Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(O)=O.[O:5]1[CH2:10][CH2:9][CH:8]([CH:11]=O)[CH2:7][CH2:6]1.[NH2:13][C:14]1[CH:15]=[C:16]([C@H:20]([OH:24])[CH2:21][C:22]#[N:23])[CH:17]=[CH:18][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[OH:24][C@@H:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([NH:13][CH2:11][CH:8]2[CH2:7][CH2:6][O:5][CH2:10][CH2:9]2)[CH:15]=1)[CH2:21][C:22]#[N:23]
Reactant: N#CC[C@@H](O)c1cccc(N)c1
Reactant: O=CC1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: N#CC[C@@H](O)c1cccc(NCC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
CH3COOH (1 mL) was added to a solution of tetrahydro-2H-pyran-4-carbaldehyde (0.7 g, 6.12 mmol) and (R)-3-(3-aminophenyl)-3-hydroxypropanenitrile (1.0 g, 6.12 mmol) in CH2Cl2 (20 mL) at 0° C. followed by the addition of Na(OAc)3BH (3.89 g, 18.34 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with NaHCO3 (50 mL), extracted with EtOAc (200 mL), organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (50% EtOAc: hexanes) gave (R)-3-hydroxy-3-(3-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)propanenitrile as a pale yellow liquid. Yield (1.0 g, 63%); 1H NMR (400 MHz, DMSO-d6) δ 7.02 (t, J=8.0 Hz, 1H), 6.62 (s, 1H), 6.51 (d, J=7.2 Hz, 1H), 6.47 (d, J=7.6 Hz, 1H), 5.77 (d, J=4.4 Hz, 1H), 5.68 (t, J=5.2 Hz, 1H), 4.73 (dd, J=10.8, 4.8 Hz, 1H), 3.85 (dd, J=10.8, 2.8 Hz, 2H), 3.26 (t, J=11.2 Hz, 2H), 2.89 (t, J=6.0 Hz, 2H), 2.82 (dd, J=16.8, 4.8 Hz, 1H), 2.73 (dd, J=16.8, 6.8 Hz, 1H), 1.81-1.75 (m, 1H), 1.66 (d, J=12.8 Hz, 2H), 1.23-1.19 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[CH3:66][O:67][C:68](=[O:77])[C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([CH2:75][NH2:76])[CH:70]=1>C(Cl)Cl>[CH3:66][O:67][C:68](=[O:77])[C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([CH2:75][NH:76][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:30])[CH:70]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)c1cccc(CN)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(CNC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (150 mg, 0.26 mmol) in methylene chloride (10 mL), HATU (Aldrich, 177 mg, 0.46 mmol) was added followed by the addition of DIPEA (0.36 mL, 2.06 mmol) and 3-aminomethyl-benzoic acid methyl ester hydrochloride salt (Aldrich, 104 mg, 0.52 mmol). The mixture was stirred at rt for overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 5-15% EtOAc/hexanes) to give a white solid. 118 mg.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][CH2:5][N:6]([C:21]1[C:26]([N+:27]([O-])=O)=[CH:25][CH:24]=[CH:23][N:22]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14].[OH-].[Na+]>C(O)C.O.[Zn]>[CH3:30][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]([C:21]1[C:26]([NH2:27])=[CH:25][CH:24]=[CH:23][N:22]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:14]
Reactant: CN(C)CCCN(c1ccccc1C(=O)c1ccccc1)c1ncccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: CN(C)CCCN(c1ccccc1C(=O)c1ccccc1)c1ncccc1N

