Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1.[CH3:16][NH:17][NH2:18]>ClCCl>[CH3:16][N:17]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1)[NH2:18]
Reactant: CNN
Reactant: FC(F)(F)c1nc(Cl)c2ccccc2n1
Solvent: ClCCl
Product: CN(N)c1nc(C(F)(F)F)nc2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
To a solution of 4-chloro-2-(trifluoromethyl)quinazoline (8 g, 0.0344 mol) in dry dichloromethane (100 ml) under nitrogen was added methyl hydrazine (1.74 g, 0.037 mol) and the mixture was stirred at room temperature for 5 h. The reaction mixture was washed with water (2×100 ml), brine and dried. The solvent was removed under vacuum to afford 8 g (96%) of the titled compound as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[CH2:10][CH:9]1[C:29]([OH:31])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]1([CH3:44])[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:33]=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:16]=[C:17]([C:25]([F:28])([F:26])[F:27])[CH:18]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:20]=2)[CH2:10][C@H:9]1[C:29]([N:41]1[CH2:42][CH2:43][N:38]([C:34]2[CH:33]=[C:32]([CH3:44])[CH:37]=[CH:36][CH:35]=2)[CH2:39][CH2:40]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1CC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1Cc1ccccc1
Reactant: Cc1cccc(N2CCNCC2)c1
Product: Cc1cccc(N2CCN(C(=O)[C@@H]3C[C@H](NCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CN3Cc3ccccc3)CC2)c1
Yield: 8.5 %

Procedure:
As described for Example 56d, 1-benzyl-4-(3,5-bis-trifluoromethyl-benzylamino)-pyrrolidine-2-carboxylic acid (65 mg, 0.146 mmol) was converted, using 1-m-tolyl-piperzine instead of 1-(3-trifluoromethyl-phenyl)-piperazine, to the title compound (7.5 mg, 8.5%) as light yellow oil. MS m/e=605.4 [M+H]+.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:12][CH2:13][P:14]([O:18]C)([O:16]C)=[O:15])[C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.CCOCC>Br.C(O)(=O)C>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]([NH:12][CH2:13][P:14]([OH:18])([OH:16])=[O:15])[C:9]([OH:11])=[O:10])=[CH:5][CH:6]=1
Reactant: COP(=O)(CN[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O)OC
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C(O)[C@H](Cc1ccc(-c2ccccc2)cc1)NCP(=O)(O)O
Reaction time: 2 h

Procedure:
(S)-3-(Biphenyl-4-yl)-2-(dimethylphosphonomethyl-amino)-propionic acid (278 mg, 0.76 mmol) is dissolved in a 30% solution of hydrobromic acid in acetic acid (10 mL) under nitrogen. After 2 hours, ether (50 mL) is added and the product precipitates. The mixture is kept at 0° for 18 hours and then filtered. The solid is dissolved in 0.1N sodium hydroxide (25 mL) and the insoluble material is filtered. The filtrate is acidified with 2N hydrochloric acid (5 mL). The gelatinous solid is filtered, washed with water and dried under high vacuum at 75° to give the (S)-3-(biphenyl-4-yl)-2-(phosphonomethyl-amino)-propionic acid as a white powder; m.p.: 241° (dec.); [α]D =+33.16 (c 0.95, 0.1N NaOH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][C@H:13]3[N:10]([C:11](=[O:18])[C@@H:12]3[C@H:15]([OH:17])[CH3:16])[C:9]=2[C:19]([O:21][CH2:22][O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[O:20])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:39](Cl)(=[O:41])[CH3:40]>ClCCl>[C:39]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][C@H:13]3[N:10]([C:11](=[O:18])[C@@H:12]3[C@H:15]([OH:17])[CH3:16])[C:9]=2[C:19]([O:21][CH2:22][O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[O:20])=[CH:4][CH:3]=1)(=[O:41])[CH3:40]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(c3ccc(N)cc3)C[C@H]12
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(C2=C(C(=O)OCOC(=O)C(C)(C)C)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Temperature: 0 °C

