Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[C:11]([N+:12]([O-])=O)=[CH:10][N:9]=[C:8]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:7]=1)[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[C:11]([NH2:12])=[CH:10][N:9]=[C:8]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:7]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)Cc1cc(N2CCN(C)CC2)ncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)Cc1cc(N2CCN(C)CC2)ncc1N
Reaction time: 2.5 h

Procedure:
[2-(4-Methyl-piperazin-1-yl)-5-nitro-pyridin-4-yl]-acetic acid ethyl ester (2.78 g, 9.02 mmol) is dissolved in MeOH (28 ml). Palladium on carbon (10%, 96 mg, 0.90 mmol) is added, and the reaction flask is connected to a balloon filled with hydrogen. After vigorous stirring for 2.5 h, TLC analysis indicated complete conversion. The reaction mixture is filtered, the organic solvent removed, and the residue purified by FCC (CH2Cl2/MeOH, gradient from 97:3 to 70:30) to yield [5-amino-2-(4-methyl-piperazin-1-yl)-pyridin-4-yl]-acetic acid ethyl ester. 1H NMR (CDCl3, 400 MHz): δ 1.27 (t, J=7 Hz, 3H), 2.35 (s, 3H), 2.54 (m, 4H), 3.40 (m, 4H), 3.55 (s, 2H), 3.62 (s, broad, 2H), 4.16 (q, J=7 Hz, 2H), 6.50 (s, 1H), 7.79 (s, 1H). ES+−MS: 279.3 [M+H]+.
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15]C)=[O:14])=[CH:8][CH:7]=1.[OH-].[Li+].O>CO>[I:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:10][CH:11]=1
Reactant: COC(=O)Cc1ccc(CCCCI)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1ccc(CCCCI)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.9 %

Procedure:
Methyl 4-(4-iodo-1-butyl)phenylacetate (21.28 g, 0.064 mol) was dissolved in methanol (160 mL). Lithium hydroxide (6.72 g, 0.16 mol) and water (10 mL) were added, and the reaction mixture was stirred for 18 hours at room temperature. The solvents were removed under reduced pressure, the residue was treated with ethyl acetate (600 mL), and the organic solution was washed with 1N HCl (3×300 mL), brine (3×300 mL), dried over MgSO4, and filtered. The filtrate was concentrated and dried in vacuo to give 17.5 g (85.9%) of 4-(4-iodo-1-butyl)phenylacetic acid as a yellow solid. 1H NMR (300 MHz, CD3OD) δ: 1.68-1.84 (m, 4H), 2.61 (t, 2H, J=7.35 Hz), 3.24 (t, 2H, J=6.75 Hz), 3.55 (s, 2H), 7.16 (ab quartet, 4H, J=8.26 Hz). FAB-MS m/z=319 (M+H); HRMS calcd for C12H16O2I (M+H) 319.0194, found 319.0208.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][CH:10]([CH3:40])[C:11]([O:13][C@@H:14]1[C@@H:18]([CH2:19][O:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[O:17][C@@H:16]([N:26]2[C:30]3[N:31]=[C:32]([NH:37][CH:38]=[O:39])[N:33]=[C:34]([O:35][CH3:36])[C:29]=3[CH:28]=[CH:27]2)[CH2:15]1)=[O:12]>C(Cl)Cl>[Cl:1][C:28]1[C:29]2[C:34]([O:35][CH3:36])=[N:33][C:32]([NH:37][CH:38]=[O:39])=[N:31][C:30]=2[N:26]([C@@H:16]2[O:17][C@H:18]([CH2:19][O:20][C:21](=[O:25])[CH:22]([CH3:23])[CH3:24])[C@@H:14]([O:13][C:11](=[O:12])[CH:10]([CH3:40])[CH3:9])[CH2:15]2)[CH:27]=1
Reactant: COc1nc(NC=O)nc2c1ccn2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: COc1nc(NC=O)nc2c1c(Cl)cn2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.1 %

