Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:3]=1[CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C([Li])CCC.[C:26]1(=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1>[Si:6]([O:5][CH2:4][C:3]1[CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=[CH:16][C:2]=1[C:26]1([OH:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: O=C1CCCCC1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(C(F)(F)F)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cc(C(F)(F)F)ccc1C1(O)CCCCC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of (2-bromo-5-(trifluoromethyl)benzyloxy)(tert-butyl)dimethylsilane (140 mg; 0.379 mmol) in tetrahydrofuran (0.5 mL) at −78° C. was added dropwise n-butyllithium (0.4 mL; 0.64 mmol; 1.6M in hexanes). The reaction was stirred at −78° C. for 15 minutes. Cyclohexanone (0.8 mL; 7.7 mmol) was added stirred at −78° C. for 10 minutes. The reaction was then stirred at room temperature for 15 minutes. The reaction was quenched with 2 drops of water. It was diluted with ethyl acetate and filtered through a column containing silica gel and sodium sulfate. The crude was then purified over a 12 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 10-40% ethyl acetate in heptane) to give 112 mg (76%) as a liquid. MS (ES+): Calc: 388.5, Found: 433.2 (M+HCO2−) 1H NMR (400 MHz, CDCl3) δ ppm 7.58 (s, 1H), 7.51 (d, J=8.30 Hz, 1H), 7.45 (d, J=8.30 Hz, 1H), 5.05 (s, 2H), 3.92 (s, 1H), 1.94-1.73 (m, 6H), 1.68-1.6 (m, 2H), 1.31 (m, 2H), 0.93 (s, 9H), 0.12 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[CH:3]=1.[N:9]1([CH2:14][CH2:15][NH2:16])[CH2:13][CH2:12][CH2:11][CH2:10]1>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:16][CH2:15][CH2:14][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:3]=1
Reactant: Fc1cc(Br)ccn1
Reactant: NCCN1CCCC1
Solvent: CN(C)C=O
Product: Brc1ccnc(NCCN2CCCC2)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a 4 mL screw-cap vial was added 4-bromo-2-fluoro-pyridine (100 mg, 0.57 mmol), 2-pyrrolidin-1-ylethanamine (1.1 equiv., 0.63 mmol, 71 mg), and dimethylformamide (0.25 mL). The reaction was capped and shaken at 100° C. for 3 h. TLC showed new spot, with no starting material present. The reaction was concentrated, and 4-bromo-N-(2-pyrrolidin-1-ylethyl)pyridin-2-amine was carried directly on to the Suzuki cross-coupling step.
Reaction SMILES: B(F)(F)F.CCOCC.C(C1OC1)Cl.[CH:15]([NH:18][C:19](=O)[C:20]([C:22]1[S:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)=[O:21])([CH3:17])[CH3:16]>CCOCC>[CH:15]([NH:18][CH2:19][CH:20]([C:22]1[S:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[OH:21])([CH3:17])[CH3:16]
Reactant: COc1ccc(C(=O)C(=O)NC(C)C)s1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCC1CO1
Product: COc1ccc(C(O)CNC(C)C)s1
Temperature: 25 °C
Reaction time: 56 h