Procedure:
A mixture of [(2,2-dimethylpropanoyl)oxy]methyl (5R,6S)-3-(4-aminophenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate prepared by example 26, diisopropylethylamine and dichloromethane was cooled at 0° C., and thereto was dropped acetyl chloride. After stirring, the reaction mixture was poured into ice water. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution in the order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography, to give [(2,2-dimethylpropanoyl)oxymethyl (5R,6S)-3-[4-(acetylamino)phenyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].[Li+].CC([N-]C(C)C)C.C1C=CC(N[S:24]([C:27]([F:30])([F:29])[F:28])(=[O:26])=[O:25])=CC=1>C1COCC1>[F:28][C:27]([F:30])([F:29])[S:24]([O:7][C:3]1[C:2]([CH3:8])([CH3:1])[CH2:6][CH2:5][CH:4]=1)(=[O:26])=[O:25]
Reactant: CC1(C)CCCC1=O
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CCC=C1OS(=O)(=O)C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2,2-dimethylcyclopentanone T1.1 (commercially available from ChemSampCo) (3.00 g, 26.75 mmol) in THF (100 mL), was slowly added LDA (14.7 mL, 2.0 M, in heptane) at −78° C. The resulting mixture was stirred at −78° C. for 1 hour. A solution of N-phenyltriflamide (10.00 g, 28.00 mmol) was added to the mixture at −78° C., and stirring was continued at 0° C. for 2 hours and then at room temperature for 16 hours. The reaction mixture was extracted with hexane (80×2 mL). The organic layer was then washed with saturated Na2CO3 (30 mL), brine (20 mL), and dried with MgSO4. The solvent was removed, and the residue was purified by CombiFlash® silica gel chromatography (eluent was EtOAc and hexane) to give T1.2. 1H NMR (CDCl3) δ ppm 5.56 (m, 1H), 2.36 (t, J=7.1 Hz, 2H), 1.86 (t, J=7.1 Hz, 2H), 1.16 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:16].C(O)C>CCOCC>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([NH2:16])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1
Reactant: N
Reactant: Cc1ccc(-c2c(Cl)ncnc2Cl)cc1
Solvent: CCO
Solvent: CCOCC
Product: Cc1ccc(-c2c(N)ncnc2Cl)cc1

Procedure:
To a solution of 4,6-dichloro-5-(4-methylphenyl)pyrimidine (4.14 g) in ether (20 ml) is added 27% ammonia-ethanol solution (30 ml), and the reaction mixture is reacted at room temperature in a sealed tube for three days. The mixture is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (solvent; hexane/ethyl acetate=(10:1)~ethyl acetate) to give 6-chloro-5-(4-methylphenyl)pyrimidin-4-amine (1.89 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH2:11][C:12]([NH:16][C:17](=[O:29])[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1)([C:14]#[N:15])[CH3:13])[C:6]=2[O:30][CH3:31].[C:32](Cl)(=[O:34])[CH3:33]>>[C:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH2:11][C:12]([NH:16][C:17](=[O:29])[C:18]1[CH:19]=[CH:20][C:21]([O:24][C:25]([F:28])([F:26])[F:27])=[CH:22][CH:23]=1)([C:14]#[N:15])[CH3:13])[C:6]=2[O:30][CH3:31])(=[O:34])[CH3:33]
Reactant: COc1c2ccc(N)cc2nn1CC(C)(C#N)NC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: CC(=O)Cl
Product: COc1c2ccc(NC(C)=O)cc2nn1CC(C)(C#N)NC(=O)c1ccc(OC(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using N-[2-(6-amino-3-methoxy-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide (23 mg, described in Example 129) and acetyl chloride, the title compound was isolated as a white solid (8 mg, 32%). MS (ES): M/Z [M+H]=476. 1H NMR: (400 MHz, DMSO-d6): 1.71 (s, 3H), 2.05 (s, 3H), 4.16 (s, 3H), 4.71 (d, 1H), 4.82 (d, 1H), 6.88 (dd, J=9.2, 1.6 Hz, 1H), 7.52 (d, J=8.0 Hz, 2H), 7.74 (d, J=9.1 Hz, 1H), 7.86 (s, 1H), 7.99 (d, J=8.8 Hz, 2H), 8.95 (s, 1H) and 9.89 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −57.1 (s, 3F).
Reaction SMILES: B.[F:2][C:3]1[CH:4]=[C:5]([CH:10]2[CH2:15][C:14](=[CH2:16])[CH2:13][CH2:12][N:11]2[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH:6]=[CH:7][C:8]=1[F:9].[OH-:27].[Na+].OO>O1CCCC1>[F:2][C:3]1[CH:4]=[C:5]([C@H:10]2[CH2:15][C@@H:14]([CH2:16][OH:27])[CH2:13][CH2:12][N:11]2[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: [OH-]
Reactant: C=C1CCN(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)C1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC[C@H](CO)C[C@@H]1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.6 %

