Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[C:7]1([CH2:19]O)[CH:8]=[N:9][N:10]2[CH:15]=[CH:14][C:13]3[O:16][CH2:17][CH2:18][C:12]=3[C:11]=12>ClCCl.C(=O)([O-])O.[Na+]>[C:7]1([CH2:19][C:5]#[N:6])[CH:8]=[N:9][N:10]2[CH:15]=[CH:14][C:13]3[O:16][CH2:17][CH2:18][C:12]=3[C:11]=12
Reactant: C[Si](C)(C)C#N
Reactant: OCc1cnn2ccc3c(c12)CCO3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#CCc1cnn2ccc3c(c12)CCO3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.6 %

Procedure:
To a solution of boron trifluoride diethyl ether complex (1.26 mL, 9.94 mmol) and trimethylsilyl cyanide (1.77 mL, 13.3 mmol) in dichloromethane (13 mL) was added a solution of 8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridin-1-ylmethanol (630 mg, 3.31 mmol) in dichloromethane (39 mL) under ice-cooling and an argon atmosphere, and the mixture was stirred at room temperature for 30 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→40/60) to give the title compound (274 mg, yield 42%).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].CC(C)([O-])C.[K+].Cl[CH2:12][C:13]([N:15]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14].O>CN(C=O)C>[OH:3][CH2:2][CH2:1][O:4][CH2:12][C:13]([N:15]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14]
Reactant: OCCO
Reactant: CC(C)CN(C(=O)CCl)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CN(C(=O)COCCO)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
To a solution of ethylene glycol (12.4 g, 200 mmol) in DMF (50 ml) was carefully added potassium tert-butoxide (16.8 g, 150 mmol) while the temperature was kept below 70° C. The resulting mixture was stirred at ambient temperature for 30 min, then a solution of the above acetamide (11.3 g, 50 mmol) in DMF (5 ml) was added in one portion and the mixture was stirred at room temperature for 1.5 h. The reaction mixture was poured into iced water (400 ml) and extracted with dichloromethane (2×50 ml). The combined organic phases were dried (MgSO4) and the solvent was evaporated in vacuo to give 12.5 g of 2-(2-hydroxyethoxy)-N-(2-methyl-1-propyl)-N-phenylacetamide.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=2)[N:3]=1.O.[SH-:22].[Na+].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[I:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][NH:12][C:4]1[N:3]=[C:2]([S:22][C:27]2[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=2)[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[CH3:11]
Reactant: Cn1cnc2c(NCc3cccc(I)c3)nc(Cl)nc21
Reactant: c1ccncc1
Reactant: [SH-]
Agent: [Na+]
Solvent: O
Product: Cn1cnc2c(NCc3cccc(I)c3)nc(Sc3ccncc3)nc21
Temperature: 100 °C
Yield: 27.4 %

Procedure:
A mixture of compound 6 (20.4 mg, 0.051 mmol) and sodium hydrosulfide hydrate (11 mg, 0.2 mmol) in pyridine (1.5 mL) was heated for 5 days at 100° C. After cooling, the reaction mixture was concentrated to dryness and the residue was purified on preparative TLC (chloroform-methanol, 20:1) to give compound 17 (6.5 mg, 27.4%) as a yellow solid. 1H NMR (DMSO-d6) δ 3.78 (s, 3 H, CH3), 4.70 (br s, 2 H, CH2), 7.13 (pseudo t, J=7.6 and 7.5 Hz, 1 H, H-16), 7.29 (d, J=7.2 Hz, 2 H, pyr), 7.45 (d, J=7.2 Hz, 1 H, H-17), 7.60 (d, J=8.2 Hz, 1 H, H-15), 7.86 (s, 1 H, H-13), 8.22 (s, 1 H, H-8), 8.73 (d, J=7.2 Hz, 2 H, pyr), 9.03 (br s, 1 H, exchangeable with D2O, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.[C:23]1([N:29]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[N:31]([CH2:38][C:39]#[CH:40])[C:30]2=[O:41])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:40]#[C:39][CH2:38][N:31]3[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[N:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:30]3=[O:41])[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1
Reactant: C#CCn1c(=O)n(-c2ccccc2)c2ccccc21
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2
Solvent: CCO
Solvent: ClCCl
Product: Cc1nnc2n1-c1sc(C#CCn3c(=O)n(-c4ccccc4)c4ccccc43)cc1C(c1ccccc1Cl)=NC2