Procedure:
To freshly distilled boron trifluoride etherate (61.0 mmoles) dissolved in 30 ml anhydrous ether, distilled epichlorohydrin (4.19 g, 46.0 mmoles) is added at such a rate to cause the solution to reflux. After addition, the solution is heated at reflux for 1.5 hr with vigorous stirring. The reaction mixture is cooled and most of the ether is removed with a pipette and the solid residue is dried with a stream of dry nitrogen. Anhydrous methylene chloride (50 ml) and the N-isopropyl-5-methoxy-2-thiopheneglyoxylamide (8.0 g, 39.0 mmole), described above, is added and the solution is stirred at room temperature for 56 hr. The methylene chloride is evaporated and replaced with 50 ml anhydrous methanol. The solution is cooled to 0° C. and sodium borohydride (4.0 g) is added portionwise over a period of 4 hr. The mixture is brought to room temperature, stirred for 24 hr then quenched with ice-water. The aqueous solution is extracted several times with ether. The combined ether extract are washed with water and brine, dried (MgSO4) and concentrated. The product is purified by chromatography on silica gel (400 g, chloroformmethanol, 8:2). Evaporation of the eluate and recrystallization of the residue from hexane gives the title compound; mp 81° C, γmaxCHCl3 3300, 3100, 1650, 1505, 1220 cm-1.
Reaction SMILES: F[C:2](F)(F)[C:3](=O)[CH2:4][C:5]([O:7]CC)=O.Cl.Cl[C:15]1[CH:16]=[C:17]([NH:21][NH2:22])[CH:18]=[CH:19][CH:20]=1>C(O)(=O)C>[C:17]1([N:21]2[C:5](=[O:7])[CH2:4][C:3]([C:2]3[CH:17]=[CH:16][CH:15]=[CH:20][CH:19]=3)=[N:22]2)[CH:18]=[CH:19][CH:20]=[CH:15][CH:16]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Solvent: CC(=O)O
Product: O=C1CC(c2ccccc2)=NN1c1ccccc1
Temperature: 100 °C
Yield: 96.8 %

Procedure:
A mixture of ethyl trifluoroacetoacetate (5 g, 27.2 mmol), 3-chlorophenylhydrazine hydrochloride (4.86 g, 27.2 mmol) and acetic acid (50 mL) was heated at 100° C. overnight. The reaction mixture was concentrated in vacuo, CH2Cl2 (80 mL) and hexane (40 mL) were added to the residue and the solid which formed was collected by filtration to afford 3.11 g of 2,4-dihydro-2-(3-chlorophenyl)-5-trifluoromethyl-3H-pyrazol-3-one (Formula III: R1 =3-Cl--Ph; R2 =CF3 ; R3 =H).
Reaction SMILES: B(O)(O)[C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C1COCC1.Br[C:24]1[CH:29]=[C:28]([Br:30])[CH:27]=[CH:26][C:25]=1[N+:31]([O-:33])=[O:32].[OH-].[Na+]>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.O>[Br:30][C:28]1[CH:27]=[CH:26][C:25]([N+:31]([O-:33])=[O:32])=[C:24]([C:2]2[C:15]3[C:10]([C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[CH:3]=2)=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:29]=1
Reactant: OB(O)c1cc2ccccc2c2ccccc12
Reactant: O=[N+]([O-])c1ccc(Br)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(Br)cc1-c1cc2ccccc2c2ccccc12
Yield: 61.6 %

Procedure:
A 2 L round bottom flask was charged with phenanthracene-9-boronic acid (76.61 g, 345 mmol), THF (700 mL), and H2O (350 mL), and the mixture was dissolved. To the resultant mixture, 2,4-dibromo-1-nitrobenzene (146 g, 518 mmol), NaOH (42 g, 1035 mmol), and Pd(PPh3)4 (20 g, 17.3 mmol) were sequentially added, followed by reaction at 80° C. for 24 hours. After the reaction was completed, the resultant product was extracted with methylene chloride, water, and brine, and the organic layer was dried with MgSO4. The obtained organic layer was purified by silica gel column (methylene chloride:hexane=1:3) so as to give 80.4 g of a product (62%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.C([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14](=O)[NH:15][CH:16]=[N:17]2)=[C:12]([O:21][CH:22]([CH3:24])[CH3:23])[CH:11]=1)(=O)C.C(N(C(C)C)CC)(C)C.[NH2:34][C:35]1[CH:36]=[N:37][N:38]([CH2:40][C:41]([NH:43][C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[C:45]=2[F:51])=[O:42])[CH:39]=1>ClCCCl.O>[F:51][C:45]1[C:46]([F:50])=[CH:47][CH:48]=[CH:49][C:44]=1[NH:43][C:41](=[O:42])[CH2:40][N:38]1[CH:39]=[C:35]([NH:34][C:14]2[C:13]3[C:18](=[CH:19][C:10]([OH:9])=[CH:11][C:12]=3[O:21][CH:22]([CH3:23])[CH3:24])[N:17]=[CH:16][N:15]=2)[CH:36]=[N:37]1
Reactant: CC(=O)Oc1cc(OC(C)C)c2c(=O)[nH]cnc2c1
Reactant: Nc1cnn(CC(=O)Nc2cccc(F)c2F)c1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)Oc1cc(O)cc2ncnc(Nc3cnn(CC(=O)Nc4cccc(F)c4F)c3)c12
Temperature: 80 °C
Reaction time: 2 h
Yield: 59.4 %