Procedure:
A solution of borane (1 M in tetrahydrofuran, 4.58 mL) was added to a solution of phenylmethyl 2-(3,4-difluorophenyl)-4-methylidenepiperidine-1-carboxylate (0.79 g, 2.3 mmol) in tetrahydrofuran (20 mL) at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for 18 hours. The mixture was then cooled to 0° C., and 2M sodium hydroxide solution (2.6 mL, 5.2 mmol) then hydrogen peroxide solution (30% in water, 1.2 mL) were added sequentially. The mixture was warmed to room temperature and stirred for 1.5 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (10 mL), diluted with water (20 mL), and partitioned with ethyl acetate (20 mL). The organic portion was separated and washed twice with saturated sodium bisulfite solution (20 mL), water, then brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (20% to 90% ethyl acetate in hexanes gradient) to give (±)-phenylmethyl (2R,4S)-2-(3,4-difluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.57 g, 69% yield), MS (EI) for C20H21F2NO3: 362 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])=[C:9]([O:23][CH3:24])[C:8]([Cl:25])=[C:7]([CH3:26])[C:6]=1[C:27](=[O:29])[CH3:28].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[Cl:25][C:8]1[C:7]([CH3:26])=[C:6]([C:27](=[O:29])[CH3:28])[C:5]([O:4][CH2:3][CH2:2][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[C:9]=1[O:23][CH3:24]
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCC(C)c1ccc(F)cc1
Reactant: C1COCCN1
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCN2CCOCC2)c1OCCC(C)c1ccc(F)cc1

Procedure:
Example 8a (100 mg, 0.21 mmol) was reacted with morpholine (6.0 eq.) as described under General Procedure G. The title compound was afforded as an oil (72 mg, 71%). 1H NMR (300 MHz, CDCl3) δ 7.18-7.13 (m, 2H), 6.99-6.89 (m, 2H), 4.05 (t, J=5.7 Hz, 2H), 3.94 (t, J=6.7 Hz, 2H), 3.82 (s, 3H), 3.70-3.67 (m, 4H), 3.02-2.95 (m, 1H), 2.59 (t, J=5.7 Hz, 2H), 2.49 (s, 3H), 2.47-2.44 (m, 4H), 2.17 (s, 3H), 2.03-1.96 (m, 2H), 1.28 (d, J=7.0 Hz, 3H). MS (ES+) m/z 493.9 (M+H+).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.CC(C)(C)C=[N:24][CH:25]1[CH2:29][CH2:28][NH:27][CH2:26]1.[ClH:32]>>[ClH:32].[NH2:24][CH:25]1[CH2:29][CH2:28][N:27]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:16])[CH2:26]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC(C)(C)C=NC1CCNC1
Agent: Cl
Product: NC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1