Procedure:
The title compound was prepared by reacting 4-(2-chlorophenyl)-2-iodo-9-methyl-6H-thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine with 1,3-dihydro-1-phenyl 3-(2-propynyl)-2H-benzimidazol-2-one under the conditions used in Example 37. The product was isolated by chromatography over the 50-fold amount of silica gel using 5% (v/v) of ethanol in methylene chloride. The clean fractions were combined and evaporated and the residue was crystallized from methanol/ethyl acetate and recrystallized from methanol to yield off white crystals of 1-{3-[4-(2-chlorophenyl)-9-methyl-6H thieno [3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]-2-propynyl }-1,3-dihydro-3-phenyl-2H-benzimidazol-2-one with m.p.176°-179°. These crystals contained 0.66 mol of water according the analytical data.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][CH3:8])=[N:5][N:6]=1.[C:9]([NH:12][C:13]1[CH:22]=[CH:21][C:16]([S:17](Cl)(=[O:19])=[O:18])=[CH:15][CH:14]=1)(=[O:11])[CH3:10].Cl>N1C=CC=CC=1>[CH2:7]([C:4]1[S:3][C:2]([NH:1][S:17]([C:16]2[CH:15]=[CH:14][C:13]([NH:12][C:9](=[O:11])[CH3:10])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[N:6][N:5]=1)[CH3:8]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCc1nnc(N)s1
Agent: Cl
Solvent: c1ccncc1
Product: CCc1nnc(NS(=O)(=O)c2ccc(NC(C)=O)cc2)s1
Temperature: 95 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
2-Amino-5-ethyl-1,3,4-thiadiazole (250 mg, 1.93 mmol) was suspended in pyridine (0.5 mL). N-Acetylsulfanilyl chloride (361 mg, 1.54 mmol) was added slowly at 0° C. The reaction mixture was then heated to 95° C. and was stirred for 1 h. The reaction mixture was then added to aqueous 3N HCl and the mixture extracted with ethyl acetate. The organic extracts were washed with water (3×20 mL), brine (3×20 mL), dried over anhydrous Na2SO4, filtered, and volatiles evaporated. The residue was crystallized from MeOH to give the product (350 mg, 1.07 mmol, 70%) as a solid, mp 197-198° C.; 1H NMR (500 MHz, DMSO) δ 1.28 (3, t, J=7.0 Hz), 2.07 (3, s), 2.82 (2, q, J=7.0 Hz), 7.72 (4, s), 10.32 (1, s), 13.91 (1, s); 13C NMR (125 MHz, DMSO) δ 12.2, 23.7, 24.1, 48.6, 118.5, 126.9, 135.6, 142.7, 159.8, 167.3, 168.9; MS (LCQ, ESI+) Calculated for C12H15N4O3S2 327.1. found 327.1 (M+H)+; HRMS (FAB+, m/z) Calculated for C12H15N4O3S2 327.0586. found 327.0585 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:30][C:31]([F:43])([F:42])[O:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([O:32][C:31]([F:30])([F:42])[F:43])[CH:34]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(OC(F)(F)F)c2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 3-trifluoromethoxybenzene boronic acid. The title compound was obtained in 73% yield as light green foam. MS (m/e): 566.4 (MH+, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C([Li])CCC.O1CCCC1.[CH3:22][C:23]([CH3:25])=[O:24].[Cl-].[NH4+]>O1CCCC1.O>[CH3:22][C:23]([OH:24])([CH3:25])[CH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: Cc1ccc2ccccc2c1
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)Cc1ccc2ccccc2c1
Temperature: -69 °C
Reaction time: 12 h