Procedure:
A mixture of (0.05 mole) [2-[[3-(dimethylamino)propyl](3-nitro-2-pyridinyl)amino]phenyl]phenylmethanone, 13 g, (0.20 mole) of zinc dust, 2 g (0.05 mole) of sodium hydroxide in 75 ml ethanol and 25 ml water is stirred under reflux for 1 hr. The mixture is filtered and evaporated under reduced pressure. The residue is dissolved in methylene chloride and the resulting solution is dried over magnesium sulfate and decolorized with charcoal and filtered. The filtrate is evaporated to dryness and to give the title compound in crude mixture.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][C:5]([O:10][CH2:11][CH2:12][O:13][CH:14]([CH3:16])[CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:18][CH:19]1[O:23][B:22]([OH:24])[C:21]2[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:20]1=2>>[Cl:1][C:2]1[C:3]([O:29][C:27]2[CH:26]=[CH:25][C:21]3[B:22]([OH:24])[O:23][CH:19]([CH3:18])[C:20]=3[CH:28]=2)=[N:4][C:5]([O:10][CH2:11][CH2:12][O:13][CH:14]([CH3:16])[CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: CC1OB(O)c2ccc(O)cc21
Reactant: CC(C)OCCOc1nc(Cl)c(Cl)cc1C#N
Product: CC(C)OCCOc1nc(Oc2ccc3c(c2)C(C)OB3O)c(Cl)cc1C#N

Procedure:
This compound was prepared from 5,6-dichloro-2-(2-isopropoxyethoxy)nicotinonitrile and 3-methylbenzo[c][1,2]oxaborole-1,5(3H)-diol in a similar manner to that of D230. 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 1.0 (d, J=4.5 Hz, 6H), 1.40 (d, J=4.8 Hz, 3H), 3.4-3.47 (m, 3H), 4.07-4.1 (m, 2H), 5.2-5.22 (m, 1H), 7.23 (dd, J=6.0, 1.5 Hz, 1H), 7.36 (s, 1H), 7.75 (d, J=6.0 Hz, 1H), 8.59 (s, 1H), 9.18 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH3:27])[C:8]([C:10]1[N:11]=[C:12](Cl)[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9].[CH3:37][NH2:38]>>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH3:27])[C:8]([C:10]1[N:11]=[C:12]([NH:38][CH3:37])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9]
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1nc(Cl)c2ccccc2c1-c1ccccc1
Reactant: CN
Product: CNc1nc(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(-c2ccccc2)c2ccccc12

Procedure:
The compound obtained in Example 275 was reacted with methylamine by a method similar to Example 271 to yield the title compound as colorless crystals.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1cccc(CNc2nc(Cl)nc3sc4c(c23)CCCC4)c1
Product: O=[N+]([O-])c1cccc(CNc2nc(-n3ccnc3)nc3sc4c(c23)CCCC4)c1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5,6,7,8-tetrahydro-4-(3-nitrobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5,6,7,8-tetrahydro-4-(3-nitrobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][O:8][C:9]2[C:14]([N:15]3[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)=[C:13]([CH3:22])[CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.CO[CH:27](OC)[N:28]([CH3:30])[CH3:29]>>[CH3:27][N:28]([CH:30]=[C:17]1[C:18](=[O:21])[CH2:19][CH2:20][N:15]([C:14]2[C:9]([O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:24][CH:23]=3)=[N:10][CH:11]=[CH:12][C:13]=2[CH3:22])[CH2:16]1)[CH3:29]
Reactant: COc1ccc(COc2nccc(C)c2N2CCC(=O)CC2)cc1
Reactant: COC(OC)N(C)C
Product: COc1ccc(COc2nccc(C)c2N2CCC(=O)C(=CN(C)C)C2)cc1
Temperature: 100 °C

Procedure:
A mixture of 2′-(4-Methoxybenzyloxy)-4′-methyl-2,3,5,6-tetrahydro[1,3′]bipyridinyl-4-one (6.40 g, 19.61 mmol) in N,N-dimethylformamide-dimethylacetal (44.63 ml, 333.37 mmol) from a freshly opened bottle was heated at 100° C. for 48 hours. The solvent was removed in vacuo and the residue was eluted through a flash column (silica gel 60, 230-400 mesh, EtOAc to 8% methanol in EtOAc) to give title compound as an orange, viscous oil which slowly solidified on standing (5.21 g, 70%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]1)[N:9]=[CH:8]2.C([S-])C.[Na+]>CN(C=O)C>[OH:20][C@H:17]1[CH2:16][CH2:15][C@H:14]([NH:13][C:10]2[N:9]=[CH:8][C:7]3[C:12](=[C:3]([OH:2])[CH:4]=[CH:5][CH:6]=3)[N:11]=2)[CH2:19][CH2:18]1
Reactant: COc1cccc2cnc(N[C@H]3CC[C@H](O)CC3)nc12
Agent: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1cccc2cnc(N[C@H]3CC[C@H](O)CC3)nc12
Temperature: 11 °C