Procedure:
If, for example, 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is reacted with 3-(2,2-dimethylpropylideneamino)-pyrrolidine and the reaction product is treated with hydrochloric acid, 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride is obtained.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[C:18](=[O:19])[C:17]([CH3:21])([CH3:20])[NH:16][C:15]2=[O:22])=[CH:5][CH:4]=1.Cl[CH2:24][CH2:25][CH2:26][CH2:27][S:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1.O>CN(C)C=O>[N:32]1[CH:33]=[CH:34][C:29]([S:28][CH2:27][CH2:26][CH2:25][CH2:24][N:16]2[C:17]([CH3:20])([CH3:21])[C:18](=[O:19])[N:14]([CH2:13][CH2:12][CH2:11][CH2:10][S:9][C:6]3[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=3)[C:15]2=[O:22])=[CH:30][CH:31]=1
Reactant: ClCCCCSc1ccncc1
Reactant: CC1(C)NC(=O)N(CCCCSc2ccncc2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(CCCCSc2ccncc2)C(=O)N1CCCCSc1ccncc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.7 %

Procedure:
To a suspension of 96 mg (2.4 mmol) of 60% sodium hydride (oily) in 15 ml of dimethylformamide, 587 mg (2.0 mmol) of 3-[4-(4-pyridylthio)butyl]-5,5-dimethylhydantoin was added, and the mixture was stirred at room temperature for 10 minutes. To this reaction mixture, 807 mg (4.0 mmol) of 4-(4-chlorobutylthio)pyridine was added with stirring under ice-cooling, and the mixture was stirred at 80° C. for 16 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried and the solvent was distilled off. The residue was purified by column chromatography (eluent:ethyl acetate/ethanol=10:1) to give 0.74 g of the desired product (80.7% yield, yellow oil).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[F:25][C:26]1[CH:27]=[CH:28][C:29]([C:34]([F:37])([F:36])[F:35])=[C:30]([CH:33]=1)[CH:31]=O>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH:24][CH2:31][C:30]2[CH:33]=[C:26]([F:25])[CH:27]=[CH:28][C:29]=2[C:34]([F:36])([F:35])[F:37])[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Reactant: O=Cc1cc(F)ccc1C(F)(F)F
Product: Fc1ccc(C(F)(F)F)c(CNc2cccc(-c3c(-c4ccccc4)nnc4c(Cl)cccc34)c2)c1

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and 5-fluoro-2-trifluoromethylbenzaldehyde according to the procedure of Step 5 Example 6. MS (ESI) m/z 506.
Reaction SMILES: [Na].[OH:2][C:3]([CH:8]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])=[CH:4][N+:5]([O-:7])=[O:6].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].O>C1COCC1>[CH2:29]([O:28][C:26]([CH2:25][O:2][C:3]([CH:8]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])=[CH:4][N+:5]([O-:7])=[O:6])=[O:27])[CH3:30]
Reactant: COc1ccccc1OC(C(O)=C[N+](=O)[O-])c1ccccc1
Reactant: CCOC(=O)CBr
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)COC(=C[N+](=O)[O-])C(Oc1ccccc1OC)c1ccccc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 70 %