Procedure:
N-Chlorosuccinimide (87 mg, 0.67 mmol) is added to a solution of compound (18) (300 mg, 0.67 mmol in 5 ml of DMF). After it has been stirred (at room temperature for 20 h), the solution is added to a mixture of CH2Cl2/5% aq. NaHCO3 (50 ml, 9:1). The organic layer is separated off, washed with water, dried over Na2SO4, filtered and evaporated. The evaporated residue is dissolved in CH2Cl2 and this solution is chromatographed on silica gel (column: 5×20 cm, CH2Cl2/acetone, 95:5). The main zone is concentrated, and n-hexane is added to the residue. The precipitated colorless crystals (230 mg, 71%) are isolated. Melting point: 119-120° C. 1H-NMR ([D6] DMSO): δ=1.09 (d, J=7.0, CH3), 1.15 (d, J=6.9, CH3), 2.45, 2.60, 2.63, 2.89 (4m, CH and Hα,β-C(2′)), 4.06 (s, OCH3), 4.18 (m, H—C(5′)), 4.28 (m, H—C(4′)), 5.35 (m, H—C(3′)), 6.47 (m, H—C(1′)), 7.58 (s, H—C(6)), 9.45 (d, J=8.9, NH), 10.84 (d, J=9.6, HCO). Anal. calculated for C21H27CIN4O7 (482.9): C 52.23, H 5.64, N 11.60; found: C 52.51, H 5.69, N 11.65.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Cl[CH2:11][O:12][CH3:13].C(N(C(C)C)CC)(C)C>>[CH3:11][O:12][CH2:13][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: COCCl
Reactant: O=Cc1cccc(O)c1
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cccc(C=O)c1
Temperature: 0 °C

Procedure:
A solution of 3-hydroxybenzaldehyde (20 g), chloromethylmethyl ether (25 ml) and diisopropylethylamine (114 ml) intetrahydrofuran (300 ml) was stirred at room temperature overnight. To the reaction mixture was added ice water and was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate, water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane : ethyl acetate =25:1) to give the title compound (23 g) having the following physical data.
Reaction SMILES: C(O[C:4]1[C:5](=[O:18])[C:6](=[O:17])[C:7]=1[NH:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[OH:16])C.[NH2:19][C@@H:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:21]>C(O)C.ClCCl>[OH:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:9]=1[NH:8][C:7]1[C:6](=[O:17])[C:5](=[O:18])[C:4]=1[NH:19][C@H:20]([CH3:21])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CCOc1c(Nc2c(C)cccc2O)c(=O)c1=O
Reactant: C[C@@H](N)C(C)(C)C
Solvent: CCO
Solvent: ClCCl
Product: Cc1cccc(O)c1Nc1c(N[C@H](C)C(C)(C)C)c(=O)c1=O

Procedure:
3-Ethoxy-4-(2-hydroxy-6-methyl-phenylamino)-cyclobut-3-ene-1,2-dione (0.4 g, 1.62 mmol) and (R)-2-amino-3,3-dimethylbutane (16 mL of a 0.2M solution in absolute ethanol, 3.20 mmol) in dichloromethane (4 mL) was heated at 80° C. for 4 hours. The reaction mixture was cooled, concentrated under reduced pressure, and the resulting residue was trituated with hexane:ethyl acetate (1:1) to produce a solid, which was filtered and rinsed with hexane:ethyl acetate (1:1). Chromatography with 10% methanol in dichloromethane gave (R)-3-(2-hydroxy-6-methylphenylamino)-4-(2,2,1-trimethylpropyl-amino)-cyclobut-3-ene-1,2-dione, 0.24 g (0.79 mmol, 49%).
Reaction SMILES: C(O)(=O)/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7]C)[CH:5]=1.[OH-].[K+].[CH3:17]C1NC=CN=1>CN(C)C=O>[CH:3]([C:4]1[CH:5]=[C:6]([OH:7])[C:9]([O:10][CH3:17])=[CH:11][CH:12]=1)=[CH2:2]
Reactant: Cc1ncc[nH]1
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: C=Cc1ccc(OC)c(O)c1
Yield: 64 %