Procedure:
To a solution of trans-4-[(8-methoxyquinazolin-2-yl)amino]cyclohexanol (5.90 g, 21.6 mmol) in DMF (300 mL) was added sodium ethanethiolate (5.45 g, 65 mmol) and the mix heated to 11° C. for 3 hours under nitrogen. The reaction was cooled to ambient temperature and the DMF removed in-vacuo. The residue was diluted with MeOH (20 mL), DCM (200 mL) and EtOAc (100 mL) and then acidified with 1 M HCl to pH=1. The mix was concentrated in-vacuo where a yellow ppt crashed out. This was filtered off, washed with water (2×50 mL), EtOAc (100 mL) and dried to yield the title compound as a yellow solid, 4.9 g, 88%. 1H NMR (400 MHz, DMSO-D6) δ ppm 9.00 (2H, s) 7.21 (1H, d, J=6.32 Hz) 7.16 (1H, s) 6.98-7.09 (2H, m) 4.55 (1H, s) 3.36 (2H, d, J=23.75 Hz) 1.86 (4H, dd, J=28.30, 8.59 Hz) 1.22-1.48 (4H, m); MS (API+) for C14H17N3O2 m/z 260.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10](O)[C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[C:4]#[N:5].CCN(S(F)(F)[F:22])CC>C(Cl)Cl>[F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]([F:22])[C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCN(CC)S(F)(F)F
Reactant: N#Cc1cc(C(O)C(F)(F)F)ccc1F
Solvent: ClCCl
Product: N#Cc1cc(C(F)C(F)(F)F)ccc1F
Yield: 100.2 %

Procedure:
2-Fluoro-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-benzonitrile (1 g, 4.56 mmol) in DCM (5 mL) was treated with DAST (Aldrich, 1.12 mL, 9.13 mmol) at −78° C. for 2 hours. The reaction was quenched with saturated NaHCO3 and extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude material, purified by silica gel column (hexanes:ethyl acetate 4:1) to afford the title compound as colorless solid (1.01 g, 100%).
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][C:6]=1[F:16])([CH3:4])([CH3:3])[CH3:2].[Cl-].ClC1N(C)CC[NH+]1C.Cl.[NH2:27][C@@H:28]([C:30]1[CH:35]=[CH:34][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[C:32]([CH3:41])[CH:31]=1)[CH3:29]>C(N(CC)CC)C>[C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([NH:27][C@@H:28]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[C:32]([CH3:41])[CH:31]=2)[CH3:29])=[O:13])=[CH:7][C:6]=1[F:16])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc([C@@H](C)N)ccc1NS(C)(=O)=O
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1F
Agent: CN1CC[NH+](C)C1Cl
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: Cc1cc([C@@H](C)NC(=O)COc2ccc(C(C)(C)C)c(F)c2)ccc1NS(C)(=O)=O
Yield: 43.5 %

Procedure:
(4-tert-Butyl-3-fluorophenoxy) acetic acid (153 mg, 0.68 mmol), 2-chloro-1,3-dimethylimidazolinium chloride (CDI) (110 mg, 0.68 mmol), triethylamine (0.5 ml) and N-{4-[(1R)-1-aminoethyl]-2-methylphenyl}methanesulfonamide hydrochloride (180 mg, 0.68 mmol) were mixed in the same procedure described in Example 2(b) to give 129 mg (44% yield) of the title compound as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3](=[NH:8])[NH:4][N+:5]([O-:7])=[O:6].[C:9](OC(=O)C)(=[O:11])[CH3:10]>N1C=CC=CC=1>[C:9]([NH:8][C:3](=[N:4][N+:5]([O-:7])=[O:6])[S:2][CH3:1])(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: CSC(=N)N[N+](=O)[O-]
Solvent: c1ccncc1
Product: CSC(=N[N+](=O)[O-])NC(C)=O
Reaction time: 0.17 h

