Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([CH2:44][CH2:45][OH:46])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:41]3[CH2:42][CH2:43][N:38]([CH2:44][CH2:45][OH:46])[CH2:39][CH2:40]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: OCCN1CCNCC1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCO)CC1

Procedure:
In a manner analogous to the method described in example 5, (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 4) was reacted with 2-piperazin-1-yl-ethanol (Chemical Dynamics) to give the title compound. HR-MS (ES, m/z) calculated for C36H45N4O3Cl2 [(M+H)+] 651.2863, observed 651.2863.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:18]([OH:20])=O)[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:6]=2[N:7]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][NH:31][C:30]([CH3:40])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C.O>CN(C=O)C>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:18]([C:4]2[C:5]3[C:10]([CH3:11])=[N:9][N:8]([CH:12]4[CH2:17][CH2:16][CH2:15][CH2:14][O:13]4)[C:6]=3[N:7]=[C:2]([Cl:1])[CH:3]=2)=[O:20])[C:30]([CH3:40])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: Cc1nn(C2CCCCO2)c2nc(Cl)cc(C(=O)O)c12
Reactant: CC(C)(C)OC(=O)N1CCNC(C)(c2ccccc2)C1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nn(C2CCCCO2)c2nc(Cl)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3(C)c3ccccc3)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.7 %

Procedure:
A mixture of 6-chloro-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (325 mg), 3-methyl-3-phenyl-piperazine-1-carboxylic acid tert-butyl ester (319 mg), DIPEA (0.38 mL) and BEP (331 mg) in DMF (8.1 mL) was stirred at r.t. for 90 min. The mixture was poured into water. A solid precipitated which was filtered off and dried in a desiccator vacuum over sodium hydroxide. 540 mg (89%) of the title compound were obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[N:27][CH:26]=[C:25]([CH3:29])[N:24]=2)[CH2:19][CH2:18]1)C(=O)OC(C)(C)C>ClCCl>[CH3:8][NH:9][CH:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:28]=[N:27][CH:26]=[C:25]([CH3:29])[N:24]=2)[CH2:21][CH2:22]1
Reactant: Cc1cncc(N2CCC(N(C)C(=O)OC(C)(C)C)CC2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC1CCN(c2cncc(C)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (2 ml) was added at 0° C. to a solution of tert-butyl methyl(1-(6-methylpyrazin-2-yl)piperidin-4-yl)carbamate (250 mg, 0.816 mmol, 1 eq) in dichloromethane (10 ml) and the reaction mixture was stirred for 2 h at room temperature. Concentration under reduced pressure was then carried out. The crude product so obtained was used in the next stage without being purified further.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:15]1[CH2:17][CH:16]1[CH2:18]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:18][CH:16]3[CH2:17][O:15]3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OCC2CO2)c1
Product: Clc1ccc(N2CCN(CC3CO3)CC2)cc1Cl
Yield: 97 %

Procedure:
The same method as employed in the preparation of Intermediate 1 but starting from 1-(3,4-dichloro-phenyl)-piperazine) and 3-nitro-benzenesulfonic acid oxiranylmethyl ester gives after Biotage chromatography the title compound as a yellow oil in a 97% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:11])[C:7]([NH2:10])=[CH:8][CH:9]=1)([O-:3])=[O:2].[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](=O)[C:18](O)=[O:19]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][C:18](=[O:19])[C:17]([C:13]1[S:12][CH:16]=[CH:15][CH:14]=1)=[N:11]2)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: O=C(O)C(=O)c1cccs1
Product: O=c1[nH]c2ccc([N+](=O)[O-])cc2nc1-c1cccs1

Procedure:
The quinoxalin-2-one of the present example is prepared with 4-Nitro-benzene-1,2-diamine and (thiophen-2-yl) oxo-acetic acid via the method described in Example 12 to afford 6-Nitro-3-thiophen-2-yl-1H-quinoxalin-2-one.
Reaction SMILES: C([Li])CCC.C[N:7]([CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])C.CN1C=CN=C1.[Sn:20](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24]>>[CH3:12][N:11]1[C:10]([Sn:20]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:9][N:7]=[CH:13]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CN(C)CCN(C)C
Agent: Cn1ccnc1
Agent: [Li]CCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.8 %