Procedure:
2-Methylnaphthalene (7.11 g) was dissolved in tetrahydrofuran (100 ml) and the solution was cooled to −69° C. To the solution was added dropwise a 1.6M n-butyllithium-tetrahydrofuran solution (34 ml), and then a solution of acetone (4.41 ml) in tetrahydrofuran (4.41 ml). The reaction mixture was stirred for 12 hr while allowing to warm to room temperature. To the reaction mixture was added dropwise saturated ammonium chloride solution (6 ml), and the resulting mixture was poured into water (200 ml) and extracted with diethyl ether. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=85:15) to give the title compound (3.80 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:11]2[C:15]3[C:16]([CH3:30])=[C:17]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:18]([CH3:21])=[C:19]([CH3:20])[C:14]=3[O:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:10])[CH3:9].[CH2:31]([O:33][C:34](=[O:37])[CH2:35]Br)[CH3:32].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O.[I-].[K+]>[CH3:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([NH:22][C:17]1[C:18]([CH3:21])=[C:19]([CH3:20])[C:14]2[O:13][CH2:12][CH:11]([C:4]3[CH:5]=[CH:6][C:7]([CH:8]([CH3:10])[CH3:9])=[C:2]([CH:3]=3)[O:1][CH2:35][C:34]([O:33][CH2:31][CH3:32])=[O:37])[C:15]=2[C:16]=1[CH3:30])=[O:29]
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)c(O)c1)CO2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)ccc1C(C)C
Yield: 90.6 %

Procedure:
A mixed solution of N-(3-(3-hydroxy-4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (500 mg, 1.22 mmol) obtained in Example 186, ethylbromoacetate (245 mg, 1.47 mmol), potassium carbonate (253 mg, 1.83 mmol) and potassium iodide (10 mg) in acetone (10 mL) was heated for 16 hours under an argon atmosphere. Water was added to the reaction solution and the product was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 548 mg (yield: 91%) of the title compound. Melting point: 149-150° C. (ethyl acetate-hexane).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CC#N>[CH2:18]([O:11][C:7]1[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][OH:1])[CH:10]=[CH:9][CH:8]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: OCCCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: OCCCc1cccc(OCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(3-hydroxypropyl)phenol (1.27 g) in MeCN (12.7 mL) were added K2CO3 (1.73 g) and benzyl bromide (1.05 mL) at ambient temperature and the mixture was stirred at 60° C. for 16 hours. Water (15 mL) was added to the mixture at ambient temperature and the resulting mixture was extracted with EtOAc (20 mL, two times). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=3:1) to afford 3-[3-(benzyloxy)phenyl]-1-propanol (1.77 g) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH:22]1[CH2:24][CH2:23]1>CN(C)C=O>[CH:22]1([CH2:21][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][CH:11]([F:12])[F:13])[CH:5]=[O:6])[CH2:24][CH2:23]1
Reactant: BrCC1CC1
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 104.8 %