Procedure:
A mixture of Ferulic acid (0.0083 mol), KOH (10%, 3 ml), methylimidazole (1 mL) and dimethylformamide (10 ml) were taken in a 100 ml round bottom flask fitted with reflux condenser. The flask was placed inside the microwave oven and irradiated (150 W, 150° C.) for 12 minutes. The cooled mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with dil HCl, water, saturated sodium bicarbonate, brine and then organic layer dried over sodium sulphate. The solvent was evaporated under reduced pressure to obtain liquid which was purified on silica gel column chromatography using mixture of hexane and ethyl acetate (9:1 to 6:4), provided sweet and pleasant smelling viscous liquid. 64% yield; 1H NMR (CDCl3) δ 6.90 (3H, m), 6.70 (1H, dd, J=10.90 Hz and J=17.36 Hz), 5.79 (1H, s), 5.59 (1H, d, J=17.36 Hz), 5.11 (1H, d, J=10.90 Hz), 3.83 (3H, s); 13C NMR (CDCl3) δ 146.7, 145.7, 136.7, 130.3, 120.1, 114.5, 111.4, 108.1, 55.9.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22].CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([NH:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:9])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)c1cccc(NC(=O)C(CSC(C)=O)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
2-Acetylthiomethyl-3-phenylpropionic acid (11.9 g) and ethyl 3-aminobenzoate (8.26 g) are dissolved in dichloromethane (150 ml), and thereto are added 4-dimethylaminopyridine (0.61 g) and EDC.HCl (10.54 g), and the mixture is stirred at room temperature overnight. The reaction mixture is washed with saturated aqueous citric acid solution, saturated aqueous sodium chloride solution and saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution in this order, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is washed with diethyl ether to give the title compound (13 g).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]1[CH2:9][N:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][CH:6]1[CH2:14][OH:15].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([O:15][CH2:14][CH:6]1[CH2:7][N:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:9][CH:5]1[CH2:4][OH:3])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: CS(=O)(=O)N1CC(CO)C(CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CC(CO)C(COCc2ccccc2)C1
Temperature: -12 °C
Reaction time: 0.08 h
Yield: 58.9 %

Procedure:
To a suspension of 60% NaH (66 mg, 1.64 mmol) in DMF (3 ml) was added a solution of ([3RS,4RS]-4-hydroxymethyl-1-methanesulfonyl-pyrrolidin-3-yl)-methanol (327 mg, 1.56 mmol) in DMF (5 ml) at −12° C. After 5 min, benzylbromide (286 mg, 1.64 mmol) was added and the mixture was stirred at −12° C. for 30 min. The mixture was allowed to warm to room temperature. The solvent was evaporated. Water was added and extracted with dichloromethane. The organic phase was dried, filtered and evaporated. Flash chromatography (hexane/EtOAc 2:1=>1:1) gave 275 mg (58%) of ([3RS,4RS]-4-benzyloxymethyl-1-methanesulfonyl-pyrrolidin-3-yl)-methanol as a colorless oil, MS: 358 (M+OAc)−.
Reaction SMILES: C(P(CCCC)CCCC)CCC.Cl[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH3:21][SiH:22]([Cl:24])[Cl:23]>>[Cl:23][Si:22]([Cl:24])([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:21]
Reactant: C[SiH](Cl)Cl
Reactant: CCCCCCCl
Agent: CCCCP(CCCC)CCCC
Product: CCCCCC[Si](C)(Cl)Cl
Yield: 16.7 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.15 g (0.75 mmol) of tri-n-butylphosphine, 0.90 g (7.5 mmol) of 1-chlorohexane, and 3.90 ml (37.5 mmol) of methyldichlorosilane were reacted at 150° C. for 12 hrs. The resulting mixture was distilled to give 0.25 g of 2,2-dichloro-2-silaoctane (yield:16%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[NH:11][C:10](=O)[C:9]=2[C:21]#[N:22])[CH:5]=[CH:6][CH:7]=1.O=P(Cl)(Cl)[Cl:25]>CCOC(C)=O>[Cl:25][C:10]1[C:9]([C:21]#[N:22])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=1
Reactant: COc1ccc2[nH]c(=O)c(C#N)c(-c3cccc(F)c3)c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1ccc2nc(Cl)c(C#N)c(-c3cccc(F)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(3-fluorophenyl)-6-methoxy-2-oxo-1,2-dihydroquinoline-3-carbonitrile (1.10 g, 3.74 mmol) in 30 mL of phosphorus oxytrichloride was heated in a sealed pressure tube at 90° C. for 2 hours. The solution was cooled to room temperature and allowed to stand overnight. The mixture was diluted with EtOAc, cooled to 0° C., and quenched by the careful addition of saturated NaHCO3 solution. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the titled compound. ESI+ MS: 313.0 [M+H]+.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:49])[C@@H:14]([NH:30][C:31](=[O:48])[C@@H:32]([NH:36][C:37](=[O:47])[C@H:38]([CH3:46])[C@H:39]([O:44][CH3:45])[CH2:40][CH2:41][CH:42]=[CH2:43])[CH:33]([CH3:35])[CH3:34])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:17]=2)[NH:8]1)=[O:6].C([O-])(=O)C.[NH4+]>O1CCCC1.O.[Zn]>[C:26]([Si:23]([CH3:25])([CH3:24])[O:22][C:18]1[CH:17]=[C:16]([CH2:15][C@H:14]([NH:30][C:31](=[O:48])[C@@H:32]([NH:36][C:37](=[O:47])[C@H:38]([CH3:46])[C@H:39]([O:44][CH3:45])[CH2:40][CH2:41][CH:42]=[CH2:43])[CH:33]([CH3:34])[CH3:35])[C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@@H:7]([C:5]([OH:6])=[O:4])[NH:8]2)=[O:49])[CH:21]=[CH:20][CH:19]=1)([CH3:28])([CH3:27])[CH3:29]
Reactant: C=CCC[C@@H](OC)[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](Cc1cccc(O[Si](C)(C)C(C)(C)C)c1)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1)C(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: C=CCC[C@@H](OC)[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](Cc1cccc(O[Si](C)(C)C(C)(C)C)c1)C(=O)N1CCC[C@@H](C(=O)O)N1)C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 102.3 %