Procedure:
Phosphoryl chloride (3.7 ml, 40 mmol) was added to a solution of 5-isopropoxy-4-oxo-3,4-dihydroquinazolin-7-yl acetate (2.6 g, 10 mmol) and di-iso-propylethylamine (14 ml, 80 mmol) in 1,2-dichloroethane (75 ml) and the reaction was heated at 80° C. for 1 hour. The mixture was evaporated under reduced pressure and the residue suspended in dimethylacetamide (30 ml). 2-(4-Amino-1H-pyrazol-1-yl)-N-(2,3-difluorophenyl)acetamide (2.5 g, 10 mmol) was added and the mixture was then heated at 90° C. for 1 hour. The mixture was evaporated under reduced pressure and the residue stirred in a 7N solution of ammonia in methanol (100 ml) at ambient temperature for 2 hours. The mixture was evaporated under reduced pressure to leave a yellow solid which was stirred in water (50 ml) for 1 hour, then filtered and the residue purified by silica gel chromatography eluting with a 0 to 10% mixture of methanol in dichloromethane to give N-(2,3-difluorophenyl)-2-{4-[(7-hydroxy-5-isopropoxyquinazolin-4-yl)amino]-1H-pyrazol-1-yl}acetamide (2.7 g, 60% yield):
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:30][C@H:31]2[CH2:51][CH2:50][C:33]3([O:37][C@H:36]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C@@H:35]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[O:34]3)[CH2:32]2)[C:13](=O)[CH2:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[O:28]CCO3)=[CH:20][N:19]=2)=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C([O-])(=O)C.[NH4+:56].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([C:13]2[NH:56][C:16]([C:18]3[N:19]=[CH:20][C:21]([CH:24]=[O:28])=[CH:22][CH:23]=3)=[CH:15][CH:14]=2)[CH2:30][C@H:31]2[CH2:51][CH2:50][C:33]3([O:37][C@H:36]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[C@@H:35]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[O:34]3)[CH2:32]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)C(=O)CCC(=O)c2ccc(C3OCCO3)cn2)cc1Cl
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)c2ccc(-c3ccc(C=O)cn3)[nH]2)cc1Cl
Temperature: 110 °C
Reaction time: 1 h
Yield: 31.7 %