Procedure:
To a mixture of 3-hydroxy-4-difluoromethoxybenzaldehyde (19.55 g, 104 mmol) and potassium carbonate (21.56 g, 156 mmol) in dimethylformamide (150 mL) under an argon atmosphere at 60° C. was added bromomethylcyclopropane (15.13 mL, 156 mmol) and the mixture was stirred and heated at 65° C. After 1.5 h, the mixture was allowed to cool and was filtered. The filtrate was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water and was extracted four times with ethyl acetate. The organic extract was washed twice with water and was dried (sodium sulfate). The solvent was removed in vacuo to provide an oil (26.4 g).
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[CH3:13][CH:14]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:15][C:16](OC(CC)C)=[O:17].C(O)(=O)C>CCCCCC.O1CCCC1>[O:17]=[C:16]([CH2:15][CH:14]([CH3:13])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: CCCCC(C)CC(=O)OC(C)CC
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CCCCC(C)CC(=O)CP(=O)(OC)OC
Temperature: -70 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
Under an atmosphere of nitrogen, 375 ml of a 1.33 M solution of n-butyllithium in n-hexane were added dropwise to a solution of 61.9 g of dimethyl methylphosphonate in 587 ml of tetrahydrofuran at -70° C. After stirring the mixture for one hour at -70° C., a solution of 40 g of sec-butyl 3-methylheptanoate (prepared as described in Reference Example 1) in 70 ml of tetrahydrofuran was added dropwise at -70° C., and the mixture was stirred at the same temperature for 4 hours and then stirred overnight at room temperature. The reaction mixture was then acidified with acetic acid and filtered to remove the precipitated solid, and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by distillation under reduced pressure to give 42 g of the title compound having the following physical characteristics:
Reaction SMILES: C(N(C(C)C)CC)(C)C.CC1C=CN=C(N)C=1C.[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20].[CH2:30]([N:37]1[CH2:41][CH:40]([C:42]2[S:43][CH:44]=[C:45]([Br:47])[CH:46]=2)[CH:39]([CH2:48][OH:49])[CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl>[CH2:30]([N:37]1[CH2:41][CH:40]([C:42]2[S:43][CH:44]=[C:45]([Br:47])[CH:46]=2)[CH:39]([CH2:48][O:49][S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:38]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: OCC1CN(Cc2ccccc2)CC1c1cc(Br)cs1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cc1ccnc(N)c1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)OCC2CN(Cc3ccccc3)CC2c2cc(Br)cs2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
Diisopropylethylamine (20.2 g, 0.156 mol), dimethyl aminopyridine (320 mg, 2.6 mmol) and TsCl were (9.88 g, 0.052 mol) were added, respectively, to the product of step b) (9.1 g, 0.026 mol) in 150 mL of dichloromethane at 0° C. The reaction mixture was stirred overnight at room temperature and then was quenched with 75 mL of 1 M HCl and extracted with dichloromethane (3×100 mL). The combined organic extracts were washed with brine (100 mL), dried with MgSO4 and evaporated in vacuo to give the crude product that was purified by column chromatography (SiO2) using a 0-50% methanol-dichloromethane gradient to give the subtitle compound (6.7 g, yield: 51%). MS calculated for C23H24BrNO3S2+H: 506, observed: 506 and 508.
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[C:15]([NH2:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.[C:17]([C:21]1[CH:32]=[CH:31][C:24]([CH:25]=[CH:26][C:27](OC)=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].CO>ClCCCl>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([CH:25]=[CH:26][C:27]([NH:16][C:15]2[C:6]([Cl:5])=[N:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:28])=[CH:31][CH:32]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)C=Cc1ccc(C(C)(C)C)cc1
Reactant: Nc1cc2ccccc2nc1Cl
Agent: C[Al](C)C
Solvent: ClCCCl
Solvent: CO
Product: CC(C)(C)c1ccc(C=CC(=O)Nc2cc3ccccc3nc2Cl)cc1

Procedure:
A solution of trimethylaluminum (2.0 M, 0.61 mL, 1.22 mmol) was added to a solution of 2-chloro-quinolin-3-ylamine (0.2 g, 1.12 mmol) and methyl 4-tert-butylcinnamate (0.241 g, 1.11 mmol) in 1,2-dichloroethane (10 mL). The solution was heated at reflux for 6 hours. The solution was cooled and treated with methanol (˜1 mL). The product was preabsorbed on silica gel and eluted with 20% ethyl acetate in hexane, to give the product as a colorless solid, 0.288 g (71%). MS: m/z 365 (MH+). 1H NMR (DMSO-d6): δ 1.31 (m, 9 H), 7.16 (d, 1 H), 7.50 (d, 2 H), 7.59-7.69 (m, 4 H), 7.75 (t, 1 H), 7.95 (d, 1 H), 8.05 (d, 1 H), 8.94 (s, 1 H), and 9.97 (s, 1 H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Br[CH2:30][CH2:31][C:32]#[N:33]>C(Cl)Cl>[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]([N:23]1[CH2:28][CH2:27][N:26]([CH2:30][CH2:31][C:32]#[N:33])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#CCCBr
Reactant: c1ccc(C(c2ccccn2)N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#CCCN1CCN(C(c2ccccc2)c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.7 %