Procedure:
To a mixture of 5.0g of S-methyl-N-nitroisothiourea and 25ml of pyridine was dropwise added 11.3g of acetic anhydride at room temperature, taking for 10 minutes, followed by stirring for 5 hours at the same temperature. The reaction mixture was concentrated, and the residue was poured into 50ml of 2N-hydrochloric acid. The resulting solid was collected by filtration and dried to obtain 5.lg of N-acetyl-S-methyl-N'-nitroisothiourea. mp. 109-110° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:25]([F:28])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([NH:20][OH:21])=[NH:19])=[C:16]([CH3:24])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:29](Cl)(=O)[CH3:30].O.CCOC(C)=O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:25]([F:26])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[CH:23]=[CH:22][C:17]([C:18]4[N:19]=[C:29]([CH3:30])[O:21][N:20]=4)=[C:16]([CH3:24])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(=O)Cl
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=N)NO
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2C)no1
Yield: 65.3 %

Procedure:
To a solution of 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-N-hydroxy-2-methyl-benzamidine (i.e product of Step 1, 400 mg, 0.93 mmol) in pyridine (10 mL) was added acetyl chloride (0.13 mL, 0.15 g, 1.85 mmol) via syringe and the mixture was stirred at reflux for 30 min. Water and EtOAc were added after cooling and the aqueous layer was extracted with EtOAc. Combined organic layers were dried (Na2SO4) and concentrated in vacuum. The residue was purified by flash chromatography on silica gel and yielded the title compound (277 mg, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:13])[O:11][CH:12]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=[CH2:21].O>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:13])[O:11][C:12]=2[CH:20]([CH3:21])[C:19]([O:23][CH3:24])=[O:22])=[CH:6][CH:7]=1
Reactant: C=CC(=O)OC
Reactant: O=c1[nH]c(-c2ccc(Cl)cc2)co1
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: O
Product: COC(=O)C(C)c1oc(=O)[nH]c1-c1ccc(Cl)cc1
Temperature: 10 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
To a solution of 4-(4-chlorophenyl)-2-oxo-4-oxazoline (794.3 g) in acetonitrile (2383 mL) was added dropwise conc. sulfuric acid (1195 g) under ice-cooling at not higher than 10° C. Then methyl acrylate (731 mL) was added at not higher than 10° C., and the mixture was taken out from an ice-bath and stirred at room temperature for 3 h. Water (7.94 L) was added under ice-cooling at not higher than 20° C. The precipitated crystals were collected by filtration and washed successively with 1% aqueous sodium hydrogencarbonate, water, isopropyl ether to give methyl 2-(4-(4-chlorophenyl)-2-oxo-4-oxazolin-5-yl)propionate (1017.8 g; yield 89%). Recrystallization from methanol gave colorless crystals.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[CH:8]=[C:9]([C:13]2([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[CH2:15][CH:14]2[CH2:16]Cl)[CH:10]=[CH:11][CH:12]=1>C(O)C>[CH3:1][N:2]([CH2:16][CH:14]1[CH2:15][C:13]1([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[CH:8]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)[CH2:3][CH2:4][OH:5]
Reactant: CNCCO
Reactant: ClCC1CC1(c1cccc(Cl)c1)c1cccc(Cl)c1
Solvent: CCO
Product: CN(CCO)CC1CC1(c1cccc(Cl)c1)c1cccc(Cl)c1