Procedure:
Butyllithium (3.75 mL, 9.40 mmol) and TMEDA (2.24 mL, 14.85 mmol) were stirred at −20° C. in hexanes (7 mL) in an ethanol/dry ice/water bath for 30 minutes. 1-Methylimidazole (0.5 mL, 6.27 mmol) was added and the mixture stirred at room temperature for 1 h. After cooling to −20° C., Bu3SnCl (1.70 mL, 15.67 mmol) was added dropwise. The reaction stirred for 15 minutes at −20° C. then at room temperature overnight before being quenched with 1:1 EtOAc/water (20 mL). The layers were separated and the aqueous layer extracted with EtOAc (3×). The combined organics were washed with water, dried over Na2SO4, concentrated, and chromatographed (4:96 MeOH/EtOAc) to give 1-methyl-5-tributylstannanyl-1H-imidazole (0.486 g).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]3[CH2:19][N:20]([C:23](=[O:25])[CH3:24])[CH2:21][CH2:22][C:17]=3[NH:16][N:15]=2)=[CH:10][CH:9]=1.[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>CN(C=O)C.CCOC(C)=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:18]3[CH2:19][N:20]([C:23](=[O:25])[CH3:24])[CH2:21][CH2:22][C:17]=3[N:16]([CH2:26][CH:28]3[CH2:29][O:30]3)[N:15]=2)=[CH:12][CH:13]=1
Reactant: CC(=O)N1CCc2[nH]nc(-c3ccc(Br)cc3)c2C1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2c(c(-c3ccc(Br)cc3)nn2CC2CO2)C1
Reaction time: 18 h
Yield: 55.8 %