Procedure:
1.05 g of N,N-diisopropyl-N-ethylamine was added, with stirring, to a solution of 2.0 g of 4-[α-(2-pyridyl)benzyl]piperazine and 1.0 g of 3-bromopropionitrile in 20 ml of methylene chloride, whilst ice-cooling, and the mixture was stirred at room temperature for 16 hours. At the end of this time, the mixture was poured into ice-water and extracted with chloroform. The extracts were combined and dried over anhydrous sodium sulfate, after which the solvent as removed by evaporation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 20:1 by volume mixture of ethyl acetate and ethanol as the eluent, to give 2:1 g (yield 88%) of the title compound as crystals, melting at 114°-116° C.
Reaction SMILES: [O-2].[Nd+3:2].[O-2].[O-2].[Nd+3].[Nd].[CH2:7]([CH:9]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:10][O:11][P:12](=[O:23])([OH:22])[O:13][CH2:14][CH:15]([CH2:20][CH3:21])[CH2:16][CH2:17][CH2:18][CH3:19])[CH3:8].CC1CCCCC1>O.CC(O)=O>[CH2:7]([CH:9]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:10][O:11][P:12]([O-:23])([O:13][CH2:14][CH:15]([CH2:20][CH3:21])[CH2:16][CH2:17][CH2:18][CH3:19])=[O:22])[CH3:8].[Nd+:2]
Reactant: CCCCC(CC)COP(=O)(O)OCC(CC)CCCC
Reactant: [Nd+3]
Agent: [Nd]
Agent: [O-2]
Solvent: CC1CCCCC1
Solvent: CC(=O)O
Solvent: O
Product: CCCCC(CC)COP(=O)([O-])OCC(CC)CCCC
Product: [Nd+]
Reaction time: 0.5 h
Yield: 100 %

Procedure:
3.03 g of neodymium oxide containing 72.4% by weight of neodymium, 17.39 g of di(2-ethylhexyl)phosphoric acid (DEHPA), 80 g of methylcyclohexane (MCH) and 0.054 g acetic acid at 99.8% are introduced into a reactor made inert beforehand with argon. This amount of acetic acid corresponds to 0.06 molar equivalent of CH3COOH relative to the neodymium. The mixture is stirred and brought to 80° C. until the presence of solid can no longer be distinguished visually, i.e., in this case, 1 h. The mixture is cooled. Three washes with 20 g of water are successively carried out in order to remove the inorganic residues. Each wash comprises a step of stirring for 30 minutes and then a step of separating by settling out, also for 30 minutes, except for the final separating by settling out, which is for an overnight period. 16 g, 24.2 g and then 17.1 g are thus recovered. The water/MCH azeotrope is subsequently distilled with a Dean Stark apparatus. A solution of neodymium di(2-ethylhexyl)phosphate in MCH, with a clear appearance, is thus obtained. It is characterized by a content of neodymium in solution of 2.3%, a residual free acidity expressed as percentage by weight of DEHPA of 2.65%, and a water content of 77 ppm. In this case, the molar ratios are the following: DEHPA/Nd=0.51 and water/Nd=0.026. The attack yield is 100%.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[Cl:9][C:10]1[C:11]([C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]([CH3:38])[CH:30]=2)=[N:12][C:13]([NH:16][C:17]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[C:20](F)=[CH:19][C:18]=2[O:27][CH3:28])=[N:14][CH:15]=1>CC(N(C)C)=O>[Cl:9][C:10]1[C:11]([C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]([CH3:38])[CH:30]=2)=[N:12][C:13]([NH:16][C:17]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[C:20]([N:5]3[CH2:6][CH2:7][C@@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]3)=[CH:19][C:18]=2[O:27][CH3:28])=[N:14][CH:15]=1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Solvent: CC(=O)N(C)C
Product: COc1cc(N2CC[C@@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Temperature: 140 °C
Yield: 286.2 %

Procedure:
(3R)—N,N-Dimethylpyrrolidin-3-amine (126 mg, 1.11 mmol) was added to a suspension of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 87, 215 mg, 0.50 mmol) in DMA (5 mL) and the mixture was heated in a microwave at 140° C. for 0.5 h. The mixture was then concentrated in vacuo and combined with material from the reaction below for work up. (3R)—N,N-dimethylpyrrolidin-3-amine (276 mg, 2.42 mmol) was added to a suspension of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 87, 470 mg, 1.10 mmol) in DMA (10 mL) and the mixture was heated in a microwave at 140° C. for 0.5 h. The mixture was concentrated in vacuo and combined with the material from the first procedure described above, for work-up. The combined residues were dissolved in CH2Cl2 (100 mL), and the resulting solution was washed with water (2×100 mL) and sat. brine (100 mL), and then dried (MgSO4) and concentrated in vacuo, Purification by FCC, eluting with 1-10% CH3OH in CH2Cl2 gave the title compound (747 mg, 89%) as an orange gum; m/z: ES+ M+ 522.30.