Procedure:
To a solution of 2-methylaminoethanol (0.29 g) in ethanol (5 ml) was added a solution of 2,2-di(m-chlorophenyl)cyclopropylmethyl chloride (0.40 g) in ethanol (10 ml) at room temperature, and stirring was carried out under reflux for 10 hours. The reaction mixture was evaporated and poured into a 10 % aqueous solution of sodium hydroxide. The chloroform extract was dried and chromatographed to afford N-methyl-N-(2-hydroxyethyl)-2,2-di(m-chlorophenyl)-cyclopropylmethylamine as an oily substance. M.P. 152° - 154° C. (hydrochoride).
Reaction SMILES: [CH3:1][N:2]([C:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH:19]([C:24]2[CH:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:26][C:25]=2[CH3:35])[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:14][CH:13]=1)=[O:11])[CH2:3][CH2:4][C:5]([O:7]CC)=[O:6]>C(O)C.CCCCCC>[CH3:1][N:2]([C:10]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH:19]([C:24]2[CH:28]=[C:27]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[O:26][C:25]=2[CH3:35])[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:16][CH:17]=1)=[O:11])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CC(C)C)c2cc(-c3ccccc3)oc2C)cc1
Solvent: CCCCCC
Solvent: CCO
Product: Cc1oc(-c2ccccc2)cc1C(CC(C)C)Nc1ccc(C(=O)N(C)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
Ethyl 3-{methyl[(4-{[3-methyl-1-(2-methyl-5-phenylfuran-3-yl)butyl]amino}phenyl)carbonyl]amino}propanoate (2.54 g) which is a synthetic intermediate in Example 125 was dissolved in ethanol-hexane (1:1, volume ratio), and the solution was subjected to HPLC using CHIRALPAK AD (50 mmID×500 mL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.) and eluted with ethanol-hexane (1:1, volume ratio) as mobile phase at 30° C., a flow rate 60 mL/min. The fractions showing a peak with retention time 12 min was collected, and concentrated. The obtained amorphous compound (1.24 g) was dissolved in ethanol (5 mL) and tetrahydrofuran (5 mL), 1N lithium hydroxide (5.5 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (20 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (1.1 g, 97%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH2:23]([N:27]=[C:28]=[O:29])[CH2:24][CH2:25][CH3:26]>CN(C)C=O.ClCCl.CO>[CH2:16]([N:13]1[CH2:12][CH2:11][N:10]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:28]([NH:27][CH2:23][CH2:24][CH2:25][CH3:26])=[O:29])=[N:7][CH:6]=2)=[O:9])[CH2:15][CH2:14]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1ccc(C(=O)N2CCN(Cc3ccccc3)CC2)cn1
Reactant: CCCCN=C=O
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCNC(=O)Nc1ccc(C(=O)N2CCN(Cc3ccccc3)CC2)cn1
Temperature: 100 °C
Yield: 48.2 %

Procedure:
(6-Aminopyridin-3-yl)(4-benzylpiperazin-1-yl)methanone (90 mg, 0.304 mmol) and n-butyl isocyanate (103 μl, 91 mg, 0.914 mmol) were combined in dimethylformamide (3 mL) and the mixture was heated to 100° C. for 6 hours. After this time the mixture was taken up in dichloromethane/methanol and loaded on to a strong cation exchange column (2 g) and washed with dichloromethane/methanol. Elution of the column with 2M ammonia in methanol gave a residue that was further purified by silica chromatography (eluting with 5% methanol/dichloromethane) to give the title compound (58 mg).
Reaction SMILES: [Si]([O:8][C:9]([CH3:44])([CH3:43])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[C:27]3[N:26]=[C:25]([C:28]4[C:33]([Br:34])=[CH:32][C:31]([F:35])=[CH:30][C:29]=4[Br:36])[NH:24][C:23]=3[C:22]3[C:17](=[CH:18][C:19]([O:37][CH2:38][CH2:39][CH:40]4[CH2:42][CH2:41]4)=[CH:20][CH:21]=3)[C:15]=2[CH:16]=1)(C(C)(C)C)(C)C.[Si](OC(C)(C)CC1C=CC2C3N=C(C4C(Br)=CC=CC=4Br)NC=3C3C(=CC(OCC4CC4)=CC=3)C=2C=1)(C(C)(C)C)(C)C>>[CH:40]1([CH2:39][CH2:38][O:37][C:19]2[CH:18]=[C:17]3[C:22](=[CH:21][CH:20]=2)[C:23]2[NH:24][C:25]([C:28]4[C:29]([Br:36])=[CH:30][C:31]([F:35])=[CH:32][C:33]=4[Br:34])=[N:26][C:27]=2[C:14]2[CH:13]=[CH:12][C:11]([CH2:10][C:9]([CH3:44])([OH:8])[CH3:43])=[CH:16][C:15]3=2)[CH2:42][CH2:41]1
Reactant: CC(C)(Cc1ccc2c(c1)c1cc(OCCC3CC3)ccc1c1[nH]c(-c3c(Br)cc(F)cc3Br)nc21)O[Si](C)(C)C(C)(C)C
Agent: CC(C)(Cc1ccc2c(c1)c1cc(OCC3CC3)ccc1c1[nH]c(-c3c(Br)cccc3Br)nc21)O[Si](C)(C)C(C)(C)C
Product: CC(C)(O)Cc1ccc2c(c1)c1cc(OCCC3CC3)ccc1c1[nH]c(-c3c(Br)cc(F)cc3Br)nc21