Procedure:
To 3.23 g of 2-hydroxy-3-phenyl-3-(2-methoxy-phenoxy)-1-nitro-propene sodium salt dissolved in 50 ml of anhydrous THF there was added at 0° C. 16.7 g of ethyl bromoacetate. After 2 hours at 0° C. the mixture was stirred at room temperature for 48 hours. The mixture was poured into water and extracted with ethyl acetate. The organic extracts were washed with water, dried over Na2SO4 and concentrated to dryness. The residue was separated by column chromatography on silica gel (mobile phase: ethyl acetate/cyclohexane 1/1), to obtain 2.70 g of 2-ethoxycarbonylmethyloxy-3-phenyl-3-(2-methoxy-phenoxy)-1-nitropropene (oil).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:15]([OH:17])=O)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:42]([O:46][C:47](=[O:60])[NH:48][CH2:49][C:50]1[CH:55]=[CH:54][N:53]=[C:52]([C:56]2([NH2:59])[CH2:58][CH2:57]2)[CH:51]=1)([CH3:45])([CH3:44])[CH3:43].Cl>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C:12]1([C:15](=[O:17])[NH:59][C:56]2([C:52]3[CH:51]=[C:50]([CH2:49][NH:48][C:47]([O:46][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:60])[CH:55]=[CH:54][N:53]=3)[CH2:58][CH2:57]2)[CH2:13][CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCc1ccnc(C2(N)CC2)c1
Reactant: O=C(NC1(C(=O)O)CC1)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccnc(C2(NC(=O)C3(NC(=O)OCc4ccccc4)CC3)CC2)c1
Reaction time: 0.08 h
Yield: 56.6 %

Procedure:
1-Benzyloxycarbonylamino-cyclopropanecarboxylic acid (1.251 g, 5.316 mmol) and HATU (2.527 g, 6.645 mmol) were dissolved in dry DMF (15 mL) and stirred for 5 min. This solution was added to the solution of [2-(1-Amino-cyclopropyl)-pyridin-4-ylmethyl]-carbamic acid tert-butyl ester (2.8 g, 10.633 mmol) in dry DMF (5 mL). TEA (2.2 mL, 16 mmol) was then added and the reaction was stirred at room temperature for 25 min. The reaction was diluted with EtOAc (450 mL) and then acidified with 1N HCl (20 mL) to pH 1. Without separation of the layers, the mixture was basified with saturated NaHCO3 (140 mL) to pH 8.5. Layers were separated. The organic layer was further washed with water (3×350 mL). The organics was dried with anhydrous Na2SO4, filtered, and concentrated to afford 3.73 g of the crude product which was purified by Biotage flash column using 0-2% MeOH/DCM as the gradient to afford 1.447 g of (1-{1-[4-(tert-Butoxycarbonylamino-methyl)-pyridin-2-yl]-cyclopropylcarbamoyl}-cyclopropyl)-carbamic acid benzyl ester as a light brown foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].O.ON1C2C=CC=CC=2N=N1.[Br:38][C:39]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:40]=1[CH2:46][CH2:47][NH2:48].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[Br:38][C:39]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:40]=1[CH2:46][CH2:47][NH:48][C:17]([C:16]1[CH:20]=[CH:21][C:13]([O:12][C:11]2[CH:10]=[C:9]3[C:4]([CH:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:6][CH2:7][O:8]3)=[CH:3][C:2]=2[Cl:1])=[CH:14][CH:15]=1)=[O:19]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: NCCc1ccc(Cl)cc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4Br)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.9 %

Procedure:
To a stirred solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1; 1.32 g; 3.52 mmol), 1-hydroxybenzotriazole hydrate (0.59 g; 3.85 mmol) and 2-(2-bromo-4-chlorophenyl)ethanamine (Preparation 5; 0.904 g; 3.85 mmol) in dry dimethylformamide (10 mL) was added 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.806 g; 4.02 mmol) at ambient temperature. After stirring at ambient temperature for 5 hours, the solution was diluted with 100 mL of water, stirred for 10 minutes longer and then extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (Biotage 40M), eluting with hexane and ethyl acetate to provide ethyl 7-(4-(2-bromo-4-chlorophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate as a white solid (1.21 g). MS (apci, pos) m/z=594.
Reaction SMILES: [CH3:1][SiH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[CH3:1][Si:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C=CCCCCCC
Reactant: CCCCCCCC[SiH2]C
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCCCCCC[Si](C)(CCCCCCCC)CCCCCCCC
Yield: 86 %