Procedure:
To a solution of (S)-1-{(S)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2-[(S)-2-((2R,3R)-3-methoxy-2-methyl-hept-6-enoylamino)-3-methyl-butyrylamino]-propionyl}-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (560 mg, 0.71 mmol) in tetrahydrofuran (16 mL) was added zinc dust (1.0 g, 15.6 mmol) followed by a solution of ammonium acetate (817 mg, 10.6 mmol) in water (7 mL). The reaction mixture was stirred vigorously at room temperature for 24 hours. The reaction mixture was filtered through celite and the filter pad was washed with dichloromethane. The aqueous layer was acidified to pH 4-5 with 2 M hydrochloric acid and the mixture was extracted with dichloromethane. The organic layers were combined and dried by passing through a hydrophobic frit. The solvent was evaporated and dried to afford (S)-1-{(S)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2-[(S)-2-((2R,3R)-3-methoxy-2-methyl-hept-6-enoylamino)-3-methyl-butyrylamino]-propionyl}-hexahydro-pyridazine-3-carboxylic acid (480 mg) which was used crude in the next step. LCMS (m/z) 661 [M+H], Tr=5.46 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1)[CH3:11].[I:20]N1C(=O)CCC1=O>C(#N)C.C(O)(=O)C>[I:20][C:17]1[CH:18]=[C:13]([O:12][CH:10]([C:3]2[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[Cl:1])[CH3:11])[C:14]([NH2:19])=[N:15][CH:16]=1
Reactant: CC(Oc1cccnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(Oc1cc(I)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.1 %

Procedure:
To a solution of 3-[1-(2,6-Dichloro-3-fluoro-phenyl)ethoxy]-pyridin-2-ylamine (10.0 g, 33.2 mmol) in acetonitrile (600 mL) and acetic acid (120 mL) was added N-iodosuccinimide (11.2 g, 49.8 mmol). The mixture was stirred at room temperature for 4 h and the reaction was quenched with Na2S2O5 solution. After evaporation, the residue was partitioned between ethyl acetate and water. The organic layer was washed with 2N NaOH solution, brine, and dried over Na2SO4. The crude product was purified on a silica gel column to provide 5-iodo-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine (7.1 g, 50% yield). MS m/z 427 [M+1]. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.74 (d, J=6.57 Hz, 3H) 5.91-5.99 (m, 3H) 6.82 (d, J=1.26 Hz, 1H) 7.46 (t, J=8.72 Hz, 1H) 7.56 (dd, J=8.97, 4.93 Hz, 1H) 7.62 (d, J=1.52 Hz, 1H).
Reaction SMILES: [N-:1]([C:4]#[N:5])[C:2]#[N:3].[Na+].[Cl:7][C:8]1[CH:9]=[C:10]([CH:12]=[C:13]([Cl:15])[CH:14]=1)[NH2:11]>Cl.O>[C:2]([NH:1][C:4]([NH:11][C:10]1[CH:9]=[C:8]([Cl:7])[CH:14]=[C:13]([Cl:15])[CH:12]=1)=[NH:5])#[N:3]
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: N#C[N-]C#N
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#CNC(=N)Nc1cc(Cl)cc(Cl)c1
Yield: 76.4 %