Procedure:
Cs2CO3 (11.58 g, 35.5 mmol) was added to a solution of 1-[3-(4-bromo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (7.59 g, 23.7 mmol) and epichlorohydrin (20 mL, 234 mmol) in DMF (100 mL). The mixture was stirred for 18 h then diluted with EtOAc (800 mL) and washed with saturated aqueous NaHCO3 (2×100 mL), H2O (2×100 mL), and brine (100 mL). The NaHCO3 layer was extracted with EtOAc (2×150 mL). The combined washes were extracted with EtOAc (2×100 mL). The combined extracts were dried over Na2SO4 and concentrated. Column chromatography (silica, 10-20% acetone/CH2Cl2) afforded 4.98 g (56%) of the title compound. HPLC, tR=4.90 min. (Reverse phase conditions: HP 1100 LCMS, Phenomenex luna 2.1×150 mm column, 60% MeOH/H2O (0.5% AcOH) to 90% MeOH/H2O (0.5% AcOH), held at initial conditions for 2 min then ramped to final conditions over 5 min.) MS (electrospray): m/z calculated for C17H1979BrN3O2, [M+H]+, 376.07. found 376.0. 1H NMR (CDCl3, 400 MHz, a mixture of amide rotamers): 7.47 (d with fine splittings, J=8.5, Hz, 2H), 7.44 (m, 4H), 7.38 (d with fine splittings, J=8.5, Hz, 2H), 4.71 and 4.64 (A and B of AB quartet, Jab=15.7 Hz, 2H), 4.51 (s, 2H), 4.39 (dd, J=15.1, 2.5 Hz, 1H), 4.34 (dd, J=15.0, 2.9 Hz, 1H), 4.02 (dd, J=5.2, 3.9 Hz, 1H), 3.98 (dd, J=5.3, 3.7 Hz, 1H), 3.83 (m, 2H), 3.64 (m, 2H), 3.25 (br m, 2H), 2.80-2.60 (m, 6H), 2.46 (dd, J=4.6, 2.6 Hz, 1H), 2.38 (dd, J=4.6, 2.6 Hz, 1H), 2.10 (s, 3H), 2.06 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][S@@](C(C)(C)C)=O)[CH3:9])=[C:4]([O:17][CH3:18])[CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[C:23]([O:26][CH3:27])=[N:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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(O)C>[Cl:19][C:20]1[CH:21]=[C:22]([C:2]2[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[C:4]([O:17][CH3:18])[CH:3]=2)[C:23]([O:26][CH3:27])=[N:24][CH:25]=1
Reactant: COc1ncc(Cl)cc1B(O)O
Reactant: COc1cc(Br)ccc1C(C)N[S@](=O)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc(-c2cc(Cl)cnc2OC)ccc1[C@@H](C)N
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of 4-bromo-2-hydroxyacetophenone (0.460 g, 2.0 mmol), titanium tetraethoxide (1.0 g, 4.0 mmol) and (R)-2-methyl-2-propanesulfinamide (0.266 g, 2.2 mmol) in dichloromethane (3.0 ml) was heated in a microwave oven at 120° C. for 15 min. The mixture was cooled in ice and added to a stirred mixture of sodium borohydride (0.30 g, 8.0 mmol) in tetrahydrofuran (50 ml). This mixture was stirred for 1 h at ambient temperature, treated with brine (30 ml) and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and the solvent evaporated The residue was flash chromatographed on silica gel eluting with 3:1 heptane/ethyl acetate to give (R)-2-methyl-propane-2-sulfinic acid [1-(4-bromo-2-methoxy-phenyl)-ethyl]-amide. A mixture of (R)-2-methyl-propane-2-sulfinic acid [1-(4-bromo-2-methoxy-phenyl)-ethyl]-amide (0.130 g, 0.4 mmol), 5-chloro-2-methoxy-pyridine-3-boronic acid (0.150 g, 0.8 mmol), tetrakis(triphenylphosphine)palladium (0) (0.025 g, 0.02 mmol), 2M aqueous sodium carbonate solution (2 ml), toluene (1 ml) and ethanol (1 ml) was heated in a microwave oven at 120° C. for 15 min. The mixture was partitioned between ethyl acetate and dilute aqueous sodium carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the solvent evaporated and the residue dissolved in methanol. This solution was treated with 2M hydrogen chloride in diethyl ether solution. After standing for 2 hours, the mixture was poured onto an SCX column, washed with methanol and then eluted with 1M ammonia in methanol solution. The solvent was evaporated and the residue flash chromatographed on silica gel eluting with 98:2 ethyl acetate/2M ammonia in methanol to give (R)-1-[4-(5-chloro-2-methoxy-pyridin-3-yl)-2-methoxy-phenyl]-ethylamine. The title compound was prepared in a similar manner to 1-methyl-3-trifluoromethyl-1H-pyrazole-4-sulfonic acid [1-(3,5′-difluoro-2′-methoxy-biphenyl-4-yl)-ethyl]-amide (Example 30) using (R)-1-[4-(5-chloro-2-methoxy-pyridin-3-yl)-2-methoxy-phenyl]-ethylamine instead of 1-(3,5′-difluoro-2′-methoxy-biphenyl-4-yl)-ethylamine. MS (ESI) m/z: 505.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)[CH3:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[O-]S([O-])(=O)=O.[Na+].[Na+].Cl[C:35]([O:37][CH3:38])=[O:36]>C1COCC1.C(OCC)(=O)C.O>[CH3:20][C:12]1[N:11]=[C:10]([N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:35]([O:37][CH3:38])=[O:36])=[CH:3][CH:4]=2)[CH3:9])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: COC(=O)Cl
Reactant: Cc1nc(N(C)c2ccc(N)cc2)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)Nc1ccc(N(C)c2nc(C)nc3ccccc23)cc1
Temperature: 0 °C
Yield: 71.4 %