Procedure:
A mixture of 61 grams of methyloctylsilane and 186 grams of 1-octene was reacted in the presence of 0.0075 gram of chlorotris(triphenylphosphine)rhodium(I) for 2.5 hours at 85°-89° C. Analysis by GLC showed a total of 15 percent of unsaturated product. After removing unreacted octene by stripping, the residue was hydrogenated as in Example 1. Distillation revealed an 86 percent yield of methyltri(octyl)silane having a boiling point of 188°-189° C. (0.9 mm).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][NH2:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:11]1(NN)[CH:16]=CC=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:16]=[CH:11][C:12]([CH3:13])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NNc1ccc(Cl)c(Cl)c1
Reactant: NNc1ccccc1
Product: Cc1ccn(-c2ccc(Cl)c(Cl)c2)n1

Procedure:
This compound was prepared by the same methodology described for EXAMPLE 1 with 3,4-dichlorophenyl hydrazine · HCl substituted for phenyl hydrazine. There was obtained the title compound; HRMS (M+H)+ : calc. 501.055493; found 501.053920.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH:23]=[CH2:24].Cl>CN(C=O)C>[CH2:24]([O:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)[CH:23]=[CH2:22]
Reactant: Cc1ccc(Oc2ccc(O)cc2)cc1
Reactant: C=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(Oc2ccc(C)cc2)cc1

Procedure:
A solution of 4-(4′-methylphenoxy)phenol (4.75 g, 23.30 mmol), potassium carbonate (4.17 g, 30.30 mmol) and allyl bromide (2.22 mL, 25.60 mmol) in DMF (50 mL) was stirred for 5 h at 60° C. After cooling, the reaction mixture was neutralized with 1 N HCl and extracted with ethyl acetate. The organic extract was washed with brine, dried over sodium sulfate, filtered and concentrated to afford an oil which was chromatographed on silica gel (15% ethyl acetate/hexane) to afford 4-(4′-methylphenoxy)phenyl allyl ether.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Br:10][CH2:11][CH2:12]Br.[OH-].[Na+].C(O)C>ClCCl>[Br:10][CH2:11][CH2:12][O:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cc(I)ccc1O
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(I)ccc1OCCBr

Procedure:
A mixture of 2-methyl-4-iodophenol (5.00 grams), 1,2-dibromoethane (2.76 mL), sodium hydroxide (1.3 grams) and ethanol (100 mL) was stirred at reflux for 5 hours before being poured into ice. The crude solid was dissolved in dichloromethane and washed with 1N NaOH. The organic layer was evaporated in vacuo to give 2-Bromo-1-(2-methyl-4-iodophenoxy)ethane Compound 21a as a tan solid. 1H NMR (CDCl3) δ 6.54 (d, 1H), 4.25 (t, 2H), 3.66 (t, 2H), 2.20 (s, 3H).
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[N:15]=[C:14]([CH3:16])[N:13]=[C:12]2[C:8]=1[NH:9][C:10](=[O:26])[N:11]2[C:17]1[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=1[CH3:25])[CH2:4][CH3:5])[CH3:2].[CH3:27][Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH2:1]([CH:3]([NH:6][C:7]1[N:15]=[C:14]([CH3:16])[N:13]=[C:12]2[C:8]=1[N:9]([CH3:27])[C:10](=[O:26])[N:11]2[C:17]1[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=1[CH3:25])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1nc(C)nc2c1[nH]c(=O)n2-c1c(C)cc(C)cc1C
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)Nc1nc(C)nc2c1n(C)c(=O)n2-c1c(C)cc(C)cc1C

Procedure:
The title compound was prepared by methylation of 6-(1-ethyl-propylamino)-2-methyl-9-(2,4,6-trimethyl-phenyl)-7,9-dihydro-purin-8-one with lithium bis(trimethylsilyl)amide in THF, followed by quenching with methyl iodide. 1H NMR(CDCl3) d 6.98(s,2H), 4.45(d,1H), 4.3(m,1H), 3.7(s,3H), 2.4(s,3H), 2.3(s,3H), 2.1(s,6H), 1.5-1.8(m,4H), 1.0(t,6H), ppm.