Procedure:
To a solution of 4.45 g (0.05 mol) of sodium dicyanamide in 50 ml of 1N HCl is added 8.1 g (0.05 mol) of 3,5-dichloroaniline in 50 ml of H2O. The mixture is heated to about 80° C. to 100° C. for two hours. The mixture is then cooled, and the precipitated solids are recovered by filtration, washed and dried to give 8.75 g of the desired product having a melting point of 196° C.-198° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[N:3]=1.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[NH2:1][C:2]1[N:3]=[C:4]([CH3:11])[C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:14]3[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[CH3:12])[CH2:21][CH2:22]2)=[O:8])=[CH:9][CH:10]=1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: Cc1nc(N)ccc1C(=O)O
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N)nc3C)CC2)c(C)c1
Yield: 16.9 %

Procedure:
Using 6-amino-2-methylnicotinic acid (500 mg) and 1-(2,4-dimethylphenyl)piperazine (657 mg) and by the reaction and treatment in the same manner as in Preparation Example 109, the title compound (180 mg) was obtained.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH-].[Na+].Br[CH2:20][CH2:21][CH2:22][Cl:23].C(OCC)C>CC(C)=O>[Cl:23][CH2:22][CH2:21][CH2:20][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH2:6][CH2:5]1
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCOCC
Product: ClCCCN1CCN(c2ccc3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Dissolving 853 mg of 2-piperazin-1-ylquinoline as prepared in above Step 1-1-A in 5 ml of acetone, 5 ml of an aqueous solution containing 160 mg of sodium hydroxide was added to the solution, and into which 0.5 ml of 1-bromo-3-chloropropane was dropped, followed by stirring for an overnight at room temperature. Then diethyl ether was added, followed by washing with saturated aqueous sodium hydrogencarbonate solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified on silica gel column chromatography (chloroform:methanol=50:1) to provide 1.10 g (95%) of 2-[4-(3-chloropropyl)piperazin-1-yl]quinoline.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([CH2:17][NH:18][C:19](=[O:23])[C@@H:20]([OH:22])[CH3:21])[CH:14]=[CH:15][CH:16]=3)=[C:8]([CH3:24])[C:6]=2[N:7]=1.[NH:31]1[C:39]2[C:34](=[CH:35][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:37][N:38]=2)[CH:33]=[CH:32]1>>[OH:22][C@@H:20]([CH3:21])[C:19]([NH:18][CH2:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:9]2[S:10][C:5]3[C:4]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[N:3][C:2]([C:36]4[CH:35]=[C:34]5[CH:33]=[CH:32][NH:31][C:39]5=[N:38][CH:37]=4)=[N:7][C:6]=3[C:8]=2[CH3:24])[CH:12]=1)=[O:23]
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: Cc1c(-c2cccc(CNC(=O)[C@H](C)O)c2)sc2c(N3CCOCC3)nc(Cl)nc12
Product: Cc1c(-c2cccc(CNC(=O)[C@H](C)O)c2)sc2c(N3CCOCC3)nc(-c3cnc4[nH]ccc4c3)nc12

Procedure:
Crude (2S)-N-(3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)methyl-2-hydroxypropanamide (65 mg) was coupled to 7-azaindole-5-boronic acid pinacol ester via General Procedure A. The product was purified by reverse phase HPLC to yield 48.4 mg of 421. MS (Q1) 529.2 (M)+
Reaction SMILES: CN1C=CN=C1.[NH2:7][C:8]1[S:9][CH:10]=[C:11]([C:13](=[N:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[C:14]([O:16]CC)=[O:15])[N:12]=1.CO.O1CCCC1>[OH-].[Na+]>[NH2:7][C:8]1[S:9][CH:10]=[C:11]([C:13](=[N:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[C:14]([OH:16])=[O:15])[N:12]=1
Reactant: CCOC(=O)C(=NOCc1ccc(Cl)cc1Cl)c1csc(N)n1
Agent: Cn1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(C(=NOCc2ccc(Cl)cc2Cl)C(=O)O)cs1
Reaction time: 6 h
Yield: 90.1 %