Procedure:
To a solution of 5-[3-chloro-4-(methylsulfonyl)phenyl]-1-[5-(1,3-dioxolan-2-yl)pyridin-2-yl]-6-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]hexane-1,4-dione (276 mg) in acetic acid (2 mL) was added ammonium acetate (466 mg), and the mixture was stirred at 110° C. for 1 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (80.0 mg, yield 32%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
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]([N:17]([CH3:27])[C@H:18]([CH3:26])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.O.[NH2:29][NH2:30]>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]([N:17]([CH3:27])[C@H:18]([CH3:26])[CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:5]=3)=[CH:15][CH:14]=2)[NH:30][N:29]=1
Reactant: NN
Reactant: C[C@H](Cc1ccccc1)N(C)c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Solvent: O
Solvent: CCO
Product: C[C@H](Cc1ccccc1)N(C)c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-(2-amino-6-{methyl[(1R)-1-methyl-2-phenylethyl]amino}-4-pyrimidinyl)-2-fluorobenzonitrile (200 mg, 0.55 mmol) in ethanol (2 mL) was added hydrazine hydrate (2.0 mL, 99%), and the reaction mixture was heated at 120° C. under microwave conditions with stirring for 1 hour. The mixture was cooled to room temperature and concentrated. The resulting residue was washed with Et2O (30 mL) and dried in vacuo to afford the title compound (156 mg) as a yellow solid. LC-MS (ES) m/z=374 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.12 (d, J=6.0 Hz, 3H), 2.77-2.89 (m, 6H), 5.36 (s, 2H), 5.99 (s, 2H), 6.35 (s, 1H), 7.12-7.16 (m, 1H), 7.23-7.27 (m, 4H), 7.49-7.52 (m, 1H), 7.68-7.70 (m, 1H), 7.88 (s, 1H), 11.50 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:14])=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].[NH2:15][OH:16]>CCO>[OH:16][N:15]=[C:1]([C:3]1[C:4]([CH3:14])=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])[NH2:2]
Reactant: COC(=O)c1cc(C#N)c(C)cc1C
Reactant: NO
Solvent: CCO
Product: COC(=O)c1cc(C(N)=NO)c(C)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A solution of methyl 5-cyano-2,4-dimethylbenzoate (compound 2.3, 6 g, 28.54 mmol, 1.00 equiv, 90%) and NH2OH (10 mL, 5.00 equiv, 50% in water) in EtOH (20 mL) was stirred at 100° C. in an oil bath. After 2 h, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with 100 mL of ethyl acetate, washed with 2×20 mL of brine, dried (Na2SO4), and concentrated under reduced pressure to yield 4.66 g (66%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][S:29](=[O:32])[CH2:28][CH2:27]1>>[CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16]([N:26]3[CH2:31][CH2:30][S:29](=[O:32])[CH2:28][CH2:27]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc(N2CCSCC2)c2ncnc(SCc3ccccc3)c2n1
Reactant: O=S1CCNCC1
Product: O=S1CCN(c2nc(N3CCSCC3)c3ncnc(SCc4ccccc4)c3n2)CC1

Procedure:
This compound was prepared analogous to Example 1 from 8-benzylthio-2-chloro-4-thiomorpholino-pyrimido[5,4-d]pyrimidine (melting point: 175°-177° C.) and thiomorpholine1-oxide.
Reaction SMILES: BrC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)(=O)=O)=CC=1.[CH3:28][C@@H:29]1[NH:34][CH2:33][CH2:32][N:31]([C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]=2)[CH2:30]1>CS(C)=O.C(=O)(O)[O-].[Na+]>[CH3:26][C:21]1[CH:20]=[CH:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14][C@H:13]([CH2:12][N:34]4[CH2:33][CH2:32][N:31]([C:35]5[CH:44]=[CH:43][C:42]6[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=6)[N:36]=5)[CH2:30][C@@H:29]4[CH3:28])[O:27][C:17]3=2)[N:22]=1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Reactant: C[C@H]1CN(c2ccc3ccccc3n2)CCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CN1CCN(c2ccc4ccccc4n2)C[C@@H]1C)O3
Temperature: 50 °C
Yield: 61.9 %

Procedure:
A mixture of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-bromobenzenesulfonate (0.165 g, 0.367 mmol) and (S)-2-(3-methyl-piperazin-1-yl)-quinoline (250 mg, 1.10 mmol) in anhydrous dimethylsulfoxide (4 mL) was heated at 50° C. overnight. The cooled reaction was diluted with saturated aqueous sodium bicarbonate (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography on silica gel (2/2/96 methanol/2 M ammonia in methanol/methylene chloride) afforded 100 mg (62%) of the title compound as an off-white solid: mp 141–144° C.; MS (ES) m/z 441 [M+H]+; [α]D −36.5° (c 1.0, DMSO).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:23])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(O[CH:29](N(C)C)[N:30]([CH3:32])[CH3:31])(C)(C)C.CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[CH:29][N:30]([CH3:32])[CH3:31])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNC(=O)Cc2ccc(C)cc2)cc1OC
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CCNC(=O)C(=CN(C)C)c2ccc(C)cc2)cc1OC
Temperature: 90 °C
Reaction time: 3 h
Yield: 101.8 %