Procedure:
To a mixture of (4-amino-phenyl)-(2-methyl-quinazolin-4-yl)-methylamine (75 mg, 0.28 mmol) in 5 mL of THF with K2CO3 (80 mg, 0.58 mmol) and Na2SO4 (80 mg, 0.56 mmol) cooled at 0° C. was added methyl chloroformate (200 uL, 2.6 mmol), followed by 500 uL of water dropwise while stirring vigorously. The mixture was stirred for 5 min at 0° C., and diluted with 25 mL of ethyl acetate. The mixture was washed with saturated NaHCO3, the organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by column chromatography (45% ethyl acetate/hexane) to give the title compound (65 mg, 0.20 mmol, 71%). 1H NMR (CDCl3): 7.74 (m, 1H), 7.53 (ddd, J=8.4, 6.6, 1.8, 1H), 7.40 (m, 2H), 7.04-7.12 (m, 3H), 6.97 (m, 1H), 6.73 (s, broad, 1H), 3.80 (s, 3H), 3.60 (s, 3H), 2.73 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([Cl:26])[CH:20]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.CCN(CC)CC.Cl[C:35]([O:37][CH3:38])=[O:36].O>C(Cl)Cl>[Cl:26][C:21]1[CH:20]=[C:19]([C@H:5]([O:4][CH2:3][CH2:2][NH:1][C:35]([O:37][CH3:38])=[O:36])[C@@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[CH:24]=[C:23]([F:25])[CH:22]=1
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cc(F)cc(Cl)c2)C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)NCCO[C@@H](c1cc(F)cc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 69.4 %

Procedure:
A solution of (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chloro-5-fluorophenyl)methyl)piperidine-1-carboxylate (24 g, 0.062 mol) in dry CH2Cl2 (300 mL) and Et3N (31.4 g, 43 mL) was cooled to 0° C. in ice-water bath, a solution of methyl chloroformate (11.8 g, 0.124 mol) in dry CH2Cl2 (100 mL) was added dropwise. After addition, the reaction mixture was stirred for 1-2 h at 0-5° C. Water (200 mL) was added to quench the reaction. The aqueous layer was extracted with CH2Cl2 (3×100 mL), the combined organic layers were washed with 10% citric acid (2×80 mL) and brine, then dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by column chromatography to give (R)-tert-butyl 3-((R)-(3-chloro-5-fluorophenyl)(2-(methoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate (19 g, 0.043 mol). 1H NMR (CD3OD) δ 7.17 (s, 1H), 7.16-7.08 (m, 1H), 7.07-7.00 (m, 1H), 4.20-4.00 (m, 2H), 3.90-3.78 (d, 1H), 3.61 (s, 3H), 3.28-3.20 (m, 2H), 2.92-2.68 (dd, 2H), 1.52-1.74 (m, 2H), 1.42 (s, 9H), 1.35-1.10 (m, 3H),
Reaction SMILES: [NH2:1][C:2](=[C:10]([C:15](=O)[CH:16]([CH3:18])[CH3:17])[C:11]([O:13][CH3:14])=[O:12])[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.CNS(C)(=O)=O.C(O)(C)(C)C.[C:31]([N:33]([CH3:38])[S:34]([CH3:37])(=[O:36])=[O:35])#[N:32].CC(C)([O-])C.[Na+]>>[F:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:15]([CH:16]([CH3:18])[CH3:17])[N:32]=[C:31]([N:33]([S:34]([CH3:37])(=[O:36])=[O:35])[CH3:38])[N:1]=2)=[CH:4][CH:5]=1
Reactant: COC(=O)C(C(=O)C(C)C)=C(N)c1ccc(F)cc1
Reactant: CN(C#N)S(C)(=O)=O
Agent: CC(C)(C)[O-]
Agent: CNS(C)(=O)=O
Agent: [Na+]
Solvent: CC(C)(C)O
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Temperature: 50 °C
Reaction time: 19.9 h
Yield: 68.1 %

