][CH:8]=1)C.[CH2:21]([O:23][C@@H:24]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][C@@H:36]([C:38](=[O:55])[NH:39][CH2:40][CH2:41]C2C=CC(OC3C=CC=CC=3)=CC=2)C)=[CH:31][CH:30]=1)[C:25]([OH:27])=[O:26])C>>[C:7]1([CH:6]([C:5]2[CH:4]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:41][CH2:40][NH:39][C:38]([CH2:36][O:35][C:32]2[CH:31]=[CH:30][C:29]([CH2:28][C@H:24]([O:23][CH3:21])[C:25]([OH:27])=[O:26])=[CH:34][CH:33]=2)=[O:55])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Product: CO[C@@H](Cc1ccc(OCC(=O)NCCC(c2ccccc2)c2ccccc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 3,3-eiphenyl-propylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a yellow oil. MS (ES) for C27H29NO5 [M+H]+: 448.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][C:10]=2[O:18][CH3:19])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][O:22][C:23]1[C:24]([NH2:42])=[CH:25][C:26]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH2:29][CH2:28][C:27]=2[CH:41]=1>>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][C:10]=2[O:18][CH3:19])=[N:7][C:2]([NH:42][C:24]2[C:23]([O:22][CH3:21])=[CH:41][C:27]3[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[CH2:31][CH2:32][C:26]=3[CH:25]=2)=[N:3][CH:4]=1
Reactant: COc1cc(N(C)C)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CCN1CCOCC1)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N(C)C)cc3OC)n1)CCN(CCN1CCOCC1)CC2
Yield: 22 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from N(1)-(2,5-Dichloro-pyrimidin-4-yl)-2-methoxy-N(4),N(4)-dimethyl-benzene-1,4-diamine and 8-Methoxy-3-(2-morpholin-4-yl-ethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamine. Product was isolated as a light yellow foam (40 mg, 22%). mp: 115° C. (glass @ 75) MS (ESI+): 582 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.16 (s, 1H), 8.14 (s, 1H), 8.01 (s, 1H), 7.45 (s, 1H), 7.43 (s, 1H), 6.64 (s, 1H), 6.38 (s, 1H), 6.35 (s, 1H), 3.93 (s, 3H), 3.87 (s, 3H), 3.74 (t, J=5 Hz, 4H), 2.99 (s, 6H), 2.87 (m, 2H), 2.82 (m, 2H), 2.70 (t, J=7 Hz, 6H), 2.56 (m, 2H), 2.51 (m, 4H).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1B(O)O)=[O:6].[CH2:22]([C@@H:29]1[C@@H:38]([OH:39])[C:37]2[C:32](=[CH:33][C:34](Br)=[CH:35][CH:36]=2)[O:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][O:4][C:5](=[O:6])[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[C:34]1[CH:33]=[C:32]2[C:37]([C@H:38]([OH:39])[C@@H:29]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:30][O:31]2)=[CH:36][CH:35]=1
Reactant: O[C@H]1c2ccc(Br)cc2OC[C@@H]1Cc1ccccc1
Reactant: CC(C)(C)COC(=O)c1ccc(C(F)(F)F)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)COC(=O)c1ccc(C(F)(F)F)cc1-c1ccc2c(c1)OC[C@H](Cc1ccccc1)[C@H]2O
Temperature: 25 °C
Yield: 83.3 %