Procedure:
A solution of 1-methylimidazole (0.5 g.) in 1N sodium hydroxide aqueous solution (48 ml.) was added to a solution of ethyl 2-(2-aminothiazol-4-yl)-2-(2,4-dichlorobenzyloxyimino)acetate (syn isomer, 12.0 g.), methanol (120 ml.) and tetrahydrofuran (100 ml.) at 15° to 20° C., and stirred at 35° to 40° C. for 6 hours. After removing methanol and tetrahydrofuran in vacuo from the resultant mixture, the aqueous residue was washed with ethyl acetate. Ethyl acetate was completely removed from the aqueous solution and adjusted to pH 2.0 with hydrochloric acid. The precipitates were collected by filtration to give 2-(2-aminothiazol-4-yl)-2-(2,4-dichlorobenzyloxyimino)acetic acid (syn isomer, 10.0 g.).
Reaction SMILES: Cl.[F:2][C@@:3]12[C@:16]3([CH3:17])[C:11](=[CH:12][C:13](=[O:18])[CH:14]=[CH:15]3)[C@@H:10]([F:19])[CH2:9][C@H:8]1[C@@H:7]1[CH2:20][C@@H:21]3[C@:25]([C:26](=[O:32])[CH2:27][O:28][C:29](=[O:31])[CH3:30])([C@@:6]1([CH3:33])[CH2:5][C@@H:4]2[OH:34])[CH2:24][NH:23][CH2:22]3.FC(F)(F)S(O[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[Si](C)(C)C)(=O)=O.[F-].[Cs+]>C(#N)C.O>[F:2][C@@:3]12[C@:16]3([CH3:17])[C:11](=[CH:12][C:13](=[O:18])[CH:14]=[CH:15]3)[C@@H:10]([F:19])[CH2:9][C@H:8]1[C@@H:7]1[CH2:20][C@@H:21]3[C@:25]([C:26](=[O:32])[CH2:27][O:28][C:29](=[O:31])[CH3:30])([C@@:6]1([CH3:33])[CH2:5][C@@H:4]2[OH:34])[CH2:24][N:23]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:22]3
Reactant: CC(=O)OCC(=O)[C@@]12CNC[C@@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCC(=O)[C@@]12CN(c3ccccc3)C[C@@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 30.3 %

Procedure:
In a nitrogen atmosphere compound 20 (150 mg, 0.300 mmol) is suspended in Acetonitrile (4 ml). 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.146 ml, 0.600 mmol) and CsF (182 mg, 1.200 mmol) are added and the mixture is stirred for 45 minutes at RT. Additional CsF (137 mg, 0.900 mmol) (not dried) is added and the mixture is stirred for 5 hours then it is poured in water. Acetonitrile is evaporated and the reaction mixture is partitioned between water and AcOEt. The organic layer is separated dried over Na2SO4 and concentrated. The crude is purified by silica gel flash chromatography (eluent DCM/MeOH 98/2) affording the title compound (49 mg, 0.091 mmol, 30.3% yield).
Reaction SMILES: [CH:1]([C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O:8][CH3:9])[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:23](Br)[C:24]#[CH:25]>CN(C)C=O>[CH:1]([C:4]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([O:8][CH3:9])[C:5]([O:7][CH2:25][C:24]#[CH:23])=[O:6])([CH3:3])[CH3:2]
Reactant: COC(C(=O)O)(c1ccccc1)C(C)C
Reactant: C#CCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#CCOC(=O)C(OC)(c1ccccc1)C(C)C

Procedure:
A solution of 4.2 g of α-(iso-propyl)-α-methoxyphenyl acetic acid, 3.0 g of triethylamine and 2.6 of propargyl bromide in 20 cc of dimethylformamide was stirred for 2 hours, whereby white precipitates were deposited. The reaction mixture was poured in water, and the resultant was subjected to extraction with ether. The extract was washed with an aqueous solution saturated with sodium chloride and dried over anhydrous sodium sulfate, and thereafter evaporation of ether gave 4.5 g of oily propargyl α-(iso-propyl)-α-methoxyphenylacetate, nD25 1.5071.