Procedure:
One gram (1.0 g) of N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(4-methylphenyl) acetamide (3.2 mmol), 1.68 g (9.64 mmol) of t-butoxybis(dimethylamino)methane and 15 ml of N,N-dimethylformamide were mixed and stirred at 90° C. for 3 hours and then at 110° C. for 3 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with saturated brine twice, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 1.20 g of crude N-[2-(3,4-dimethoxyphenyl)ethyl]-3-dimethylamino-2-(4-methylphenyl)acrylamide.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([CH3:16])=[CH:11][C:12](=O)[NH:13][N:14]=2)=[CH:5][CH:4]=1)#[N:2].P(Cl)(Cl)([Cl:19])=O>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12]([Cl:19])=[CH:11][C:10]=2[CH3:16])=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1cc(=O)[nH]nc1-c1ccc(C#N)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)nnc1-c1ccc(C#N)cc1

Procedure:
A 2.0 portion of 6-(p-cyanophenyl)-5-methyl-3(2H)-pyridazinone and 10 ml. of phosphorus oxychloride are heated at steam bath temperature for 4 hours. The reaction mixture is poured into crushed ice and the resulting solid, after decomposition of the unreacted phosphorus oxychloride, is recovered by filtration, washed with water and dried. This product is recrystallized several times from methanol giving 6-(p-cyanophenyl)-5-methyl-3-chloropyridazine, m.p. 218°-220° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Si:6]([O:23][CH2:24][C@@H:25]1[C@@H:29]([CH2:30][O:31][Si:32]([C:45]([CH3:48])([CH3:47])[CH3:46])([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:28][CH2:27][C@@H:26]1[OH:49])([C:19]([CH3:22])([CH3:21])[CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.P([O-])([O-])([O-])=O>C(Cl)Cl>[CH3:1][S:2]([O:49][C@H:26]1[CH2:27][CH2:28][C@H:29]([CH2:30][O:31][Si:32]([C:45]([CH3:48])([CH3:47])[CH3:46])([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@H:25]1[CH2:24][O:23][Si:6]([C:19]([CH3:20])([CH3:21])[CH3:22])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)[Si](OC[C@H]1CC[C@H](O)[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](OC[C@H]1CC[C@H](OS(C)(=O)=O)[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.4 %