Procedure:
A bi-phasic solution of 2-(2,2-dimethyl-propoxycarbonyl)-5-trifluoromethyl-benzeneboronic acid (1.72 g, 5.66 mmol), (3S,4R)-3-benzyl-7-bromo-chroman-4-ol (1.80 g, 6.63 mmol), sodium carbonate (1.82 g, 17.2 mmol), and tretrakis(triphenyl-phosphine)palladium(0) (12 mg, 0.19 mol %) in toluene (15 mL) and water (9 mL) was stirred at reflux for 100 minutes. The reaction mixture was cooled to room temperature, poured into water (40 mL) and extracted with diisopropylether (75 mL). The organic extracts were washed with brine (50 mL), treated with Darco® G-60, dried over magnesium sulfate, filtered through Celite®, and concentrated. The crude product was purified by chromatography on silica gel (ethyl acetate/hexanes 20/80) to provide (3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoic acid 2,2-dimethylpropyl ester as a white foam (2.35 g, 84% yield): Rf : 0.32 (ethyl acetate/hexanes 25/75); IR 3407 (br), 2961, 1721, 1336, 1292, 1252, 1172, 1134, 1110, 1022, 848, 749 cm- ; 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J=8.1 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.63 (s, 1H), 7.19-7.37 (m, 6H), 6.88-6.93 (m, 2H), 4.53 (t, J=4.4 Hz, 1H), 4.22 (dd, J=11.2, 2.5 Hz, 1H), 3.99 (dd, J=11.2, 3.3 Hz, 1H), 3.78 (s, 2H), 2.73 (dd, J=13.8, 6.3 Hz, 1H), 2.54 (dd, J=13.6, 9.4 Hz, 1H), 2.20-2.80 (m, 1H), 1.81 (d, J=5.2 Hz, 1H), 0.74 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 26.64, 30.96, 34.62, 41.53, 64.76, 67.42, 75.33, 116.77, 121.07, 122.97, 124.13, 126.44, 127.50, 127.54, 128.45, 128.60, 128.92, 129.11, 130.25, 130.31, 139.08, 141.69, 142.03, 154.44, 168.14.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[C:8]([CH:20]=1)[C:9]([O:11]CC1C=CC(F)=CC=1)=[O:10]>O.O1CCCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)=[C:8]([CH:20]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(OCc1ccc(F)cc1)c1cc(Br)ccc1OCc1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)ccc1OCc1ccc(F)cc1
Reaction time: 8 h

Procedure:
Lithium hydroxide (0.43 g, 18.14 mmol) was added to a solution of (4-fluorophenyl)methyl 5-bromo-2-{[(4-fluorophenyl)methyl]oxy}benzoate (may be prepared as described in Description 86) (2.62 g, 6.05 mmol) in water (5 ml) and tetrahydrofuran (20 ml). The mixture was stirred overnight and the solvent removed in vacuo. The residue was redissolved in water (30 ml) and acidified to pH=2 using 1N HCl and then extracted with ethyl acetate (3×25 ml). The combined organic layers were dried (MgSO4) and the solvent removed in vacuo to yield the titled compound as a white solid. 1.97 g.
Reaction SMILES: [CH2:1]([SH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Na].[CH2:21]1O[CH2:22]1>COCCOCCOC>[CH2:1]([S:19][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][CH2:21][CH3:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C1CO1
Reactant: CCCCCCCCCCCCCCCCCCS
Agent: [Na]
Solvent: COCCOCCOC
Product: CCCCCCCCCCCCCCCCCCSCCCCCCCCCCCCCCCCCC
Yield: 65 %

Procedure:
1-Octadecanethiol, 250 g. (0.87 mole), was dissolved in 250 ml of bis-(2-methoxyethyl) ether. Three grams (0.13 mole) of cut sodium spheres were added and the reaction mixture was transferred to a rocking autoclave and ~462 g. of ethylene oxide was bled into the autoclave over a period of 3 hours at 140°-160° C. The maximum pressure observed was 540 lbs. After all the ethylene oxide had been added, rocking was continued for an additional hour. The mixture was cooled, the bis-(2-methoxyethyl) ether was evaporated under reduced pressure, and the residue crystallized from hexane to give a white solid in 65% yield based on the octadecane thiol.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[H-].[Na+].[NH2:8][C:9]1[C:18]2[C:13](=[C:14](F)[C:15]([N:19]3[C:27]4[CH2:26][C:25]([CH3:29])([CH3:28])[CH2:24][C:23](=[O:30])[C:22]=4[C:21]([CH3:31])=[CH:20]3)=[CH:16][CH:17]=2)[N:12]=[CH:11][N:10]=1>CN(C=O)C>[NH2:8][C:9]1[C:18]2[C:13](=[C:14]([NH:5][CH2:4][CH2:3][O:2][CH3:1])[C:15]([N:19]3[C:27]4[CH2:26][C:25]([CH3:28])([CH3:29])[CH2:24][C:23](=[O:30])[C:22]=4[C:21]([CH3:31])=[CH:20]3)=[CH:16][CH:17]=2)[N:12]=[CH:11][N:10]=1
Reactant: COCCN
Reactant: Cc1cn(-c2ccc3c(N)ncnc3c2F)c2c1C(=O)CC(C)(C)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCNc1c(-n2cc(C)c3c2CC(C)(C)CC3=O)ccc2c(N)ncnc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In a small microwave vial with a stir bar, 2-Methoxy-ethylamine (0.1 mmol, 75 mg) is dissolved in 1 mL DMF. To this solution is added sodium hydride (60% suspension in mineral oil) (0.1 mmol, 4 mg) and the mixture is stirred at rt for 5 min. and then 1-(4-Amino-8-fluoro-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.044 mmol, 15 mg) is added. The reaction is sealed and placed in the microwave reactor where it is heated to 150° C. for 30 min. The reaction is cooled and quenched by pouring into 10 mL of Sat'd. NH4Cl aq. and extracted 3 times with 2 mL CH2Cl2. The combined organics are dried with Na2SO4, concentrated, and purified by silica gel chromatography on Biotage using a gradient of 0-50% MeOH in CH2Cl2. 1-[4-Amino-8-(2-methoxy-ethylamino)-quinazolin-7-yl]-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one is isolated (8 mg, LC/MS m/z=393 [M+H]+) as a tan powder.
Reaction SMILES: [Cl-].[NH4+].[N+:3]([C:6]1[CH:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]([OH:25])[CH:22]([F:24])[F:23])=[CH:17][CH:16]=2)[CH:9]=[C:10]([N+:12]([O-])=O)[CH:11]=1)([O-])=O>C(O)C.O.[Fe]>[NH2:3][C:6]1[CH:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]([OH:25])[CH:22]([F:23])[F:24])=[CH:17][CH:16]=2)[CH:9]=[C:10]([NH2:12])[CH:11]=1
Reactant: O=[N+]([O-])c1cc(-c2ccc([C@@H](O)C(F)F)cc2)cc([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cc(N)cc(-c2ccc([C@@H](O)C(F)F)cc2)c1