Procedure:
2.97 g (11.2 mmol) of methyl 2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate were introduced into 2.45 g (22.4 mmol) of N-methylmethanesulphonamide (MMSA) and 4.19 g (55.9 mmol) of tert-butanol together with 4.51 g (36.6 mmol) of N-cyano-N-methylmethanesulphonamide (CMMSA). 2.22 g (22.4 mmol) of sodium tert-butoxide were added to this suspension at room temperature in portions. An orange-coloured suspension was obtained. It was heated to 50° C. and stirred at 50° C. for 19.9 h. The suspension was poured onto 20 g of ice water, and the precipitate was filtered off and washed with water (2×5 ml). After drying in a high vacuum, 2.91 g of methyl 4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)pyrimidine-5-carboxylate were obtained in the form of a pale beige solid having a concentration of 76.4% (HPLC), which corresponds to a yield of 52.1%.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:21])([CH3:20])[CH3:19])[N:13]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH3:22]I>CN(C=O)C>[Si:3]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:21][CH3:22])([CH3:20])[CH3:19])[N:13]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: CC(C)(O)c1cccc(CO[Si](C)(C)C(C)(C)C)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(C)(C)c1cccc(CO[Si](C)(C)C(C)(C)C)n1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 57 %

Procedure:
NaH (285 mg, 7.12 mmol) was added portionwise to a stirred solution of 2-tert-butyldimethylsilyloxymethyl-6-(1-hydroxy-1-methylethyl)pyridine (2.0 g, 7.12 mmol) in DMF (30 mL) at room temperature. After 20 min, methyl iodide (1.33 mL, 21.4 mmol) was added, the mixture was warmed to 50° C. and stirred for 16 h at this temperature. The mixture was poured onto water, extracted with EtOAc (×3), the combined extracts were dried (MgSO4), filtered evaporated and the residue purified by column chromatography (20:1 to 10:1, isohexane:EtOAc) to give the title compound (1.20 g, 57%) as a colorless oil; NMR δH (400 MHz, CDCl3) 7.69-7.65 (1H, m), 7.38-7.34 (2H, m), 4.81 (2H, s), 3.15 (3H, s), 1.53 (6H, s), 0.96 (9H, s), 0.12 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CN1CCNCC1
Product: CN1CCN(c2ccc(Cl)nn2)CC1
Temperature: 100 °C
Yield: 59.7 %

Procedure:
A 25-mL single-neck round bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 3,6-dichloropyridazine (1.49 g, 10.0 mmol) and N-methylpiperazine (1.17 g, 11.7 mmol), and the flask was placed in an oil bath, which was heated to 100° C. After 1.5 h the flask was cooled to room temperature, and the resulting cake was crushed and triturated with acetonitrile (10 mL). The suspension was filtered, and the filter cake was mixed with 10% aqueous potassium carbonate (15 mL). The resulting mixture was extracted with MtBE (2×35 mL). The organic extracts were combined, dried over sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to afford a 60% yield (1.27 g) of 122e as a white solid: mp 106-107° C.; 1H NMR (300 MHz, CDCl3) δ 7.20 (d, 1H, J=9.5 Hz), 6.89 (d, 1H, J=9.6 Hz), 3.65 (t, 4H, J=5.1 Hz), 2.53 (t, 4H, J=5.1 Hz), 2.35 (s, 3H); MS (ESI+) m/z 213.1 (M+H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]1([CH2:17][CH2:18][N:19]([CH3:35])[CH2:20][CH2:21][CH2:22][C:23]([CH:32]([CH3:34])[CH3:33])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:24]#N)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S(=O)(=O)(O)[OH:37].C(O)(=O)C(C(C(O)=O)O)O.[OH-].[K+]>CCCCCC.C(OCC)C>[C:11]1([CH2:17][CH2:18][N:19]([CH3:35])[CH2:20][CH2:21][CH2:22][C:23]2([CH:32]([CH3:34])[CH3:33])[CH:24]=[CH:29][CH:30]=[CH:31][CH:26]2[CH2:27][CH:28]=[O:37])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S(=O)(O)O
Reactant: CC(C)C(C#N)(CCCN(C)CCc1ccccc1)c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [H-]
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)C1(CCCN(C)CCc2ccccc2)C=CC=CC1CC=O
Reaction time: 1.5 h