Procedure:
At 0° C., methanesulfonyl chloride (0.20 ml, 2.6 mmoles) was added to a solution of (1S, 2S, 3S)-2,3-bis-(t-butyldiphenylsilyloxymethyl)-1-cyclopentanol (1.08 g, 1.73 mmoles) and triethylamine (0.44 ml, 3.2 mmoles) in methylene chloride (9 ml). After stirring the mixture at 0° C. for 15 minutes, 0.2M phosphate buffer (pH 7.0) was added to the reaction mixture and the mixture was subjected to extraction with ethyl ether. The ether extract solution was dried on anhydrous sodium sulfate and then the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:9, v/v) to obtain (1S,2S,3S)-2,3-bis-(t-butyldiphenylsilyloxymethyl)-1-cyclopentyl methanesulfonate (1.169 g, Yield 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:44])[CH:5]=[C:6]([Cl:43])[C:7]=1[CH2:8][C@@H:9]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)[O:10][C:11](=[O:27])[CH2:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([N+:23]([O-])=O)[CH:19]=2)[C:14]1=[O:26].O.O.[Sn](Cl)Cl>C1COCC1>[NH2:23][C:18]1[CH:17]=[CH:16][CH:15]=[C:20]2[C:19]=1[C:14](=[O:26])[N:13]([CH2:12][C:11]([O:10][C@H:9]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:36])[F:37])=[C:30]([O:38][CH2:39][CH:40]3[CH2:41][CH2:42]3)[CH:29]=1)[CH2:8][C:7]1[C:6]([Cl:43])=[CH:5][N+:4]([O-:44])=[CH:3][C:2]=1[Cl:1])=[O:27])[C:21]2=[O:22]
Reactant: O=C(CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Solvent: O
Product: Nc1cccc2c1C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.3 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-nitro-1,3-dioxoisoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide (80 mg, 0.123 mmol) was dissolved in THF (10 ml), and added with tin(II) chloride dihydrate (80 mg, 0.355 mmol). The reaction was stirred at RT for 3 days. The reaction was quenched by addition of K2CO3/H2O. The solid precipitated was filtered and the solution extracted with EtOAc (50 ml). The organic phase was washed with K2CO3/H2O conc. (×3), dried over Na2SO4 and the solvent removed under reduced pressure to yield the title compound (50.0 mg, 66% yield).). 1H NMR (400 MHz, acetone) ppm 8.20 (s, 2H), 7.50 (d, J=7.50 Hz, 1H), 7.14-7.24 (m, 2H), 7.01-7.13 (m, 3H), 6.92 (t, J=75.00 Hz, 1H), 6.17 (dd, J=9.48, 5.07 Hz, 3H), 4.37 (d, J=7.50 Hz, 2H), 4.00 (dd, J=7.06, 3.09 Hz, 2H), 3.53 (m, 1H), 3.34 (d, J=4.41 Hz, 1H), 1.30 (br. s., 2H), 0.56-0.68 (m, 2H), 0.41 (d, J=4.41 Hz, 2H); MS/ESI+ 608.39 [MH]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH2:23][C:22]1=[O:31].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][N:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:21][C:22](=[O:31])[CH2:23]2)[CH:7]=1
Reactant: O=C1CNc2ccccc2N1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CN1CC(=O)Nc2ccccc21)C(F)(F)F

Procedure:
A solution of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (105 mg) and 3,4-dihydro-1H-quinoxalin-2-one (R. E. TenBrink et al., J. Med. Chem., 1994, 37, pp. 758-768) (267 mg) in dimethylformamide (0.75 mL) was heated at 140° C. for 45 hours. The resulting mixture was poured into water and extracted twice with diethyl ether. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 30% ethyl acetate-hexanes) to give the title compound as a pale yellow solid (67.8 mg), m.p. 69° C.-71° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:32]=[CH:31][C:9]3[N:10]=[C:11]([C:13]4[N:18]=[CH:17][C:16]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:30])[O:25][C:26](C)(C)C)[CH3:22])=[CH:15][CH:14]=4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.Cl.C(OCC)(=O)C>C(OCC)(=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:32]=[CH:31][C:9]3[N:10]=[C:11]([C:13]4[N:18]=[CH:17][C:16]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:30])[O:25][CH3:26])[CH3:22])=[CH:15][CH:14]=4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1
Reactant: C[C@@H](COc1ccc(-c2nc3ccc(OCC4CC4)cc3o2)nc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)N[C@@H](C)COc1ccc(-c2nc3ccc(OCC4CC4)cc3o2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.9 %

Procedure:
A mixture of tert-butyl [(1S)-2-({6-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]pyridin-3-yl}oxy)-1-methylethyl]carbamate (84.6 mg), ethyl acetate (2 mL) and 4M hydrogen chloride/ethyl acetate (2 mL) was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure, and the residue was mixed with triethylamine (0.5 mL), THF (2 mL) and methyl chloroformate (0.044 ml) at 0° C., and the obtained mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (17.5 mg).