Procedure:
Ammonium chloride (102 mg, 1.91 mmol) was added to a stirred (room temperature) mixture of (1R)-1-(3′,5′-dinitrobiphenyl-4-yl)-2,2-difluoroethanol (517 mg, 1.60 mmol) and iron (1070 mg, 19.1 mmol) in ethanol (5.32 mL) and water (2.66 mL), and then the reaction mixture was stirred at 80° C. for 2 hours. The reaction mixture was filtered over CELITE while still warm. The filtrate was concentrated in vacuo, diluted with water, extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes) afforded (1R)-1-(3′,5′-diaminobiphenyl-4-yl)-2,2-difluoroethanol. MS ESI calc'd. for C14H15F2N2O [M+H]+ 265, found 265.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH2:16][CH2:15][C:14]=3[CH:18]=2)[C:5]([NH2:19])=[N:4][CH:3]=1.[N:20]([O-])=O.[Na+]>CC(O)=O.O>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:9][C:10]3[CH:11]=[CH:12][C:13]4[O:17][CH2:16][CH2:15][C:14]=4[CH:18]=3)[N:20]=[N:19][C:5]2=[N:4][CH:3]=1
Reactant: Nc1ncc(Br)nc1NCc1ccc2c(c1)CCO2
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Brc1cnc2nnn(Cc3ccc4c(c3)CCO4)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
To a solution of 6-bromo-N2-(2,3-dihydro-benzofuran-5-ylmethyl)-pyrazine-2,3-diamine (1.0 g, 3.12 mmol) in AcOH:H2O (8 mL: 8 mL) was added the solution of NaNO2 (2.12 g, 31.2 mmol) in water (5 mL). The mixture was stirred at room temperature for 1 hour, and then heated at 65° C. for 16 hours. The solvents were removed, and then EtOAc (20 mL) and water (20 mL) were added. The aqueous layer was extracted with EtOAc (3×20 mL). The combined extracts were dried over Na2SO4, concentrated and purified by silica gel chromatography with EtOAc: Hexanes to provide 6-bromo-1-(2,3-dihydro-benzofuran-5-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (543 mg, 52% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][OH:10].Cl[C:12]1[CH:13]=[C:14]2[N:21]([CH3:22])[CH:20]([CH3:23])[CH2:19][N:15]2[C:16](=[O:18])[N:17]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C:12]1[CH:13]=[C:14]2[N:21]([CH3:22])[CH:20]([CH3:23])[CH2:19][N:15]2[C:16](=[O:18])[N:17]=1
Reactant: OCc1ccc(F)cc1F
Reactant: CC1Cn2c(cc(Cl)nc2=O)N1C
Product: CC1Cn2c(cc(OCc3ccc(F)cc3F)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (2,4-difluorophenyl)methanol and 7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([P:19]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20])[C:17]#[N:18])[CH:8]=[CH:9][C:10]=1[O:11][C:12](=[O:14])[CH3:13])(=[O:3])[CH3:2].[H][H]>C(OC(=O)C)(=O)C.[Pd]>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:15][CH:16]([P:19]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20])[C:17]#[N:18])[CH:8]=[CH:9][C:10]=1[O:11][C:12](=[O:14])[CH3:13])(=[O:3])[CH3:2]
Reactant: CCOP(=O)(OCC)C(C#N)=Cc1ccc(OC(C)=O)c(OC(C)=O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Product: CCOP(=O)(OCC)C(C#N)Cc1ccc(OC(C)=O)c(OC(C)=O)c1