Procedure:
This imidazole was prepared as described in Step 8 of Route A of Example 168, substituting 6-(2-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-9-(2-cyclopropylethoxy)-2-(2,6-dibromo-4-fluorophenyl)-1H-phenanthro[9,10-d]imidazole from Step 5 above for 6-(2-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-9-(cyclopropylmethoxy)-2-(2,6-dibromophenyl)-1H-phenanthro[9,10-d]imidazole.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH:24]([C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[NH:28]1)([CH3:26])[CH3:25]>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:28]4[C@H:27]([CH:24]([CH3:26])[CH3:25])[CH2:31][O:30][C:29]4=[O:32])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: CC(C)[C@@H]1COC(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C(C)C)cc3)CC2)c(C)c1
Yield: 36.9 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (567 mg) described in Preparation Example 77 and (R)-4-isopropyloxazolidin-2-one (192 mg), the title compound (210 mg) was obtained.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]2[CH2:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[O:18][C:10]=12.Cl>>[C:1]([C:21]1[CH:20]=[CH:19][C:17]2[O:18][C:10]3=[N:9][CH:14]=[CH:13][CH:12]=[C:11]3[CH2:15][C:16]=2[CH:22]=1)(=[O:3])[CH3:2]
Reactant: c1ccc2c(c1)Cc1cccnc1O2
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1ccc2c(c1)Cc1cccnc1O2
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
30.5 g of acetyl chloride is placed in a four-necked flask fitted with a stirrer. A mixture of 49 g of crushed aluminum chloride and 20 g of crushed 5H-[1]benzopyrano[2,3-b]pyridine is added in small portions over a period of 30 minutes, keeping the temperature at 10°-20°C by cooling with ice water. After the addition the temperature is raised to 50°-60°C over 1 hour. Violent release of hydrogen chloride takes place. The contents gradually become viscous, and stirring becomes difficult. The contents are allowed to stand at 80°-85°C for 2 hours without stirring. The contents are broken to pieces and thrown into 1 liter of ice water. The crystalline precipitate is filtered off, washed with water, dried, and then recrystallized from ethyl acetate to give 18.5 g of 7-acetyl-5H-[1]benzopyrano[2,3-b]pyridine melting at 142°-144°C.
Reaction SMILES: O1CCCC1.[CH3:6][O:7][C:8](=[O:17])[CH2:9][CH:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1.[CH3:18][NH2:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(=O)(O)[O-].[Na+].C(O)(=O)C>[CH3:6][O:7][C:8](=[O:17])[CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([NH:19][CH3:18])[CH2:12][CH2:11]1
Reactant: COC(=O)CC1CCC(=O)CC1
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNC1CCC(CC(=O)OC)CC1
Reaction time: 4 h
Yield: 35 %

Procedure:
To a tetrahydrofuran (60 mL) solution of (4-oxo-cyclohexyl)-acetic acid methyl ester (2.14 g) obtained in Example (1c), methylamine (2.0 M tetrahydrofuran solution, 12.5 mL), acetic acid (0.72 mL), and sodium triacetoxyborohydride (2.67 g) were added at room temperature. After 4 hours, the reaction mixture was diluted with saturated sodium bicarbonate (100 mL). The organic solvent was removed under reduced pressure. The aqueous mixture was subjected to extraction with dichloromethane (×3). The dichloromethane layer was dried over sodium sulfate and then concentrated. The residue was purified by column chromatography (NH silica gel, dichloromethane/methanol) to obtain the title compound (822 mg, 35%) as a brown oil.