Procedure:
180 ml of a 1M solution of diisobutylaluminum hydride in hexane were added dropwise, at -5° C., to a solution of 33.4 g (0.1 mole) of 2-[3-[(phenylethyl)-methylamino]-propyl]-isopropylphenylacetonitrile in 400 ml of diethyl ether. The mixture was stirred for 1.5 hours, after which 500 ml of 10% strength sulfuric acid were added. 30 g of tartaric acid were introduced, the mixture was rendered alkaline with concentrated potassium hydroxide solution, and the ether phase was separated off and washed several times with sodium chloride solution. After the ether phase had been dried over sodium sulfate, the ether was distilled off, the remaining oily residue was dissolved in 300 ml of ethyl acetate, and hydrochloric acid in isopropanol was added. The mixture was left to stand overnight, after which the precipitated hydrochloride was filtered off under suction.
Reaction SMILES: [CH2:1]([Sn:11]([CH2:26][C:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([CH3:29])[CH3:28])(C1C=CC(F)=CC=1)[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Cl:36]Cl>C(Cl)(Cl)Cl>[CH2:1]([Sn:11]([Cl:36])([CH2:26][C:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([CH3:29])[CH3:28])[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C[Sn](CC(C)(C)c1ccccc1)(c1ccc(F)cc1)c1ccc(F)cc1)c1ccccc1
Reactant: ClCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C[Sn](Cl)(CC(C)(C)c1ccccc1)c1ccc(F)cc1)c1ccccc1
Yield: 101.3 %

Procedure:
Dineophyl-di(parafluorophenyl)tin (62.1 g, 0.108 mol) prepared above was dissolved in chloroform (200 g). While the resulting solution was maintained at -15° to -20° C., chlorine gas (7.6 g, 0.216 gram atom,) was introduced. The mixture was then concentrated under reduced pressure to give 56 g of dineophyl-parafluorophenyltin chloride as a pale-yellow liquid. Gas chromatography analysis indicated 87.5% purity of the desired product.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[O:15][C:11]3([CH2:14][CH2:13][CH2:12]3)[CH2:10][C:9](=[O:16])[C:8]=2[CH:17]=1>CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[O:15][C:11]3([CH2:12][CH2:13][CH2:14]3)[CH2:10][CH:9]([OH:16])[C:8]=2[CH:17]=1
Reactant: O=C1CC2(CCC2)Oc2ccc(Cl)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CC2(CCC2)Oc2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Sodium borohydride (40 mmol) was added to a solution of 6-Chloro-3,4-dihydro-4-oxo-spiro[2H-1-benzopyran-2,1′-cyclobutane] (10 mmol) in methanol (10 ml). at about 0° C. and the reaction mixture was stirred at room temperature for about 2 h and compound was extracted in ethyl acetate. Organic layer was washed with water, brine and separated. It was then dried on anhydrous sodium sulfate and concentrated to afford the desired product as a white solid.
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1.C(N(CC)CC)C>C(OCC)C.C(OCC)(=O)C>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[O:21][CH2:2][C:3](=[O:10])[C:4]=2[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:15][CH:14]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: COc1ccc(N=C=O)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(Nc2ccc(OC)cc2)OCC1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Under a nitrogen atmosphere, to a mixed solution of ethyl 4-chloroacetoacetate (0.82 mL, 6.0 mmol) and 4-methoxyphenyl isocyanate 1.1 g, 7.2 mmol) in diethyl ether/ethyl acetate (10 mL/1.0 mL) that cooled with ice bath, triethylamine (0.96 mL, 6.9 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 1.5 h then the precipitate was collected by filtration, washed with diethyl ether, 1M hydrochloric acid solution, water and diethyl ether, and then dried to afford ethyl 2-[(4-methoxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (1.3 g, y. 78%).