Procedure:
3-(3,4-Diacetoxyphenyl)-2-(diethoxyphosphinyl) acrylonitrile (Table 1, No. 56; 2.5 g; 0.0066 mol) was hydrogenated in 100 ml of acetic anhydride over 0.5 g of 10 percent Pd/C catalyst in a Parr hydrogenation apparatus under an initial pressure of 3.45 bar until hydrogen uptake was complete (16 hours), adding an additional 0.3 g of catalyst after 8 hours had elapsed. Finally, the catalyst was filtered off and the filtrate was evaporated under reduced pressure. The residue was chromatographed on silica gel, eluted with the solvent mixture dichloromethane:ethyl acetate (7:3). This results in the title compound as a pale oil in a yield of 1.7 g (67.7% of theory).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.Cl.[Br:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.[C:21](=[O:23])=[O:22]>C1COCC1>[Br:14][C:15]1[C:20]([C:21]([OH:23])=[O:22])=[CH:19][N:18]=[CH:17][CH:16]=1
Reactant: Brc1ccncc1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1cnccc1Br
Temperature: -55 °C
Reaction time: 1 h

Procedure:
Butyllithium (82.0 mL, 205.6 mmol, 2.0 eq.) was added dropwise to a solution of diisopropylamine (20.8 g, 205.6 mmol, 2.0 eq.) in THF (100 mL) at −78° C., under nitrogen. The resulting solution was stirred for 1 hour at approximately −60 to −50° C. The resulting solution was added dropwise to a solution of 4-bromopyridine hydrochloride (20.0 g, 102.9 mmol, 1.0 eq.) in THF (100 mL) at −78° C. The resulting solution was stirred for 2 hours. Carbon dioxide gas was introduced into the reaction vessel for 30 minutes. The resulting solution was stirred overnight at room temperature. The reaction was then quenched with water (100 mL). The resulting solution was extracted with EtOAc (3×200 mL) and the aqueous layers were combined. The pH of the solution was adjusted to 3-4 with 1N HCl to yield 4-bromonicotinic acid (16.8 g) as a white solid. ES m/z: [M+H]+ 202.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][C@H:19]([C:21]2[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=2)[CH3:20])=[N:4][C:5]([NH:11][C:12]2[CH:16]=[C:15]([CH3:17])[NH:14][N:13]=2)=[C:6]([N+:8]([O-])=O)[CH:7]=1.O.O.Cl[Sn]Cl.[CH:33](OCC)(OCC)OCC>CCO>[F:1][C:2]1[CH:7]=[C:6]2[N:8]=[CH:33][N:11]([C:12]3[CH:16]=[C:15]([CH3:17])[NH:14][N:13]=3)[C:5]2=[N:4][C:3]=1[NH:18][C@H:19]([C:21]1[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=1)[CH3:20]
Reactant: CCOC(OCC)OCC
Reactant: Cc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)c(F)cc2[N+](=O)[O-])n[nH]1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(-n2cnc3cc(F)c(N[C@@H](C)c4ncc(F)cn4)nc32)n[nH]1
Temperature: 70 °C

Procedure:
To a solution of 3-fluoro-N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N6-(5-methyl-1H-pyrazol-3-yl)-5-nitropyridine-2,6-diamine (Intermediate 42, 3.05 mmol) in EtOH (5 ml) were added SnCl2.2H2O (1.74 g, 9.18 mmol) and triethyl orthoformate (0.652 ml). The resulting solution was heated to 70° C. overnight. The mixture was allowed to cool to room temperature and filtered through Celite® and washed with EtOAc. Evaporation of the volatiles under reduced pressure gave a colored residue that was purified by Gilson (5%→95% MeCN/H2O) to give the title compound. LC-MS: 357 [M+1]. 1H NMR δ 2.01 (d, 3H) 2.34 (s, 3H) 6.46-6.55 (m, 1H) 8.20 (s, 1H) 8.72 (s, 1H) 8.87 (s, 2H) 9.72 (s, 1H) 9.86 (s, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.[CH:13]1([C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>CO>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:3]([CH:1]=[N:23][C:22]2[CH:24]=[CH:25][C:19]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:20][CH:21]=2)=[CH:4][CH:5]=1
Reactant: Nc1ccc(C2CCCCC2)cc1
Reactant: COC(=O)c1ccc(C=O)cc1
Solvent: CO
Product: COC(=O)c1ccc(C=Nc2ccc(C3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 99014.6 %

Procedure:
Methyl 4-formylbenzoate (47 g, 285 mmol) was dissolved in methanol (400 mL) and a solution of 4-cyclohexylaniline (50 g, 0.285 mmol) in methanol (200 mL) is slowly added with mechanical stirring. More methanol (1 L) was added and the suspension was stirred at room temperature for 3 days. Filtration, washing and drying in vacuo afforded 90.7 g (99%) of 4-[(4-cyclohexylphenylimino)methyl]benzoic acid methyl ester. This was dissolved in N-methylpyrrolidone (855 mL) and methanol (45 mL). With mechanical stirring sodium borohydride pellets (42.4 g, 1.12 mol) was added in portions keeping the temperature below 40° C. The mixture was then stirred at room temperature for 2 hours and at 40° C. for 16 hours. The mixture was cooled to 5° C. and water (2 L) was slowly added. Then acetone (350 mL) was added and the mixture was stirred at 5° C. for 1 hour. Filtration, washing with water (2×500 mL) and drying in vacuo afforded 78 g (86%) of 4-[(4-cyclohexylphenylamino)-methyl]benzoic acid methyl ester as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[NH:11][N:10]=1.[CH3:31]OC(OC)N(C)C>>[Cl:19][C:6]1[CH:5]=[C:4]([N:20]2[C:21](=[O:30])[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]2=[O:29])[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH3:31])[N:10]=1
Reactant: COC(OC)N(C)C
Reactant: CC(C)c1cc(Oc2c(Cl)cc(N3C(=O)c4ccccc4C3=O)cc2Cl)n[nH]c1=O
Product: CC(C)c1cc(Oc2c(Cl)cc(N3C(=O)c4ccccc4C3=O)cc2Cl)nn(C)c1=O
Temperature: 25 °C
Yield: 73 %

Procedure:
A suspension of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-isoindole-1,3-dione (65) (84.5 g, 190.2 mmol) in N,N-dimethylformamide dimethyl acetal (250 mL) was heated to reflux for 5 h. At this time, the reaction was cooled to room temperature. The solids that resulted were collected by filtration, washed with a 1:1 mixture of methyl tert-butyl ether:heptane (70 mL) followed by heptane (70 mL) and dried under vacuum to afford 2-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-isoindole-1,3-dione (66) (63.57 g, 73%) as an off-white solid; ES(+)-LRMS for C22H17Cl2N3O4 (M+H)+ at m/z=458. Exact Mass=457.0596; Molecular Weight=458.30.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[CH:6]=[C:5]([C:14](=O)[C:15]([CH3:21])([CH3:20])[C:16](OC)=[O:17])[CH:4]=1.Cl.Cl.[NH:25]1[CH2:30][CH2:29][CH:28]([NH:31][NH2:32])[CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:12])([CH3:13])[CH2:8][C:7]=2[CH:6]=[C:5]([C:14]2[C:15]([CH3:21])([CH3:20])[C:16](=[O:17])[N:31]([CH:28]3[CH2:29][CH2:30][NH:25][CH2:26][CH2:27]3)[N:32]=2)[CH:4]=1
Reactant: COC(=O)C(C)(C)C(=O)c1cc2c(c(OC)c1)OC(C)(C)C2
Reactant: NNC1CCNCC1
Agent: Cl
Product: COc1cc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc2c1OC(C)(C)C2

Procedure:
Prepared analogous as described for the example B1 (Alternative 2) using methyl 3-(7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2,2-dimethyl-3-oxopropanoate (compound D12) and piperidin-4-yl-hydrazine dihydrochloride as starting compounds resulting in the title compound. (compound B12)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:12]1([CH:18]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:19][NH2:20])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[O:6]
Reactant: Cc1ccc(Cl)c(C(=O)O)c1
Reactant: NCC(c1cccnc1)N1CCOCC1
Product: Cc1ccc(Cl)c(C(=O)NCC(c2cccnc2)N2CCOCC2)c1

Procedure:
From 2-chloro-5-methylbenzoic acid and (2-morpholin-4-yl-2-pyridin-3-ylethyl)amine. LCMS (MH+): m/z=360.0, tR (minutes, Method A)=0.77